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    Self-organization of action hierarchy and compositionality by reinforcement learning with recurrent neural networks

    Publication date: Available online 6 June 2020

    Source: Neural Networks

    Author(s): Dongqi Han, Kenji Doya, Jun Tani

    in Neural Networks on June 06, 2020 06:00 PM.

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    A spiking neural network-based long-term prediction system for biogas production

    Publication date: Available online 5 June 2020

    Source: Neural Networks

    Author(s): Giacomo Capizzi, Grazia Lo Sciuto, Christian Napoli, Marcin Woźniak, Gianluca Susi

    in Neural Networks on June 06, 2020 06:00 PM.

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    Encoding primitives generation policy learning for robotic arm to overcome catastrophic forgetting in sequential multi-tasks learning

    Publication date: Available online 5 June 2020

    Source: Neural Networks

    Author(s): Fangzhou Xiong, Zhiyong Liu, Kaizhu Huang, Xu Yang, Hong Qiao, Amir Hussain

    in Neural Networks on June 06, 2020 06:00 PM.

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    Batch process fault detection for multi-stage broad learning system

    Publication date: Available online 5 June 2020

    Source: Neural Networks

    Author(s): Chang Peng, Lu RuiWei, Olivia Kang, Wang Kai

    in Neural Networks on June 06, 2020 06:00 PM.

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    Parallel processing streams in the hippocampus

    Publication date: October 2020

    Source: Current Opinion in Neurobiology, Volume 64

    Author(s): Heekyung Lee, Douglas GoodSmith, James J Knierim

    in Current Opinion in Neurobiology on June 06, 2020 01:00 PM.

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    Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain

    Neurons communicate by the activity-dependent release of small-molecule neurotransmitters packaged into synaptic vesicles (SVs). Although many molecules have been identified as neurotransmitters, technical limitations have precluded a full metabolomic analysis of synaptic vesicle content. Here, we present a workflow to rapidly isolate SVs and to interrogate their metabolic contents at a high-resolution using mass spectrometry. We validated the enrichment of glutamate in SVs of primary cortical neurons using targeted polar metabolomics. Unbiased and extensive global profiling of SVs isolated from these neurons revealed that the only detectable polar metabolites they contain are the established neurotransmitters glutamate and GABA. Finally, we adapted the approach to enable quick capture of SVs directly from brain tissue and determined the neurotransmitter profiles of diverse brain regions in a cell-type specific manner. The speed, robustness, and precision of this method to interrogate SV contents will facilitate novel insights into the chemical basis of neurotransmission.

    in bioRxiv: Neuroscience on June 06, 2020 12:00 AM.

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    Anesthetics uniquely decorrelate hippocampal network activity, alter spine dynamics and affect memory consolidation

    General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side-effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. Iso anesthesia most closely resembled wakefulness, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

    in bioRxiv: Neuroscience on June 06, 2020 12:00 AM.

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    AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

    Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their products (IL1b and IL18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

    in bioRxiv: Neuroscience on June 06, 2020 12:00 AM.

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    Compensatory hippocampal neurogenesis in the absence of cognitive impairment following experimental hippocampectomy in adult rats

    Temporal lobe epilepsy (TLE) is the commonest type of focal epilepsy in adult humans. In refractory TLE, patients are indicated for unilateral resection of the affected hippocampus (hippocampectomy), which generally does not cause any cognitive impairment. Once adult hippocampus is a region of endogenous neurogenesis, we have hypothesized that a compensatory increase in hippocampal neurogenesis might occur in the remaining hippocampus after unilateral hippocampectomy. To test this hypothesis, we performed unilateral hippocampectomy in adult Wistar rats (n=12). Sham animals were not hippocampectomized (n=6). Animals were deeply anesthetized and adjacent cortex and hippocampus of the left hemisphere were completely removed. They were perfused at 15 (G15, n=6) or 30 (G30, n=6) days post-surgery. Behavioral tests were performed to address possible cognitive impairments. We did not find any cognitive impairment in the hippocampectomized animals. Histopathology was performed using thionine staining and mature neurons and migratory neuroblasts were immunolabeled using anti-NeuN and anti-doublecortin (DCX) antibodies, respectively. The remaining hippocampus presented higher numbers of DCX positive cells compared to control (p<0.001) at both G15 and G30. The results suggest increased compensatory adult neurogenesis following experimental unilateral hippocampectomy in adult rats, which may contribute to absence of cognitive impairments.

    in bioRxiv: Neuroscience on June 06, 2020 12:00 AM.

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    In vivo fluorescence imaging with a flat, lensless microscope

    Fluorescence imaging over large areas of the brain in freely behaving animals would allow researchers to better understand the relationship between brain activity and behavior; however, traditional microscopes capable of high spatial resolution and large fields of view (FOVs) require large and heavy lenses that restrict animal movement. While lensless imaging has the potential to achieve both high spatial resolution and large FOV with a thin lightweight device, lensless imaging has yet to be achieved in vivo due to two principal challenges: (a) biological tissue typically has lower contrast than resolution targets, and (b) illumination and filtering must be integrated into this non-traditional device architecture. Here, we show that in vivo fluorescence imaging is possible with a thin lensless microscope by optimizing the phase mask and computational reconstruction algorithms, and integrating fiber optic illumination and thin-film color filters. This technology is an important step towards high-resolution, large-FOV fluorescence imaging in freely behaving animals.

    in bioRxiv: Neuroscience on June 06, 2020 12:00 AM.

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    Detecting differential alternative splicing events in scRNA-seq with or without Unique Molecular Identifiers

    by Yu Hu, Kai Wang, Mingyao Li

    The emergence of single-cell RNA-seq (scRNA-seq) technology has made it possible to measure gene expression variations at cellular level. This breakthrough enables the investigation of a wider range of problems including analysis of splicing heterogeneity among individual cells. However, compared to bulk RNA-seq, scRNA-seq data are much noisier due to high technical variability and low sequencing depth. Here we propose SCATS (Single-Cell Analysis of Transcript Splicing) for differential splicing analysis in scRNA-seq, which achieves high sensitivity at low coverage by accounting for technical noise. SCATS models scRNA-seq data either with or without Unique Molecular Identifiers (UMIs). For non-UMI data, SCATS explicitly models technical noise by accounting for capture efficiency and amplification bias through the use of external spike-ins; for UMI data, SCATS models capture efficiency and further accounts for transcriptional burstiness. A key aspect of SCATS lies in its ability to group “exons” that originate from the same isoform(s). Grouping exons is essential in splicing analysis of scRNA-seq data as it naturally aggregates spliced reads across different exons, making it possible to detect splicing events even when sequencing depth is low. To evaluate the performance of SCATS, we analyzed both simulated and real scRNA-seq datasets and compared with existing methods including Census and DEXSeq. We show that SCATS has well controlled type I error rate, and is more powerful than existing methods, especially when splicing difference is small. In contrast, Census suffers from severe type I error inflation, whereas DEXSeq is more conservative. When applied to mouse brain scRNA-seq datasets, SCATS identified more differential splicing events with subtle difference across cell types compared to Census and DEXSeq. With the increasing adoption of scRNA-seq, we believe SCATS will be well-suited for various splicing studies. The implementation of SCATS can be downloaded from https://github.com/huyustats/SCATS.

    in PLoS Computational Biology on June 05, 2020 09:00 PM.

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    Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes

    by David Conesa, Blas Echebarria, Angelina Peñaranda, Inmaculada R. Cantalapiedra, Yohannes Shiferaw, Enrique Alvarez-Lacalle

    Ventricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ion channels modify the general equilibrium, as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression.

    in PLoS Computational Biology on June 05, 2020 09:00 PM.

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    Epidemiological consequences of enduring strain-specific immunity requiring repeated episodes of infection

    by Rebecca H. Chisholm, Nikki Sonenberg, Jake A. Lacey, Malcolm I. McDonald, Manisha Pandey, Mark R. Davies, Steven Y. C. Tong, Jodie McVernon, Nicholas Geard

    Group A Streptococcus (GAS) skin infections are caused by a diverse array of strain types and are highly prevalent in disadvantaged populations. The role of strain-specific immunity in preventing GAS infections is poorly understood, representing a critical knowledge gap in vaccine development. A recent GAS murine challenge study showed evidence that sterilising strain-specific and enduring immunity required two skin infections by the same GAS strain within three weeks. This mechanism of developing enduring immunity may be a significant impediment to the accumulation of immunity in populations. We used an agent-based mathematical model of GAS transmission to investigate the epidemiological consequences of enduring strain-specific immunity developing only after two infections with the same strain within a specified interval. Accounting for uncertainty when correlating murine timeframes to humans, we varied this maximum inter-infection interval from 3 to 420 weeks to assess its impact on prevalence and strain diversity, and considered additional scenarios where no maximum inter-infection interval was specified. Model outputs were compared with longitudinal GAS surveillance observations from northern Australia, a region with endemic infection. We also assessed the likely impact of a targeted strain-specific multivalent vaccine in this context. Our model produced patterns of transmission consistent with observations when the maximum inter-infection interval for developing enduring immunity was 19 weeks. Our vaccine analysis suggests that the leading multivalent GAS vaccine may have limited impact on the prevalence of GAS in populations in northern Australia if strain-specific immunity requires repeated episodes of infection. Our results suggest that observed GAS epidemiology from disease endemic settings is consistent with enduring strain-specific immunity being dependent on repeated infections with the same strain, and provide additional motivation for relevant human studies to confirm the human immune response to GAS skin infection.

    in PLoS Computational Biology on June 05, 2020 09:00 PM.

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    Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice

    by Jia Li, Yang Zhao, Jaesung Choi, Ka Ka Ting, Paul Coleman, Jinbiao Chen, Victoria C. Cogger, Li Wan, Zhongsong Shi, Thorleif Moller, Xiangjian Zheng, Mathew A. Vadas, Jennifer R. Gamble

    Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.

    in PLoS Biology on June 05, 2020 09:00 PM.

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    The brain of Cataglyphis ants: Neuronal organization and visual projections

    The brain of Cataglyphis ants: Neuronal organization and visual projections

    Three‐dimensional reconstruction of a Cataglyphis brain based on immunohistochemical staining and fluorescent tracing. We provide a detailed atlas of the Cataglyphis brain including 33 brain neuropils and 30 fiber tracts. We further focus on the description of the major optical tracts/commissures and their projections in the central brain.


    Abstract

    Cataglyphis ants are known for their outstanding navigational abilities. They return to their inconspicuous nest after far‐reaching foraging trips using path integration, and whenever available, learn and memorize visual features of panoramic sceneries. To achieve this, the ants combine directional visual information from celestial cues and panoramic scenes with distance information from an intrinsic odometer. The largely vision‐based navigation in Cataglyphis requires sophisticated neuronal networks to process the broad repertoire of visual stimuli. Although Cataglyphis ants have been subjected to many neuroethological studies, little is known about the general neuronal organization of their central brain and the visual pathways beyond major circuits. Here, we provide a comprehensive, three‐dimensional neuronal map of synapse‐rich neuropils in the brain of Cataglyphis nodus including major connecting fiber systems. In addition, we examined neuronal tracts underlying the processing of visual information in more detail. This study revealed a total of 33 brain neuropils and 30 neuronal fiber tracts including six distinct tracts between the optic lobes and the cerebrum. We also discuss the importance of comparative studies on insect brain architecture for a profound understanding of neuronal networks and their function.

    in Journal of Comparative Neurology on June 05, 2020 07:00 PM.

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    Epileptic Activity Intrinsically Generated in the Human Cerebellum

    Neoplastic or dysplastic neuronal tissue in the brain stem and cerebellum can become epileptogenic in pediatric patients. However, it is unknown whether such tissue may transform intrinsic properties of the human cerebellum, making it capable of generating epileptic population activity. We noninvasively detected epileptiform signals unaveraged in a pediatric patient with epilepsy due to a tumor in the middle cerebellar peduncle. Analysis of generators of the signals revealed that the cerebellum ipsilateral and contralateral to the tumor was the dominant interictal spike generator and could initiate ictal activity, suggesting that human cerebellum may become capable of intrinsically generating epileptic activity. ANN NEUROL 2020

    in Annals of Neurology on June 05, 2020 07:00 PM.

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    Structure learning with similarity preserving

    Publication date: September 2020

    Source: Neural Networks, Volume 129

    Author(s): Zhao Kang, Xiao Lu, Yiwei Lu, Chong Peng, Wenyu Chen, Zenglin Xu

    in Neural Networks on June 05, 2020 06:00 PM.

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    Australia's mysterious rock paintings

    Australia's mysterious rock paintings


    Abstract

    Jack Pettigrew spent much of his time and energy over the last decade after his retirement exploring the mysterious Bradshaw figures, which are part of the rock art found in the Kimberley region of Western Australia.

    in Journal of Comparative Neurology on June 05, 2020 04:45 PM.

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    A Novel Update Mechanism for Q-Networks Based On Extreme Learning Machines. (arXiv:2006.02986v1 [cs.NE])

    Reinforcement learning is a popular machine learning paradigm which can find near optimal solutions to complex problems. Most often, these procedures involve function approximation using neural networks with gradient based updates to optimise weights for the problem being considered. While this common approach generally works well, there are other update mechanisms which are largely unexplored in reinforcement learning. One such mechanism is Extreme Learning Machines. These were initially proposed to drastically improve the training speed of neural networks and have since seen many applications. Here we attempt to apply extreme learning machines to a reinforcement learning problem in the same manner as gradient based updates. This new algorithm is called Extreme Q-Learning Machine (EQLM). We compare its performance to a typical Q-Network on the cart-pole task - a benchmark reinforcement learning problem - and show EQLM has similar long-term learning performance to a Q-Network.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Sparsity in Reservoir Computing Neural Networks. (arXiv:2006.02957v1 [cs.LG])

    Reservoir Computing (RC) is a well-known strategy for designing Recurrent Neural Networks featured by striking efficiency of training. The crucial aspect of RC is to properly instantiate the hidden recurrent layer that serves as dynamical memory to the system. In this respect, the common recipe is to create a pool of randomly and sparsely connected recurrent neurons. While the aspect of sparsity in the design of RC systems has been debated in the literature, it is nowadays understood mainly as a way to enhance the efficiency of computation, exploiting sparse matrix operations. In this paper, we empirically investigate the role of sparsity in RC network design under the perspective of the richness of the developed temporal representations. We analyze both sparsity in the recurrent connections, and in the connections from the input to the reservoir. Our results point out that sparsity, in particular in input-reservoir connections, has a major role in developing internal temporal representations that have a longer short-term memory of past inputs and a higher dimension.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    The growth and form of knowledge networks by kinesthetic curiosity. (arXiv:2006.02949v1 [q-bio.NC])

    Throughout life, we might seek a calling, companions, skills, entertainment, truth, self-knowledge, beauty, and edification. The practice of curiosity can be viewed as an extended and open-ended search for valuable information with hidden identity and location in a complex space of interconnected information. Despite its importance, curiosity has been challenging to computationally model because the practice of curiosity often flourishes without specific goals, external reward, or immediate feedback. Here, we show how network science, statistical physics, and philosophy can be integrated into an approach that coheres with and expands the psychological taxonomies of specific-diversive and perceptual-epistemic curiosity. Using this interdisciplinary approach, we distill functional modes of curious information seeking as searching movements in information space. The kinesthetic model of curiosity offers a vibrant counterpart to the deliberative predictions of model-based reinforcement learning. In doing so, this model unearths new computational opportunities for identifying what makes curiosity curious.

    in arXiv: Quantitative Biology: Neurons and Cognition on June 05, 2020 01:30 AM.

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    Neural Network for Low-Memory IoT Devices and MNIST Image Recognition Using Kernels Based on Logistic Map. (arXiv:2006.02824v1 [cs.NE])

    The study presents a neural network, which uses filters based on logistic mapping (LogNNet). LogNNet has a feedforward network structure, but possesses the properties of reservoir neural networks. The input weight matrix, set by a recurrent logistic mapping, forms the kernels that transform the input space to the higher-dimensional feature space. The most effective MNIST handwritten digit recognition occurs under chaotic behavior of logistic map. An advantage of LogNNet implementation on IoT Devices is the significant savings in used memory (more than 10 times) compared to other neural networks. The presented network architecture uses an array of weights with a total memory size from 1 kB to 29 kB and achieves a classification accuracy of 80.3-96.3 %.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Overcoming Overfitting and Large Weight Update Problem in Linear Rectifiers: Thresholded Exponential Rectified Linear Units. (arXiv:2006.02797v1 [cs.LG])

    In past few years, linear rectified unit activation functions have shown its significance in the neural networks, surpassing the performance of sigmoid activations. RELU (Nair & Hinton, 2010), ELU (Clevert et al., 2015), PRELU (He et al., 2015), LRELU (Maas et al., 2013), SRELU (Jin et al., 2016), ThresholdedRELU, all these linear rectified activation functions have its own significance over others in some aspect. Most of the time these activation functions suffer from bias shift problem due to non-zero output mean, and high weight update problem in deep complex networks due to unit gradient, which results in slower training, and high variance in model prediction respectively. In this paper, we propose, "Thresholded exponential rectified linear unit" (TERELU) activation function that works better in alleviating in overfitting: large weight update problem. Along with alleviating overfitting problem, this method also gives good amount of non-linearity as compared to other linear rectifiers. We will show better performance on the various datasets using neural networks, considering TERELU activation method compared to other activations.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Markov Blankets in the Brain. (arXiv:2006.02741v1 [q-bio.NC])

    Recent characterisations of self-organising systems depend upon the presence of a Markov blanket: a statistical boundary that mediates the interactions between what is inside of and outside of a system. We leverage this idea to provide an analysis of partitions in neuronal systems. This is applicable to brain architectures at multiple scales, enabling partitions into single neurons, brain regions, and brain-wide networks. This treatment is based upon the canonical micro-circuitry used in empirical studies of effective connectivity, so as to speak directly to practical applications. This depends upon the dynamic coupling between functional units, whose form recapitulates that of a Markov blanket at each level. The nuance afforded by partitioning neural systems in this way highlights certain limitations of modular perspectives of brain function that only consider a single level of description.

    in arXiv: Quantitative Biology: Neurons and Cognition on June 05, 2020 01:30 AM.

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    Using Tabu Search Algorithm for Map Generation in the Terra Mystica Tabletop Game. (arXiv:2006.02716v1 [cs.AI])

    Tabu Search (TS) metaheuristic improves simple local search algorithms (e.g. steepest ascend hill-climbing) by enabling the algorithm to escape local optima points. It has shown to be useful for addressing several combinatorial optimization problems. This paper investigates the performance of TS and considers the effects of the size of the Tabu list and the size of the neighbourhood for a procedural content generation, specifically the generation of maps for a popular tabletop game called Terra Mystica. The results validate the feasibility of the proposed method and how it can be used to generate maps that improve existing maps for the game.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Neuroevolutionary Transfer Learning of Deep Recurrent Neural Networks through Network-Aware Adaptation. (arXiv:2006.02655v1 [cs.NE])

    Transfer learning entails taking an artificial neural network (ANN) that is trained on a source dataset and adapting it to a new target dataset. While this has been shown to be quite powerful, its use has generally been restricted by architectural constraints. Previously, in order to reuse and adapt an ANN's internal weights and structure, the underlying topology of the ANN being transferred across tasks must remain mostly the same while a new output layer is attached, discarding the old output layer's weights. This work introduces network-aware adaptive structure transfer learning (N-ASTL), an advancement over prior efforts to remove this restriction. N-ASTL utilizes statistical information related to the source network's topology and weight distribution in order to inform how new input and output neurons are to be integrated into the existing structure. Results show improvements over prior state-of-the-art, including the ability to transfer in challenging real-world datasets not previously possible and improved generalization over RNNs trained without transfer.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Unifying Activation- and Timing-based Learning Rules for Spiking Neural Networks. (arXiv:2006.02642v1 [cs.NE])

    For the gradient computation across the time domain in Spiking Neural Networks (SNNs) training, two different approaches have been independently studied. The first is to compute the gradients with respect to the change in spike activation (activation-based methods), and the second is to compute the gradients with respect to the change in spike timing (timing-based methods). In this work, we present a comparative study of the two methods and propose a new supervised learning method that combines them. The proposed method utilizes each individual spike more effectively by shifting spike timings as in the timing-based methods as wells as generating and removing spikes as in the activation-based methods. Experimental results showed that the proposed method achieves higher performance in terms of both accuracy and efficiency than the previous approaches.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Decomposition in Decision and Objective Space for Multi-Modal Multi-Objective Optimization. (arXiv:2006.02628v1 [cs.NE])

    Multi-modal multi-objective optimization problems (MMMOPs) have multiple solution vectors mapping to the same objective vector. For MMMOPs, it is important to discover equivalent solutions associated with each point in the Pareto-Front for allowing end-users to make informed decisions. Prevalent multi-objective evolutionary algorithms are incapable of searching for multiple solution subsets, whereas, algorithms designed for MMMOPs demonstrate degraded performance in the objective space. This motivates the design of better algorithms for addressing MMMOPs. The present work highlights the disadvantage of using crowding distance in the decision space when solving MMMOPs. Subsequently, an evolutionary framework, called graph Laplacian based Optimization using Reference vector assisted Decomposition (LORD), is proposed, which is the first algorithm to use decomposition in both objective and decision space for dealing with MMMOPs. Its filtering step is further extended to present LORD-II algorithm, which demonstrates its dynamics on multi-modal many-objective problems. The efficacy of the frameworks are established by comparing their performance on 34 test instances (obtained from the CEC 2019 multi-modal multi-objective test suite) with the state-of-the-art algorithms for MMMOPs and other multi- and many-objective evolutionary algorithms. The manuscript is concluded mentioning the limitations of the proposed frameworks and future directions to design still better algorithms for MMMOPs.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    An Improved LSHADE-RSP Algorithm with the Cauchy Perturbation: iLSHADE-RSP. (arXiv:2006.02591v1 [cs.NE])

    A new method for improving the optimization performance of a state-of-the-art differential evolution (DE) variant is proposed in this paper. The technique can increase the exploration by adopting the long-tailed property of the Cauchy distribution, which helps the algorithm to generate a trial vector with great diversity. Compared to the previous approaches, the proposed approach perturbs a target vector instead of a mutant vector based on a jumping rate. We applied the proposed approach to LSHADE-RSP ranked second place in the CEC 2018 competition on single objective real-valued optimization. A set of 30 different and difficult optimization problems is used to evaluate the optimization performance of the improved LSHADE-RSP. Our experimental results verify that the improved LSHADE-RSP significantly outperformed not only its predecessor LSHADE-RSP but also several cutting-edge DE variants in terms of convergence speed and solution accuracy.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Stochastic-based Neural Network hardware acceleration for an efficient ligand-based virtual screening. (arXiv:2006.02505v1 [cs.NE])

    Artificial Neural Networks (ANN) have been popularized in many science and technological areas due to their capacity to solve many complex pattern matching problems. That is the case of Virtual Screening, a research area that studies how to identify those molecular compounds with the highest probability to present biological activity for a therapeutic target. Due to the vast number of small organic compounds and the thousands of targets for which such large-scale screening can potentially be carried out, there has been an increasing interest in the research community to increase both, processing speed and energy efficiency in the screening of molecular databases. In this work, we present a classification model describing each molecule with a single energy-based vector and propose a machine-learning system based on the use of ANNs. Different ANNs are studied with respect to their suitability to identify biochemical similarities. Also, a high-performance and energy-efficient hardware acceleration platform based on the use of stochastic computing is proposed for the ANN implementation. This platform is of utility when screening vast libraries of compounds. As a result, the proposed model showed appreciable improvements with respect previously published works in terms of the main relevant characteristics (accuracy, speed and energy-efficiency).

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Evaluating Adversarial Robustness for Deep Neural Network Interpretability in fMRI Decoding. (arXiv:2004.11114v2 [cs.LG] UPDATED)

    While deep neural networks (DNNs) are being increasingly used to make predictions from high-dimensional, complex data, they are widely seen as uninterpretable "black boxes", since it can be difficult to discover what input information is used to make predictions. This ability is particularly important for applications in cognitive neuroscience and neuroinformatics. A saliency map is a common approach for producing interpretable visualizations of the relative importance of input features for a prediction. However, many methods for creating these maps fail due to focusing too much on the input or being extremely sensitive to small input noise. It is also challenging to quantitatively evaluate how well saliency maps correspond to the truly relevant input information. In this paper, we develop two quantitative evaluation procedures for saliency methods, using the fact that the Human Connectome Project (HCP) dataset contains functional magnetic resonance imaging (fMRI) data from multiple tasks per subject to create ground truth saliency maps. We then introduce an adversarial training method that makes DNNs robust to small input noise, and demonstrate that it measurably improves interpretability.

    in arXiv: Quantitative Biology: Neurons and Cognition on June 05, 2020 01:30 AM.

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    Brain-inspired self-organization with cellular neuromorphic computing for multimodal unsupervised learning. (arXiv:2004.05488v2 [cs.NE] UPDATED)

    Cortical plasticity is one of the main features that enable our capability to learn and adapt in our environment. Indeed, the cerebral cortex has the ability to self-organize itself through two distinct forms of plasticity: the structural plasticity that creates (sprouting) or cuts (pruning) synaptic connections between neurons, and the synaptic plasticity that modifies the synaptic connections strength. These mechanisms are very likely at the basis of an extremely interesting characteristic of the human brain development: the multimodal association. [...] To model such a behavior, Edelman and Damasio proposed respectively the Reentry and the Convergence Divergence Zone frameworks where bi-directional neural communications can lead to both multimodal fusion (convergence) and inter-modal activation (divergence). [...] In this paper, we build a brain-inspired neural system based on the Reentry principles, using Self-Organizing Maps and Hebbian-like learning. We propose and compare different computational methods for unsupervised learning and inference, then quantify the gain of both convergence and divergence mechanisms in a multimodal classification task. The divergence mechanism is used to label one modality based on the other, while the convergence mechanism is used to improve the overall accuracy of the system. We perform our experiments on a constructed written/spoken digits database and a DVS/EMG hand gestures database. Finally, we implement our system on the Iterative Grid, a cellular neuromorphic architecture that enables distributed computing with local connectivity. We show the gain of the so-called hardware plasticity induced by our model, where the system's topology is not fixed by the user but learned along the system's experience through self-organization.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Hierarchical Quantized Autoencoders. (arXiv:2002.08111v2 [cs.LG] UPDATED)

    Despite progress in training neural networks for lossy image compression, current approaches fail to maintain both perceptual quality and abstract features at very low bitrates. Encouraged by recent success in learning discrete representations with Vector Quantized Variational Autoencoders (VQ-VAEs), we motivate the use of a hierarchy of VQ-VAEs to attain high factors of compression. We show that the combination of stochastic quantization and hierarchical latent structure aids likelihood-based image compression. This leads us to introduce a novel objective for training hierarchical VQ-VAEs. Our resulting scheme produces a Markovian series of latent variables that reconstruct images of high-perceptual quality which retain semantically meaningful features. We provide qualitative and quantitative evaluations on the CelebA and MNIST datasets.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    High-parallelism Inception-like Spiking Neural Networks for Unsupervised Feature Learning. (arXiv:2001.01680v4 [cs.NE] UPDATED)

    Spiking Neural Network (SNN) is a brain-inspired, event-driven machine learning algorithm that has recognized potential in producing ultra-high-energy-efficient hardware. Among existing SNNs, unsupervised SNNs are based on synaptic plasticity and considered to have more potential in imitating the learning process of biological brain. Most unsupervised SNNs are trained through competitive learning with Spike-Timing-Dependent Plasticity (STDP). However, the STDP-based SNNs are limited by slow learning speed and/or constrained learning capability. In this paper, to overcome these limitations, we: 1) designed a high-parallelism network architecture, inspired by the Inception module in the Artificial Neural Network (ANN) literature; 2) extended a widely used vote-based spike decoding scheme to a Vote-for-All (VFA) decoding layer to reduce the information loss in the spike decoding; 3) proposed to use adaptive repolarization (i.e. resetting) in the spiking neuron model to enhance the spiking activities and thus further accelerate the network's learning. We evaluated our contributions on the two established benchmark datasets (MNIST/EMNIST). Our experimental results show that our architecture exhibits superior performance than widely used Fully-Connected (FC) and Locally-Connected (LC) architectures. Our SNN not only achieves comparable results with the state-of-the-art unsupervised SNNs (95.64%/80.11% accuracy on the MNIST/EMNISE dataset), but also shows superior learning efficiency and robustness against hardware damage. Our SNN trained with only hundreds of iterations can achieve a great classification accuracy, and random destruction of large numbers of synapses and neurons only leads to negligible performance degradation.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Neural networks-based backward scheme for fully nonlinear PDEs. (arXiv:1908.00412v2 [math.OC] UPDATED)

    We propose a numerical method for solving high dimensional fully nonlinear partial differential equations (PDEs). Our algorithm estimates simultaneously by backward time induction the solution and its gradient by multi-layer neural networks, while the Hessian is approximated by automatic differentiation of the gradient at previous step. This methodology extends to the fully nonlinear case the approach recently proposed in \cite{HPW19} for semi-linear PDEs. Numerical tests illustrate the performance and accuracy of our method on several examples in high dimension with nonlinearity on the Hessian term including a linear quadratic control problem with control on the diffusion coefficient, Monge-Amp{\`e}re equation and Hamilton-Jacobi-Bellman equation in portfolio optimization.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Fully-Asynchronous Fully-Implicit Variable-Order Variable-Timestep Simulation of Neural Networks. (arXiv:1907.00670v3 [cs.DC] UPDATED)

    State-of-the-art simulations of detailed neural models follow the Bulk Synchronous Parallel execution model. Execution is divided in equidistant communication intervals, equivalent to the shortest synaptic delay in the network. Neurons stepping is performed independently, with collective communication guiding synchronization and exchange of synaptic events.

    The interpolation step size is fixed and chosen based on some prior knowledge of the fastest possible dynamics in the system. However, simulations driven by stiff dynamics or a wide range of time scales - such as multiscale simulations of neural networks - struggle with fixed step interpolation methods, yielding excessive computation of intervals of quasi-constant activity, inaccurate interpolation of periods of high volatility solution, and being incapable of handling unknown or distinct time constants. A common alternative is the usage of adaptive stepping methods, however they have been deemed inefficient in parallel executions due to computational load imbalance at the synchronization barriers that characterize the BSP execution model.

    We introduce a distributed fully-asynchronous execution model that removes global synchronization, allowing for longer variable timestep interpolations. Asynchronicity is provided by active point-to-point communication notifying neurons' time advancement to synaptic connectivities. Time stepping is driven by scheduled neuron advancements based on synaptic delays across neurons, yielding an "exhaustive yet not speculative" adaptive-step execution. Execution benchmarks on 64 Cray XE6 compute nodes demonstrate a reduced number of interpolation steps, higher numerical accuracy and lower time to solution, compared to state-of-the-art methods. Efficiency is shown to be activity-dependent, with scaling of the algorithm demonstrated on a simulation of a laboratory experiment.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 05, 2020 01:30 AM.

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    Author Correction: A conserved dendritic-cell regulatory program limits antitumour immunity

    Nature, Published online: 05 June 2020; doi:10.1038/s41586-020-2326-5

    Author Correction: A conserved dendritic-cell regulatory program limits antitumour immunity

    in Nature on June 05, 2020 12:00 AM.

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    Author Correction: Quantifying the dynamics of failure across science, startups and security

    Nature, Published online: 05 June 2020; doi:10.1038/s41586-020-2325-6

    Author Correction: Quantifying the dynamics of failure across science, startups and security

    in Nature on June 05, 2020 12:00 AM.

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    Targeting transport in CNS oedema

    Nature Reviews Neuroscience, Published online: 05 June 2020; doi:10.1038/s41583-020-0324-0

    In a rat model of spinal cord injury, inhibiting calmodulin-mediated relocalization of aquaporin 4 to the blood–spinal cord barrier after injury reduced CNS oedema and promoted functional recovery.

    in Nature Reviews on June 05, 2020 12:00 AM.

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    Differential contributions of the two cerebral hemispheres to temporal and spectral speech feedback control

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16743-2

    Speech production is thought to rely on speech motor programs in the left cerebral hemisphere and on auditory feedback control by the right halve of the human brain. Here, the authors reveal that the left hemisphere preferentially controls temporal speech features while the right hemisphere controls speech by analyzing spectral features of the auditory feedback.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Spitzenkörper assembly mechanisms reveal conserved features of fungal and metazoan polarity scaffolds

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16712-9

    The Spitzenkörper (SPK) is a polarized accumulation of proteins and secretory vesicles associated with tip growth of fungal hyphae. Here, Zheng et al. study SPK assembly and dynamics, identify SPK protein scaffolds and associated proteins, and reveal similarities with other scaffolds from metazoans.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16696-6

    Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy. Here, the authors show that Rab35 forms a complex with genes implicated in CMT, MTMR13 and MTMR2, which regulates myelin growth by controlling mTORC1 signaling through lipid turnover.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Single-atom Pt in intermetallics as an ultrastable and selective catalyst for propane dehydrogenation

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16693-9

    Propylene production via propane dehydrogenation demands a highly stable catalyst that works without deactivation even at high temperatures. Here, the authors show that single-atom Pt included in thermally stable intermetallic PtGa works as an active and selective catalyst for propane dehydrogenation even at 600 °C for 96 h without deactivation.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Global correlates of range contractions and expansions in terrestrial mammals

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16684-w

    Understanding why many species ranges are contracting while others are stable or expanding is important to inform conservation in an increasingly human-modified world. Here, Pacifici and colleagues investigate changes in the ranges of 204 mammals, showing that human factors mostly explain range contractions while life history explains both contraction and expansion.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16625-7

    Type I IFN has apposing effects in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Here the authors perform molecular profiling of NMOSD patients and mouse mechanistic experiments of neuro-inflammation to show that IFN-I stimulates pathogenic Th17 via IL-6 production by B cells.

    in Nature Communications on June 05, 2020 12:00 AM.

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    The effect of flow on swimming bacteria controls the initial colonization of curved surfaces

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16620-y

    Bacterial colonization of surfaces has a profound environmental, technological and medical impact. Here, Secchi et al. show how fluid flow affects the magnitude and location of bacterial colonization on curved surfaces through its coupling with cell morphology and motility.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Interpreting molecular similarity between patients as a determinant of disease comorbidity relationships

    Nature Communications, Published online: 05 June 2020; doi:10.1038/s41467-020-16540-x

    Disease comorbidity is attracting increasing attention, but the involvement of molecular factors in forecasting risk of a disease in the presence of other diseases is poorly understood. Here the authors build a disease interaction network based on gene expression profile and discover new comorbidity relationships in patient subgroups.

    in Nature Communications on June 05, 2020 12:00 AM.

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    Frozen cells and empty cages: researchers struggle to revive stalled experiments after the lockdown

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01704-y

    Abandoned experiments have to be restarted — sometimes from scratch.

    in Nature on June 05, 2020 12:00 AM.

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    Coronapod: The heavy toll on people of colour

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01698-7

    The coronavirus is killing a disproportionate number of people of colour. As systemic injustices are brought to the fore across the world, what can be done to address the virus's unequal burden?

    in Nature on June 05, 2020 12:00 AM.

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    Coronavirus diaries: taking leave, but not holiday

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01696-9

    A stressful return to work after two days’ absence forces John Tregoning to prioritize his growing to-do list more ruthlessly.

    in Nature on June 05, 2020 12:00 AM.

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    High-profile coronavirus retractions raise concerns about data oversight

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01695-w

    Retracted studies had relied on health-record analyses from a company that declined to share its raw data for an audit.

    in Nature on June 05, 2020 12:00 AM.

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    Murder hornets, park robots and planet formation — May’s best science images

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01556-6

    The month’s sharpest science shots — selected by Nature’s photo team.

    in Nature on June 05, 2020 12:00 AM.

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    The biggest mystery: what it will take to trace the coronavirus source

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01541-z

    SARS-CoV-2 came from an animal but finding which one will be tricky, as will laying to rest speculation of a lab escape.

    in Nature on June 05, 2020 12:00 AM.

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    The pandemic mixed up what scientists study – and some won’t go back

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-01525-z

    Thousands of researchers have jumped into studying coronavirus and many want to continue: part 8 in a series on science after the pandemic.

    in Nature on June 05, 2020 12:00 AM.

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    Coronavirus research updates: Surfaces could pose only a modest risk for household spread

    Nature, Published online: 05 June 2020; doi:10.1038/d41586-020-00502-w

    Nature wades through the literature on the new coronavirus — and summarizes key papers as they appear.

    in Nature on June 05, 2020 12:00 AM.

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    Methyltransferase 3 Mediated miRNA m6A Methylation Promotes Stress Granule Formation in the Early Stage of Acute Ischemic Stroke

    The modification of methyltransferase-like (METTL) enzymes plays important roles in various cellular responses by regulating microRNA expression. However, how m6A modification is involved in stress granule (SG) formation in the early stage of acute ischemic stroke by affecting the biogenesis processing of microRNAs remains unclear. Here, we established a middle cerebral artery occlusion (MCAO) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary cortical neurons and PC12 cells to explore the potential mechanism between m6A modification and SG formation. The in vivo results showed that the level of infarction and apoptosis increased while SG formation decreased significantly within the ischemic cortex with improved reperfusion time after 2 h of ischemia. Consistent with the in vivo data, an inverse association between the apoptosis level and SG formation was observed in PC12 cells during the reperfusion period after 6 h of OGD stimulation. Both in vivo and in vitro results showed that the expression of METTL3 protein, m6A and miR-335 was significantly decreased with the reperfusion period. Overexpression of the METTL3 and METTL3 gene-knockdown in PC12 cells were achieved via plasmid transfection and CRISPR-Cas9 technology, respectively. Overexpression or knockdown of METTL3 in oxygen-glucose deprivation of PC12 cells resulted in functional maturation of miR-335, SG formation and apoptosis levels. In addition, we found that miR-335 enhanced SG formation through degradation of the mRNA of the eukaryotic translation termination factor (Erf1). In conclusion, we found that METTL3-mediated m6A methylation increases the maturation of miR-335, which promotes SG formation and reduces the apoptosis level of injury neurons and cells, and provides a potential therapeutic strategy for AIS.

    in Frontiers in Molecular Neuroscience on June 05, 2020 12:00 AM.

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    Hypothermia-Induced Ubiquitination of Voltage-Dependent Anion Channel 3 Protects BV2 Microglia Cells From Cytotoxicity Following Oxygen-Glucose Deprivation/Recovery

    Background: Hypothermia attenuates microglial activation and exerts a potential neuroprotective effect against cerebral ischemic-reperfusion (I/R) injury. However, the underlying mechanism remains to be elucidated. In this in vitro study, a model of oxygen-glucose deprivation, followed by recovery (OGD/R), was used to investigate whether hypothermia exerts anti-inflammatory and anti-apoptosis properties via enhanced ubiquitination and down-regulation of voltage-dependent anion channel 3 (VDAC3) expression.

    Methods: BV2 microglia were cultured under OGD for 4 h following reperfusion with or without hypothermia for 2, 4, or 8 h. M1 and M2 microglia markers [inducible nitric oxide synthase (iNOS) and arginase (Arg)1] were detected using immunofluorescence. The levels of pro-inflammatory cytokines [tumor necrosis factor (TNF) α, interleukin (IL)-1β], and anti-inflammatory factor (IL-10) were determined using enzyme-linked immunosorbent assay (ELISA). Mitochondrial membrane potential (ΔΨm) was assayed by JC-1 staining using a flow cytometer. Expression of caspase-3, cleaved caspase-3, and VDAC3 were assessed using western blot analysis. The cellular locations and interactions of ubiquitin and VDAC3 were identified using double immunofluorescence staining and immunoprecipitation (IP) assay. Also, the level of the VDAC3 mRNA was determined using a quantitative polymerase chain reaction (qPCR).

    Results: Hypothermia inhibited the OGD/R–induced microglia activation and differentiation into the M1 type with pro-inflammatory effect, whereas it promoted differentiation to the M2 type with anti-inflammatory effect. Hypothermia attenuated OGD/R-induced loss of Δψm, as well as the expression of apoptosis-associated proteins. Compared to normothermia, hypothermia increased the level of ubiquitinated VDAC3 in the BV2 microglia at both 2 and 8 h of reperfusion. Furthermore, hypothermia did not attenuate VDAC3 mRNA expression in OGD/R-induced microglia.

    Conclusions: Hypothermia treatment during reperfusion, attenuated OGD/R-induced inflammation, and apoptosis in BV2 microglia. This might be due to the promotion of VDAC3 ubiquitination, identifying VDAC3 as a new target of hypothermia.

    in Frontiers in Molecular Neuroscience on June 05, 2020 12:00 AM.

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    Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation

    Epileptogenesis is a common consequence of brain insults, however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy (TLE), and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3 g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.

    in Frontiers in Molecular Neuroscience on June 05, 2020 12:00 AM.

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    MicroRNA-146a Is a Wide-Reaching Neuroinflammatory Regulator and Potential Treatment Target in Neurological Diseases

    Progressive functional deterioration and loss of neurons underlies neurological diseases and constitutes an important cause of disability and death worldwide. The causes of various types of neurological diseases often share several critical nerve-related cellular mechanisms and pathological features, particularly the neuroinflammatory response in the nervous system. A rapidly growing body of evidence indicates that various microRNAs play pivotal roles in these processes in neurological diseases and might be viable therapeutic targets. Among these microRNAs, microRNA-146a (miR-146a) stands out due to the rapid increase in recent literature on its mechanistic involvement in neurological diseases. In this review, we summarize and highlight the critical role of miR-146a in neurological diseases. MiR-146a polymorphisms are associated with the risk of neurological disease. Alterations in miR-146a expression levels are crucial events in the pathogenesis of numerous neurological diseases that are spatially and temporally diverse. Additionally, the target genes of miR-146a are involved in the regulation of pathophysiological processes in neurological diseases, particularly the neuroinflammatory response. In summary, miR-146a mainly plays a critical role in neuroinflammation during the progression of neurological diseases and might be a prospective biomarker and therapeutic target. Understanding the mechanisms by which miR-146a affects the neuroinflammatory response in different neurological injuries, different cell types, and even different stages of certain neurological diseases will pave the way for its use as a therapeutic target in neurodegenerative diseases.

    in Frontiers in Molecular Neuroscience on June 05, 2020 12:00 AM.

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    Non-invasive Neurophysiology in Learning and Training: Mechanisms and a SWOT Analysis

    Although many scholars deem non-invasive measures of neurophysiology to have promise in assessing learning, these measures are currently not widely applied, neither in educational settings nor in training. How can non-invasive neurophysiology provide insight into learning and how should research on this topic move forward to ensure valid applications? The current article addresses these questions by discussing the mechanisms underlying neurophysiological changes during learning followed by a SWOT (strengths, weaknesses, opportunities, and threats) analysis of non-invasive neurophysiology in learning and training. This type of analysis can provide a structured examination of factors relevant to the current state and future of a field. The findings of the SWOT analysis indicate that the field of neurophysiology in learning and training is developing rapidly. By leveraging the opportunities of neurophysiology in learning and training (while bearing in mind weaknesses, threats, and strengths) the field can move forward in promising directions. Suggestions for opportunities for future work are provided to ensure valid and effective application of non-invasive neurophysiology in a wide range of learning and training settings.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 05, 2020 12:00 AM.

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    Accurate MR Image Registration to Anatomical Reference Space for Diffuse Glioma

    To summarize the distribution of glioma location within a patient population, registration of individual MR images to anatomical reference space is required. In this study, we quantified the accuracy of MR image registration to anatomical reference space with linear and non-linear transformations using estimated tumor targets of glioblastoma and lower-grade glioma, and anatomical landmarks at pre- and post-operative time-points using six commonly used registration packages (FSL, SPM5, DARTEL, ANTs, Elastix, and NiftyReg). Routine clinical pre- and post-operative, post-contrast T1-weighted images of 20 patients with glioblastoma and 20 with lower-grade glioma were collected. The 2009a Montreal Neurological Institute brain template was used as anatomical reference space. Tumors were manually segmented in the patient space and corresponding healthy tissue was delineated as a target volume in the anatomical reference space. Accuracy of the tumor alignment was quantified using the Dice score and the Hausdorff distance. To measure the accuracy of general brain alignment, anatomical landmarks were placed in patient and in anatomical reference space, and the landmark distance after registration was quantified. Lower-grade gliomas were registered more accurately than glioblastoma. Registration accuracy for pre- and post-operative MR images did not differ. SPM5 and DARTEL registered tumors most accurate, and FSL least accurate. Non-linear transformations resulted in more accurate general brain alignment than linear transformations, but tumor alignment was similar between linear and non-linear transformation. We conclude that linear transformation suffices to summarize glioma locations in anatomical reference space.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 05, 2020 12:00 AM.

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    Features of Postnatal Hippocampal Development in a Rat Model of Sporadic Alzheimer’s Disease

    Aging is the major risk factor of the most common (∼95% of cases) sporadic Alzheimer’s disease (AD). Accumulating data indicate middle age as a critical period for the relevant pathological processes, however, the question of when AD starts to develop remains open. It has been reported only recently that in the early postnatal period—when brain development is completing—preconditions for a decrease in cognitive abilities and for accelerated aging can form. Here, we hypothesized that specific features of early postnatal brain development may be considered some of the prerequisites of AD development at an advanced age. To test this hypothesis, we used OXYS rats, which are a suitable model of sporadic AD. The duration of gestation, litter size, and weight at birth were lower in OXYS rats compared to control Wistar rats. The shortened duration of gestation may result in developmental retardation. Indeed, we noted decreased locomotor activity and increased anxiety in OXYS rats already at a young age: possible signs of altered brain development. We demonstrated retardation of the peak of postnatal neurogenesis in the hippocampal dentate gyrus of OXYS rats. Delayed neuronal maturation led to alterations of mossy-fiber formation: a shortened suprapyramidal bundle and longer infrapyramidal bundle, less pronounced fasciculation of granule cells’ axons, and smaller size and irregular shape of nuclei in the CA3 pyramidal layer. These changes were accompanied by altered astrocytic migration. The observed features of early development may be considered some of the risk factors of the AD-like pathology that manifests itself in OXYS rats late in life.

    in Frontiers in Neuroscience: Neurodegeneration on June 05, 2020 12:00 AM.

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    Non-invasive Transcranial Electrical Stimulation in Movement Disorders

    Dysfunction within large-scale brain networks as the basis for movement disorders is an accepted hypothesis. The treatment options for restoring network function are limited. Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation are now being studied to modify the network. Transcranial electrical stimulation (tES) is also a portable, cost-effective, and non-invasive way of network modulation. Transcranial direct current stimulation and transcranial alternating current stimulation have been studied in Parkinson’s disease, dystonia, tremor, and ataxia. Transcranial pulsed current stimulation and transcranial random noise stimulation are not yet studied enough. The literature in the use of these techniques is intriguing, yet many unanswered questions remain. In this review, we highlight the studies using these four potential tES techniques and their electrophysiological basis and consider the therapeutic implication in the field of movement disorders. The objectives are to consolidate the current literature, demonstrate that these methods are feasible, and encourage the application of such techniques in the near future.

    in Frontiers in Neuroscience: Neurodegeneration on June 05, 2020 12:00 AM.

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    Protracted Morphological Changes in the Corticospinal Tract Within the Cervical Spinal Cord After Intracerebral Hemorrhage in the Right Striatum of Mice

    Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. Currently, there is no promising treatment that improves prognosis significantly. While a thorough investigation of the pathological process within the primary site of injury in the brain has been conducted by the research field, the focus was mainly on gray matter injury, which partly accounted for the failure of discovery of clinically efficacious treatments. It is not until recent years that white matter (WM) injury in the brain after subcortical ICH was examined. As WM tracts form networks between different regions, damage to fibers should impair brain connectivity, resulting in functional impairment. Although WM changes have been demonstrated in the brain after ICH, alterations distant from the initial injury site down in the spinal cord are unclear. This longitudinal study, for the first time, revealed prolonged morphological changes of the contralesional dorsal corticospinal tract (CST) in the spinal cord 5 weeks after experimental ICH in mice by confocal microscopy and transmission electron microscopy, implying that the structural integrity of the CST was compromised extensively after ICH. Given the important role of CST in motor function, future translational studies targeting motor recovery should delineate the treatment effects on CST integrity.

    in Frontiers in Neuroscience: Neurodegeneration on June 05, 2020 12:00 AM.

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    Pre-dopa Deep Brain Stimulation: Is Early Deep Brain Stimulation Able to Modify the Natural Course of Parkinson’s Disease?

    Deep brain stimulation (DBS) is an established therapy for the management of Parkinson’s disease (PD). However, DBS is indicated as the disease progresses and motor complications derived from pharmacological therapy arise. Here, we evaluate the potential of DBS prior to levodopa (L-Dopa) in improving quality of life (QoL), challenging the state of the art for DBS therapy. We present data on clinical manifestation, decision finding during early indication to DBS, and trajectories after DBS. We further discuss current paradigms for DBS and hypothesize on possible mechanisms. Six patients, between 50 and 67 years old, presenting at least 5 years of PD symptoms, and without L-Dopa therapy initiation, received subthalamic nucleus (STN) DBS implantation. In the six PD cases, indication for DBS was not driven by motor complications, as supported by current guidelines, but by relevant QoL impairment and patient’s reluctance to initiate L-Dopa treatment. All patients treated with STN-DBS prior to L-Dopa presented improvement in motor and non-motor symptoms and significant QoL improvement. All patients reduced the intake of dopamine agonists, and five are currently free from L-Dopa medication, with no reported adverse events. We introduce a multicenter observational study to investigate whether early DBS treatment may affect the natural course of PD. Early application of DBS instead of L-Dopa administration could have a pathophysiological basis and be prompted by a significant incline on QoL through disease progression; however, the clinical value of this proposed paradigm shift should be addressed in clinical trials aimed at modulating the natural course of PD.

    in Frontiers in Neuroscience: Neurodegeneration on June 05, 2020 12:00 AM.

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    Bloodletting Puncture at Hand Twelve Jing-Well Points Improves Neurological Recovery by Ameliorating Acute Traumatic Brain Injury-Induced Coagulopathy in Mice

    Traumatic brain injury (TBI) contributes to hypocoagulopathy associated with prolonged bleeding and hemorrhagic progression. Bloodletting puncture therapy at hand twelve Jing-well points (BL-HTWP) has been applied as a first aid measure in various emergent neurological diseases, but the detailed mechanisms of the modulation between the central nervous system and systemic circulation after acute TBI in rodents remain unclear. To investigate whether BL-HTWP stimulation modulates hypocoagulable state and exerts neuroprotective effect, experimental TBI model of mice was produced by the controlled cortical impactor (CCI), and treatment with BL-HTWP was immediately made after CCI. Then, the effects of BL-HTWP on the neurological function, cerebral perfusion state, coagulable state, and cerebrovascular histopathology post-acute TBI were determined, respectively. Results showed that BL-HTWP treatment attenuated cerebral hypoperfusion and improve neurological recovery post-acute TBI. Furthermore, BL-HTWP stimulation reversed acute TBI-induced hypocoagulable state, reduced vasogenic edema and cytotoxic edema by regulating multiple hallmarks of coagulopathy in TBI. Therefore, we conclude for the first time that hypocoagulopathic state occurs after acute experimental TBI, and the neuroprotective effect of BL-HTWP relies on, at least in part, the modulation of hypocoagulable state. BL-HTWP therapy may be a promising strategy for acute severe TBI in the future.

    in Frontiers in Neuroscience: Neurodegeneration on June 05, 2020 12:00 AM.

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    Neural Dynamics of Cognitive Control in Various Types of Incongruence

    Conflict-control is a core function of cognitive control. Although numerous studies have considered cognitive control to be domain-general, the shared and distinct brain responses to different types of incongruence or conflict remain unclear. Using a hybrid flanker task, the present study explored the temporal dynamics of brain activation to three types of incongruence: flanker interference, rule-based response switch (rule-switch), and action-based response switch (response-alternation). The results showed that: (1) all three types of incongruence evoked larger N2 amplitudes than the congruent condition in the frontal region, with the N2 amplitudes and topographical distribution of the N2 effect differing between the different types of incongruence; and (2) in the P300 time window, the flanker interference condition yielded the most delayed P300 latency, whereas the rule-switch and response-alternation conditions yielded smaller P300 amplitudes with a longer interval from P300 peak to a keypress. These findings suggest that different types of incongruence are first monitored similarly by the cognitive control system and then resolved differently.

    in Frontiers in Human Neuroscience on June 05, 2020 12:00 AM.

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    Better Phonological Short-Term Memory Is Linked to Improved Cortical Memory Representations for Word Forms and Better Word Learning

    Language learning relies on both short-term and long-term memory. Phonological short-term memory (pSTM) is thought to play an important role in the learning of novel word forms. However, language learners may differ in their ability to maintain word representations in pSTM during interfering auditory input. We used magnetoencephalography (MEG) to investigate how pSTM capacity in better and poorer pSTM groups is linked to language learning and the maintenance of pseudowords in pSTM. In particular, MEG was recorded while participants maintained pseudowords in pSTM by covert speech rehearsal, and while these brain representations were probed by presenting auditory pseudowords with first or third syllables matching or mismatching the rehearsed item. A control condition included identical stimuli but no rehearsal. Differences in response strength between matching and mismatching syllables were interpreted as the phonological mapping negativity (PMN). While PMN for the first syllable was found in both groups, it was observed for the third syllable only in the group with better pSTM. This suggests that individuals with better pSTM maintained representations of trisyllabic pseudowords more accurately during interference than individuals with poorer pSTM. Importantly, the group with better pSTM learned words faster in a paired-associate word learning task, linking the PMN findings to language learning.

    in Frontiers in Human Neuroscience on June 05, 2020 12:00 AM.

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    Differential Functional Connectivity in Anterior and Posterior Hippocampus Supporting the Development of Memory Formation

    Neuroimaging evidence suggests that the development of the hippocampus, a brain structure critical for memory function, contributes to the improvements of episodic memory between middle childhood to adulthood. However, investigations on age differences in hippocampal activation and functional connectivity and their contributions to the development of memory have yielded mixed results. Given the known structural and functional heterogeneity along the long axis of the hippocampus, we investigated age differences in the activation and functional connectivity in hippocampal subregions with a cross-sectional sample of 96 participants ages 8–25 years. We found that anterior and posterior hippocampus supported memory formation, and there was overall stability in memory-related hippocampal activation with age. Without taking account of memory outcome, direct contrast between subregions showed higher functional connectivity of anterior, compared to the posterior hippocampus, with regions in the inferior frontal and lateral temporal lobes, and higher functional connectivity of posterior, compared to the anterior hippocampus, with regions in the medial and superior frontal, inferior parietal, and occipital lobes. A direct contrast between the memory-related connectivity patterns of anterior and posterior hippocampus identified a region in the medial frontal cortex, with which anterior and posterior hippocampus was differentially functionally connected. Finally, we identified age differences in memory-related differential hippocampal functional connectivity with several frontal and visual/sensory cortices, underscoring the importance of examining age differences in the patterns of hippocampal connectivity. Moreover, the specific patterns of differential anterior and posterior functional connectivity indicate an increase in the functional specialization along the long axis of the hippocampus and a dynamic shift in hippocampal connectivity patterns that supports memory development.

    in Frontiers in Human Neuroscience on June 05, 2020 12:00 AM.

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    The Role of Moderating Variables on BOLD fMRI Response During Semantic Verbal Fluency and Finger Tapping in Active and Educated Healthy Seniors

    Semantic verbal fluency is among the most employed tasks in cognitive aging research and substantial work is devoted to understanding the underlying mechanisms behind age-related differences at the neural and behavioral levels. The present investigation aimed to evaluate the role of moderating variables, such as age, sex, MMSE, and proxies of cognitive reserve (CR) on the hemodynamic response evoked by semantic verbal fluency in healthy young and healthy older adults. So far, no study has been conducted to this end. To elucidate the exclusive effect of the mentioned variables on brain activation during semantic fluency, finger tapping was included as a control task. Results showed that disregarding adjustments for age, older adults displayed important parietal activations during semantic fluency as well as during finger-tapping. Specifically, the anterior intra-parietal sulcus (IPS) and left inferior parietal lobule (IPL) were areas activated in both tasks in the older group. Younger adults, only displayed parietal activations related to age and sex when these demographics were employed as predictors. Concerning proxies of CR in semantic fluency, the only vocabulary was an important moderator in both age groups. Higher vocabulary scores were associated with lesser activation in occipital areas. Education did not show significant correlations with brain activity during semantic fluency in any of the groups. However, both CR proxies were significantly correlated to brain activations of older adults during finger tapping. Specifically, vocabulary was associated with frontal regions, while education correlated with parietal lobe and cingulate gyrus. Finally, the effects of MMSE were mostly observed on brain activation of older adults in both tasks. These findings demonstrate that the effects of moderating variables on shaping brain activation are intricate and not exclusive of complex verbal tasks. Thus, before adjusting for “nuisance variables,” their importance needs to be established. This is especially true for samples including older adults for whom a motor task may be a demanding operation due to normal age-related processes of dedifferentiation.

    in Frontiers in Human Neuroscience on June 05, 2020 12:00 AM.

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    Alterations of Interhemispheric Functional Connectivity in Parkinson’s Disease With Depression: A Resting-State Functional MRI Study

    Background

    Depression is the most common non-motor symptom in patients with Parkinson’s disease (PD) with unknown mechanisms, but the diagnostic criteria of PD with depression (PDD) are not uniform.

    Purpose

    The aim of the study was to investigate interhemispheric interactions between PDD patients and patients with PD without depression (PDND).

    Methods

    The voxel-mirrored homotopic connectivity (VMHC) combined with the seed-based method was used to investigate intrinsic resting-state functional connectivity (RSFC) in 33 PDD patients, 60 PDND, and 47 healthy controls (HCs).

    Results

    PDD patients exhibited a decreased VMHC in the bilateral medial frontal gyrus and paracentral lobule (MFG/PCL) than did PDND patients. Parkinson’s disease with depression had a decreased VMHC in the bilateral precentral gyrus than had PDND and HC (p < 0.05). Parkinson’s disease with depression had a decreased homotopic RSFC from the medial frontal gyrus (MFG)/PCL to the contralateral supplementary motor area (SMA) than had PDND (p < 0.05). The decreased homotopic RSFC from the right MFG/PCL to the left SMA was negatively correlated with Hamilton Depression Rating Scale scores (p < 0.05), but not with illness duration, Beck’s Depression Inventory, and Unified Parkinson’s Disease Rating Scale in PD patients.

    Conclusions

    Our findings indicated that the occurrence of depression in Parkinson’s disease is associated with the dysfunctional connectivity from the MFG/PCL to the contralateral SMA, which could be used as potential neuroimaging markers for the diagnosis of depression in PD patients.

    in Frontiers in Human Neuroscience on June 05, 2020 12:00 AM.

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    The Association Between Experimentally Induced Stress, Performance Monitoring, and Response Inhibition: An Event-Related Potential (ERP) Analysis

    Psychological stress is increasingly associated with alterations in performance and affect. Yet, the relationship between experimentally induced psychological stress and neural indices of performance monitoring and error processing, as well as response inhibition, are unclear. Using scalp-recorded event-related potentials (ERPs), we tested the relationship between experimental stress, using the Trier Social Stress Test (TSST), and the error-related negativity (ERN), error positivity (Pe), and N2 ERP components. A final sample of 71 undergraduate students were randomly assigned to go through the TSST (n = 36; 18 female) or a brief mindfulness relaxation exercise (n = 35; 16 female) immediately followed by a go/no-go task while electroencephalogram (EEG) data were collected. Salivary cortisol, heart rate, and blood pressure confirmed increased physiological stress in the TSST group relative to control. Reaction times, accuracy, and post-error slowing did not differ by stress group. Two-group (TSST, control) by 2-trial type (correct, incorrect for ERN/Pe; go correct, no-go correct for N2) repeated measures ANOVAs for the ERN, Pe, and N2 showed the expected main effects of trial type; neither the ERN nor the N2 ERP components showed interactions with the stress manipulation. In contrast, the Pe component showed a significant Group by Trial interaction, with reduced Pe amplitude following the stress condition relative to control. Pe amplitude did not, however, correlate with cortisol reactivity. Findings suggest a reduction in Pe amplitude following experimental stress that may be associated with reduced error awareness or attention to errors following the TSST. Given the variability in the extant literature on the relationship between experimentally induced stress and neurophysiological reflections of performance monitoring, we provide another point of data and conclude that better understanding of moderating variables is needed followed by high-powered replication studies to get at the nuance that is not yet understood in the relationship between induced stress and performance monitoring/response inhibition processes.

    in Frontiers in Human Neuroscience on June 05, 2020 12:00 AM.

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    Corrigendum: A General Model of Ion Passive Transmembrane Transport Based on Ionic Concentration

    in Frontiers in Computational Neuroscience on June 05, 2020 12:00 AM.

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    Transfer Entropy as a Measure of Brain Connectivity: A Critical Analysis With the Help of Neural Mass Models

    Objective: Assessing brain connectivity from electrophysiological signals is of great relevance in neuroscience, but results are still debated and depend crucially on how connectivity is defined and on mathematical instruments utilized. Aim of this work is to assess the capacity of bivariate Transfer Entropy (TE) to evaluate connectivity, using data generated from simple neural mass models of connected Regions of Interest (ROIs).

    Approach: Signals simulating mean field potentials were generated assuming two, three or four ROIs, connected via excitatory or by-synaptic inhibitory links. We investigated whether the presence of a statistically significant connection can be detected and if connection strength can be quantified.

    Main Results: Results suggest that TE can reliably estimate the strength of connectivity if neural populations work in their linear regions, and if the epoch lengths are longer than 10 s. In case of multivariate networks, some spurious connections can emerge (i.e., a statistically significant TE even in the absence of a true connection); however, quite a good correlation between TE and synaptic strength is still preserved. Moreover, TE appears more robust for distal regions (longer delays) compared with proximal regions (smaller delays): an approximate a priori knowledge on this delay can improve the procedure. Finally, non-linear phenomena affect the assessment of connectivity, since they may significantly reduce TE estimation: information transmission between two ROIs may be weak, due to non-linear phenomena, even if a strong causal connection is present.

    Significance: Changes in functional connectivity during different tasks or brain conditions, might not always reflect a true change in the connecting network, but rather a change in information transmission. A limitation of the work is the use of bivariate TE. In perspective, the use of multivariate TE can improve estimation and reduce some of the problems encountered in the present study.

    in Frontiers in Computational Neuroscience on June 05, 2020 12:00 AM.

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    Spatial Updating Depends on Gravity

    As we move through an environment the positions of surrounding objects relative to our body constantly change. Maintaining orientation requires spatial updating, the continuous monitoring of self-motion cues to update external locations. This ability critically depends on the integration of visual, proprioceptive, kinesthetic, and vestibular information. During weightlessness gravity no longer acts as an essential reference, creating a discrepancy between vestibular, visual and sensorimotor signals. Here, we explore the effects of repeated bouts of microgravity and hypergravity on spatial updating performance during parabolic flight. Ten healthy participants (four women, six men) took part in a parabolic flight campaign that comprised a total of 31 parabolas. Each parabola created about 20–25 s of 0 g, preceded and followed by about 20 s of hypergravity (1.8 g). Participants performed a visual-spatial updating task in seated position during 15 parabolas. The task included two updating conditions simulating virtual forward movements of different lengths (short and long), and a static condition with no movement that served as a control condition. Two trials were performed during each phase of the parabola, i.e., at 1 g before the start of the parabola, at 1.8 g during the acceleration phase of the parabola, and during 0 g. Our data demonstrate that 0 g and 1.8 g impaired pointing performance for long updating trials as indicated by increased variability of pointing errors compared to 1 g. In contrast, we found no support for any changes for short updating and static conditions, suggesting that a certain degree of task complexity is required to affect pointing errors. These findings are important for operational requirements during spaceflight because spatial updating is pivotal for navigation when vision is poor or unreliable and objects go out of sight, for example during extravehicular activities in space or the exploration of unfamiliar environments. Future studies should compare the effects on spatial updating during seated and free-floating conditions, and determine at which g-threshold decrements in spatial updating performance emerge.

    in Frontiers in Neural Circuits on June 05, 2020 12:00 AM.

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    Targeting Microglial Population Dynamics in Alzheimer’s Disease: Are We Ready for a Potential Impact on Immune Function?

    Alzheimer’s disease (AD) is the most common form of dementia, affecting two-thirds of people with dementia in the world. To date, no disease-modifying treatments are available to stop or delay the progression of AD. This chronic neurodegenerative disease is dominated by a strong innate immune response, whereby microglia plays a central role as the main resident macrophage of the brain. Recent genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) located in microglial genes and associated with a delayed onset of AD, highlighting the important role of these cells on the onset and/or progression of the disease. These findings have increased the interest in targeting microglia-associated neuroinflammation as a potentially disease-modifying therapeutic approach for AD. In this review we provide an overview on the contribution of microglia to the pathophysiology of AD, focusing on the main regulatory pathways controlling microglial population dynamics during the neuroinflammatory response, such as the colony-stimulating factor 1 receptor (CSF1R), its ligands (the colony-stimulating factor 1 and interleukin 34) and the transcription factor PU.1. We also discuss the current therapeutic strategies targeting proliferation to modulate microglia-associated neuroinflammation and their potential impact on peripheral immune cell populations in the short and long-term. Understanding the effects of immunomodulatory approaches on microglia and other immune cell types might be critical for developing specific, effective, and safe therapies for neurodegenerative diseases.

    in Frontiers in Cellular Neuroscience on June 05, 2020 12:00 AM.

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    A Whole-Brain Cell-Type-Specific Sparse Neuron Labeling Method and Its Application in a Shank3 Autistic Mouse Model

    Single neurons, as the basic unit of the brain, consist of a cell body and processes, including dendrites and axons. Even neurons of the same type show various subtle process characteristics to fit into the diverse neural circuits. Different cell types of neurons form complicated circuits in the brain. Therefore, detailed neuronal morphology is required to understand normal neuronal function and pathological mechanisms, such as those that occur in autism. Here, we developed a strategy to sparsely label the same type of neurons throughout the whole brain and tested its application in an autistic animal model—Shank3 knockout (KO) mice. To achieve this, we designed an adeno-associated virus (AAV) that expresses Cre recombinase-dependent regular and membrane-targeted enhanced green fluorescent protein (EGFP) under a human synapsin 1 promoter and verified it in several Cre transgenic mice. We could sparsely label the projection neurons in multiple brain areas by retro-ocular injection of the virus into CaMKIIα-Cre mice. Then, we analyzed the morphology of the projection neurons in Shank3 KO mice with this method. We found differential dendritic complexity and dendritic spine changes in projection neurons in Shank3 KO mice crossed with CaMKIIα-Cre mice compared with littermate control mice in the striatum, cortex, and hippocampus. By combining this method with various Cre mouse lines crossed with mouse models of disease, we can screen the morphological traits of distinct types of neurons throughout the whole brain that will help us to understand the exact role of the specific cell types of neurons not only in autism spectrum disorder (ASD) mouse models but also in other psychiatric disorder mouse models.

    in Frontiers in Cellular Neuroscience on June 05, 2020 12:00 AM.

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    The Basal Forebrain Modulates Neuronal Response in an Active Olfactory Discrimination Task

    Successful completion of sensory decision-making requires focusing on relevant stimuli, adequate signal/noise ratio for stimulus discrimination, and stimulus valence evaluation. Different brain regions are postulated to play a role in these computations; however, evidence suggests that sensory and decision-making circuits are required to interact through a common neuronal pathway to elicit a context-adequate behavioral response. Recently, the basal forebrain (BF) region has emerged as a good candidate, since its heterogeneous projecting neurons innervate most of the cortical mantle and sensory processing circuits modulating different aspects of the sensory decision-making process. Moreover, evidence indicates that the BF plays an important role in attention and in fast modulation of neuronal activity that enhance visual and olfactory sensory perception. Here, we study in awake mice the involvement of BF in initiation and completion of trials in a reward-driven olfactory detection task. Using tetrode recordings, we find that BF neurons (including cholinergics) are recruited during sensory discrimination, reward, and interestingly slightly before trial initiation in successful discrimination trials. The precue neuronal activity was correlated with animal performance, indicating that this circuit could play an important role in adaptive context-dependent behavioral responses.

    in Frontiers in Cellular Neuroscience on June 05, 2020 12:00 AM.

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    Gestational Exposure to Sodium Valproate Disrupts Fasciculation of the Mesotelencephalic Dopaminergic Tract, With a Selective Reduction of Dopaminergic Output From the Ventral Tegmental Area

    Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD). Available data are scarce on the neuromorphological changes in VPA-exposed animals. Here, we focused on alterations of the dopaminergic system, which is implicated in motivation and reward, with relevance to social cohesion. Whole brains from 7-day-old mice born to mothers given a single injection of VPA (400 mg/kg b.wt.) on E13.5 were immunostained against tyrosine hydroxylase (TH). They were scanned using the iDISCO method with a laser light-sheet microscope, and the reconstructed images were analyzed in 3D for quantitative morphometry. A marked reduction of mesotelencephalic (MT) axonal fascicles together with a widening of the MT tract were observed in VPA treated mice, while other major brain tracts appeared anatomically intact. We also found a reduction in the abundance of dopaminergic ventral tegmental (VTA) neurons, accompanied by diminished tissue level of DA in ventrobasal telencephalic regions (including the nucleus accumbens (NAc), olfactory tubercle, BST, substantia innominata). Such a reduction of DA was not observed in the non-limbic caudate-putamen. Conversely, the abundance of TH+ cells in the substantia nigra (SN) was increased, presumably due to a compensatory mechanism or to an altered distribution of TH+ neurons occupying the SN and the VTA. The findings suggest that defasciculation of the MT tract and neuronal loss in VTA, followed by diminished dopaminergic input to the ventrobasal telencephalon at a critical time point of embryonic development (E13-E14) may hinder the patterning of certain brain centers underlying decision making and sociability.

    in Frontiers in Neuroanatomy on June 05, 2020 12:00 AM.

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    Dilated Perivascular Space in the Midbrain May Reflect Dopamine Neuronal Degeneration in Parkinson’s Disease

    Background: The imbalance between the production and clearance of alpha-synuclein and its consequent accumulation plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). The diminished clearance of alpha-synuclein may be partly attributable to impaired interstitial fluid, which can be reflected by the extent of dilated perivascular space (dPVS). We studied the association between dPVS and dopamine neuronal degeneration.

    Method: We screened 71 healthy controls (HCs) and 88 patients from the Parkinson Progression Markers Initiative (PPMI) database. The dPVS was evaluated in different brain regions on axial T2-weighted images, and dopamine transporter (DAT) imaging data was used to elucidate the extent of dopaminergic neuronal degeneration. Patients with PD were further divided into two groups (SN + PD and SN − PD groups) according to whether dPVS was observed in the substantia nigra (SN). DAT uptake values and clinical scales were compared between the patients with PD and HCs and against dPVS scores. We also investigated the correlation between baseline dPVS scores and longitudinal DAT changes.

    Results: Relative to the HCs, patients with PD had more dPVS in the SN and basal ganglia (BG). PD patients with dPVS in the SN region exhibited greater expression of tau protein in cerebrospinal fluid (P = 0.038) and a trend towards decreased DAT binding (P = 0.086) relative to those without SN dPVS. No correlations were found between dPVS scores and DAT uptake values or between dPVS scores and longitudinal DAT changes.

    Conclusion: The dPVS in the SN of patients with PD may reflect the degeneration of dopaminergic neurons.

    in Frontiers in Ageing Neuroscience on June 05, 2020 12:00 AM.

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    Serum Uric Acid, Alzheimer-Related Brain Changes, and Cognitive Impairment

    Background

    Despite known associations of lower serum uric acid (UA) with Alzheimer’s disease (AD) dementia or AD-related cognitive impairment, little is known regarding the underlying patho-mechanisms. We aimed to examine the relationships of serum UA with in vivo AD pathologies including cerebral beta-amyloid (Aβ) and tau deposition, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensities (WMH). We also investigated the association between serum UA and cognitive performance, and then assessed whether such an association is mediated by the brain pathologies.

    Methods

    A total of 430 non-demented older adults underwent comprehensive clinical assessments, measurement of serum UA level, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging scans. Mini-Mental State Examination (MMSE) and word list recall (WLR) test scores were used to measure cognitive performance.

    Results

    Serum UA level was significantly associated with AD-CM, but not with Aβ deposition, tau deposition, or WMH volume. Serum UA levels also had significant association with WLR and marginal association with MMSE; such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a mediating effect.

    Conclusion

    The findings of the present study indicate that there is an association of low serum UA with AD-related cerebral hypometabolism, and whether this represents a causal relationship remains to be determined.

    in Frontiers in Ageing Neuroscience on June 05, 2020 12:00 AM.

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    Translation Imaging in Parkinson’s Disease: Focus on Neuroinflammation

    Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the appearance of α-synuclein insoluble aggregates known as Lewy bodies. Neurodegeneration is accompanied by neuroinflammation mediated by cytokines and chemokines produced by the activated microglia. Several studies demonstrated that such an inflammatory process is an early event, and contributes to oxidative stress and mitochondrial dysfunctions. α-synuclein fibrillization and aggregation activate microglia and contribute to disease onset and progression. Mutations in different genes exacerbate the inflammatory phenotype in the monogenic compared to sporadic forms of PD. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) with selected radiopharmaceuticals allow in vivo imaging of molecular modifications in the brain of living subjects. Several publications showed a reduction of dopaminergic terminals and dopamine (DA) content in the basal ganglia, starting from the early stages of the disease. Moreover, non-dopaminergic neuronal pathways are also affected, as shown by in vivo studies with serotonergic and glutamatergic radiotracers. The role played by the immune system during illness progression could be investigated with PET ligands that target the microglia/macrophage Translocator protein (TSPO) receptor. These agents have been used in PD patients and rodent models, although often without attempting correlations with other molecular or functional parameters. For example, neurodegeneration and brain plasticity can be monitored using the metabolic marker 2-Deoxy-2-[18F]fluoroglucose ([18F]-FDG), while oxidative stress can be probed using the copper-labeled diacetyl-bis(N-methyl-thiosemicarbazone) ([Cu]-ATSM) radioligand, whose striatal-specific binding ratio in PD patients seems to correlate with a disease rating scale and motor scores. Also, structural and functional modifications during disease progression may be evaluated by Magnetic Resonance Imaging (MRI), using different parameters as iron content or cerebral volume. In this review article, we propose an overview of in vivo clinical and non-clinical imaging research on neuroinflammation as an emerging marker of early PD. We also discuss how multimodal-imaging approaches could provide more insights into the role of the inflammatory process and related events in PD development.

    in Frontiers in Ageing Neuroscience on June 05, 2020 12:00 AM.

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    Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

    Introduction

    While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages.

    Methods

    Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models.

    Results

    Stages differed at baseline on APOE-ε4 status (early < middle = late; p-values < 0.03) and CSF Aβ (early > middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03).

    Discussion

    Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets.

    in Frontiers in Ageing Neuroscience on June 05, 2020 12:00 AM.

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    The Comparative Efficacy of Multiple Interventions for Mild Cognitive Impairment in Alzheimer's Disease: A Bayesian Network Meta-Analysis

    Background: Mild cognitive impairment (MCI) is the early phase of Alzheimer's disease (AD). The aim of early intervention for MCI is to decrease the rate of conversion from MCI to AD. However, the efficacy of multiple interventions in MCI, and the optimal methods of delivery, remain controversial. We aimed to compare and rank the treatment methods for MCI in AD, in order to find an optimal intervention for MCI and a way to prevent or delay the occurrence of AD.

    Methods: Pair-wise and network meta-analysis were conducted to integrate the treatment effectiveness through direct and indirect evidence. Four English databases and three Chinese databases were searched for international registers of eligible published, single or double blind, randomized controlled trials up to September 31st 2019. We included nine comparative interventions: pharmacological therapies which incorporated cholinesterase inhibitors (ChEI), ginkgo, nimodipine, and Chinese medicine; non-pharmacological therapies comprising of acupuncture, music therapy, exercise therapy, and nutrition therapy; and a placebo group. The primary outcome was the Mini-Mental State Examination (MMSE) score. The secondary outcome was the AD Assessment Scale-cognitive subscale (ADAS-cog).

    Results: Twenty-eight trials were eligible, including 6,863 participants. In the direct meta-analysis, as for the Mini-Mental State Examination scale, the ChEIs (MD: −0.38; 95% CI: −0.74, −0.01), Chinese medicine (MD: −0.31; 95% CI: −0.75, 0.13), exercise therapy (MD: −0.50; 95% CI: −0.65, −0.35), music therapy (MD: −1.71; 95% CI: −4.49, 1.07), were statistically more efficient than placebo. For AD Assessment Scalecognitive subscale outcome, ChEIs (MD: 1.20; 95% CI: 0.73, 1.68), Acupuncture (MD: 1.36; 95% CI: 1.28, 1.44), Chinese medicine (MD: 0.61; 95% CI: 0.49, 0.73) and exercise (MD: 0.61; 95% CI: 0.49, 0.73) were better than placebo. In the network meta-analysis, the MMSE outcome ranked music therapy (59%) as the best and Acupuncture (26%) as second. Nutrition and Ginkgo treatment had the lowest rank among all interventions. For ADAS-cog outcome, acupuncture (52) ranked the best.

    Conclusion: Among the nine treatments studied, music therapy appears to be the best treatment for MCI, followed by acupuncture. Our study provides new insights into potential clinical treatments for MCI due to AD, and may aid the development of guidelines for MCI in AD.

    in Frontiers in Ageing Neuroscience on June 05, 2020 12:00 AM.

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    We need to act now

    eLife, like the rest of science, must tackle the many inequalities experienced by Black scientists.

    in eLife on June 05, 2020 12:00 AM.

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    Diverse nucleosome site-selectivity among histone deacetylase complexes

    Histone acetylation regulates chromatin structure and gene expression and is removed by histone deacetylases (HDACs). HDACs are commonly found in various protein complexes to confer distinct cellular functions, but how the multi-subunit complexes influence deacetylase activities and site-selectivities in chromatin is poorly understood. Previously we reported the results of studies on the HDAC1 containing CoREST complex and acetylated nucleosome substrates which revealed a notable preference for deacetylation of histone H3 acetyl-Lys9 vs. acetyl-Lys14 (M. Wu et al, 2018). Here we analyze the enzymatic properties of five class I HDAC complexes: CoREST, NuRD, Sin3B, MiDAC and SMRT with site-specific acetylated nucleosome substrates. Our results demonstrate that these HDAC complexes show a wide variety of deacetylase rates in a site-selective manner. A Gly13 in the histone H3 tail is responsible for a sharp reduction in deacetylase activity of the CoREST complex for H3K14ac. These studies provide a framework for connecting enzymatic and biological functions of specific HDAC complexes.

    in eLife on June 05, 2020 12:00 AM.

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    Flexible motor sequence generation during stereotyped escape responses

    Complex animal behaviors arise from a flexible combination of stereotyped motor primitives. Here we use the escape responses of the nematode Caenorhabditis elegans to study how a nervous system dynamically explores the action space. The initiation of the escape responses is predictable: the animal moves away from a potential threat, a mechanical or thermal stimulus. But the motor sequence and the timing that follow are variable. We report that a feedforward excitation between neurons encoding distinct motor states underlies robust motor sequence generation, while mutual inhibition between these neurons controls the flexibility of timing in a motor sequence. Electrical synapses contribute to feedforward coupling whereas glutamatergic synapses contribute to inhibition. We conclude that C. elegans generates robust and flexible motor sequences by combining an excitatory coupling and a winner-take-all operation via mutual inhibition between motor modules.

    in eLife on June 05, 2020 12:00 AM.

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    An image-based data-driven analysis of cellular architecture in a developing tissue

    Quantitative microscopy is becoming increasingly crucial in efforts to disentangle the complexity of organogenesis, yet adoption of the potent new toolbox provided by modern data science has been slow, primarily because it is often not directly applicable to developmental imaging data. We tackle this issue with a newly developed algorithm that uses point cloud-based morphometry to unpack the rich information encoded in 3D image data into a straightforward numerical representation. This enabled us to employ data science tools, including machine learning, to analyze and integrate cell morphology, intracellular organization, gene expression and annotated contextual knowledge. We apply these techniques to construct and explore a quantitative atlas of cellular architecture for the zebrafish posterior lateral line primordium, an experimentally tractable model of complex self-organized organogenesis. In doing so, we are able to retrieve both previously established and novel biologically relevant patterns, demonstrating the potential of our data-driven approach.

    in eLife on June 05, 2020 12:00 AM.

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    Mechanisms of nucleotide selection by telomerase

    Telomerase extends telomere sequences at chromosomal ends to protect genomic DNA. During this process it must select the correct nucleotide from a pool of nucleotides with various sugars and base pairing properties, which is critically important for the proper capping of telomeric sequences by shelterin. Unfortunately, how telomerase selects correct nucleotides is unknown. Here, we determined structures of Tribolium castaneum telomerase reverse transcriptase (TERT) throughout its catalytic cycle and mapped the active site residues responsible for nucleoside selection, metal coordination, triphosphate binding, and RNA template stabilization. We found that TERT inserts a mismatch or ribonucleotide ~1 in 10,000 and ~1 in 14,000 insertion events, respectively. At biological ribonucleotide concentrations, these rates translate to ~40 ribonucleotides inserted per 10 kilobases. Human telomerase assays determined a conserved tyrosine steric gate regulates ribonucleotide insertion into telomeres. Cumulatively, our work provides insight into how telomerase selects the proper nucleotide to maintain telomere integrity.

    in eLife on June 05, 2020 12:00 AM.

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    TGFβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration

    Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGFβ signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFβ-dependent and  TGFβ-independent mechanisms underlying tendon regeneration. Importantly, functional recovery depended on canonical TGFβ signaling and loss of function is due to impaired tenogenic cell recruitment from both Scleraxis-lineage and non-Scleraxis-lineage sources.  We show that TGFβ signaling is directly required in neonatal tenocytes for recruitment and that TGFβ ligand is positively regulated in tendons. Collectively, these results show a functional role for canonical TGFβ signaling in tendon regeneration and offer new insights toward the divergent cellular activities that distinguish regenerative vs fibrotic healing.

    in eLife on June 05, 2020 12:00 AM.

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    JNK signalling regulates antioxidant responses in neurons

    Reactive oxygen species (ROS) are generated during physiological bouts of synaptic activity and as a consequence of pathological conditions in the central nervous system. How neurons respond to and distinguish between ROS in these different contexts is currently unknown. In Drosophila mutants with enhanced JNK activity, lower levels of ROS are observed and these animals are resistant to both changes in ROS and changes in synapse morphology induced by oxidative stress. In wild type flies, disrupting JNK-AP-1 signalling perturbs redox homeostasis suggesting JNK activity positively regulates neuronal antioxidant defense. We validated this hypothesis in mammalian neurons, finding that JNK activity regulates the expression of the antioxidant gene Srxn-1, in a c-Jun dependent manner. We describe a conserved 'adaptive' role for neuronal JNK in the maintenance of redox homeostasis that is relevant to several neurodegenerative diseases.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Properties of Glial Cell at the Neuromuscular Junction are Incompatible with synaptic repair in the SOD1G37R ALS mouse model

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motoneurons in a motor-unit (MU) dependent manner. Glial dysfunction contributes to numerous aspects of the disease. At the neuromuscular junction (NMJ), early alterations in perisynaptic Schwann cell (PSC), glial cells at this synapse, may impact their ability to regulate NMJ stability and repair. Indeed, muscarinic receptors (mAChR) regulate the repair phenotype of PSCs and are overactivated at disease-resistant NMJs (Soleus muscle) in SOD1G37R mice. However, it remains unknown whether this is the case at disease-vulnerable NMJs and whether it translates into an impairment of PSC-dependent repair mechanisms. We used Soleus and Sternomastoid muscles from SOD1G37R mice and performed Ca2+-imaging to monitor PSC activity and used immunohistochemistry to analyze their repair and phagocytic properties. We show that PSC mAChR-dependent activity was transiently increased at disease-vulnerable NMJs (Sternomastoid muscle). Furthermore, PSCs from both muscles extended disorganized processes from denervated NMJs and failed to initiate or guide nerve terminal sprouts at disease-vulnerable NMJs, a phenomenon essential for compensatory reinnervation. This was accompanied by a failure of numerous PSCs to upregulate Galectin-3 (MAC-2), a marker of glial axonal debris phagocytosis, upon NMJ denervation in SOD1 mice. Finally, differences in these PSC-dependent NMJ repair mechanisms were MU-type dependent, thus reflecting MU vulnerability in ALS. Together, these results reveal that neuron-glia communication is ubiquitously altered at the NMJ in ALS. This appears to prevent PSCs from adopting a repair phenotype, resulting in a maladapted response to denervation at the NMJ in ALS.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Enhancing the sensitivity of the envelope-following response for cochlear synaptopathy screening in humans: the role of stimulus envelope

    Auditory de-afferentation, a permanent reduction in the number of inner-hair-cells and auditory-nerve synapses due to cochlear synaptopathy or damage, can reliably be quantified using temporal bone histology and immunostaining. There is, however, an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) based markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or measurement sensitivity. To render AEP-based markers of synaptopathy more robust and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve physiology, we optimized the stimulus envelope for envelope-following-responses (EFRs) to optimally and synchronously stimulate the available auditory-nerve population and consequently generate a strong AEP. We additionally used model simulations to explore which stimuli evoked a response which was sensitive to synaptopathy, while being insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who either had normal or impaired audiograms. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120 Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recorded conditions, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25% duty cycle and a 95% modulation depth.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Individual differences in theta-band oscillations in a spatial memory network revealed by EEG predict rapid place learning

    Spatial memory has been closely related to the medial temporal lobe (MTL), and theta-oscillations are thought to play a key role. However, it remains difficult to investigate medio-temporal lobe (MTL) activation related to spatial memory with non-invasive electrophysiological methods in humans. Here, we combined the virtual delayed-matching-to-place (DMP) task, reverse-translated from the watermaze DMP task in rats, with high-density electroencephalography (EEG) recordings. Healthy young volunteers performed this computerised task in a virtual circular arena, which contained a hidden target whose location moved to a new place every four trials, allowing the assessment of rapid memory formation. Using behavioural measures as predictor variables for source reconstructed frequency specific EEG power, we found that inter-individual differences in search preference during probe trials, a measure of 1-trial place learning known from rodent studies to be particularly hippocampus dependent, correlated predominantly with distinct theta-band oscillations (approx. 7 Hz), particularly in the right temporal lobe, the right striatum and inferior occipital cortex or cerebellum. Notably, this pattern was found with very high consistency during both encoding and retrieval/expression, but not in control analyses and could not be explained by motor confounds. Alpha-activity in sensorimotor and parietal cortex contralateral to the hand used for navigation also correlated with search preference, which likely reflected movement-related factors associated with task performance. Relating inter-individual differences in ongoing brain activity to behaviour in a continuous rapid place learning task that is suitable for a variety of populations, we could demonstrate that memory related theta-band activity in temporal lobe can be measured with EEG recordings, revealing a presumed network of MTL, striatum and cerebellum and/or inferior occipital cortex that may interact through theta oscillations. This approach holds great potential for further studies investigating the interactions within this network during encoding and retrieval, as well as neuromodulatory impacts and age-related changes.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Scaling of gene transcriptional gradients with brain size across mouse development

    The structure of the adult brain is the result of complex physical mechanisms acting through development. Accordingly, the brain's spatial embedding plays a key role in its structural and functional organization, including the gradient-like patterning of gene expression that encodes the molecular underpinning of functional specialization. But we do not understand how this transcriptional heterogeneity is spatially organized across the major alterations in brain geometry that occur through development. Here we investigate the spatial embedding of transcriptional patterns of over 1800 genes across seven time points through mouse-brain development using data from the Allen Developing Mouse Brain Atlas. We find that the similarity of transcriptional patterns decreases exponentially with separation distance across all developmental time points, with a correlation length scale that satisfies a power-law scaling relationship with a linear dimension of brain size. This scaling suggests that the mouse brain achieves a characteristic spatial balance between local transcriptional similarity (within functionally specialized brain areas) and longer-range diversity (between functionally specialized brain areas) throughout its development. Extrapolating this mouse-developmental scaling relationship to predict the correlation length of gene expression in the human cortex yields a slight overestimate, consistent with the human cortex being more molecularly diverse and functionally specialized than the mouse brain. We develop a simple model of brain growth as spatially autocorrelated gene-expression gradients that expand through development, which captures key features of the mouse developmental data. Complementing the well-known exponential distance rule for structural connectivity, our findings thus characterize an exponential distance rule for transcriptional gradients that scales across mouse-brain development, providing new understanding of the molecular patterns underlying the functional specialization in the brain.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Post-weaning social isolation increases ΔFosB/FosB protein expression in the prefrontal cortex and hippocampus in mice

    Social isolation is a growing public health concern across the lifespan. Specifically, isolation early in life, during critical periods of brain development, increases the risk of psychiatric disorders later in life. Previous studies of isolation models in mice have shown distinct neurological abnormalities in various regions of the brain, but the mechanism linking the experience of isolation to these phenotypes is unclear. In this study, we show that {Delta}FosB, a long-lived transcription factor associated with chronic stress responses and drug-induced neuroplasticity, is upregulated in the medial prefrontal cortex and hippocampus of adult C57BL/6J mice isolated for two weeks post-weaning. Additionally, a related transcription factor, FosB, is also increased in the medial prefrontal cortex in socially isolated females. These results show that short-term isolation during the critical post-weaning period has long-lasting and sex-dependent effects on gene expression in brain.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Three-photon imaging of synthetic dyes in deep layers of the neocortex

    Multiphoton microscopy has emerged as the primary imaging tool for studying the structural and functional dynamics of neural circuits in brain tissue, which is highly scattering to light. Recently, three-photon microscopy has enabled high-resolution fluorescence imaging of neurons in deeper brain areas that lie beyond the reach of conventional two-photon microscopy, which is typically limited to ~450 microns. Three-photon imaging of neuronal calcium signals, through the genetically-encoded calcium indicator GCaMP6, has been used to successfully record neuronal activity in deeper neocortical layers and parts of the hippocampus. Bulk-loading cells in deeper cortical layers with synthetic calcium indicators could provide an alternative strategy for labelling that obviates dependence on viral tropism and promoter penetration. Here we report a strategy for visualized injection of a calcium dye, Oregon Green BAPTA-1 AM (OGB-1 AM), at 500-600 microns below the surface of the mouse visual cortex in vivo. We demonstrate successful OGB-1 AM loading of cells in cortical layers 5-6 and subsequent three-photon imaging of orientation- and direction- selective visual responses from these cells.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Ventral pallidum neurons signal relative threat

    Ventral pallidum (VP) neurons scale firing increases to reward value and decrease firing to aversive cues. Anatomical connectivity suggests a critical role for the VP in threat-related behavior. Here we tested whether firing decreases in VP neurons conform to relative threat by recording single units while male rats discriminated cues predicting unique foot shock probabilities. Rats behavior and VP single unit firing discriminated danger, uncertainty and safety cues. We found that two VP populations (Low firing and Intermediate firing) signaled relative threat, proportionally decreased firing according shock probability: danger < uncertainty < safety. Low firing neurons showed reward firing increases, consistent with a general signal for relative value. Intermediate firing neurons were unresponsive to reward, revealing a specific signal for relative threat. The results suggest an integral role for the VP in threat-related behavior.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Multivariate analysis reveals a generalizable human electrophysiological signature of working memory load

    Working memory (WM) is an online memory system that is critical for holding information in a rapidly accessible state during ongoing cognitive processing. Thus, there is strong value in methods that provide a temporally-resolved index of WM load. While univariate EEG signals have been identified that vary with WM load, recent advances in multivariate analytic approaches suggest that there may be rich sources of information that do not generate reliable univariate signatures. Here, using data from 4 published studies (n = 286 and >250,000 trials), we demonstrate that multivariate analysis of EEG voltage topography provides a sensitive index of the number of items stored in WM that generalizes to novel human observers. Moreover, multivariate load detection can provide robust information at the single-trial level, exceeding the sensitivity of extant univariate approaches. We show that this method tracks WM load in a manner that is (1) independent of the spatial position of the memoranda, (2) precise enough to differentiate item-by-item increments in the number of stored items, (3) generalizable across distinct tasks and stimulus displays and (4) correlated with individual differences in WM behavior. Thus, this approach provides a powerful complement to univariate analytic approaches, enabling temporally-resolved tracking of online memory storage in humans.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Synchronization, stochasticity and phase waves in neuronal networks with spatially-structured connectivity

    Oscillations in the beta/low gamma range (10-45 Hz) are recorded in diverse neural structures. They have successfully been modeled as sparsely synchronized oscillations arising from reciprocal interactions between randomly connected excitatory (E) pyramidal cells and local interneurons (I). The synchronization of spatially distant oscillatory spiking E-I modules has been well studied in the rate model framework but less so for modules of spiking neurons. Here, we first show that previously proposed modifications of rate models provide a quantitative description of spiking E-I modules of Exponential Integrate-and-Fire (EIF) neurons. This allows us to analyze the dynamical regimes of sparsely synchronized oscillatory E-I modules connected by long-range excitatory interactions, for two modules, as well as for a chain of such modules. For modules with a large number of neurons (>105), we obtain results similar to previously obtained ones based on the classic deterministic Wilson-Cowan rate model, with the added bonus that the results quantitatively describe simulations of spiking EIF neurons. However, for modules with a moderate (~104) number of neurons, stochastic variations in the spike emission of neurons are important and need to be taken into account. On the one hand, they modify the oscillations in a way that tends to promote synchronization between different modules. On the other hand, independent fluctuations on different modules tend to disrupt synchronization. The correlations between distant oscillatory modules can be described by stochastic equations for the oscillator phases that have been intensely studied in other contexts. On shorter distances, we develop a description that also takes into account amplitude modes and that quantitatively accounts for our simulation data. Stochastic dephasing of neighboring modules produces transient phase gradients and the transient appearance of phase waves. We propose that these stochastically-induced phase waves provide an explanative framework for the observations of traveling waves in the cortex during beta oscillations.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

    The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury triggers an ad hoc upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for the formation and maintenance of glial scars in vivo. In turn, DBN loss leads to defective glial scar formation and excessive neurodegeneration following mild brain injuries. At the cellular level, DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds and facilitates the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesive responses, such as {beta}1-integrin. Our work identifies DBN as pathology-specific actin regulator, and establishes DBN-dependent membrane trafficking as crucial mechanism in protecting the brain from escalating damage following traumatic injuries.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    The coupling of global brain activity and cerebrospinal fluid inflow is correlated with Alzheimer's disease related pathology

    The glymphatic system plays an important role in clearing the amyloid-{beta} and tau proteins that are closely linked to Alzheimer's disease (AD) pathology. Glymphatic clearance, as well as amyloid-{beta} accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state fMRI, is coupled with the CSF movements, suggesting their potential link to the glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer's Disease Neuroimaging Initiative project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical amyloid-{beta} level, and the cognitive decline over a two-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    A generative modeling approach for interpreting population-level variability in brain structure

    Understanding how neural structure varies across individuals is critical for characterizing the effects of disease, learning, and aging on the brain. However, disentangling the different factors that give rise to individual variability is still an outstanding challenge. In this paper, we introduce a deep generative modeling approach to find different modes of variation across many individuals. To do this, we start by training a variational autoencoder on a collection of auto-fluorescence images from a little over 1,700 mouse brains at 25 micron resolution. To then tap into the learned factors and validate the model's expressiveness, we developed a novel bi-directional technique to interpret the latent space--by making structured perturbations to both, the high-dimensional inputs of the network, as well as the low-dimensional latent variables in its bottleneck. Our results demonstrate that through coupling generative modeling frameworks with structured perturbations, it is possible to probe the latent space to provide insights into the representations of brain structure formed in deep neural networks.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Variance in cortical depth across the brain surface

    The distance between the surface of the scalp and the surface of the grey matter of the brain is a key factor in determining the effective dose of non-invasive brain stimulation for an individual person. The highly folded nature of the cortical surface means that the depth of a particular brain area is likely to vary between individuals. The question addressed here is: what is the variability of this measure of cortical depth? 94 anatomical MRI images were taken from the OASIS database. For each image, the minimum distance from each point in the grey matter to the scalp surface was determined. Transforming these estimates into standard space meant that the coefficient of variation could be determined across the sample. The results indicated that depth variability is high across the cortical surface, even when taking sulcal depth into account. This was true even for the primary visual and motor areas, which are often used in setting TMS dosage. The correlation of the depth of these areas and the depth of other brain areas was low. The results suggest that dose-setting of TMS based on visual or evoked potentials may offer poor reliability, and that individual brain images should be used when targeting non-primary brain areas.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Structural basis of GIRK2 channel modulation by cholesterol and PIP2

    G protein-gated inwardly rectifying potassium (GIRK) channels play important roles in controlling cellular excitability in the heart and brain. While structural data begin to unravel the molecular basis for G protein and alcohol dependent activation of GIRK channels, little is known about the modulation by cholesterol. Here, we present cryo-electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS), and PIP2. The structures and their comparison reveal that CHS binds near PIP2 in lipid-facing hydrophobic pockets of the transmembrane domain (TMD). CHS potentiates the effects of PIP2, which stabilizes the inter-domain region and promotes the engagement of the cytoplasmic domain (CTD) onto the transmembrane region. The results suggest that CHS acts as a positive allosteric modulator and identify novel therapeutic sites for modulating GIRK channels in the brain.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Divergent behavioral consequences of manipulations enhancing pyramidal neuron excitability in the prelimbic cortex

    Background: Drug-induced neuroadaptations in the prefrontal cortex are thought to underlie impaired executive functions that reinforce addictive behaviors. Repeated cocaine exposure increased layer 5/6 pyramidal neuron excitability in the mouse prelimbic cortex (PL), an adaptation attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK/Kir3) channel activity. GIRK channel suppression in the PL of drug-naive mice enhanced the motor-stimulatory effect of cocaine. The impact of cocaine on PL GABA neurons, key pyramidal neuron regulators, and the behavioral relevance of increased PL pyramidal neuron excitability, remain unclear. Methods: The effect of repeated cocaine on mouse layer 5/6 PL GABA neurons was assessed using slice electrophysiology. Adaptations enhancing PL pyramidal neuron excitability were modeled in drug-naive mice using persistent viral Cre ablation and acute chemogenetic approaches. The impact of these manipulations on PL-dependent behavior was assessed in motor activity and trace fear conditioning tests. Results: Repeated cocaine treatment did not impact GIRK channel activity in, or excitability of, layer 5/6 PL GABA neurons. GIRK channel ablation in PL pyramidal neurons enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or fear learning. In contrast, direct or indirect chemogenetic activation of PL pyramidal neurons increased baseline and cocaine-induced motor activity and disrupted fear learning. These effects were mirrored by chemogenetic activation of PL pyramidal neurons projecting to the ventral tegmental area. Conclusions: Manipulations enhancing the excitability of PL pyramidal neurons, including those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Differentiation of ciliated human midbrain-derived LUHMES neurons

    Many human cell types are ciliated, including neural progenitors and differentiated neurons. Ciliopathies are characterized by defective cilia and comprise various disease states, including brain phenotypes, where the underlying biological pathways are largely unknown. Our understanding of neuronal cilia is rudimentary and an easy-to-maintain, ciliated human neuronal cell model is missing. LUHMES is a ciliated neuronal cell line derived from human fetal mesencephalon. LUHMES cells can easily be maintained and differentiated into mature, functional neurons within one week. They have a single primary cilium as proliferating progenitor cells and as post-mitotic, differentiating neurons. These developmental stages are completely separable within one day of culture condition change. The Sonic Hedgehog (SHH) signaling pathway is active in differentiating LUHMES neurons. RNA-seq time course analyses reveal molecular pathways and gene-regulatory networks critical for ciliogenesis and axon outgrowth at the interface between progenitor cell proliferation, polarization and neuronal differentiation. Gene expression dynamics of cultured LUHMES neurons faithfully mimic the corresponding in vivo dynamics of human fetal midbrain. In LUHMES, neuronal cilia biology can be investigated along a complete timeline: from proliferation through differentiation to mature neurons.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Wistar rats and C57BL/6J mice differ in their motivation to seek social interaction versus food in the Social versus Food Preference Test

    Here we characterized the Social versus Food Preference Test, a behavioral paradigm designed to investigate the competition between the choice to seek social interaction versus the choice to seek food. We assessed how this competition was modulated by internal cues (social isolation, food deprivation), external cues (time-of-testing, stimulus salience), sex (males, females), age (adolescents, adults), and rodent model (Wistar rats, C57BL/6J mice). We found that changes in stimulus preference in response to the internal and external cue manipulations were similar across cohorts. Specifically, social over food preference scores were reduced by food deprivation and social familiarly in Wistar rats and C57BL/6J mice of both sexes. Interestingly, the degree of food deprivation-induced changes in stimulus investigation patterns were greater in adolescents compared to adults in Wistar rats and C57BL/6J mice. Strikingly, baseline stimulus preference and investigation times varied greatly between rodent models: across manipulations, Wistar rats were generally more social-preferring and C57BL/6J mice were generally more food-preferring. Adolescent Wistar rats spent more time investigating the social and food stimuli than adult Wistar rats, while adolescent and adult C57BL/6J mice investigated the stimuli a similar amount. Neither social isolation nor time-of-testing altered behavior in the Social versus Food Preference Test. Together, our results indicate that the Social versus Food Preference Test is a flexible behavioral paradigm suitable for future interrogations of the peripheral and central systems that can coordinate the expression of stimulus preference related to multiple motivated behaviors.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Neural divergence and convergence for interoceptive and somatosensory attention and detection

    Body awareness is constructed by signals originating from within and outside the body. How do these apparently divergent signals converge? We developed a signal detection task to study the neural convergence and divergence of interoceptive and somatosensory signals. Participants focused on either cardiac or tactile events and reported their presence or absence. Beyond some evidence of divergence, we observed a robust overlap in the pattern of activation evoked across both conditions in frontal areas including the insular cortex, as well as parietal and occipital areas, and for both attention and detection of these signals. Psycho-physiological interaction analysis revealed that right insular cortex connectivity was modulated by the conscious detection of both types of sensations, but with greater connectivity to occipito-parietal regions when attending to cardiac signals. Our findings speak in favour of the inherent convergence of bodily-related signals and move beyond the apparent antagonism between exteroception and interoception.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Multimodal in vivo recording using transparent graphene microelectrodes illuminates spatiotemporal seizure dynamics at the microscale

    Neurological disorders such as epilepsy arise from disrupted brain networks. Our capacity to treat these disorders is limited by our inability to map these networks at sufficient temporal and spatial scales to target interventions. Current best techniques either sample broad areas at low temporal resolution (e.g. calcium imaging) or record from discrete regions at high temporal resolution (e.g. electrophysiology). This limitation hampers our ability to understand and intervene in aberrations of network dynamics. Here we present a technique to map the onset and spatiotemporal spread of acute epileptic seizures in vivo by simultaneously recording high bandwidth microelectrocorticography and calcium fluorescence using transparent graphene microelectrode arrays. We integrate dynamic data features from both modalities using non-negative matrix factorization to identify sequential spatiotemporal patterns of seizure onset and evolution, revealing how the temporal progression of ictal electrophysiology is linked to the spatial evolution of the recruited seizure core. This integrated analysis of multimodal data reveals otherwise hidden state transitions in the spatial and temporal progression of acute seizures. The techniques demonstrated here may enable future targeted therapeutic interventions and novel spatially embedded models of local circuit dynamics during seizure onset and evolution.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    When Gaze-Pattern Similarity May Interfere With Future Memory

    Human brains have a remarkable ability to separate streams of visual input into distinct memory-traces. It is unclear, however, how this ability relates to the way these inputs are explored via unique gaze-patterns. Moreover, it is yet unknown how motivation to forget or remember influences the gaze similarity and memory relationship. In two experiments, we therefore used a modified directed-forgetting paradigm and either showed blurred versions of the encoded scenes (Experiment 1) or pink noise images (Experiment 2) during attempted memory control. Both experiments demonstrated that higher levels of across-stimulus gaze similarity relate to worse future memory. Although this across-stimulus interference effect was unaffected by motivation, it depended on the perceptual overlap between stimuli and was more pronounced for different scene comparisons, than scene-pink noise comparisons. Intriguingly, these findings echo the pattern similarity effects from the neuroimaging literature and pinpoint a mechanism that could aid the regulation of unwanted memories.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Synaptic dynamics as convolutional units

    Synaptic dynamics differ markedly across connections and strongly regulate how action potentials are being communicated. To model the range of synaptic dynamics observed in experiments, we develop a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Sleeping While Awake: The Intrusion of Neural Activity Associated with Sleep Onset in the Awake Human Brain

    Sleep can intrude into the awake human brain when sleep deprived or fatigued, even while performing cognitive tasks. However, how the brain activity associated with sleep onset can co-exist with the activity associated with cognition in the awake humans remains unexplored. Here, we used simultaneous fMRI and EEG to generate fMRI activity maps associated with EEG theta (4-7 Hz) activity associated with sleep onset. We implemented a method to track these fMRI activity maps in individuals performing a cognitive task after well-rested and sleep-deprived nights. We found frequent intrusions of the fMRI maps associated with sleep-onset in the task-related fMRI data. These sleep events elicited a pattern of transient fMRI activity, which was spatially distinct from the task-related activity in the frontal and parietal areas of the brain. They were concomitant with reduced arousal as indicated by decreased pupil size and increased response time. Graph theoretical modelling showed that the activity associated with sleep onset emerges from the basal forebrain and spreads anterior-posteriorly via the brains structural connectome. We replicated the key findings in an independent dataset, which suggests that the approach can be reliably used in understanding the neuro-behavioural consequences of sleep and circadian disturbances in humans.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    CHMP2B regulates TDP-43 phosphorylation and proteotoxicity via modulating CK1 turnover independent of the autophagy-lysosomal pathway

    Protein inclusions containing phosphorylated TDP-43 are a shared pathology in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, most ALS/FTD patients do not have a mutation in TDP-43 or the enzymes directly regulating its phosphorylation. It is intriguing how TDP-43 becomes hyperphosphorylated in each disease condition. In a genetic screen for novel TDP-43 modifiers, we found that knockdown (KD) of CHMP2B, a key component of the endosomal sorting complex required for transport (ESCRT) machinery, suppressed TDP-43-mediated neurodegeneration in Drosophila. Further investigation using mammalian cells indicated that CHMP2B KD decreased whereas its overexpression (OE) increased TDP-43 phosphorylation levels. Moreover, a known FTD-causing mutation CHMP2Bintron5 promoted hyperphosphorylation, insolubility and cytoplasmic accumulation of TDP-43. Interestingly, CHMP2B did not manifest these effects by its well-known function in the autophagy-lysosomal pathway. Instead, the kinase CK1 tightly regulated TDP-43 phosphorylation level in cells, and CHMP2B OE or CHMP2BIntron5 significantly decreased ubiquitination levels and the turnover of CK1 via the ubiquitin-proteasome (UPS) pathway. Finally, we showed that CHMP2B protein levels increased in the cerebral cortices of aged mice, which might underlie the age-associated TDP-43 pathology and disease onset. Together, our findings reveal a molecular link between the two ALS/FTD-pathogenic proteins CHMP2B and TDP-43, and provide an autophagy-independent mechanism for CHMP2B in pathogenesis.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    Hierarchical disruption in the cortex of anesthetized monkeys as a new signature of consciousness loss

    Anesthesia induces a reconfiguration of the repertoire of functional brain states leading to a high function-structure similarity. However, it is unclear how these functional changes lead to loss of consciousness. Here we suggest that the mechanism of conscious access is related to a general dynamical rearrangement of the intrinsic hierarchical organization of the cortex. To measure cortical hierarchy, we applied the Intrinsic Ignition analysis to resting-state fMRI data acquired in awake and anesthetized macaques. Our results reveal the existence of spatial and temporal hierarchical differences of neural activity within the macaque cortex, with a strong modulation by the depth of anesthesia and the employed anesthetic agent. Higher values of Intrinsic Ignition correspond to rich and flexible brain dynamics whereas lower values correspond to poor and rigid, structurally driven brain dynamics. Moreover, spatial and temporal hierarchical dimensions are disrupted in a different manner, involving different hierarchical brain networks. All together suggest that disruption of brain hierarchy is a new signature of consciousness loss.

    in bioRxiv: Neuroscience on June 05, 2020 12:00 AM.

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    HemoMIPs—Automated analysis and result reporting pipeline for targeted sequencing data

    by Philip Kleinert, Beth Martin, Martin Kircher

    Targeted sequencing of genomic regions is a cost- and time-efficient approach for screening patient cohorts. We present a fast and efficient workflow to analyze highly imbalanced, targeted next-generation sequencing data generated using molecular inversion probe (MIP) capture. Our Snakemake pipeline performs sample demultiplexing, overlap paired-end merging, alignment, MIP-arm trimming, variant calling, coverage analysis and report generation. Further, we support the analysis of probes specifically designed to capture certain structural variants and can assign sex using Y-chromosome-unique probes. In a user-friendly HTML report, we summarize all these results including covered, incomplete or missing regions, called variants and their predicted effects. We developed and tested our pipeline using the hemophilia A & B MIP design from the “My Life, Our Future” initiative. HemoMIPs is available as an open-source tool on GitHub at: https://github.com/kircherlab/hemoMIPs

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    Discriminating between negative cooperativity and ligand binding to independent sites using pre-equilibrium properties of binding curves

    by Federico Sevlever, Juan Pablo Di Bella, Alejandra C. Ventura

    Negative cooperativity is a phenomenon in which the binding of a first ligand or substrate molecule decreases the rate of subsequent binding. This definition is not exclusive to ligand-receptor binding, it holds whenever two or more molecules undergo two successive binding events. Negative cooperativity turns the binding curve more graded and cannot be distinguished from two independent and different binding events based on equilibrium measurements only. The need of kinetic data for this purpose was already reported. Here, we study the binding response as a function of the amount of ligand, at different times, from very early times since ligand is added and until equilibrium is reached. Over those binding curves measured at different times, we compute the dynamic range: the fold change required in input to elicit a change from 10 to 90% of maximum output, finding that it evolves in time differently and controlled by different parameters in the two situations that are identical in equilibrium. Deciphering which is the microscopic model that leads to a given binding curve adds understanding on the molecular mechanisms at play, and thus, is a valuable tool. The methods developed in this article were tested both with simulated and experimental data, showing to be robust to noise and experimental constraints.

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    Atomistic mechanism of transmembrane helix association

    by Jan Domański, Mark S. P. Sansom, Phillip J. Stansfeld, Robert B. Best

    Transmembrane helix association is a fundamental step in the folding of helical membrane proteins. The prototypical example of this association is formation of the glycophorin dimer. While its structure and stability have been well-characterized experimentally, the detailed assembly mechanism is harder to obtain. Here, we use all-atom simulations within phospholipid membrane to study glycophorin association. We find that initial association results in the formation of a non-native intermediate, separated by a significant free energy barrier from the dimer with a native binding interface. We have used transition-path sampling to determine the association mechanism. We find that the mechanism of the initial bimolecular association to form the intermediate state can be mediated by many possible contacts, but seems to be particularly favoured by formation of non-native contacts between the C-termini of the two helices. On the other hand, the contacts which are key to determining progression from the intermediate to the native state are those which define the native binding interface, reminiscent of the role played by native contacts in determining folding of globular proteins. As a check on the simulations, we have computed association and dissociation rates from the transition-path sampling. We obtain results in reasonable accord with available experimental data, after correcting for differences in native state stability. Our results yield an atomistic description of the mechanism for a simple prototype of helical membrane protein folding.

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    10 simple rules for teaching wet-lab experimentation to computational biology students, i.e., turning computer mice into lab rats

    by Joseph C. Ayoob, Joshua D. Kangas

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    Disease evolution in reaction networks: Implications for a diagnostic problem

    by Abolfazl Ramezanpour, Alireza Mashaghi

    We study the time evolution of symptoms (signs) with some defects in the dynamics of a reaction network as a (microscopic) model for the progress of disease phenotypes. To this end, we take a large population of reaction networks and follow the stochastic dynamics of the system to see how the development of defects affects the macroscopic states of the signs probability distribution. We start from some plausible definitions for the healthy and disease states along with a dynamical model for the emergence of diseases by a reverse simulated annealing algorithm. The healthy state is defined as a state of maximum objective function, which here is the sum of mutual information between a subset of signal variables and the subset of assigned response variables. A disease phenotype is defined with two parameters controlling the rate of mutations in reactions and the rate of accepting mutations that reduce the objective function. The model can provide the time dependence of the sign probabilities given a disease phenotype. This allows us to obtain the accuracy of diagnosis as a function of time by using a probabilistic model of signs and diseases. The trade-off between the diagnosis accuracy (increasing in time) and the objective function (decreasing in time) can be used to suggest an optimal time for medical intervention. Our model would be useful in particular for a dynamical (history-based) diagnostic problem, to estimate the likelihood of a disease hypothesis given the temporal evolution of the signs.

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    Taste of time: A porous-medium model for human tongue surface with implications for early taste perception

    by Zhenxing Wu, Kai Zhao

    Most sensory systems are remarkable in their temporal precision, reflected in such phrases as “a flash of light” or “a twig snap”. Yet taste is complicated by the transport processes of stimuli through the papilla matrix to reach taste receptors, processes that are poorly understood. We computationally modeled the surface of the human tongue as a microfiber porous medium and found that time-concentration profiles within the papilla zone rise with significant delay that well match experimental ratings of perceived taste intensity to a range of sweet and salty stimuli for both rapid pulses and longer sip-and-hold exposures. Diffusivity of these taste stimuli, determined mostly by molecular size, correlates greatly with time and slope to reach peak intensity: smaller molecular size may lead to quicker taste perception. Our study demonstrates the novelty of modeling the human tongue as a porous material to drastically simplify computational approaches and that peripheral transport processes may significantly affect the temporal profile of taste perception, at least to sweet and salty compounds.

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    G-OnRamp: Generating genome browsers to facilitate undergraduate-driven collaborative genome annotation

    by Luke Sargent, Yating Liu, Wilson Leung, Nathan T. Mortimer, David Lopatto, Jeremy Goecks, Sarah C. R. Elgin

    Scientists are sequencing new genomes at an increasing rate with the goal of associating genome contents with phenotypic traits. After a new genome is sequenced and assembled, structural gene annotation is often the first step in analysis. Despite advances in computational gene prediction algorithms, most eukaryotic genomes still benefit from manual gene annotation. This requires access to good genome browsers to enable annotators to visualize and evaluate multiple lines of evidence (e.g., sequence similarity, RNA sequencing [RNA-Seq] results, gene predictions, repeats) and necessitates many volunteers to participate in the work. To address the technical barriers to creating genome browsers, the Genomics Education Partnership (GEP; https://gep.wustl.edu/) has partnered with the Galaxy Project (https://galaxyproject.org) to develop G-OnRamp (http://g-onramp.org), a web-based platform for creating UCSC Genome Browser Assembly Hubs and JBrowse genome browsers. G-OnRamp also converts a JBrowse instance into an Apollo instance for collaborative genome annotations in research and educational settings. The genome browsers produced can be transferred to the CyVerse Data Store for long-term access. G-OnRamp enables researchers to easily visualize their experimental results, educators to create Course-based Undergraduate Research Experiences (CUREs) centered on genome annotation, and students to participate in genomics research. In the process, students learn about genes/genomes and about how to utilize large datasets. Development of G-OnRamp was guided by extensive user feedback. Sixty-five researchers/educators from >40 institutions participated through in-person workshops, which produced >20 genome browsers now available for research and education. Genome browsers generated for four parasitoid wasp species have been used in a CURE engaging students at 15 colleges and universities. Our assessment results in the classroom demonstrate that the genome browsers produced by G-OnRamp are effective tools for engaging undergraduates in research and in enabling their contributions to the scientific literature in genomics. Expansion of such genomics research/education partnerships will be beneficial to researchers, faculty, and students alike.

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    Sample-based modeling reveals bidirectional interplay between cell cycle progression and extrinsic apoptosis

    by Dirke Imig, Nadine Pollak, Frank Allgöwer, Markus Rehm

    Apoptotic cell death can be initiated through the extrinsic and intrinsic signaling pathways. While cell cycle progression promotes the responsiveness to intrinsic apoptosis induced by genotoxic stress or spindle poisons, this has not yet been studied conclusively for extrinsic apoptosis. Here, we combined fluorescence-based time-lapse monitoring of cell cycle progression and cell death execution by long-term time-lapse microscopy with sampling-based mathematical modeling to study cell cycle dependency of TRAIL-induced extrinsic apoptosis in NCI-H460/geminin cells. In particular, we investigated the interaction of cell death timing and progression of cell cycle states. We not only found that TRAIL prolongs cycle progression, but in reverse also that cell cycle progression affects the kinetics of TRAIL-induced apoptosis: Cells exposed to TRAIL in G1 died significantly faster than cells stimulated in S/G2/M. The connection between cell cycle state and apoptosis progression was captured by developing a mathematical model, for which parameter estimation revealed that apoptosis progression decelerates in the second half of the cell cycle. Similar results were also obtained when studying HCT-116 cells. Our results therefore reject the null hypothesis of independence between cell cycle progression and extrinsic apoptosis and, supported by simulations and experiments of synchronized cell populations, suggest that unwanted escape from TRAIL-induced apoptosis can be reduced by enriching the fraction of cells in G1 phase. Besides novel insight into the interrelation of cell cycle progression and extrinsic apoptosis signaling kinetics, our findings are therefore also relevant for optimizing future TRAIL-based treatment strategies.

    in PLoS Computational Biology on June 04, 2020 09:00 PM.

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    Broken sleep predicts hardened blood vessels

    by Raphael Vallat, Vyoma D. Shah, Susan Redline, Peter Attia, Matthew P. Walker

    Why does poor-quality sleep lead to atherosclerosis? In a diverse sample of over 1,600 individuals, we describe a pathway wherein sleep fragmentation raises inflammatory-related white blood cell counts (neutrophils and monocytes), thereby increasing atherosclerosis severity, even when other common risk factors have been accounted for. Improving sleep quality may thus represent one preventive strategy for lowering inflammatory status and thus atherosclerosis risk, reinforcing public health policies focused on sleep health.

    in PLoS Biology on June 04, 2020 09:00 PM.

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    Longitudinal development of hippocampal subregions from early‐ to mid‐childhood

    Abstract

    Early childhood is characterized by vast changes in behaviors supported by the hippocampus and an increased susceptibility of the hippocampus to environmental influences. Thus, it is an important time to investigate the development of the hippocampus. Existing research suggests subregions of the hippocampus (i.e., head, body, tail) have dissociable functions and that the relations between subregions and cognitive abilities vary across development. However, longitudinal research examining age‐related changes in subregions in humans, particularly during early childhood (i.e., 4–6 years), is limited. Using a large sample of 184 healthy 4‐ to 8‐year‐old children, the present study is the first to characterize developmental changes in hippocampal subregion volume from early‐ to mid‐childhood. Results reveal differential developmental trajectories in hippocampal head, body, and tail during this period. Specifically, head volume showed a quadratic pattern of change, and both body and tail showed linear increases, resulting in a pattern of cubic change for total hippocampal volume. Further, main effects of sex on hippocampal volume (males > females) and hemispheric differences in developmental trajectories were observed. These findings provide an improved understanding of the development of the hippocampus and have important implications for research investigating a range of cognitive abilities and behaviors.

    in Hippocampus on June 04, 2020 06:29 PM.

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    Radiologically Isolated Syndrome: 10‐Year Risk Estimate of a Clinical Event

    Objective

    We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5‐year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. We investigate here risk factors for the development of a clinical event using a 10‐year, multi‐national, retrospectively‐identified RIS dataset.

    Methods

    RIS subjects were identified according to 2009 RIS criteria and longitudinally followed as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and MRI characteristics, and the risk of developing a first clinical event were determined using multivariate Cox regression models.

    Results

    Additional follow‐up data was available in 277/451 RIS subjects (86% female). Mean age at RIS diagnosis was 37.2 y (range:11–74 y) with a median clinical follow‐up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive CSF, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium enhancing lesions during follow‐up was also associated with the risk of a seminal event. Reason for MRI and gadolinium enhancing lesions at baseline did not influence the risk of a subsequent clinical event.

    Interpretation

    Approximately half of individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on June 04, 2020 05:39 PM.

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    3D DWI with cinematic rendering for epidermoid cyst

    in Annals of Neurology on June 04, 2020 10:25 AM.

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    Exponential trajectories, cell size fluctuations, and the adder property in bacteria follow from simple chemical dynamics and division control

    Author(s): Parth Pratim Pandey, Harshant Singh, and Sanjay Jain

    Experiments on steady-state bacterial cultures have uncovered several quantitative regularities at the system level. These include, first, the exponential growth of cell size with time and the balanced growth of intracellular chemicals between cell birth and division, which are puzzling given the no...


    [Phys. Rev. E 101, 062406] Published Thu Jun 04, 2020

    in Physical Review E: Biological physics on June 04, 2020 10:00 AM.

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    Reader response: Comparison of the Response to Rituximab between Myelin Oligodendrocyte Glycoprotein and Aquaporin‐4 Antibody Diseases.

    in Annals of Neurology on June 04, 2020 09:58 AM.

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    MRI IN NEUROMUSCULAR DISEASES: AN EMERGING DIAGNOSTIC TOOL AND BIOMARKER FOR PROGNOSIS AND EFFICACY

    There is an unmet need to identify biomarkers sensitive to change in rare, slowly progressive neuromuscular diseases. Quantitative MRI of muscle may offer this opportunity, is non‐invasive and can be carried out almost independent of patient‐cooperation and disease severity.

    Muscle fat content correlates with muscle function in neuromuscular diseases, and changes in fat content precede changes in function, which suggests that muscle MRI is a strong biomarker candidate to predict prognosis and treatment efficacy. In this paper, we review the evidence suggesting that muscle MRI may be an important biomarker for diagnosis and to monitor change in disease severity.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on June 04, 2020 08:50 AM.

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    NOTCH2NLC GGC repeat expansions are associated with sporadic essential tremor: Variable disease expressivity on long‐term follow‐up

    We screened 662 subjects comprising 462 essential tremor, ET (285 sporadic, 125 with family history and 52 probands from well‐characterized ET pedigrees and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in four sporadic ET patients. Two patients were followed up for over a decade: one with 90 repeats remained an ET phenotype that did not evolve after forty years, while another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10舁years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion‐weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats above 60舁units were detected in familial ET cases and controls, though four ET patients carried 47–53 “intermediate” repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to four decades after initial tremor onset.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on June 04, 2020 08:09 AM.

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    Lyapunov spectra of chaotic recurrent neural networks. (arXiv:2006.02427v1 [nlin.CD])

    Brains process information through the collective dynamics of large neural networks. Collective chaos was suggested to underlie the complex ongoing dynamics observed in cerebral cortical circuits and determine the impact and processing of incoming information streams. In dissipative systems, chaotic dynamics takes place on a subset of phase space of reduced dimensionality and is organized by a complex tangle of stable, neutral and unstable manifolds. Key topological invariants of this phase space structure such as attractor dimension, and Kolmogorov-Sinai entropy so far remained elusive.

    Here we calculate the complete Lyapunov spectrum of recurrent neural networks. We show that chaos in these networks is extensive with a size-invariant Lyapunov spectrum and characterized by attractor dimensions much smaller than the number of phase space dimensions. We find that near the onset of chaos, for very intense chaos, and discrete-time dynamics, random matrix theory provides analytical approximations to the full Lyapunov spectrum. We show that a generalized time-reversal symmetry of the network dynamics induces a point-symmetry of the Lyapunov spectrum reminiscent of the symplectic structure of chaotic Hamiltonian systems. Fluctuating input reduces both the entropy rate and the attractor dimension. For trained recurrent networks, we find that Lyapunov spectrum analysis provides a quantification of error propagation and stability achieved. Our methods apply to systems of arbitrary connectivity, and we describe a comprehensive set of controls for the accuracy and convergence of Lyapunov exponents.

    Our results open a novel avenue for characterizing the complex dynamics of recurrent neural networks and the geometry of the corresponding chaotic attractors. They also highlight the potential of Lyapunov spectrum analysis as a diagnostic for machine learning applications of recurrent networks.

    in arXiv: Quantitative Biology: Neurons and Cognition on June 04, 2020 01:30 AM.

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    Optimizing Neural Networks via Koopman Operator Theory. (arXiv:2006.02361v1 [cs.NE])

    Koopman operator theory, a powerful framework for discovering the underlying dynamics of nonlinear dynamical systems, was recently shown to be intimately connected with neural network training. In this work, we take the first steps in making use of this connection. As Koopman operator theory is a linear theory, a successful implementation of it in evolving network weights and biases offers the promise of accelerated training, especially in the context of deep networks, where optimization is inherently a non-convex problem. We show that Koopman operator theory methods allow for accurate predictions of the weights and biases of a feedforward, fully connected deep network over a non-trivial range of training time. During this time window, we find that our approach is at least 10x faster than gradient descent based methods, in line with the results expected from our complexity analysis. We highlight additional methods by which our results can be expanded to broader classes of networks and larger time intervals, which shall be the focus of future work in this novel intersection between dynamical systems and neural network theory.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    From Probability to Consilience: How Explanatory Values Implement Bayesian Reasoning. (arXiv:2006.02359v1 [q-bio.NC])

    Recent work in cognitive science has uncovered a diversity of explanatory values, or dimensions along which we judge explanations as better or worse. We propose a Bayesian account of how these values fit together to guide explanation. The resulting taxonomy provides a set of predictors for which explanations people prefer and shows how core values from psychology, statistics, and the philosophy of science emerge from a common mathematical framework. In addition to operationalizing the explanatory virtues associated with, for example, scientific argument-making, this framework also enables us to reinterpret the explanatory vices that drive conspiracy theories, delusions, and extremist ideologies.

    in arXiv: Quantitative Biology: Neurons and Cognition on June 04, 2020 01:30 AM.

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    CNN-based Speed Detection Algorithm for Walking and Running using Wrist-worn Wearable Sensors. (arXiv:2006.02348v1 [eess.SP])

    In recent years, there have been a surge in ubiquitous technologies such as smartwatches and fitness trackers that can track the human physical activities effortlessly. These devices have enabled common citizens to track their physical fitness and encourage them to lead a healthy lifestyle. Among various exercises, walking and running are the most common ones people do in everyday life, either through commute, exercise, or doing household chores. If done at the right intensity, walking and running are sufficient enough to help individual reach the fitness and weight-loss goals. Therefore, it is important to measure walking/ running speed to estimate the burned calories along with preventing them from the risk of soreness, injury, and burnout. Existing wearable technologies use GPS sensor to measure the speed which is highly energy inefficient and does not work well indoors. In this paper, we design, implement and evaluate a convolutional neural network based algorithm that leverages accelerometer and gyroscope sensory data from the wrist-worn device to detect the speed with high precision. Data from $15$ participants were collected while they were walking/running at different speeds on a treadmill. Our speed detection algorithm achieved $4.2\%$ and $9.8\%$ MAPE (Mean Absolute Error Percentage) value using $70-15-15$ train-test-evaluation split and leave-one-out cross-validation evaluation strategy respectively.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    Non-Euclidean Universal Approximation. (arXiv:2006.02341v1 [cs.LG])

    Modifications to a neural network's input and output layers are often required to accommodate the specificities of most practical learning tasks. However, the impact of such changes on architecture's approximation capabilities is largely not understood. We present general conditions describing feature and readout maps that preserve an architecture's ability to approximate any continuous functions uniformly on compacts. As an application, we show that if an architecture is capable of universal approximation, then modifying its final layer to produce binary values creates a new architecture capable of deterministically approximating any classifier. In particular, we obtain guarantees for deep CNNs, deep ffNN, and universal Gaussian processes. Our results also have consequences within the scope of geometric deep learning. Specifically, when the input and output spaces are Hadamard manifolds, we obtain geometrically meaningful feature and readout maps satisfying our criteria. Consequently, commonly used non-Euclidean regression models between spaces of symmetric positive definite matrices are extended to universal DNNs. The same result allows us to show that the hyperbolic feed-forward networks, used for hierarchical learning, are universal. Our result is also used to show that the common practice of randomizing all but the last two layers of a DNN produces a universal family of functions with probability one.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    FastONN -- Python based open-source GPU implementation for Operational Neural Networks. (arXiv:2006.02267v1 [cs.NE])

    Operational Neural Networks (ONNs) have recently been proposed as a special class of artificial neural networks for grid structured data. They enable heterogenous non-linear operations to generalize the widely adopted convolution-based neuron model. This work introduces a fast GPU-enabled library for training operational neural networks, FastONN, which is based on a novel vectorized formulation of the operational neurons. Leveraging on automatic reverse-mode differentiation for backpropagation, FastONN enables increased flexibility with the incorporation of new operator sets and customized gradient flows. Additionally, bundled auxiliary modules offer interfaces for performance tracking and checkpointing across different data partitions and customized metrics.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    A Multi-modal Neural Embeddings Approach for Detecting Mobile Counterfeit Apps: A Case Study on Google Play Store. (arXiv:2006.02231v1 [cs.CR])

    Counterfeit apps impersonate existing popular apps in attempts to misguide users to install them for various reasons such as collecting personal information or spreading malware. Many counterfeits can be identified once installed, however even a tech-savvy user may struggle to detect them before installation. To this end, this paper proposes to leverage the recent advances in deep learning methods to create image and text embeddings so that counterfeit apps can be efficiently identified when they are submitted for publication. We show that a novel approach of combining content embeddings and style embeddings outperforms the baseline methods for image similarity such as SIFT, SURF, and various image hashing methods. We first evaluate the performance of the proposed method on two well-known datasets for evaluating image similarity methods and show that content, style, and combined embeddings increase precision@k and recall@k by 10%-15% and 12%-25%, respectively when retrieving five nearest neighbours. Second, specifically for the app counterfeit detection problem, combined content and style embeddings achieve 12% and 14% increase in precision@k and recall@k, respectively compared to the baseline methods. Third, we present an analysis of approximately 1.2 million apps from Google Play Store and identify a set of potential counterfeits for top-10,000 popular apps. Under a conservative assumption, we were able to find 2,040 potential counterfeits that contain malware in a set of 49,608 apps that showed high similarity to one of the top-10,000 popular apps in Google Play Store. We also find 1,565 potential counterfeits asking for at least five additional dangerous permissions than the original app and 1,407 potential counterfeits having at least five extra third party advertisement libraries.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    FBNetV3: Joint Architecture-Recipe Search using Neural Acquisition Function. (arXiv:2006.02049v1 [cs.CV])

    Neural Architecture Search (NAS) yields state-of-the-art neural networks that outperform their best manually-designed counterparts. However, previous NAS methods search for architectures under one training recipe (i.e., training hyperparameters), ignoring the significance of training recipes and overlooking superior architectures under other training recipes. Thus, they fail to find higher-accuracy architecture-recipe combinations. To address this oversight, we present JointNAS to search both (a) architectures and (b) their corresponding training recipes. To accomplish this, we introduce a neural acquisition function that scores architectures and training recipes jointly. Following pre-training on a proxy dataset, this acquisition function guides both coarse-grained and fine-grained searches to produce FBNetV3. FBNetV3 is a family of state-of-the-art compact ImageNet models, outperforming both automatically and manually-designed architectures. For example, FBNetV3 matches both EfficientNet and ResNeSt accuracy with 1.4x and 5.0x fewer FLOPs, respectively. Furthermore, the JointNAS-searched training recipe yields significant performance gains across different networks and tasks.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    Proximity-based Networking: Small world overlays optimized with particle swarm optimization. (arXiv:2006.02006v1 [cs.NI])

    Information dissemination is a fundamental and frequently occurring problem in large, dynamic, distributed systems. In order to solve this, there has been an increased interest in creating efficient overlay networks that can maintain decentralized peer-to-peer networks. Within these overlay networks nodes take the patterns of small world networks, whose connections are based on proximity. These small-world systems can be incredibly useful in the dissemination and lookup of information within an internet network. The data can be efficiently transferred and routing with minimal information loss through forward error correct (FEC) and the User Datagram Protocol (UDP). We propose a networking scheme that incorporates geographic location in chord for the organization of peers within each node's partitioned key space. When we combine this with a proximity-based neighborhood set {based on the small world structure} we can mimic the efficient of solutions designed to solve traditional small-world problems, with the additional benefit of resilience and fault-tolerance. Furthermore, the routing and address book can be updated based on the neighborhood requirements. The flexibility of our proposed schemes enables a variety of swarm models, and agents. This enables our network to as an underlying networking model that can be applied to file-sharing, streaming, and synchronization of networks.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    Open-Set Recognition with Gaussian Mixture Variational Autoencoders. (arXiv:2006.02003v1 [cs.LG])

    In inference, open-set classification is to either classify a sample into a known class from training or reject it as an unknown class. Existing deep open-set classifiers train explicit closed-set classifiers, in some cases disjointly utilizing reconstruction, which we find dilutes the latent representation's ability to distinguish unknown classes. In contrast, we train our model to cooperatively learn reconstruction and perform class-based clustering in the latent space. With this, our Gaussian mixture variational autoencoder (GMVAE) achieves more accurate and robust open-set classification results, with an average F1 improvement of 29.5%, through extensive experiments aided by analytical results.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    Training End-to-End Analog Neural Networks with Equilibrium Propagation. (arXiv:2006.01981v1 [cs.NE])

    We introduce a principled method to train end-to-end analog neural networks by stochastic gradient descent. In these analog neural networks, the weights to be adjusted are implemented by the conductances of programmable resistive devices such as memristors [Chua, 1971], and the nonlinear transfer functions (or `activation functions') are implemented by nonlinear components such as diodes. We show mathematically that a class of analog neural networks (called nonlinear resistive networks) are energy-based models: they possess an energy function as a consequence of Kirchhoff's laws governing electrical circuits. This property enables us to train them using the Equilibrium Propagation framework [Scellier and Bengio, 2017]. Our update rule for each conductance, which is local and relies solely on the voltage drop across the corresponding resistor, is shown to compute the gradient of the loss function. Our numerical simulations, which use the SPICE-based Spectre simulation framework to simulate the dynamics of electrical circuits, demonstrate training on the MNIST classification task, performing comparably or better than equivalent-size software-based neural networks. Our work can guide the development of a new generation of ultra-fast, compact and low-power neural networks supporting on-chip learning.

    in arXiv: Computer Science: Neural and Evolutionary Computing on June 04, 2020 01:30 AM.

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    Effects of simultaneous real-time fMRI and EEG neurofeedback in major depressive disorder evaluated with brain electromagnetic tomography. (arXiv:2006.01923v1 [q-bio.NC])

    Recently, we reported an emotion self-regulation study (Zotev et al., 2019), in which patients with major depressive disorder (MDD) used simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) to upregulate two fMRI and two EEG activity measures, relevant to MDD. The target measures included fMRI activities of the left amygdala and left rostral anterior cingulate cortex, and frontal EEG asymmetries in the alpha band (FAA) and high-beta band (FBA). Here we apply the exact low resolution brain electromagnetic tomography (eLORETA) to investigate EEG source activities during the rtfMRI-EEG-nf procedure. The analyses reveal significant changes in hemispheric lateralities of upper alpha and high-beta current source densities in the prefrontal regions, consistent with upregulation of the FAA and FBA during the rtfMRI-EEG-nf task. Similar laterality changes are observed for current source densities in the amygdala. Prefrontal upper alpha current density changes show significant negative correlations with anhedonia severity. Comparisons with results of previous LORETA studies suggest that the rtfMRI-EEG-nf training is beneficial to MDD patients, and has the ability to correct functional deficiencies associated with anhedonia and comorbid anxiety. Our findings confirm the potential of the rtfMRI-EEG-nf for treatment of major depression.

    in arXiv: Quantitative Biology: Neurons and Cognition on June 04, 2020 01:30 AM.

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    Mapping DNA single-strand breaks

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0876-y

    Mapping DNA single-strand breaks

    in Nature Methods on June 04, 2020 12:00 AM.

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    Optimized tissue clearing

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0875-z

    Optimized tissue clearing

    in Nature Methods on June 04, 2020 12:00 AM.

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    Representation matters for T cell responses

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0874-0

    Representation matters for T cell responses

    in Nature Methods on June 04, 2020 12:00 AM.

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    A digital embryo

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0873-1

    A digital embryo

    in Nature Methods on June 04, 2020 12:00 AM.

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    Harmonizing cancer variant knowledgebases

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0871-3

    Harmonizing cancer variant knowledgebases

    in Nature Methods on June 04, 2020 12:00 AM.

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    Chromatin dynamics get mapped

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0870-4

    Chromatin dynamics get mapped

    in Nature Methods on June 04, 2020 12:00 AM.

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    Watching embryos develop

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0864-2

    Embryonic development is typically hidden from view, but a window preparation technique now sheds light on this phase in the life of a mouse.

    in Nature Methods on June 04, 2020 12:00 AM.

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    PAM-less is more

    Nature Methods, Published online: 04 June 2020; doi:10.1038/s41592-020-0861-5

    Structure-guided engineering allows researchers access to an expanding number of Cas9 variants that relax the constraint imposed by target site recognition of a protospacer-adjacent motif (PAM).

    in Nature Methods on June 04, 2020 12:00 AM.

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    Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD+ degradation

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16703-w

    The Thoeris defense system is a recently discovered bacterial defense system that protects bacteria against phage infection and consists of the two genes thsA and thsB. Here, the authors present the crystal structures of Bacillus cereus ThsA and ThsB and show that ThsA is a NAD+ cleaving enzyme.

    in Nature Communications on June 04, 2020 12:00 AM.

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    Highly efficient phosphor-glass composites by pressureless sintering

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16649-z

    Phosphor-glass/ceramic composites are attractive for high-power white light-emitting diodes, but interfacial reaction leads to loss of quantum efficiency. Here the authors report a reduction sintering method for embedment of phosphors into silica glass with limited interfacial reaction.

    in Nature Communications on June 04, 2020 12:00 AM.

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    The Mi-2 nucleosome remodeler and the Rpd3 histone deacetylase are involved in piRNA-guided heterochromatin formation

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16635-5

    In S. pombe, small non-coding RNA mediates heterochromatin formation by recruiting the nucleosome remodeling and histone deacetylase complex. Here, the authors show that fly nucleosome remodeler Mi-2 and histone deacetylase Rpd3 are involved in piRNA-dependent transcriptional silencing of transposable elements.

    in Nature Communications on June 04, 2020 12:00 AM.

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    REV7 is required for processing AID initiated DNA lesions in activated B cells

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16632-8

    REV7 has emerged as a critical regulator of DNA double-strand breaks repair. Here, the authors show that REV7 is crucial for both antibody class switch recombination and somatic hypermutation in activated B cells, in addition to their survival upon AID-deamination.

    in Nature Communications on June 04, 2020 12:00 AM.

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    Precise capture and dynamic relocation of nanoparticulate biomolecules through dielectrophoretic enhancement by vertical nanogap architectures

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16630-w

    Label-free trapping of nanoparticles via dielectophoretic forces is traditionally done with electrodes in a horizontal gap layout. Here, the authors present a vertical nanogap architecture, which allows for precise capture and spatiotemporal manipulation of nanoparticles and molecular assemblies.

    in Nature Communications on June 04, 2020 12:00 AM.

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    Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16618-6

    Focal adhesion kinase (FAK) is required for tumour angiogenesis and growth. Here, the authors show that deletion of pericyte FAK upregulates Gas6-Axl mediated Cyr61 production, which increases endothelial cell proliferation and angiogenesis, while elevating tissue factor production to enhance tumour cell proliferation.

    in Nature Communications on June 04, 2020 12:00 AM.

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    Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-16564-3

    In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure.

    in Nature Communications on June 04, 2020 12:00 AM.

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    Reversible single crystal-to-single crystal double [2+2] cycloaddition induces multifunctional photo-mechano-electrochemical properties in framework materials

    Nature Communications, Published online: 04 June 2020; doi:10.1038/s41467-020-15510-7

    Porous coordination frameworks that undergo reversible structural transformations are promising for sensing, switching and separations. Here, the authors report an electroactive framework that exhibits a reversible single crystal-to-single crystal double [2+2] photocyclisation, leading to property changes.

    in Nature Communications on June 04, 2020 12:00 AM.

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    Daily briefing: Some ‘non-lethal’ crowd-control weapons can cause serious harm

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01689-8

    Some crowd-control weapons can cause serious injury, permanent disabilities or death. Plus: how the COVID-19 pandemic will change science, and a breakthrough technique for imaging molecules

    in Nature on June 04, 2020 12:00 AM.

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    Online directory makes free science talks easier to find in coronavirus era

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01687-w

    Real-time listings help researchers keep track of ballooning numbers of accessible talks.

    in Nature on June 04, 2020 12:00 AM.

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    How a lab happiness programme is helping me through the COVID-19 crisis

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01686-x

    I was cynical at first, but it’s proved a powerful tool, says Ellen J. Wehrens.

    in Nature on June 04, 2020 12:00 AM.

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    We test a home antibody kit for tracking Covid-19

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01677-y

    Easy-to-use postal tests may be important for monitoring community transmission.

    in Nature on June 04, 2020 12:00 AM.

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    How to come out to your parents as a science communicator

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01676-z

    Friends, family, peers and professors might struggle to understand your motivations for leaving the lab to work in science communication.

    in Nature on June 04, 2020 12:00 AM.

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    ‘Barcode’ microbes could help to trace goods — from lettuce to loafers

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01673-2

    Bacteria embedded with coded snippets of DNA survive microwaving, boiling and frying.

    in Nature on June 04, 2020 12:00 AM.

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    The coronavirus outbreak could make it quicker and easier to trial drugs

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01524-0

    Remote clinical trials and other changes could permanently alter pharmaceutical development: part 7 in a series on science after the pandemic.

    in Nature on June 04, 2020 12:00 AM.

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    Scientists’ worlds will shrink in the wake of the pandemic

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01523-1

    Researchers expect long-term changes that reduce travel for work and conferences: part 6 in a series on science after the pandemic.

    in Nature on June 04, 2020 12:00 AM.

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    How to beat isolation? Academic feedback groups fit the bill, and promote growth as scholars and humans

    Nature, Published online: 04 June 2020; doi:10.1038/d41586-020-01432-3

    Researchers share tips for supporting research and life at a distance.

    in Nature on June 04, 2020 12:00 AM.

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    Brain Metabolite Changes After Anodal Transcranial Direct Current Stimulation in Autism Spectrum Disorder

    Objectives

    Previous research has provided evidence that transcranial direct current stimulation (tDCS) can reduce severity of autism spectrum disorder (ASD); however, the exact mechanism of this effect is still unknown. Magnetic resonance spectroscopy has demonstrated low levels of brain metabolites in the anterior cingulate cortex (ACC), amygdala, and left dorsolateral prefrontal cortex (DLPFC) in individuals with ASD. The aim of this study was to investigate the effects of anodal tDCS on social functioning of individuals with ASD, as measured by the social subscale of the Autism Treatment Evaluation Checklist (ATEC), through correlations between pretreatment and posttreatment concentrations of brain metabolites in the areas of interest (DLPFC, ACC, amygdala, and locus coeruleus) and scores on the ATEC social subscale.

    Methods

    Ten participants with ASD were administered 1 mA anodal tDCS to the left DLPFC for 20 min over five consecutive days. Measures of the ATEC social subscale and the concentrations of brain metabolites were performed before and immediately after the treatment.

    Results

    The results showed a significant decrease between pretreatment and immediately posttreatment in the ATEC social subscale scores, significant increases in N-acetylaspartate (NAA)/creatine (Cr) and myoinositol (mI)/Cr concentrations, and a decrease in choline (Cho)/Cr concentrations in the left DLPFC and locus coeruleus after tDCS treatment. Significant associations between decreased ATEC social subscale scores and changed concentrations in NAA/Cr, Cho/Cr, and mI/Cr in the locus coeruleus were positive.

    Conclusion

    Findings suggest that beneficial effects of tDCS in ASD may be due to changes in neuronal and glia cell activity and synaptogenesis in the brain network of individuals with ASD. Further studies with larger sample sizes and control groups are warranted.

    in Frontiers in Molecular Neuroscience on June 04, 2020 12:00 AM.

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    LRRK2-Related Parkinson’s Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis

    Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large protein comprised of a GTPase and a kinase domain. All pathogenic variants converge on enhancing LRRK2 kinase substrate phosphorylation, and distinct LRRK2 kinase inhibitors are currently in various stages of clinical trials. Although the precise pathophysiological functions of LRRK2 remain largely unknown, PD-associated mutants have been shown to alter various intracellular vesicular trafficking pathways, especially those related to endolysosomal protein degradation events. In addition, biochemical studies have identified a subset of Rab proteins, small GTPases required for all vesicular trafficking steps, as substrate proteins for the LRRK2 kinase activity in vitro and in vivo. Therefore, it is crucial to evaluate the impact of such phosphorylation on neurodegenerative mechanisms underlying LRRK2-related PD, especially with respect to deregulated Rab-mediated endolysosomal membrane trafficking and protein degradation events. Surprisingly, a significant proportion of PD patients due to LRRK2 mutations display neuronal cell loss in the substantia nigra pars compacta in the absence of any apparent α-synuclein-containing Lewy body neuropathology. These findings suggest that endolysosomal alterations mediated by pathogenic LRRK2 per se are not sufficient to cause α-synuclein aggregation. Here, we will review current knowledge about the link between pathogenic LRRK2, Rab protein phosphorylation and endolysosomal trafficking alterations, and we will propose a testable working model whereby LRRK2-related PD may present with variable LB pathology.

    in Frontiers in Neuroscience: Neurodegeneration on June 04, 2020 12:00 AM.

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    Integrated Automatic Detection, Classification and Imaging of High Frequency Oscillations With Stereoelectroencephalography

    Objective

    During presurgical evaluation for focal epilepsy patients, the evidence supporting the use of high frequency oscillations (HFOs) for delineating the epileptogenic zone (EZ) increased over the past decade. This study aims to develop and validate an integrated automatic detection, classification and imaging pipeline of HFOs with stereoelectroencephalography (SEEG) to narrow the gap between HFOs quantitative analysis and clinical application.

    Methods

    The proposed pipeline includes stages of channel inclusion, candidate HFOs detection and automatic labeling with four trained convolutional neural network (CNN) classifiers and HFOs sorting based on occurrence rate and imaging. We first evaluated the initial detector using an open simulated dataset. After that, we validated our full algorithm in a 20-patient cohort against three assumptions based on previous studies. Classified HFOs results were compared with seizure onset zone (SOZ) channels for their concordance. The receiver operating characteristic (ROC) curve and the corresponding area under the curve (AUC) were calculated representing the prediction ability of the labeled HFOs outputs for SOZ.

    Results

    The initial detector demonstrated satisfactory performance on the simulated dataset. The four CNN classifiers converged quickly during training, and the accuracies on the validation dataset were above 95%. The localization value of HFOs was significantly improved by HFOs classification. The AUC values of the 20 testing patients increased after HFO classification, indicating a satisfactory prediction value of the proposed algorithm for EZ identification.

    Conclusion

    Our detector can provide robust HFOs analysis results revealing EZ at the individual level, which may ultimately push forward the transitioning of HFOs analysis into a meaningful part of the presurgical evaluation and surgical planning.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 04, 2020 12:00 AM.

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    Machine Learning Representation of Loss of Eye Regularity in a Drosophila Neurodegenerative Model

    The fruit fly compound eye is a premier experimental system for modeling human neurodegenerative diseases. The disruption of the retinal geometry has been historically assessed using time-consuming and poorly reliable techniques such as histology or pseudopupil manual counting. Recent semiautomated quantification approaches rely either on manual region-of-interest delimitation or engineered features to estimate the extent of degeneration. This work presents a fully automated classification pipeline of bright-field images based on orientated gradient descriptors and machine learning techniques. An initial region-of-interest extraction is performed, applying morphological kernels and Euclidean distance-to-centroid thresholding. Image classification algorithms are trained on these regions (support vector machine, decision trees, random forest, and convolutional neural network), and their performance is evaluated on independent, unseen datasets. The combinations of oriented gradient + gaussian kernel Support Vector Machine [0.97 accuracy and 0.98 area under the curve (AUC)] and fine-tuned pre-trained convolutional neural network (0.98 accuracy and 0.99 AUC) yielded the best results overall. The proposed method provides a robust quantification framework that can be generalized to address the loss of regularity in biological patterns similar to the Drosophila eye surface and speeds up the processing of large sample batches.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 04, 2020 12:00 AM.

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    A Nomogram Model of Radiomics and Satellite Sign Number as Imaging Predictor for Intracranial Hematoma Expansion

    Background

    We aimed to construct and validate a nomogram model based on the combination of radiomic features and satellite sign number for predicting intracerebral hematoma expansion.

    Methods

    A total of 129 patients from two institutions were enrolled in this study. The preprocessed initial CT images were used for radiomic feature extraction. The ANOVA-Kruskal–Wallis test and least absolute shrinkage and selection operator regression were applied to identify candidate radiomic features and construct the Radscore. A nomogram model was developed by integrating the Radscore with a satellite sign number. The discrimination performance of the proposed model was evaluated by receiver operating characteristic (ROC) analysis, and the predictive accuracy was assessed via a calibration curve. Decision curve analysis (DCA) and Kaplan–Meier (KM) survival analysis were performed to evaluate the clinical value of the model.

    Results

    Four optimal features were ultimately selected and contributed to the Radscore construction. A positive correlation was observed between the satellite sign number and Radscore (Pearson’s r: 0.451). The nomogram model showed the best performance with high area under the curves in both training cohort (0.881, sensitivity: 0.973; specificity: 0.787) and external validation cohort (0.857, sensitivity: 0.950; specificity: 0.766). The calibration curve, DCA, and KM analysis indicated the high accuracy and clinical usefulness of the nomogram model for hematoma expansion prediction.

    Conclusion

    A nomogram model of integrated radiomic signature and satellite sign number based on noncontrast CT images could serve as a reliable and convenient measurement of hematoma expansion prediction.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 04, 2020 12:00 AM.

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    The Mechanisms of Nuclear Proteotoxicity in Polyglutamine Spinocerebellar Ataxias

    Polyglutamine (polyQ) spinocerebellar ataxias (SCAs) are the most prevalent subset of SCAs and share the aberrant expansion of Q-encoding CAG repeats within the coding sequences of disease-responsible genes as their common genetic cause. These polyQ SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) are inherited neurodegenerative diseases characterized by the progressive atrophy of the cerebellum and connected regions of the nervous system, which leads to loss of fine muscle movement coordination. Upon the expansion of polyQ repeats, the mutated proteins typically accumulate disproportionately in the neuronal nucleus, where they sequester various target molecules, including transcription factors and other nuclear proteins. However, it is not yet clearly understood how CAG repeat expansion takes place or how expanded polyQ proteins accumulate in the nucleus. In this article, we review the current knowledge on the molecular and cellular bases of nuclear proteotoxicity of polyQ proteins in SCAs and present our perspectives on the remaining issues surrounding these diseases.

    in Frontiers in Neuroscience: Neurodegeneration on June 04, 2020 12:00 AM.

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    Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis

    Hereditary spastic paraplegias (HSP) are a group of genetically and clinically heterogeneous neurologic disorders. Hereby we describe a relatively large group of patients (pts) affected by HSP studied at baseline (31 pts) and at follow-up (mean period 28.9 ± 8.4 months; 23 pts) with multimodal advanced MRI: high-resolution T1 images for voxel-based morphometry (VBM) analysis, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI). An age-matched healthy control (HC) group underwent the same neuroimaging protocol in a time schedule matched with the HSP patients. At baseline, VBM showed gray matter (GM) reduction in HSP in the right pre-frontal cortex and bilaterally in the thalami. MRS at baseline depicted in HSP patients compared to the HC group reduction of NAA/Cr ratio in the right pre-frontal region, increase of Cho/Cr ratio in the right pre-central regions, and increase of mI/Cr ratio on the left pre-central area. At cross-sectional follow-up analysis and longitudinal evaluation, no VBM and MRS statistically significant results were obtained. Tract-based spatial statistics (TBSS) analysis showed widespread DTI brain white matter (WM) alterations in patients compared to HC at baseline, which are characterized by reduction of fractional anisotropy (FA) and increase of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity, as confirmed on cross-analysis of the follow-up dataset. A longitudinal analysis with TBSS in HSP patients did not show significant variations, while upon applying region-based analysis we found increased FA and decreased MD and AD in specific brain WM fiber complex during follow-up. The changes were not correlated with the clinical presentation (pure vs complicated HSP), motor function, and motility indexes or history of specific treatments (botulinum toxin). In conclusion, the cross-sectional analysis of the multiparametric MRI data in our HSP patients confirmed the non-prominent involvement of the cortex in the primary motor regions but rather of other more associative areas. On the contrary, DTI demonstrated a widespread involvement of the brain WM, including the primary motor regions, which was confirmed at follow-up. The longitudinal analysis revealed an apparent inversion of tendency when considering the expected evolution of a neurodegenerative process: we detected an increase of FA and a decrease of MD and AD. These time-related modifications may suggest a repair attempt by the residual central WM fibers, which requires confirmation with a larger group of patients and with a longer time interval.

    in Frontiers in Neuroscience: Neurodegeneration on June 04, 2020 12:00 AM.

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    MVPA-Light: A Classification and Regression Toolbox for Multi-Dimensional Data

    MVPA-Light is a MATLAB toolbox for multivariate pattern analysis (MVPA). It provides native implementations of a range of classifiers and regression models, using modern optimization algorithms. High-level functions allow for the multivariate analysis of multi-dimensional data, including generalization (e.g., time x time) and searchlight analysis. The toolbox performs cross-validation, hyperparameter tuning, and nested preprocessing. It computes various classification and regression metrics and establishes their statistical significance, is modular and easily extendable. Furthermore, it offers interfaces for LIBSVM and LIBLINEAR as well as an integration into the FieldTrip neuroimaging toolbox. After introducing MVPA-Light, example analyses of MEG and fMRI datasets, and benchmarking results on the classifiers and regression models are presented.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 04, 2020 12:00 AM.

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    Neurophysiological Correlates of Gait in the Human Basal Ganglia and the PPN Region in Parkinson’s Disease

    This study aimed to characterize the neurophysiological correlates of gait in the human pedunculopontine nucleus (PPN) region and the globus pallidus internus (GPi) in Parkinson’s disease (PD) cohort. Though much is known about the PPN region through animal studies, there are limited physiological recordings from ambulatory humans. The PPN has recently garnered interest as a potential deep brain stimulation (DBS) target for improving gait and freezing of gait (FoG) in PD. We used bidirectional neurostimulators to record from the human PPN region and GPi in a small cohort of severely affected PD subjects with FoG despite optimized dopaminergic medications. Five subjects, with confirmed on-dopaminergic medication FoG, were implanted with bilateral GPi and bilateral PPN region DBS electrodes. Electrophysiological recordings were obtained during various gait tasks for 5 months postoperatively in both the off- and on-medication conditions (obtained during the no stimulation condition). The results revealed suppression of low beta power in the GPi and a 1–8 Hz modulation in the PPN region which correlated with human gait. The PPN feature correlated with walking speed. GPi beta desynchronization and PPN low-frequency synchronization were observed as subjects progressed from rest to ambulatory tasks. Our findings add to our understanding of the neurophysiology underpinning gait and will likely contribute to the development of novel therapies for abnormal gait in PD.

    Clinical Trial Registration:Clinicaltrials.gov identifier; NCT02318927.

    in Frontiers in Human Neuroscience on June 04, 2020 12:00 AM.

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    Methylene Blue Prevents Retinal Damage Caused by Perinatal Asphyxia in the Rat

    Perinatal asphyxia (PA) is responsible for a large proportion of neonatal deaths and numerous neurological sequelae, including visual dysfunction and blindness. In PA, the retina is exposed to ischemia/reoxygenation, which results in nitric oxide (NO) overproduction and neurotoxicity. We hypothesized that methylene blue (MB), a guanylyl cyclase inhibitor, and free-radical scavenger currently used in the clinic, may block this pathway and prevent PA-induced retinal degeneration. Male rat pups were subjected to an experimental model of PA. Four groups were studied: normally delivered (CTL), normally delivered treated with 2 mg Kg-1 MB (MB), exposed to PA for 20 min at 37°C (PA), and exposed to PA and, then, treated with MB (PA-MB). Scotopic electroretinography performed 45 days after birth showed that PA animals had significant defects in the a- and b-waves and oscillatory potentials (OP). The same animals presented a significant increase in the thickness of the inner retina and a large number of TUNEL-positive cells. All these physiological and morphological parameters were significantly prevented by the treatment with MB. Gene expression analysis demonstrated significant increases in iNOS, MMP9, and VEGF in the eyes of PA animals, which were prevented by MB treatment. In conclusion, MB regulates key players of inflammation, matrix remodeling, gliosis, and angiogenesis in the eye and could be used as a treatment to prevent the deleterious visual consequences of PA. Given its safety profile and low cost, MB may be used clinically in places where alternative treatments may be unavailable.

    in Frontiers in Cellular Neuroscience on June 04, 2020 12:00 AM.

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    Huntingtin-Associated Protein 1 in Mouse Hypothalamus Stabilizes Glucocorticoid Receptor in Stress Response

    Huntingtin-associated protein 1 (Hap1) was initially identified as a brain-enriched protein that binds to the Huntington’s disease protein, huntingtin. Unlike huntingtin that is ubiquitously expressed in the brain, Hap1 is enriched in the brain with the highest expression level in the hypothalamus. The selective enrichment of Hap1 in the hypothalamus suggests that Hap1 may play a specific role in hypothalamic function that can regulate metabolism and stress response. Here we report that Hap1 is colocalized and interacts with the glucocorticoid receptor (GR) in mouse hypothalamic neurons. Genetic depletion of Hap1 reduced the expression level of GR in the hypothalamus. Dexamethasone, a GR agonist, treatment or fasting of mice induced stress, resulting in increased expression of Hap1 in the hypothalamus. However, when Hap1 was absent, these treatments promoted GR reduction in the hypothalamus. In cultured cells, loss of Hap1 shortened the half-life of GR. These findings suggest that Hap1 stabilizes GR in the cytoplasm and that Hap1 dysfunction or deficiency may alter animal’s stress response.

    in Frontiers in Cellular Neuroscience on June 04, 2020 12:00 AM.

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    Location of the Cell Adhesion Molecule “Coxsackievirus and Adenovirus Receptor” in the Adult Mouse Brain

    The coxsackievirus and adenovirus receptor (CAR) is a single-pass transmembrane cell adhesion molecule (CAM). CAR is expressed in numerous mammalian tissues including the brain, heart, lung, and testes. In epithelial cells, CAR functions are typical of the quintessential roles of numerous CAMs. However, in the brain the multiple roles of CAR are poorly understood. To better understand the physiological role of CAR in the adult brain, characterizing its location is a primordial step to advance our knowledge of its functions. In addition, CAR is responsible for the attachment, internalization, and retrograde transport of canine adenovirus type 2 (CAV-2) vectors, which have found a niche in the mapping of neuronal circuits and gene transfer to treat and model neurodegenerative diseases. In this study, we used immunohistochemistry and immunofluorescence to document the global location of CAR in the healthy, young adult mouse brain. Globally, we found that CAR is expressed by maturing and mature neurons in the brain parenchyma and located on the soma and on projections. While CAR occasionally colocalizes with glial fibrillary acidic protein, this overlap was restricted to areas that are associated with adult neurogenesis.

    in Frontiers in Neuroanatomy on June 04, 2020 12:00 AM.

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    Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson’s Disease and Adverse Effects of L-DOPA

    Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a “false” transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD.

    in Frontiers in Neuroanatomy on June 04, 2020 12:00 AM.

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    TDP-43 Is Elevated in Plasma Neuronal-Derived Exosomes of Patients With Alzheimer’s Disease

    Background

    Recently, TDP-43 has been recognized as a common proteinopathy in the “oldest old” and a neuropathological comorbidity in patients with Alzheimer’s disease (AD). However, since it has a low concentration in cerebrospinal fluid, the presence of TDP-43 in AD is rarely investigated in vivo.

    Methods

    Twenty-four patients with amyloid PET confirmed AD and 15 healthy controls (HCs) were included in this study. TDP-43 level in plasma neuronal-derived exosomes (NDEs) was measured by enzyme-linked immunosorbent assay.

    Results

    TDP-43 level was elevated in patients with AD compared with HCs (median 1.08 ng/ml, IQR 0.72–1.37 ng/ml vs. median 0.66 ng/ml, IQR 0.48–0.76 ng/ml, P = 0.002). There was no correlation between TDP-43 level and cognitive function, neuropsychiatric symptoms or APOE genotype in patients with AD.

    Conclusion

    This study demonstrated increased TDP-43 accumulation in AD patients by examining plasma NDEs, which may provide a window into the effects of TDP-43 on AD progression.

    in Frontiers in Ageing Neuroscience on June 04, 2020 12:00 AM.

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    Enriched Environment Decreases Cognitive Impairment in Elderly Rats With Prenatal Mobile Phone Exposure

    Mobile phone use has rapidly increased worldwide, and pregnant women are passively or actively exposed to the associated electromagnetic radiation. Maternal cell phone exposure is related to behavioral difficulties in young offspring. However, whether prenatal mobile phone exposure can predispose the elderly offspring to cognitive impairment is unclear. The enriched environment (EE) has shown positive effects on cognition in an immature brain, but its impact on aging offspring after prenatal cell phone exposure is unknown. This study aimed to investigate whether prenatal exposure to mobile phone exerts long-term effects on cognition in elderly rat offspring and whether EE during adulthood can rescue cognitive impairment by altering the synaptic plasticity. Pregnant rats were subjected to prenatal short-term or long-term cell phone exposure and offspring rats were randomly assigned to standard or EE. Spatial learning and memory were investigated using Morris water maze (MWM) in elderly rat offspring. Hippocampal cellular morphology was assessed by hematoxylin-eosin staining and synaptic ultrastructure was evaluated with transmission electron microscopy. Expression of synaptophysin (SYN), postsynaptic density-95 (PSD-95), and brain-derived neurotrophic factor (BDNF) were detected by western blot. The results demonstrated that prenatal long-term but not short-term exposure to mobile phone lead to cognitive impairment, morphological changes in the hippocampal cells, reduced synaptic number, decreased SYN, PSD-95, and BDNF expression in elderly offspring, which were alleviated by postnatal EE housing. These findings suggest that prenatal long-term mobile phone exposure may pose life-long adverse effects on elderly offspring and impair cognition by disrupting the synaptic plasticity, which may be reversed by postnatal EE housing.

    in Frontiers in Ageing Neuroscience on June 04, 2020 12:00 AM.

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    Specialization of the chromatin remodeler RSC to mobilize partially-unwrapped nucleosomes

    SWI/SNF-family chromatin remodeling complexes, such as S. cerevisiae RSC, slide and eject nucleosomes to regulate transcription. Within nucleosomes, stiff DNA sequences confer spontaneous partial unwrapping, prompting whether and how SWI/SNF-family remodelers are specialized to remodel partially-unwrapped nucleosomes. RSC1 and RSC2 are orthologs of mammalian PBRM1 (polybromo) which define two separate RSC sub-complexes. Remarkably, in vitro the Rsc1-containing complex remodels partially-unwrapped nucleosomes much better than does the Rsc2-containing complex. Moreover, a rsc1Δ mutation, but not rsc2Δ, is lethal with histone mutations that confer partial unwrapping. Rsc1/2 isoforms both cooperate with the DNA-binding proteins Rsc3/30 and the HMG protein, Hmo1, to remodel partially-unwrapped nucleosomes, but show differential reliance on these factors. Notably, genetic impairment of these factors strongly reduces the expression of genes with wide nucleosome-deficient regions (e.g. ribosomal protein genes), known to harbor partially-unwrapped nucleosomes. Taken together, Rsc1/2 isoforms are specialized through composition and interactions to manage and remodel partially-unwrapped nucleosomes.

    in eLife on June 04, 2020 12:00 AM.

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    Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

    The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance in human circuit function. In this study, we focus on neurogliaform cells, that possess specialized physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms underlying human cognitive processing and behavior.

    in eLife on June 04, 2020 12:00 AM.

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    The His-Gly motif of acid-sensing ion channels resides in a reentrant 'loop' implicated in gating and ion selectivity

    Acid-sensing ion channels (ASICs) are proton-gated members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout the central and peripheral nervous systems. The homotrimeric splice variant ASIC1a has been implicated in nociception, fear memory, mood disorders and ischemia. Here we extract full-length chicken ASIC1 (cASIC1) from cell membranes using styrene maleic acid (SMA) copolymer, elucidating structures of ASIC1 channels in both high pH resting and low pH desensitized conformations by single-particle cryo-electron microscopy (cryo-EM). The structures of resting and desensitized channels reveal a reentrant loop at the amino terminus of ASIC1 that includes the highly conserved 'His-Gly' (HG) motif. The reentrant loop lines the lower ion permeation pathway and buttresses the 'Gly-Ala-Ser' (GAS) constriction, thus providing a structural explanation for the role of the His-Gly dipeptide in the structure and function of ASICs.

    in eLife on June 04, 2020 12:00 AM.

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    Genome editing enables reverse genetics of multicellular development in the choanoflagellate Salpingoeca rosetta

    In a previous study, we established a forward genetic screen to identify genes required for multicellular development in the choanoflagellate, Salpingoeca rosetta (Levin et al., 2014). Yet, the paucity of reverse genetic tools for choanoflagellates has hampered direct tests of gene function and impeded the establishment of choanoflagellates as a model for reconstructing the origin of their closest living relatives, the animals. Here we establish CRISPR/Cas9-mediated genome editing in S. rosetta by engineering a selectable marker to enrich for edited cells. We then use genome editing to disrupt the coding sequence of a S. rosetta C-type lectin gene, rosetteless, and thereby demonstrate its necessity for multicellular rosette development. This work advances S. rosetta as a model system in which to investigate how genes identified from genetic screens and genomic surveys function in choanoflagellates and evolved as critical regulators of animal biology.

    in eLife on June 04, 2020 12:00 AM.

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    Microstructural organization of human insula is linked to its macrofunctional circuitry and predicts cognitive control

    The human insular cortex is a heterogeneous brain structure which plays an integrative role in guiding behavior. The cytoarchitectonic organization of the human insula has been investigated over the last century using postmortem brains but there has been little progress in noninvasive in vivo mapping of its microstructure and large-scale functional circuitry. Quantitative modeling of multi-shell diffusion MRI data from 413 participants revealed that human insula microstructure differs significantly across subdivisions that serve distinct cognitive and affective functions. Insular microstructural organization was mirrored in its functionally interconnected circuits with the anterior cingulate cortex that anchors the salience network, a system important for adaptive switching of cognitive control systems. Furthermore, insular microstructural features, confirmed in Macaca mulatta, were linked to behavior and predicted individual differences in cognitive control ability. Our findings open new possibilities for probing psychiatric and neurological disorders impacted by insular cortex dysfunction, including autism, schizophrenia, and fronto-temporal dementia.

    in eLife on June 04, 2020 12:00 AM.

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    Hippocampal neural stem cells facilitate access from circulation via apical cytoplasmic processes

    Blood vessels (BVs) are considered an integral component of neural stem cells (NSCs) niches. NSCs in the dentate gyrus (DG) have enigmatic elaborated apical cellular processes that are associated with BVs. Whether this contact serves as a mechanism for delivering circulating molecules is not known. Here we uncovered a previously unrecognized communication route allowing exclusive direct access of blood-borne substances to hippocampal NSCs. BBB-impermeable fluorescent tracer injected transcardially to mice is selectively uptaken by DG NSCs within a minute, via the vessel-associated apical processes. These processes, measured >30nm in diameter, establish direct membrane-to-membrane contact with endothelial cells in specialized areas of irregular endothelial basement membrane and enriched with vesicular activity. Doxorubicin, a brain-impermeable chemotherapeutic agent, is also readily and selectively uptaken by NSCs and reduces their proliferation, which might explain its problematic anti-neurogenic or cognitive side-effect. The newly-discovered NSC-BV communication route explains how circulatory neurogenic mediators are 'sensed' by NSCs.

    in eLife on June 04, 2020 12:00 AM.

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    Feedback contribution to surface motion perception in the human early visual cortex

    Human visual surface perception has neural correlates in early visual cortex, but the role of feedback during surface segmentation in human early visual cortex remains unknown. Feedback projections preferentially enter superficial and deep anatomical layers, which provides a hypothesis for the cortical depth distribution of fMRI activity related to feedback. Using ultra-high field fMRI, we report a depth distribution of activation in line with feedback during the (illusory) perception of surface motion. Our results fit with a signal re-entering in superficial depths of V1, followed by a feedforward sweep of the re-entered information through V2 and V3. The magnitude and sign of the BOLD response strongly depended on the presence of texture in the background, and was additionally modulated by the presence of illusory motion perception compatible with feedback. In summary, the present study demonstrates the potential of depth-resolved fMRI in tackling biomechanical questions on perception.

    in eLife on June 04, 2020 12:00 AM.

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    Circuits that encode and guide alcohol-associated preference

    A powerful feature of adaptive memory is its inherent flexibility. Alcohol and other addictive substances can remold neural circuits important for memory to reduce this flexibility. However, the mechanism through which pertinent circuits are selected and shaped remains unclear. We show that circuits required for alcohol-associated preference shift from population level dopaminergic activation to select dopamine neurons that predict behavioral choice in Drosophila melanogaster. During memory expression, subsets of dopamine neurons directly and indirectly modulate the activity of interconnected glutamatergic and cholinergic mushroom body output neurons (MBON). Transsynaptic tracing of neurons important for memory expression revealed a convergent center of memory consolidation within the mushroom body (MB) implicated in arousal, and a structure outside the MB implicated in integration of naïve and learned responses. These findings provide a circuit framework through which dopamine neuronal activation shifts from reward delivery to cue onset, and provide insight into the maladaptive nature of memory.

    in eLife on June 04, 2020 12:00 AM.

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    Neurodevelopmental Disorders: From Genetics to Functional Pathways

    Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function and are characterized by wide genetic and clinical variability. In this review, we discuss the multiple factors that influence the clinical presentation of NDDs, with particular attention to gene vulnerability, mutational load, and the two-hit model. Despite the complex architecture of mutational events associated with NDDs, the various proteins involved appear to converge on common pathways, such as synaptic plasticity/function, chromatin remodelers and the mammalian target of rapamycin (mTOR) pathway.

    in Trends in Neurosciences: In press on June 04, 2020 12:00 AM.

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    Sparse Activity of Hippocampal Adult-Born Neurons during REM Sleep Is Necessary for Memory Consolidation

    The neuronal population in the hippocampus responsible for memory consolidation during rapid eye movement (REM) sleep was unknown. Using in vivo imaging and optogenetics, Kumar et al. provide causal evidence that the activity of dentate gyrus adult-born neurons during REM sleep is necessary for contextual fear memory consolidation.

    in Neuron: In press on June 04, 2020 12:00 AM.

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    Incerta-thalamic Circuit Controls Nocifensive Behavior via Cannabinoid Type 1 Receptors

    Wang et al. identify the critical role of ZIv parvalbumin-positive neurons and the ZIv-Po circuit that regulate the nocifensive responses, revealing the pathway modulation by endocannabinoids for controlling nocifensive behaviors and pathological pain.

    in Neuron: In press on June 04, 2020 12:00 AM.

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    A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma

    by Hélène Ruffieux, Jérôme Carayol, Radu Popescu, Mary-Ellen Harper, Robert Dent, Wim H. M. Saris, Arne Astrup, Jörg Hager, Anthony C. Davison, Armand Valsesia

    Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyse jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637.

    in PLoS Computational Biology on June 03, 2020 09:00 PM.

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    Image style transfer with collection representation space and semantic-guided reconstruction

    Publication date: September 2020

    Source: Neural Networks, Volume 129

    Author(s): Zhuoqi Ma, Jie Li, Nannan Wang, Xinbo Gao

    in Neural Networks on June 03, 2020 06:00 PM.

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    Prediction of N6-methyladenosine sites using convolution neural network model based on distributed feature representations

    Publication date: Available online 2 June 2020

    Source: Neural Networks

    Author(s): Muhammad Tahir, Maqsood Hayat, Kil To Chong

    in Neural Networks on June 03, 2020 06:00 PM.

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    Transient sublethal hypoxia in neonatal rats causes reduced dendritic spines, aberrant synaptic plasticity, and impairments in memory

    Transient sublethal hypoxia in neonatal rats causes reduced dendritic spines, aberrant synaptic plasticity, and impairments in memory

    When neonatal rats were exposed to transient sublethal hypoxia, the hippocampal neurons developed shorter and thinner dendrites, with decreased dendritic spine density, and reduced strength in excitatory synaptic transmission. The rats also showed impaired cognitive performance in spatial learning and memory.


    Abstract

    Hypoxic/ischemic insult, a leading cause of functional brain defects, has been extensively studied in both clinical and experimental animal research, including its etiology, neuropathogenesis, and pharmacological interventions. Transient sublethal hypoxia (TSH) is a common clinical occurrence in the perinatal period. However, its effect on early developing brains remains poorly understood. The present study was designed to investigate the effect of TSH on the dendrite and dendritic spine formation, neuronal and synaptic activity, and cognitive behavior of early postnatal Day 1 rat pups. While TSH showed no obvious effect on gross brain morphology, neuron cell density, or glial activation in the hippocampus, we found transient hypoxia did cause significant changes in neuronal structure and function. In brains exposed to TSH, hippocampal neurons developed shorter and thinner dendrites, with decreased dendritic spine density, and reduced strength in excitatory synaptic transmission. Moreover, TSH‐treated rats showed impaired cognitive performance in spatial learning and memory. Our findings demonstrate that TSH in newborn rats can cause significant impairments in synaptic formation and function, and long‐lasting brain functional deficits. Therefore, this study provides a useful animal model for the study of TSH on early developing brains and to explore potential pharmaceutical interventions for patients subjected to TSH insult.

    in Journal of Neuroscience Research on June 03, 2020 05:43 PM.

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    Erratum to “Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder”

    in Annals of Neurology on June 03, 2020 05:15 PM.

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    Subthalamic Nucleus Stimulation Modulates Motor Epileptic Activity in Humans

    Objective

    Pharmaco‐refractory focal motor epileptic seizures pose a significant challenge. Deep brain stimulation (DBS) is a recently recognized therapeutic option for the treatment of refractory epilepsy. To identify the specific target for focal motor seizures, we evaluate the modulatory effects of the subthalamic nucleus (STN) stimulation because of the critical role of STN in cortico‐subcortical motor processing.

    Methods

    Seven patients with epilepsy with refractory seizures who underwent chronic stereoelectroencephalography (SEEG) monitoring were studied in presurgical evaluation. Seizure onset zone was hypothesized to be partially involved in the motor areas in 6 patients. For each patient, one electrode was temporally implanted into the STN that was ipsilateral to the seizure onset zone. The cortical–subcortical seizure propagation was systemically evaluated. The simultaneously electrophysiological responses over distributed cortical areas to STN stimulation at varied frequencies were quantitatively assessed.

    Results

    We observed the consistent downstream propagation of seizures from the motor cortex toward the ipsilateral STN and remarkable cortical responses on motor cortex to single‐pulse STN stimulation. Furthermore, we showed frequency‐dependent upstream modulatory effect of STN stimulation on motor cortex specifically. In contrast to the enhanced effects of low frequency stimulation, high‐frequency stimulation of the STN can significantly reduce interictal spikes, high‐frequency oscillations over motor cortex disclosing effective connections to the STN.

    Interpretation

    This result showed that the STN is not only engaged in as a propagation network of focal motor seizures but STN stimulation can profoundly modulate the epileptic activity of motor cortex in humans, suggesting a mechanism‐based alternative for patients suffering from refractory focal motor seizures. ANN NEUROL 2020

    in Annals of Neurology on June 03, 2020 04:49 PM.

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    Rapid Dissemination of Protocols for Managing Neurology Inpatients with COVID‐19

    in Annals of Neurology on June 03, 2020 04:00 PM.

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    A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation

    Objective

    Glycogen storage diseases (GSDs) are severe human disorders resulting from abnormal glucose metabolism, and all previously described GSDs segregate as autosomal recessive or X‐linked traits. In this study, we aimed to molecularly characterize the first family with a dominant GSD.

    Methods

    We describe a dominant GSD family with 13 affected members presenting with adult‐onset muscle weakness, and we provide clinical, metabolic, histological, and ultrastructural data. We performed exome sequencing to uncover the causative gene, and functional experiments in the cell model and on recombinant proteins to investigate the pathogenic effect of the identified mutation.

    Results

    We identified a heterozygous missense mutation in PYGM segregating with the disease in the family. PYGM codes for myophosphorylase, the enzyme catalyzing the initial step of glycogen breakdown. Enzymatic tests revealed that the PYGM mutation impairs the AMP‐independent myophosphorylase activity, whereas the AMP‐dependent activity was preserved. Further functional investigations demonstrated an altered conformation and aggregation of mutant myophosphorylase, and the concurrent accumulation of the intermediate filament desmin in the myofibers of the patients.

    Interpretation

    Overall, this study describes the first example of a dominant glycogen storage disease in humans, and elucidates the underlying pathomechanisms by deciphering the sequence of events from the PYGM mutation to the accumulation of glycogen in the muscle fibers. ANN NEUROL 2020

    in Annals of Neurology on June 03, 2020 03:58 PM.

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    The connectome of the Caenorhabditis elegans pharynx

    The connectome of the Caenorhabditis elegans pharynx

    We reconstructed the Caenorhabditis elegans adult hermaphrodite pharyngeal nervous system from serial section electron micrographs to generate a weighted pharyngeal connectome. We subjected the pharyngeal wiring diagram to a set of visual, graph theoretic, statistical, and fluorescent‐reporter analyses, revealing a shallow neural structure. Together, our study shows that most pharyngeal neurons exhibit sensory‐motor characteristics, similar to primitive nervous systems comprised of “ur‐neurons.”


    Abstract

    Detailed anatomical maps of individual organs and entire animals have served as invaluable entry points for ensuing dissection of their evolution, development, and function. The pharynx of the nematode Caenorhabditis elegans is a simple neuromuscular organ with a self‐contained, autonomously acting nervous system, composed of 20 neurons that fall into 14 anatomically distinct types. Using serial electron micrograph (EM) reconstruction, we re‐evaluate here the connectome of the pharyngeal nervous system, providing a novel and more detailed view of its structure and predicted function. Contrasting the previous classification of pharyngeal neurons into distinct inter‐ and motor neuron classes, we provide evidence that most pharyngeal neurons are also likely sensory neurons and most, if not all, pharyngeal neurons also classify as motor neurons. Together with the extensive cross‐connectivity among pharyngeal neurons, which is more widespread than previously realized, the sensory‐motor characteristics of most neurons define a shallow network architecture of the pharyngeal connectome. Network analysis reveals that the patterns of neuronal connections are organized into putative computational modules that reflect the known functional domains of the pharynx. Compared with the somatic nervous system, pharyngeal neurons both physically associate with a larger fraction of their neighbors and create synapses with a greater proportion of their neighbors. We speculate that the overall architecture of the pharyngeal nervous system may be reminiscent of the architecture of ancestral, primitive nervous systems.

    in Journal of Comparative Neurology on June 03, 2020 12:52 PM.

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    Relationship between velocities, tractions, and intercellular stresses in the migrating epithelial monolayer

    Author(s): Yoav Green, Jeffrey J. Fredberg, and James P. Butler

    The relationship between velocities, tractions, and intercellular stresses in the migrating epithelial monolayer are currently unknown. Ten years ago, a method known as monolayer stress microscopy (MSM) was suggested from which intercellular stresses could be computed for a given traction field. The...


    [Phys. Rev. E 101, 062405] Published Wed Jun 03, 2020

    in Physical Review E: Biological physics on June 03, 2020 10:00 AM.

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    Dynamics of ribosomes in mRNA translation under steady- and nonsteady-state conditions

    Author(s): Juraj Szavits-Nossan and Martin R. Evans

    Recent advances in DNA sequencing and fluorescence imaging have made it possible to monitor the dynamics of ribosomes actively engaged in messenger RNA (mRNA) translation. Here, we model these experiments within the inhomogeneous totally asymmetric simple exclusion process (TASEP) using realistic ki...


    [Phys. Rev. E 101, 062404] Published Wed Jun 03, 2020

    in Physical Review E: Biological physics on June 03, 2020 10:00 AM.

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    Author Correction: No upward trends in the occurrence of extreme floods in central Europe

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2391-9

    Author Correction: No upward trends in the occurrence of extreme floods in central Europe

    in Nature on June 03, 2020 12:00 AM.

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    Structure of the ER membrane complex, a transmembrane-domain insertase

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2389-3

    The cryo-electron microscopy structure of the ER membrane complex provides insight into its overall architecture, evolution and function in co-translational protein insertion.

    in Nature on June 03, 2020 12:00 AM.

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    The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2374-x

    The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12–cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K.

    in Nature on June 03, 2020 12:00 AM.

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    IGF1R is an entry receptor for respiratory syncytial virus

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2369-7

    Respiratory syncytial virus enters cells by binding to cell-surface IGFR1, which activates PKCζ and induces trafficking of the NCL coreceptor to the RSV particles at the cell surface.

    in Nature on June 03, 2020 12:00 AM.

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    Oncometabolites suppress DNA repair by disrupting local chromatin signalling

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2363-0

    Metabolites that are elevated in tumours inhibit the lysine demethylase KDM4B, resulting in aberrant hypermethylation of histone 3 lysine 9 and decreased homology-dependent DNA repair.

    in Nature on June 03, 2020 12:00 AM.

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    Structures of human pannexin 1 reveal ion pathways and mechanism of gating

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2357-y

    Cryo-electron microscopy structures of the ATP-permeable channel pannexin 1 reveal a gating mechanism involving multiple distinct ion-conducting pathways.

    in Nature on June 03, 2020 12:00 AM.

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    Hair-bearing human skin generated entirely from pluripotent stem cells

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2352-3

    Skin organoids generated in vitro from human pluripotent stem cells form complex, multilayered skin tissue with hair follicles, sebaceous glands and neural circuitry, and integrate with endogenous skin when grafted onto immunocompromised mice.

    in Nature on June 03, 2020 12:00 AM.

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    A map of object space in primate inferotemporal cortex

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2350-5

    Primate inferotemporal cortex contains a coarse map of object space consisting of four networks, identified using functional imaging, electrophysiology and deep networks.

    in Nature on June 03, 2020 12:00 AM.

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    Potential circadian effects on translational failure for neuroprotection

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2348-z

    Studies in rats and mice at different times of day suggest that the failure of neuroprotective strategies for stroke in translational studies might be related to the difference in circadian cycles between humans and rodents.

    in Nature on June 03, 2020 12:00 AM.

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    Insights into variation in meiosis from 31,228 human sperm genomes

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2347-0

    Thousands of sperm genomes have been analysed with a new method called Sperm-seq, revealing interconnected meiotic variation at the single-cell and person-to-person levels, and suggesting chromosome compaction as a way to explain the relationships between diverse recombination phenotypes.

    in Nature on June 03, 2020 12:00 AM.

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    Revealing enigmatic mucus structures in the deep sea using DeepPIV

    Nature, Published online: 03 June 2020; doi:10.1038/s41586-020-2345-2

    Advanced deep-sea imaging tools yield insights into the structure and function of mucus filtration houses built by midwater giant larvaceans.

    in Nature on June 03, 2020 12:00 AM.

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    The characterization of Mediator 12 and 13 as conditional positive gene regulators in Arabidopsis

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16651-5

    Mediator is a multiprotein complex required to activate gene transcription by RNAPII. Here, the authors report that MED12 and MED13 are conditional positive regulators that facilitate the expression of genes depleted in active chromatin marks and the induction of gene expression in response to environmental stimuli in Arabidopsis.

    in Nature Communications on June 03, 2020 12:00 AM.

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    Orbitofrontal control of visual cortex gain promotes visual associative learning

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16609-7

    The orbitofrontal cortex (OFC) encodes expected outcomes and plays a key role in outcome-guided behavior. The authors show here that the top-down projection from the OFC to the visual cortex drives visual associative learning by modulating the response gain of V1 neurons to non-relevant stimuli.

    in Nature Communications on June 03, 2020 12:00 AM.

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    Traceless native chemical ligation of lipid-modified peptide surfactants by mixed micelle formation

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16595-w

    Sequestration of reactants in lipid vesicles is a strategy prevalent in biological systems to raise the rate and specificity of chemical reactions. Here, the authors show that micelle-assisted reactions facilitate native chemical ligation between a peptide-thioester and a Cys-peptide modified by a lipid-like moiety.

    in Nature Communications on June 03, 2020 12:00 AM.

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    RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16592-z

    Genetic variants at the RSPO3 locus are associated with waist-to-hip ratio (adjusted for BMI). Here, Loh et al. describe two independent RSPO3 signals that associate with body fat distribution, perform fine-mapping and explore the function of RSPO3 in human adipocyte biology and body fat distribution in zebrafish

    in Nature Communications on June 03, 2020 12:00 AM.

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    Fires prime terrestrial organic carbon for riverine export to the global oceans

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16576-z

    Black carbon is a recalcitrant and unique form of organic carbon formed from incomplete combustion. Here the authors use global sampling to reduce uncertainty in the flux of terrestrial black carbon to the oceans, predicting that 34% of black carbon produced by fires has an oceanic fate.

    in Nature Communications on June 03, 2020 12:00 AM.

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    The RNA fold interactome of evolutionary conserved RNA structures in S. cerevisiae

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16555-4

    Previous study identified in vivo structured mRNA regions in Saccharomyces cerevisiae by dimethyl sulfate-sequencing. Here the authors use quantitative proteomics to identify protein interactors of 186 RNA folds in S. cerevisiae, providing functional links between RNA binding proteins and distinct mRNA fold.

    in Nature Communications on June 03, 2020 12:00 AM.

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    Publisher Correction: MethCORR modelling of methylomes from formalin-fixed paraffin-embedded tissue enables characterization and prognostication of colorectal cancer

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16538-5

    Publisher Correction: MethCORR modelling of methylomes from formalin-fixed paraffin-embedded tissue enables characterization and prognostication of colorectal cancer

    in Nature Communications on June 03, 2020 12:00 AM.

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    Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

    Nature Communications, Published online: 03 June 2020; doi:10.1038/s41467-020-16468-2

    Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

    in Nature Communications on June 03, 2020 12:00 AM.

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    Long-Term Neuroanatomical Consequences of Childhood Maltreatment: Reduced Amygdala Inhibition by Medial Prefrontal Cortex

    Similar to patients with Major depressive disorder (MDD), healthy subjects at risk for depression show hyperactivation of the amygdala as a response to negative emotional expressions. The medial prefrontal cortex is responsible for amygdala control. Analyzing a large cohort of healthy subjects, we aimed to delineate malfunction in amygdala regulation by the medial prefrontal cortex in subjects at increased risk for depression, i.e., with a family history of affective disorders or a personal history of childhood maltreatment. We included a total of 342 healthy subjects from the FOR2107 cohort (www.for2107.de). An emotional face-matching task was used to identify the medial prefrontal cortex and right amygdala. Dynamic Causal Modeling (DCM) was conducted and neural coupling parameters were obtained for healthy controls with and without particular risk factors for depression. We assigned a genetic risk if subjects had a first-degree relative with an affective disorder and an environmental risk if subjects experienced childhood maltreatment. We then compared amygdala inhibition during emotion processing between groups. Amygdala inhibition by the medial prefrontal cortex was present in subjects without those two risk factors, as indicated by negative model parameter estimates. Having a genetic risk (i.e., a family history) did not result in changes in amygdala inhibition compared to no risk subjects. In contrast, childhood maltreatment as environmental risk has led to a significant reduction of amygdala inhibition by the medial prefrontal cortex. We propose a mechanistic explanation for the amygdala hyperactivity in subjects with particular risk for depression, in particular childhood maltreatment, caused by a malfunctioned amygdala downregulation via the medial prefrontal cortex. As childhood maltreatment is a major environmentalrisk factor for depression, we emphasize the importance of this potential early biomarker.

    in Frontiers in Systems Neuroscience on June 03, 2020 12:00 AM.

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    The Role of P2X7 Receptor in Alzheimer’s Disease

    Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by a progressive cognitive decline associated with global brain damage. Initially, intracellular paired helical filaments composed by hyperphosphorylated tau and extracellular deposits of amyloid-β (Aβ) were postulated as the causing factors of the synaptic dysfunction, neuroinflammation, oxidative stress, and neuronal death, detected in AD patients. Therefore, the vast majority of clinical trials were focused on targeting Aβ and tau directly, but no effective treatment has been reported so far. Consequently, only palliative treatments are currently available for AD patients. Over recent years, several studies have suggested the involvement of the purinergic receptor P2X7 (P2X7R), a plasma membrane ionotropic ATP-gated receptor, in the AD brain pathology. In this line, altered expression levels and function of P2X7R were found both in AD patients and AD mouse models. Consequently, genetic depletion or pharmacological inhibition of P2X7R ameliorated the hallmarks and symptoms of different AD mouse models. In this review, we provide an overview of the current knowledge about the role of the P2X7R in AD.

    in Frontiers in Molecular Neuroscience on June 03, 2020 12:00 AM.

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    GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib

    Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson’s disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3aΔDat) and Gsk3b null (Gsk3bΔDat) mice, respectively. We found that Gsk3bΔDat, but not Gsk3aΔDat, showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.

    in Frontiers in Molecular Neuroscience on June 03, 2020 12:00 AM.

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    MRI Features in a Rat Model of H-ABC Tubulinopathy

    Tubulinopathies are a group of recently described diseases characterized by mutations in the tubulin genes. Mutations in TUBB4A produce diseases such as dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), which are clinically diagnosed by magnetic resonance imaging (MRI). We propose the taiep rat as the first animal model for tubulinopathies. The spontaneous mutant suffers from a syndrome related to a central leukodystrophy and characterized by tremor, ataxia, immobility, epilepsy, and paralysis. The pathological signs presented by these rats and the morphological changes we found by our longitudinal MRI study are similar to those of patients with mutations in TUBB4A. The diffuse atrophy we found in brain, cerebellum and spinal cord is related to the changes detectable in many human tubulinopathies and in particular in H-ABC patients, where myelin degeneration at the level of putamen and cerebellum is a clinical trademark of the disease. We performed Tubb4a exon analysis to corroborate the genetic defect and formulated hypotheses about the effect of amino acid 302 change on protein physiology. Optical microscopy of taiep rat cerebella and spinal cord confirmed the optical density loss in white matter associated with myelin loss, despite the persistence of neural fibers.

    in Frontiers in Neuroscience: Neurodegeneration on June 03, 2020 12:00 AM.

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    Object-Based Analyses in FIJI/ImageJ to Measure Local RNA Translation Sites in Neurites in Response to Aβ1-42 Oligomers

    Subcellular protein delivery is especially important in signal transduction and cell behavior, and is typically achieved by localization signals within the protein. However, protein delivery can also rely on localization of mRNAs that are translated at target sites. Although once considered heretical, RNA localization has proven to be highly conserved in eukaryotes. RNA localization and localized translation are especially relevant in polarized cells like neurons where neurites extend dozens to hundreds of centimeters away from the soma. Local translation confers dendrites and axons the capacity to respond to their environment in an acute manner without fully relying on somatic signals. The relevance of local protein synthesis in neuron development, maintenance and disease has not been fully acknowledged until recent years, partly due to the limited amount of locally produced proteins. For instance, in hippocampal neurons levels of newly synthesized somatic proteins can be more than 20–30 times greater than translation levels of neuritic proteins. Thus local translation events can be easily overlooked under the microscope. Here we describe an object-based analysis used to visualize and quantify local RNA translation sites in neurites. Newly synthesized proteins are tagged with puromycin and endogenous RNAs labeled with SYTO. After imaging, signals corresponding to neuritic RNAs and proteins are filtered with a Laplacian operator to enhance the edges. Resulting pixels are converted into objects and selected by automatic masking followed by signal smoothing. Objects corresponding to RNA or protein and colocalized objects (RNA and protein) are quantified along individual neurites. Colocalization between RNA and protein in neurites correspond to newly synthesized proteins arising from localized RNAs and represent localized translation sites. To test the validity of our analyses we have compared control neurons to Aβ142-treated neurons. Aβ is involved in the pathology of Alzheimer’s disease and was previously reported to induce local translation in axons and dendrites which in turn contributes to the disease. We have observed that Aβ increases the synthesis of neuritic proteins as well as the fraction of translating RNAs in distal sites of the neurite, suggesting an induction of local protein synthesis. Our results thus confirm previous reports and validate our quantification method.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 03, 2020 12:00 AM.

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    Histological Correlates of Diffusion-Weighted Magnetic Resonance Microscopy in a Mouse Model of Mesial Temporal Lobe Epilepsy

    Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy. It is frequently associated with abnormal MRI findings, which are caused by underlying cellular, structural, and chemical changes at the micro-scale. In the current study, it is investigated to which extent these alterations correspond to imaging features detected by high resolution magnetic resonance imaging in the intrahippocampal kainate mouse model of MTLE. Fixed hippocampal and whole-brain sections of mouse brain tissue from nine animals under physiological and chronically epileptic conditions were examined using structural and diffusion-weighted MRI. Microstructural details were investigated based on a direct comparison with immunohistochemical analyses of the same specimen. Within the hippocampal formation, diffusion streamlines could be visualized corresponding to dendrites of CA1 pyramidal cells and granule cells, as well as mossy fibers and Schaffer collaterals. Statistically significant changes in diffusivities, fractional anisotropy, and diffusion orientations could be detected in tissue samples from chronically epileptic animals compared to healthy controls, corresponding to microstructural alterations (degeneration of pyramidal cells, dispersion of the granule cell layer, and sprouting of mossy fibers). The diffusion parameters were significantly correlated with histologically determined cell densities. These findings demonstrate that high-resolution diffusion-weighted MRI can resolve subtle microstructural changes in epileptic hippocampal tissue corresponding to histopathological features in MTLE.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 03, 2020 12:00 AM.

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    Monitoring of Stimulus Evoked Murine Somatosensory Cortex Hemodynamic Activity With Volumetric Multi-Spectral Optoacoustic Tomography

    Sensory stimulation is an attractive paradigm for studying brain activity using various optical-, ultrasound- and MRI-based functional neuroimaging methods. Optoacoustics has been recently suggested as a powerful new tool for scalable mapping of multiple hemodynamic parameters with rich contrast and previously unachievable spatio-temporal resolution. Yet, its utility for studying the processing of peripheral inputs at the whole brain level has so far not been quantified. We employed volumetric multi-spectral optoacoustic tomography (vMSOT) to non-invasively monitor the HbO, HbR, and HbT dynamics across the mouse somatosensory cortex evoked by electrical paw stimuli. We show that elevated contralateral activation is preserved in the HbO map (invisible to MRI) under isoflurane anesthesia. Brain activation is shown to be predominantly confined to the somatosensory cortex, with strongest activation in the hindpaw region of the contralateral sensorimotor cortex. Furthermore, vMSOT detected the presence of an initial dip in the contralateral hindpaw region in the delta HbO channel. Sensorimotor cortical activity was identified over all other regions in HbT and HbO but not in HbR. Pearson’s correlation mapping enabled localizing the response to the sensorimotor cortex further highlighting the ability of vMSOT to bridge over imaging performance deficiencies of other functional neuroimaging modalities.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 03, 2020 12:00 AM.

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    Applications of Resting-State fNIRS in the Developing Brain: A Review From the Connectome Perspective

    Early brain development from infancy through childhood is closely related to the development of cognition and behavior in later life. Human brain connectome is a novel framework for describing topological organization of the developing brain. Resting-state functional near-infrared spectroscopy (fNIRS), with a natural scanning environment, low cost, and high portability, is considered as an emerging imaging technique and has shown valuable potential in exploring brain network architecture and its changes during the development. Here, we review the recent advances involving typical and atypical development of the brain connectome from neonates to children using resting-state fNIRS imaging. This review highlights that the combination of brain connectome and resting-state fNIRS imaging offers a promising framework for understanding human brain development.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 03, 2020 12:00 AM.

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    Stress-Induced Microstructural Alterations Correlate With the Cognitive Performance of Rats: A Longitudinal in vivo Diffusion Tensor Imaging Study

    Background: Stress-induced cellular changes in limbic brain structures contribute to the development of various psychopathologies. In vivo detection of these microstructural changes may help us to develop objective biomarkers for psychiatric disorders. Diffusion tensor imaging (DTI) is an advanced neuroimaging technique that enables the non-invasive examination of white matter integrity and provides insights into the microstructure of pathways connecting brain areas.

    Objective: Our aim was to examine the temporal dynamics of stress-induced structural changes with repeated in vivo DTI scans and correlate them with behavioral alterations.

    Methods: Out of 32 young adult male rats, 16 were exposed to daily immobilization stress for 3 weeks. Four DTI measurements were done: one before the stress exposure (baseline), two scans during the stress (acute and chronic phases), and a last one 2 weeks after the end of the stress protocol (recovery). We used a 4.7T small-animal MRI system and examined 18 gray and white matter structures calculating the following parameters: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). T2-weighted images were used for volumetry. Cognitive performance and anxiety levels of the animals were assessed in the Morris water maze, novel object recognition, open field, and elevated plus maze tests.

    Results: Reduced FA and increased MD and RD values were found in the corpus callosum and external capsule of stressed rats. Stress increased RD in the anterior commissure and reduced MD and RD in the amygdala. We observed time-dependent changes in several DTI parameters as the rats matured, but we found no evidence of stress-induced volumetric alterations in the brains. Stressed rats displayed cognitive impairments and we found numerous correlations between the cognitive performance of the animals and between various DTI metrics of the inferior colliculus, corpus callosum, anterior commissure, and amygdala.

    Conclusions: Our data provide further support to the translational value of DTI studies and suggest that chronic stress exposure results in similar white matter microstructural alterations that have been documented in stress-related psychiatric disorders. These DTI findings imply microstructural abnormalities in the brain, which may underlie the cognitive deficits that are often present in stress-related mental disorders.

    in Frontiers in Neuroscience: Brain Imaging Methods on June 03, 2020 12:00 AM.

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    Editorial: Bridging the Gap in Neuroelectronic Interfaces

    in Frontiers in Neuroscience: Neural Technology on June 03, 2020 12:00 AM.

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    A Nexus Model of Restricted Interests in Autism Spectrum Disorder

    Restricted interests (RIs) in autism spectrum disorder (ASD) are clinically impairing interests of unusual focus or intensity. They are a subtype of restricted and repetitive behaviors which are one of two diagnostic criteria for the disorder. Despite the near ubiquity of RIs in ASD, the neural basis for their development is not well understood. However, recent cognitive neuroscience findings from nonclinical samples and from individuals with ASD shed light on neural mechanisms that may explain the emergence of RIs. We propose the nexus model of RIs in ASD, a novel conceptualization of this symptom domain that suggests that RIs may reflect a co-opting of brain systems that typically serve to integrate complex attention, memory, semantic, and social communication functions during development. The nexus model of RIs hypothesizes that when social communicative development is compromised, brain functions typically located within the lateral surface of cortex may expand into social processing brain systems and alter cortical representations of various cognitive functions during development. These changes, in turn, promote the development of RIs as an alternative process mediated by these brain networks. The nexus model of RIs makes testable predictions about reciprocal relations between the impaired development of social communication and the emergence of RIs in ASD and suggests novel avenues for treatment development.

    in Frontiers in Human Neuroscience on June 03, 2020 12:00 AM.

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    Correlation Between the Wechsler Adult Intelligence Scale- 3rd Edition Metrics and Brain Structure in Healthy Individuals: A Whole-Brain Magnetic Resonance Imaging Study

    Background

    The Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III) is widely used to evaluate the intelligence quotient (IQ). We aimed to investigate the correlation between the WAIS-III metrics and whole-brain structures using magnetic resonance imaging.

    Methods

    The participants were 266 healthy, right-handed individuals (age: 45.6 ± 12.9 years, 98 males and 168 females). IQs were evaluated using the WAIS-III and Japanese Adult Reading Test (JART). Voxel-based morphometry and diffusion tensor imaging were performed to analyze the correlation of the WAIS-III metrics and JART score with the gray matter volume and white matter integrity, respectively.

    Results

    The verbal IQ significantly and positively correlated with the left gyrus rectus and anterior cingulate gyrus, left posterior insula and planum polare, and left superior and middle frontal gyri volumes (p < 0.05, corrected). The verbal comprehension group index significantly and positively correlated with the left superior and middle frontal gyri, left gyrus rectus and anterior cingulate gyrus, and left middle frontal gyrus volumes, while the processing speed group index significantly and positively correlated with the bilateral various regional white matter fractional anisotropy values (p < 0.05, corrected). In contrast, the JART score showed no correlation with any brain structure.

    Conclusion

    These results suggested the neurostructural bases of the WAIS-III IQs and group indices in the brain of healthy individuals.

    in Frontiers in Human Neuroscience on June 03, 2020 12:00 AM.

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    Spatial Perspective-Taking in Children With Autism Spectrum Disorders: The Predictive Role of Visuospatial and Motor Abilities

    Despite its impact on everyday functioning, spatial perspective-taking has rarely been investigated in autism spectrum disorders (ASD), and previous findings are surprisingly sparse and inconsistent. In the present study, we aimed to investigate spatial perspective-taking abilities in children and adolescents with ASD without intellectual disabilities, comparing them with a group of typically developing (TD) peers. Our objectives were: (i) to test similarities and differences between these groups in a spatial perspective-taking task; and (ii) to see whether similar or different underlying processes (i.e., fine and gross motor skills, and visuospatial abilities) might account for the groups’ performance in the spatial perspective-taking task. A group of children with ASD (N = 36) was compared with a TD group (N = 39), aged from 8 to 16 years. Participants were administered tasks assessing spatial perspective-taking, fine and gross motor skills, visuo-constructive abilities, visuospatial working memory, visual imagery, and mental rotation. Our results revealed that the ASD group had more difficulty with the spatial perspective-taking task than the TD group. The two groups also had some shared and some different processes that predicted their perspective-taking performance: a significant predictive effect of fine motor skills and visuospatial working memory emerged for both groups, while gross motor skills (i.e., walking heel-to-toe) and visuospatial imagery only revealed a role in the TD group. These findings suggest that different abilities might account for the two groups’ performance in the spatial perspective-taking task. Gross motor skills and complex visuospatial abilities seem to be more important in sustaining spatial perspective-taking ability in typical development than in the event of ASD. Some of the clinical and educational implications of these findings are discussed.

    in Frontiers in Human Neuroscience on June 03, 2020 12:00 AM.

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    Hemispheric Differences in Functional Interactions Between the Dorsal Lateral Prefrontal Cortex and Ipsilateral Motor Cortex

    Background: The dorsolateral prefrontal cortex (DLPFC) in both hemispheres have a central integrative function for motor control and behavior. Understanding the hemispheric difference between DLPFC and ipsilateral motor cortex connection in the resting-state will provide fundamental knowledge to explain the different roles DLPFC plays in motor behavior.

    Purpose: The current study tested the interactions between the ipsilateral DLPFC and the primary motor cortex (M1) in each hemisphere at rest. We hypothesized that left DLPFC has a greater inhibitory effect on the ipsilateral M1 compared to the right DLPFC.

    Methods: Fourteen right-handed subjects were tested in a dual-coil paired-pulse paradigm using transcranial magnetic stimulation. The conditioning stimulus (CS) was applied to the DLPFC and the test stimulus (TS) was applied to M1. Interstimulus intervals (ISIs) between CS and TS were 2, 4, 6, 8, 10, 15, 20, 25, and 30 ms. The result was expressed as a percentage of the mean peak-to-peak amplitude of the unconditioned test pulse.

    Results: There was stronger inhibitory effect for the left compared to the right hemisphere at ISIs of 2 (p = 0.045), 10 (p = 0.006), 15 (p = 0.029) and 20 (p = 0.024) ms. There was no significant inhibition or facilitation at any ISI in the right hemisphere.

    Conclusions: The two hemispheres have distinct DLPFC and M1 cortico-cortical connectivity at rest. Left hemisphere DLPFC is dominant in inhibiting ipsilateral M1.

    in Frontiers in Human Neuroscience on June 03, 2020 12:00 AM.

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    Joint Attention During Live Person-to-Person Contact Activates rTPJ, Including a Sub-Component Associated With Spontaneous Eye-to-Eye Contact

    Eye-to-eye contact is a spontaneous behavior between interacting partners that occurs naturally during social interactions. However, individuals differ with respect to eye gaze behaviors such as frequency of eye-to-eye contacts, and these variations may reflect underlying differences in social behavior in the population. While the use of eye signaling to indicate a shared object of attention in joint attention tasks has been well-studied, the effects of the natural variation in establishing eye contact during joint attention have not been isolated. Here, we investigate this question using a novel two-person joint attention task. Participants were not instructed regarding the use of eye contacts; thus all mutual eye contact events between interacting partners that occurred during the joint attention task were spontaneous and varied with respect to frequency. We predicted that joint attention systems would be modulated by differences in the social behavior across participant pairs, which could be measured by the frequency of eye contact behavior. We used functional near-infrared spectroscopy (fNIRS) hyperscanning and eye-tracking to measure the neural signals associated with joint attention in interacting dyads and to record the number of eye contact events between them. Participants engaged in a social joint attention task in which real partners used eye gaze to direct each other’s attention to specific targets. Findings were compared to a non-social joint attention task in which an LED cue directed both partners’ attention to the same target. The social joint attention condition showed greater activity in right temporoparietal junction than the non-social condition, replicating prior joint attention results. Eye-contact frequency modulated the joint attention activity, revealing bilateral activity in social and high level visual areas associated with partners who made more eye contact. Additionally, when the number of mutual eye contact events was used to classify each pair as either “high eye contact” or “low eye contact” dyads, cross-brain coherence analysis revealed greater coherence between high eye contact dyads than low eye contact dyads in these same areas. Together, findings suggest that variation in social behavior as measured by eye contact modulates activity in a subunit of the network associated with joint attention.

    in Frontiers in Human Neuroscience on June 03, 2020 12:00 AM.

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    Editorial: The Interface between Psychoanalysis and Neuroscience: the State of the Art

    in Frontiers in Human Neuroscience on June 03, 2020 12:00 AM.

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    Optogenetic Manipulation of Postsynaptic cAMP Using a Novel Transgenic Mouse Line Enables Synaptic Plasticity and Enhances Depolarization Following Tetanic Stimulation in the Hippocampal Dentate Gyrus

    cAMP is a positive regulator tightly involved in certain types of synaptic plasticity and related memory functions. However, its spatiotemporal roles at the synaptic and neural circuit levels remain elusive. Using a combination of a cAMP optogenetics approach and voltage-sensitive dye (VSD) imaging with electrophysiological recording, we define a novel capacity of postsynaptic cAMP in enabling dentate gyrus long-term potentiation (LTP) and depolarization in acutely prepared murine hippocampal slices. To manipulate cAMP levels at medial perforant path to granule neuron (MPP-DG) synapses by light, we generated transgenic (Tg) mice expressing photoactivatable adenylyl cyclase (PAC) in DG granule neurons. Using these Tg(CMV-Camk2a-RFP/bPAC)3Koka mice, we recorded field excitatory postsynaptic potentials (fEPSPs) from MPP-DG synapses and found that photoactivation of PAC during tetanic stimulation enabled synaptic potentiation that persisted for at least 30 min. This form of LTP was induced without the need for GABA receptor blockade that is typically required for inducing DG plasticity. The paired-pulse ratio (PPR) remained unchanged, indicating the cAMP-dependent LTP was likely postsynaptic. By employing fast fluorescent voltage-sensitive dye (VSD: di-4-ANEPPS) and fluorescence imaging, we found that photoactivation of the PAC actuator enhanced the intensity and extent of dentate gyrus depolarization triggered following tetanic stimulation. These results demonstrate that the elevation of cAMP in granule neurons is capable of rapidly enhancing synaptic strength and neuronal depolarization. The powerful actions of cAMP are consistent with this second messenger having a critical role in the regulation of synaptic function.

    in Frontiers in Neural Circuits on June 03, 2020 12:00 AM.

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    Inhibition of NLRP3 Inflammasome: A Prospective Target for the Treatment of Ischemic Stroke

    Stroke is one of the major devastating diseases with no effective medical therapeutics. Because of the high rate of disability and mortality among stroke patients, new treatments are urgently required to decrease brain damage following a stroke. In recent years, the inflammasome is a novel breakthrough point that plays an important role in the stroke, and the inhibition of inflammasome may be an effective method for stroke treatment. Briefly, inflammasome is a multi-protein complex that causes activation of caspase-1 and subsequent production of pro-inflammatory factors including interleukin (IL)-18 and IL-1β. Among them, the NLRP3 inflammasome is the most typical inflammasome, which can detect cell damage and mediate inflammatory response to tissue damage in ischemic stroke. The NLRP3 inflammasome has become a key mediator of post-ischemic inflammation, leading to a cascade of inflammatory reactions and cell death eventually. Thus, NLRP3 inflammasome is an ideal therapeutic target due to its important role in the inflammatory response after ischemic stroke. In this mini review article, we will summarize the structure, assembly, and regulation of NLRP3 inflammasome, the role of NLRP3 inflammasome in ischemic stroke, and several treatments targeting NLRP3 inflammasome in ischemic stroke. The further understanding of the mechanism of NLRP3 inflammasome in patients with ischemic stroke will provide novel targets for the treatment of cerebral ischemic stroke patients.

    in Frontiers in Cellular Neuroscience on June 03, 2020 12:00 AM.

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    Lipopolysaccharide-Induced Systemic Inflammation in the Neonatal Period Increases Microglial Density and Oxidative Stress in the Cerebellum of Adult Rats

    Inflammatory processes occurring in the perinatal period may affect different brain regions, resulting in neurologic sequelae. Injection of lipopolysaccharide (LPS) at different neurodevelopmental stages produces long-term consequences in several brain structures, but there is scarce evidence regarding alterations in the cerebellum. The aim of this study was to evaluate the long-term consequences on the cerebellum of a systemic inflammatory process induced by neonatal LPS injection. For this, neonatal rats were randomly assigned to three different groups: naïve, sham, and LPS. Saline (sham group) or LPS solution (1 mg/kg) was intraperitoneally injected on alternate postnatal days (PN) PN1, PN3, PN5, and PN7. Spontaneous activity was evaluated with the open field test in adulthood. The cerebellum was evaluated for different parameters: microglial and Purkinje cell densities, oxidative stress levels, and tumor necrosis factor alpha (TNF-α) mRNA expression. Our results show that administration of LPS did not result in altered spontaneous activity in adult animals. Our data also indicate increased oxidative stress in the cerebellum, as evidenced by an increase in superoxide fluorescence by dihydroethidium (DHE) indicator. Stereological analyses indicated increased microglial density in the cerebellum that was not accompanied by Purkinje cell loss or altered TNF-α expression in adult animals. Interestingly, Purkinje cells ectopically positioned in the granular and molecular layers of the cerebellum were observed in animals of the LPS group. Our data suggest that neonatal LPS exposure causes persistent cellular and molecular changes to the cerebellum, indicating the susceptibility of this region to systemic inflammatory insults in infancy. Further investigation of the consequences of these changes and the development of strategies to avoid those should be subject of future studies.

    in Frontiers in Cellular Neuroscience on June 03, 2020 12:00 AM.

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    G Protein-Coupled Receptors in the Mammalian Blood-Brain Barrier

    The mammalian neurovascular unit (NVU) is comprised of neurons, glia, and vascular cells. The NVU is the nexus between the cardiovascular and central nervous system (CNS). The central component of the NVU is the blood-brain barrier (BBB) which consists of a monolayer of tightly connected endothelial cells covered by pericytes and further surrounded by astrocytic endfeet. In addition to preventing the diffusion of toxic species into the CNS, the BBB endothelium serves as a dynamic regulatory system facilitating the transport of molecules from the bloodstream to the brain and vis versa. The structural integrity and transport functions of the BBB are maintained, in part, by an orchestra of membrane receptors and transporters including members of the superfamily of G protein-coupled receptors (GPCRs). Here, we provide an overview of GPCRs known to regulate mammalian BBB structure and function and discuss how dysregulation of these pathways plays a role in various neurodegenerative diseases.

    in Frontiers in Cellular Neuroscience on June 03, 2020 12:00 AM.

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    Cellular and Molecular Targets of Waterbuck Repellent Blend Odors in Antennae of Glossina fuscipes fuscipes Newstead, 1910

    Insects that transmit many of the world’s deadliest animal diseases, for instance trypanosomosis, find their suitable hosts and avoid non-preferred hosts mostly through olfactory cues. The waterbuck repellent blend (WRB) comprising geranylacetone, guaiacol, pentanoic acid, and δ-octalactone derived from waterbuck skin odor is a repellent to some savannah-adapted tsetse flies and reduces trap catches of riverine species. However, the cellular and molecular mechanisms associated with detection and coding of the repellent odors remain to be elucidated. Here, we demonstrated that WRB inhibited blood feeding in both Glossina pallidipes Austen, 1903 and Glossina fuscipes fuscipes Newstead, 1910. Using the DREAM (Deorphanization of Receptors based on Expression Alterations in odorant receptor mRNA levels) technique, combined with ortholog comparison and molecular docking, we predicted the putative odorant receptors (ORs) for the WRB in G. f. fuscipes, a non-model insect. We show that exposure of G. f. fuscipes in vivo to WRB odorant resulted in up- and downregulation of mRNA transcript of several ORs. The WRB component with strong feeding inhibition altered mRNA transcript differently as compared to an attractant odor, showing these two odors of opposing valence already segregate at the cellular and molecular levels. Furthermore, molecular dynamics simulations demonstrated that the predicted ligand–OR binding pockets consisted mostly of hydrophobic residues with a few hydrogen bonds but a stable interaction. Finally, our electrophysiological response showed the olfactory sensory neurons of G. f. fuscipes tuned to the tsetse repellent components in different sensitivity and selectivity.

    in Frontiers in Cellular Neuroscience on June 03, 2020 12:00 AM.

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    Multiparity, Brain Atrophy, and Cognitive Decline

    Background

    Multiparity – grand multiparity (i.e., five or more childbirths) in particular – has been reported to have an association with increased risk of Alzheimer’s disease (AD) dementia or related cognitive decline in women. However, the pathological links underlying this relationship are still unknown. This study was conducted to examine the relationships of multiparity with cerebral amyloid-beta (Aβ) deposition, brain atrophy, and white matter hyperintensities (WMHs).

    Methods

    In this study, total of 237 older women with 148 cognitively normal and 89 mild cognitive impairment from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. Participants underwent clinical and neuropsychological assessments in addition to 11C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. The associations of parity with Aβ deposition, hippocampal volume, cortical volume, WMH volume and mini-mental status examination (MMSE) score were examined.

    Results

    Participants with grand multiparity showed significantly reduced adjusted hippocampal volume, spatial pattern of atrophy for recognition of AD volume and spatial pattern of atrophy for recognition of brain aging volume even after controlling for potential confounders. Furthermore, MMSE score was also significantly lower in this group. In contrast, grand multiparity did not show any association with global Aβ retention, Aβ positivity rate, or WMH volume, regardless of covariates.

    Conclusion

    Our findings suggest that grand multiparity contributes to cognitive decline or increased dementia risk in older women by aggravating amyloid-independent hippocampal or cortical atrophy.

    in Frontiers in Ageing Neuroscience on June 03, 2020 12:00 AM.

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    Enriching Hippocampal Memory Function in Older Adults Through Real-World Exploration

    Age-related structural and functional changes in the hippocampus can have a severe impact on hippocampal-dependent memory performance. Here, we tested the hypothesis that a real-world spatial exploration and learning intervention would improve hippocampal-dependent memory performance in healthy older adults. We developed a scavenger hunt task that participants performed over the course of a 4-week behavioral intervention period. Following this intervention, participants’ lure discrimination index (LDI) on the Mnemonic Similarity Task was significantly higher than it was at baseline and greater than that of a No-Contact Control Group, while traditional recognition scores remained relatively unchanged. These results point to the viability of a spatial exploration intervention for improving hippocampal-dependent memory in older adults.

    in Frontiers in Ageing Neuroscience on June 03, 2020 12:00 AM.

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    Prevention of Early Alzheimer’s Disease by Erinacine A-Enriched Hericium erinaceus Mycelia Pilot Double-Blind Placebo-Controlled Study

    Objective

    To investigate the efficacy and safety of three H. erinaceus mycelia (EAHE) capsules (350 mg/capsule; containing 5 mg/g erinacine A active ingredient) per day for the treatment of patients with mild Alzheimer’s Disease (AD).

    Methods

    This study comprised a 3-week no-drug screening period, followed by a 49-week double-blind treatment period with 2-parallel groups in which eligible patients were randomized to either three 5 mg/g EAHE mycelia capsules per day or identical appearing placebo capsules. Cognitive assessments, ophthalmic examinations, biomarker collection, and neuroimaging were followed throughout the study period.

    Results

    After 49 weeks of EAHE intervention, a significant decrease in Cognitive Abilities Screening Instrument score was noted in the placebo group, a significant improvement in Mini-Mental State Examination score was observed in the EAHE group and a significant Instrumental Activities of Daily Living score difference were found between the two groups. In addition, EAHE group achieved a significantly better contrast sensitivity when compared to the placebo group. Moreover, only the placebo group observed significantly lowered biomarkers such as calcium, albumin, apolipoprotein E4, hemoglobin, and brain-derived neurotrophic factor and significantly elevated alpha1-antichymotrypsin and amyloid-beta peptide 1–40 over the study period. Using diffusion tensor imaging, the mean apparent diffusion coefficient (ADC) values from the arcuate fasciculus region in the dominant hemisphere significantly increased in the placebo group while no significant difference was found in the EAHE group in comparison to their baselines. Moreover, ADC values from the parahippocampal cingulum region in the dominant hemisphere significantly decreased in the EAHE group whereas no significant difference was found in the placebo group when compared to their baselines. Lastly, except for four subjects who dropped out of the study due to abdominal discomfort, nausea, and skin rash, no other adverse events were reported.

    Conclusion

    Three 350 mg/g EAHE capsules intervention for 49 weeks demonstrated higher CASI, MMSE, and IADL scores and achieved a better contrast sensitivity in patients with mild AD when compared to the placebo group, suggesting that EAHE is safe, well-tolerated, and may be important in achieving neurocognitive benefits.

    Clinical Trial Registration

    ClinicalTrials.gov, identifier NCT04065061.

    in Frontiers in Ageing Neuroscience on June 03, 2020 12:00 AM.

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    Excessive Production of Transforming Growth Factor β1 Causes Mural Cell Depletion From Cerebral Small Vessels

    It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer’s disease, and other neurodegenerative disorders. Under these pathologic conditions, the degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier (BBB). Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β (TGFβ) signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes a dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid (CSF) and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.

    in Frontiers in Ageing Neuroscience on June 03, 2020 12:00 AM.

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    Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits

    CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8–15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells’ whole transcriptome, can determine cell-type identity.

    in eLife on June 03, 2020 12:00 AM.

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    Synaptotagmin-1 is the Ca2+ sensor for fast striatal dopamine release

    Dopamine powerfully controls neural circuits through neuromodulation. In the vertebrate striatum, dopamine adjusts cellular functions to regulate behaviors across broad time scales, but how the dopamine secretory system is built to support fast and slow neuromodulation is not known. Here, we set out to identify Ca2+-triggering mechanisms for dopamine release. We find that synchronous dopamine secretion is abolished in acute brain slices of conditional knockout mice in which Synaptotagmin-1 is removed from dopamine neurons. This indicates that Synaptotagmin-1 is the Ca2+ sensor for fast dopamine release. Remarkably, dopamine release induced by strong depolarization and asynchronous release during stimulus trains are unaffected by Synaptotagmin-1 knockout. Microdialysis further reveals that these modes and action potential-independent release provide significant amounts of extracellular dopamine in vivo. We propose that the molecular machinery for dopamine secretion has evolved to support fast and slow signaling modes, with fast release requiring the Ca2+ sensor Synaptotagmin-1.

    in eLife on June 03, 2020 12:00 AM.

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    Damage-responsive, maturity-silenced enhancers regulate multiple genes that direct regeneration in Drosophila

    Like tissues of many organisms, Drosophila imaginal discs lose the ability to regenerate as they mature. This loss of regenerative capacity coincides with reduced damage-responsive expression of multiple genes needed for regeneration. We previously showed that two such genes, wg and Wnt6, are regulated by a single damage-responsive enhancer that becomes progressively inactivated via Polycomb-mediated silencing as discs mature (Harris et al., 2016). Here we explore the generality of this mechanism and identify additional damage-responsive, maturity-silenced (DRMS) enhancers, some near genes known to be required for regeneration such as Mmp1, and others near genes that we now show function in regeneration. Using a novel GAL4-independent ablation system we characterize two DRMS-associated genes, apontic (apt), which curtails regeneration and CG9752/asperous (aspr), which promotes it. This mechanism of suppressing regeneration by silencing damage-responsive enhancers at multiple loci can be partially overcome by reducing activity of the chromatin regulator extra sex combs (esc).

    in eLife on June 03, 2020 12:00 AM.

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    A size principle for recruitment of Drosophila leg motor neurons

    To move the body, the brain must precisely coordinate patterns of activity among diverse populations of motor neurons. Here, we use in vivo calcium imaging, electrophysiology, and behavior to understand how genetically-identified motor neurons control flexion of the fruit fly tibia. We find that leg motor neurons exhibit a coordinated gradient of anatomical, physiological, and functional properties. Large, fast motor neurons control high force, ballistic movements while small, slow motor neurons control low force, postural movements. Intermediate neurons fall between these two extremes. This hierarchical organization resembles the size principle, first proposed as a mechanism for establishing recruitment order among vertebrate motor neurons. Recordings in behaving flies confirmed that motor neurons are typically recruited in order from slow to fast. However, we also find that fast, intermediate, and slow motor neurons receive distinct proprioceptive feedback signals, suggesting that the size principle is not the only mechanism that dictates motor neuron recruitment. Overall, this work reveals the functional organization of the fly leg motor system and establishes Drosophila as a tractable system for investigating neural mechanisms of limb motor control.

    in eLife on June 03, 2020 12:00 AM.

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    A conserved RNA degradation complex required for spreading and epigenetic inheritance of heterochromatin

    Heterochromatic domains containing histone H3 lysine 9 methylation (H3K9me) can be epigenetically inherited independently of underlying DNA sequence. To gain insight into the mechanisms that mediate epigenetic inheritance, we used a Schizosaccharomyces pombe inducible heterochromatin formation system to perform a genetic screen for mutations that abolish heterochromatin inheritance without affecting its establishment. We identified mutations in several pathways, including the conserved and essential Rix1-associated complex (henceforth the rixosome), which contains RNA endonuclease and polynucleotide kinase activities with known roles in ribosomal RNA processing. We show that the rixosome is required for spreading and epigenetic inheritance of heterochromatin in fission yeast. Viable rixosome mutations that disrupt its association with Swi6/HP1 fail to localize to heterochromatin, lead to accumulation of heterochromatic RNAs, and block spreading of H3K9me and silencing into actively transcribed regions. These findings reveal a new pathway for degradation of heterochromatic RNAs with essential roles in heterochromatin spreading and inheritance.

    in eLife on June 03, 2020 12:00 AM.

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    Caenorhabditis elegans PIEZO channel coordinates multiple reproductive tissues to govern ovulation

    PIEZO1 and PIEZO2 are newly identified mechano-sensitive ion channels that exhibit a preference for calcium in response to mechanical stimuli. In this study, we discovered the vital roles of pezo-1, the sole PIEZO ortholog in C. elegans, in regulating reproduction. A number of deletion alleles as well as a putative gain-of-function mutant of PEZO-1 caused a severe reduction in brood size. In vivo observations showed that oocytes undergo a variety of transit defects as they enter and exit the spermatheca during ovulation. Post ovulation oocytes were frequently damaged during spermathecal contraction. However, the calcium signaling was not dramatically changed in the pezo-1 mutants during ovulation. Loss of PEZO-1 also revealed an inability of self-sperm to properly navigate back to the spermatheca after being pushed out of the spermatheca during ovulation. These findings suggest that PEZO-1 acts in different reproductive tissues to promote proper ovulation and fertilization in C. elegans.

    in eLife on June 03, 2020 12:00 AM.

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    A Gut Feeling about Dopamine

    In this issue of Neuron, Fernandes et al. (2020) compare intra-gastric sugar and non-caloric sweetener to investigate how post-ingestive effects can be reinforcing, revealing a role for the hepatic vagus nerve in transforming sugar sensing by the gut into behavioral reinforcement via midbrain dopamine neuron responses.

    in Neuron: Current Issue on June 03, 2020 12:00 AM.

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    Control of Channel Clustering by Cleavage

    Enrichment of sodium channels at nodes of Ranvier, a hallmark of myelinated axons, underlies effective saltatory conduction. In this issue of Neuron, Eshed-Eisenbach et al. (2020) demonstrate that proteolysis of gliomedin, which drives initial channel clustering, provides a novel mechanism to ensure fidelity of channel localization to nodes.

    in Neuron: Current Issue on June 03, 2020 12:00 AM.

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    Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders

    Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.

    in Neuron: Current Issue on June 03, 2020 12:00 AM.

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    Salty Taste: From Transduction to Transmitter Release, Hold the Calcium

    Detection of NaCl by the gustatory system is fundamental for salt intake and tissue homeostasis. Yet, signal transduction mechanisms for salty taste have remained obscure. In this issue of Neuron, Nomura et al. (2020) report that the epithelial sodium channel ENaC, which serves as the salty receptor, is co-expressed with the voltage-activated ATP release channel CALHM1/3 in a subset of taste cells and that these cells mediate amiloride-sensitive salty taste.

    in Neuron: Current Issue on June 03, 2020 12:00 AM.

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    Detecting Warm Temperatures Is a Cool Kind of Thing

    In this issue of Neuron, Paricio-Montesinos et al. (2020) unveil the essential cellular elements for warm temperature detection in mice. Surprisingly, the silencing of spontaneously firing, unmyelinated, polymodal sensory afferents harboring cold-activated TRPM8 channels is the key neural mechanism.

    in Neuron: Current Issue on June 03, 2020 12:00 AM.

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    Blowing Hot and Cold in ALS: The Duality of TBK1

    Mutations in TANK-binding kinase 1 (TBK1) are linked to ALS-FTD. In this issue of Neuron, Gerbino et al. (2020) show how missense mutations in the kinase domain of TBK1 differentially affect disease onset and progression in an ALS mouse model.

    in Neuron: Current Issue on June 03, 2020 12:00 AM.

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    Brain dynamics for confidence-weighted learning

    by Florent Meyniel

    Learning in a changing, uncertain environment is a difficult problem. A popular solution is to predict future observations and then use surprising outcomes to update those predictions. However, humans also have a sense of confidence that characterizes the precision of their predictions. Bayesian models use a confidence-weighting principle to regulate learning: for a given surprise, the update is smaller when the confidence about the prediction was higher. Prior behavioral evidence indicates that human learning adheres to this confidence-weighting principle. Here, we explored the human brain dynamics sub-tending the confidence-weighting of learning using magneto-encephalography (MEG). During our volatile probability learning task, subjects’ confidence reports conformed with Bayesian inference. MEG revealed several stimulus-evoked brain responses whose amplitude reflected surprise, and some of them were further shaped by confidence: surprise amplified the stimulus-evoked response whereas confidence dampened it. Confidence about predictions also modulated several aspects of the brain state: pupil-linked arousal and beta-range (15–30 Hz) oscillations. The brain state in turn modulated specific stimulus-evoked surprise responses following the confidence-weighting principle. Our results thus indicate that there exist, in the human brain, signals reflecting surprise that are dampened by confidence in a way that is appropriate for learning according to Bayesian inference. They also suggest a mechanism for confidence-weighted learning: confidence about predictions would modulate intrinsic properties of the brain state to amplify or dampen surprise responses evoked by discrepant observations.

    in PLoS Computational Biology on June 02, 2020 09:00 PM.

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    Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms

    by Andrew K. Smith, Glen E. P. Ropella, Mitchell R. McGill, Preethi Krishnan, Lopamudra Dutta, Ryan C. Kennedy, Hartmut Jaeschke, C. Anthony Hunt

    Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.

    in PLoS Computational Biology on June 02, 2020 09:00 PM.

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    Amygdala and ventral tegmental area differentially interact with hippocampus and cortical medial temporal lobe during rest in humans

    Abstract

    Neuromodulatory regions that detect salience, such as amygdala and ventral tegmental area (VTA), have distinct effects on memory. Yet, questions remain about how these modulatory regions target subregions across the hippocampus and medial temporal lobe (MTL) cortex. Here, we sought to characterize how VTA and amygdala subregions (i.e., basolateral amygdala and central‐medial amygdala) interact with hippocampus head, body, and tail, as well as cortical MTL areas of perirhinal cortex and parahippocampal cortex in a task‐free state. To quantify these interactions, we used high‐resolution resting state fMRI and characterized pair‐wise, partial correlations across regions‐of‐interest. We found that basolateral amygdala showed greater functional coupling with hippocampus head, hippocampus tail, and perirhinal cortex when compared to either VTA or central‐medial amygdala. Furthermore, the VTA showed greater functional coupling with hippocampus tail when compared to central‐medial amygdala. There were no significant differences in functional coupling with hippocampus body and parahippocampal cortex. These results support a framework by which neuromodulatory regions do not indiscriminately influence all MTL subregions equally, but rather bias information processing to discrete MTL targets. These findings provide a more specified model of the intrinsic properties of systems underlying MTL neuromodulation. This emphasizes the need to consider heterogeneity both across and within neuromodulatory systems to better understand affective memory.

    in Hippocampus on June 02, 2020 07:02 PM.

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    Altered hippocampal centrality and dynamic anatomical covariance of intracortical microstructure in first episode psychosis

    Abstract

    Hippocampal circuitry has been posited to be fundamental to positive symptoms in psychosis, but its contributions to other factors important for outcome remains unclear. We hypothesized that longitudinal changes in the hippocampal circuit and concomitant changes of intracortical microstructure are altered in first episode psychosis (FEP) patients and that such changes are associated with negative symptoms and verbal memory. Longitudinal brain scans (2–4 visits over 3–15 months) were acquired for 27 FEP and 29 age‐ and sex‐matched healthy controls. Quantitative T1 maps, sensitive to myelin content, were used to sample the microstructure of the hippocampal subfields and output circuitry (fimbria, alveus, fornix, mammillary bodies), and intracortical regions. Dynamic anatomical covariance in pair‐wise regional trajectories were assessed for each subject, and graph theory was used to calculate a participation coefficient metric that quantifies the similarity/divergence between hippocampal and intracortical microstructure. The mean participation coefficient of the hippocampus was significantly reduced in FEP patients compared with controls, reflecting differences in output hippocampal regions. Importantly, lower participation coefficient of the hippocampal circuit was associated with worse negative symptoms, a relationship that was mediated by changes in verbal memory. This study provides evidence for reduced hippocampal centrality in FEP and concomitant changes in intracortical anatomy. Myelin‐rich output regions of the hippocampus may be an important biological trigger in early psychosis, with cascading effects on broader cortical networks and resultant clinical profiles.

    in Hippocampus on June 02, 2020 07:01 PM.

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    A crabs’ high‐order brain center resolved as a mushroom body‐like structure

    A crabs’ high‐order brain center resolved as a mushroom body‐like structure

    Here, we show that the hemiellipsoid body of the true crab Neohelice granulata shares many of the insect mushroom body characters. In this brain center, which has previously been shown to reflect context‐dependent memory, we identified the presence of microglomeruli‐like complexes, input and output regions, aminergic innervation, adult neurogenesis, and elevated expression of proteins necessary for memory processes. In vivo calcium imaging suggests that, as in insect mushroom bodies, stimuli of different nature can trigger divergent neuronal activity patterns in the output region. The study provides a series of data that is parsimonious with a shared organization of memory centers across crustaceans and insects.


    Abstract

    The hypothesis of a common origin for high‐order memory centers in bilateral animals presents the question of how different brain structures, such as the vertebrate hippocampus and the arthropod mushroom bodies, are both structurally and functionally comparable. Obtaining evidence to support the hypothesis that crustaceans possess structures equivalent to the mushroom bodies that play a role in associative memories has proved challenging. Structural evidence supports that the hemiellipsoid bodies of hermit crabs, crayfish and lobsters, spiny lobsters, and shrimps are homologous to insect mushroom bodies. Although a preliminary description and functional evidence supporting such homology in true crabs (Brachyura) has recently been shown, other authors consider the identification of a possible mushroom body homologue in Brachyura as problematic. Here we present morphological and immunohistochemical data in Neohelice granulata supporting that crabs possess well‐developed hemiellipsoid bodies that are resolved as mushroom bodies‐like structures. Neohelice exhibits a peduncle‐like tract, from which processes project into proximal and distal domains with different neuronal specializations. The proximal domains exhibit spines and en passant ‐like processes and are proposed here as regions mainly receiving inputs. The distal domains exhibit a “trauben”‐like compartmentalized structure with bulky terminal specializations and are proposed here as output regions. In addition, we found microglomeruli‐like complexes, adult neurogenesis, aminergic innervation, and elevated expression of proteins necessary for memory processes. Finally, in vivo calcium imaging suggests that, as in insect mushroom bodies, the output regions exhibit stimulus‐specific activity. Our results support the shared organization of memory centers across crustaceans and insects.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on June 02, 2020 06:34 PM.

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    The zebrafish visual system transmits dimming information via multiple segregated pathways

    The zebrafish visual system transmits dimming information via multiple segregated pathways

    We examined the visual response properties of genetically targeted neurons in retina, optic tectum, and torus longitudinalis of larval zebrafish. Functional characterization of dimming responsive neurons within these visual areas revealed responses with varied photosensitivity profiles, including: 1) low sensitivity neurons that selectively respond to large light decrements, 2) high sensitivity neurons that selectively encode small decrements, and 3) broad sensitivity neurons that respond to a wide range of light decrements. Our data support a model in which parallel OFF channels generated in the retina remain segregated across three stages of visual processing.


    Abstract

    Vertebrate retinas contain circuits specialized to encode light level decrements. This information is transmitted to the brain by dimming‐sensitive OFF retinal ganglion cells (OFF‐RGCs) that respond to light decrements with increased firing. It is known that OFF‐RGCs with distinct photosensitivity profiles form parallel visual channels to the vertebrate brain, yet how these channels are processed by first‐ and higher‐order brain areas has not been well characterized in any species. To address this question in the larval zebrafish visual system we examined the visual response properties of a genetically identified population of tectal neurons with a defined axonal projection to a second order visual area: id2b:gal4‐ positive torus longitudinalis projection neurons (TLPNs). TLPNs responded consistently to whole‐field dimming stimuli and exhibited the strongest responses when dimming was preceded by low light levels. Functional characterization of OFF‐RGC terminals in tectum revealed responses that varied in their photosensitivities: 1) low sensitivity OFF‐RGCs that selectively respond to large light decrements, 2) high sensitivity OFF‐RGCs that selectively encode small decrements, and 3) broad sensitivity OFF‐RGCs that respond to a wide range of light decrements. Diverse photosensitivity profiles were also observed using pan‐neuronal calcium imaging to identify dimming‐responsive neurons in both tectum and torus longitudinalis. Together these data support a model in which parallel OFF channels generated in the retina remain segregated across three stages of visual processing. Segregated OFF channels with different sensitivities may allow specific aspects of dimming‐evoked behaviors to be modulated by ambient light levels.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on June 02, 2020 06:29 PM.

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    The Effect of Optic Nerve Section on Form Deprivation Myopia in the Guinea Pig

    The Effect of Optic Nerve Section on Form Deprivation Myopia in the Guinea Pig


    Abstract

    Myopia is induced when a growing eye wears a diffuser that deprives it of detailed spatial vision (form deprivation, FD). In chickens with optic nerve section (ONS), FD myopia still occurs, suggesting that the signals underlying myopia reside within the eye. As avian eyes differ from mammals, we asked whether local mechanisms also underlie FD myopia in a mammalian model. Young guinea pigs underwent either sham surgery followed by FD (SHAM+FD, n=7); or ONS followed by FD (ONS+FD, n=7); or ONS without FD (ONS, n=9). FD was initiated 3 days after surgery with a diffuser that was worn on the surgically treated eye for 14 days. Animals with ONS+FD developed ‐8.9 D of relative myopia and elongated by 135 μm more than in their untreated eyes after 2 weeks of FD. These changes were significantly greater than those in SHAM+FD animals (‐5.5 D and 40 μm of elongation after 14 days of FD), and reflected exaggerated elongation of the posterior chamber. The myopia reversed when FD was discontinued, despite ONS, but eyes did not recover back to normal (30 days after surgery, ONS+FD eyes still retained ‐3 D of relative myopia when SHAM+FD animals had returned to normal). No long‐term residual myopia was present after ONS alone, ruling out a surgical artefact. Although the gross mechanism signaling myopic ocular growth and its recovery in the young mammalian eye does not require an intact optic nerve, its fine‐tuning is disrupted by ONS.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on June 02, 2020 06:28 PM.

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    Initializing photonic feed-forward neural networks using auxiliary tasks

    Publication date: September 2020

    Source: Neural Networks, Volume 129

    Author(s): Nikolaos Passalis, George Mourgias-Alexandris, Nikos Pleros, Anastasios Tefas

    in Neural Networks on June 02, 2020 06:00 PM.

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    Deep learning for symbols detection and classification in engineering drawings

    Publication date: September 2020

    Source: Neural Networks, Volume 129

    Author(s): Eyad Elyan, Laura Jamieson, Adamu Ali-Gombe

    in Neural Networks on June 02, 2020 06:00 PM.

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    Correction for Namouchi et al., Integrative approach using Yersinia pestis genomes to revisit the historical landscape of plague during the Medieval Period [Correction]

    MICROBIOLOGY Correction for “Integrative approach using Yersinia pestis genomes to revisit the historical landscape of plague during the Medieval Period,” by Amine Namouchi, Meriam Guellil, Oliver Kersten, Stephanie Hänsch, Claudio Ottoni, Boris V. Schmid, Elsa Pacciani, Luisa Quaglia, Marco Vermunt, Egil L. Bauer, Michael Derrick, Anne Ø. Jensen, Sacha Kacki,...

    in PNAS on June 02, 2020 04:01 PM.

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    Correction for Sharma et al., Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a [Correction]

    IMMUNOLOGY Correction for “Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a,” by Amit Sharma, Manish Kumar, Jyotirmoi Aich, Manoj Hariharan, Samir K. Brahmachari, Anurag Agrawal, and Balaram Ghosh, which was first published March 23, 2009; 10.1073/pnas.0808743106 (Proc. Natl. Acad. Sci. U.S.A. 106, 5761–5766). The authors note that Fig. 4C and Fig....

    in PNAS on June 02, 2020 04:01 PM.

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    Correction for Pedercini et al., Harvesting synergy from sustainable development goal interactions [Correction]

    SUSTAINABILITY SCIENCE Correction for “Harvesting synergy from sustainable development goal interactions,” by Matteo Pedercini, Steve Arquitt, David Collste, and Hans Herren, which was first published October 30, 2019; 10.1073/pnas.1817276116 (Proc. Natl. Acad. Sci. U.S.A. 116, 23021–23028). The authors note that the following statement should be added to the Acknowledgments: “D.C....

    in PNAS on June 02, 2020 04:01 PM.

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    Spike-induced ordering: Stochastic neural spikes provide immediate adaptability to the sensorimotor system [Systems Biology]

    Most biological neurons exhibit stochastic and spiking action potentials. However, the benefits of stochastic spikes versus continuous signals other than noise tolerance and energy efficiency remain largely unknown. In this study, we provide an insight into the potential roles of stochastic spikes, which may be beneficial for producing on-site adaptability...

    in PNAS on June 02, 2020 04:01 PM.

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    New spatial analyses of Australian wildfires highlight the need for new fire, resource, and conservation policies [Sustainability Science]

    Extensive and recurrent severe wildfires present complex challenges for policy makers. This is highlighted by extensive wildfires around the globe, ranging from western North America and Europe to the Amazon and Arctic, and, most recently, the 2019–2020 fires in eastern Australia. In many jurisdictions, discussions after significant losses of life,...

    in PNAS on June 02, 2020 04:01 PM.

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    Genomic evidence for convergent evolution of gene clusters for momilactone biosynthesis in land plants [Plant Biology]

    Momilactones are bioactive diterpenoids that contribute to plant defense against pathogens and allelopathic interactions between plants. Both cultivated and wild grass species of Oryza and Echinochloa crus-galli (barnyard grass) produce momilactones using a biosynthetic gene cluster (BGC) in their genomes. The bryophyte Calohypnum plumiforme (formerly Hypnum plumaeforme) also produces momilactones,...

    in PNAS on June 02, 2020 04:01 PM.

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    Transcriptomic network analyses shed light on the regulation of cuticle development in maize leaves [Plant Biology]

    Plant cuticles are composed of wax and cutin and evolved in the land plants as a hydrophobic boundary that reduces water loss from the plant epidermis. The expanding maize adult leaf displays a dynamic, proximodistal gradient of cuticle development, from the leaf base to the tip. Laser microdissection RNA Sequencing...

    in PNAS on June 02, 2020 04:01 PM.

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    Chloroplast Sec14-like 1 (CPSFL1) is essential for normal chloroplast development and affects carotenoid accumulation in Chlamydomonas [Plant Biology]

    Plastid isoprenoid-derived carotenoids serve essential roles in chloroplast development and photosynthesis. Although nearly all enzymes that participate in the biosynthesis of carotenoids in plants have been identified, the complement of auxiliary proteins that regulate synthesis, transport, sequestration, and degradation of these molecules and their isoprenoid precursors have not been fully...

    in PNAS on June 02, 2020 04:01 PM.

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    Evaluation of plant sources for antiinfective lead compound discovery by correlating phylogenetic, spatial, and bioactivity data [Pharmacology]

    Antibiotic resistance and viral diseases are rising around the world and are becoming major threats to global health, food security, and development. One measure that has been suggested to mitigate this crisis is the development of new antibiotics. Here, we provide a comprehensive evaluation of the phylogenetic and biogeographic patterns...

    in PNAS on June 02, 2020 04:01 PM.

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    The {beta}-arrestin-biased {beta}-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility [Pharmacology]

    A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a β2-adrenergic receptor (β2AR) agonist enhances skeletal muscle strength and hypertrophy; however,...

    in PNAS on June 02, 2020 04:01 PM.

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    Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptoȷanin 1 [Neuroscience]

    Numerous genes whose mutations cause, or increase the risk of, Parkinson’s disease (PD) have been identified. An inactivating mutation (R258Q) in the Sac inositol phosphatase domain of synaptojanin 1 (SJ1/PARK20), a phosphoinositide phosphatase implicated in synaptic vesicle recycling, results in PD. The gene encoding Sac2/INPP5F, another Sac domain-containing protein, is...

    in PNAS on June 02, 2020 04:01 PM.

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    Patterns of sociocognitive stratification and perinatal risk in the child brain [Psychological and Cognitive Sciences]

    The expanding behavioral repertoire of the developing brain during childhood and adolescence is shaped by complex brain–environment interactions and flavored by unique life experiences. The transition into young adulthood offers opportunities for adaptation and growth but also increased susceptibility to environmental perturbations, such as the characteristics of social relationships, family...

    in PNAS on June 02, 2020 04:01 PM.

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    Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment [Psychological and Cognitive Sciences]

    Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational...

    in PNAS on June 02, 2020 04:01 PM.

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    Habituation as a neural algorithm for online odor discrimination [Computer Sciences]

    Habituation is a form of simple memory that suppresses neural activity in response to repeated, neutral stimuli. This process is critical in helping organisms guide attention toward the most salient and novel features in the environment. Here, we follow known circuit mechanisms in the fruit fly olfactory system to derive...

    in PNAS on June 02, 2020 04:01 PM.

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    Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection [Microbiology]

    The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during...

    in PNAS on June 02, 2020 04:01 PM.

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    l-Arginine sensing regulates virulence gene expression and disease progression in enteric pathogens [Microbiology]

    Microbiota, host and dietary metabolites/signals compose the rich gut chemical environment, which profoundly impacts virulence of enteric pathogens. Enterohemorrhagic Escherichia coli (EHEC) engages a syringe-like machinery named type-III secretion system (T3SS) to inject effectors within host cells that lead to intestinal colonization and disease. We previously conducted a high-throughput screen...

    in PNAS on June 02, 2020 04:01 PM.

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    Spatial mapping of polymicrobial communities reveals a precise biogeography associated with human dental caries [Microbiology]

    Tooth decay (dental caries) is a widespread human disease caused by microbial biofilms. Streptococcus mutans, a biofilm-former, has been consistently associated with severe childhood caries; however, how this bacterium is spatially organized with other microorganisms in the oral cavity to promote disease remains unknown. Using intact biofilms formed on teeth...

    in PNAS on June 02, 2020 04:01 PM.

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    Tenofovir prodrugs potently inhibit Epstein-Barr virus lytic DNA replication by targeting the viral DNA polymerase [Microbiology]

    Epstein–Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes life-long infection and increases the risk for the development of several cancers and autoimmune diseases. The mechanisms by which chronic EBV infection leads to subsequent disease remain incompletely understood. Lytic reactivation plays a central role in the development of EBV-driven...

    in PNAS on June 02, 2020 04:01 PM.

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    Hepsin enhances liver metabolism and inhibits adipocyte browning in mice [Medical Sciences]

    Hepsin is a transmembrane serine protease primarily expressed in the liver. To date, the physiological function of hepsin remains poorly defined. Here we report that hepsin-deficient mice have low levels of blood glucose and lipids and liver glycogen, but increased adipose tissue browning and basal metabolic rates. The phenotype is...

    in PNAS on June 02, 2020 04:01 PM.

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    Imaging lutein and zeaxanthin in the human retina with confocal resonance Raman microscopy [Medical Sciences]

    Lutein and zeaxanthin are xanthophyll carotenoids that are highly concentrated in the human macula, where they protect the eye from oxidative damage and improve visual performance. Distinguishing lutein from zeaxanthin in images of the human retina in vivo or in donor eye tissues has been challenging because no available technology...

    in PNAS on June 02, 2020 04:01 PM.

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    KLF7 promotes pancreatic cancer growth and metastasis by up-regulating ISG expression and maintaining Golgi complex integrity [Medical Sciences]

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Currently, there is no effective therapy for PDAC, and a detailed molecular and functional evaluation of PDACs is needed to identify and develop better therapeutic strategies. Here we show that the transcription factor Krüppel-like factor 7 (KLF7) is...

    in PNAS on June 02, 2020 04:01 PM.

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    Combined loss of function of two different loci of miR-15/16 drives the pathogenesis of acute myeloid leukemia [Medical Sciences]

    Double knockout of the two miR-15/16 loci in mouse resulted in the development of acute myeloid leukemia (AML). This result suggested that, at least, a fraction of human AMLs could be due to a similar mechanism. We analyzed the role of the two miR-15/16 clusters in 93 myelodysplastic syndrome (MDS)...

    in PNAS on June 02, 2020 04:01 PM.

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    Lumefantrine, an antimalarial drug, reverses radiation and temozolomide resistance in glioblastoma [Medical Sciences]

    Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of...

    in PNAS on June 02, 2020 04:01 PM.

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    Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance [Medical Sciences]

    The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo...

    in PNAS on June 02, 2020 04:01 PM.

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    TRM integrins CD103 and CD49a differentially support adherence and motility after resolution of influenza virus infection [Immunology and Inflammation]

    Tissue-resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon reexposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and...

    in PNAS on June 02, 2020 04:01 PM.

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    Marginal zone SIGN-R1+ macrophages are essential for the maturation of germinal center B cells in the spleen [Immunology and Inflammation]

    The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+ marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find...

    in PNAS on June 02, 2020 04:01 PM.

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    Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer [Immunology and Inflammation]

    PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival...

    in PNAS on June 02, 2020 04:01 PM.

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    CXCL5-mediated recruitment of neutrophils into the peritoneal cavity of Gdf15-deficient mice protects against abdominal sepsis [Immunology and Inflammation]

    Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth and differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand...

    in PNAS on June 02, 2020 04:01 PM.

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    Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-{alpha}-dependent pathways [Immunology and Inflammation]

    In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model,...

    in PNAS on June 02, 2020 04:01 PM.

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    Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation [Immunology and Inflammation]

    Foxp3-expressing regulatory T cells (Tregs) can be generated in vitro by antigenic stimulation of conventional T cells (Tconvs) in the presence of TGF-β and IL-2. However, unlike Foxp3+ naturally occurring Tregs, such in vitro induced Tregs (iTregs) are functionally unstable mainly because of incomplete Treg-type epigenetic changes at Treg signature...

    in PNAS on June 02, 2020 04:01 PM.

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    Pigment epithelium‐derived factor (PEDF) and PEDF‐receptor in the adult mouse brain: Differential spatial/temporal localization pattern

    Pigment epithelium‐derived factor (PEDF) and PEDF‐receptor in the adult mouse brain: Differential spatial/temporal localization pattern

    A schematic drawing is depicted indicating of the detection of PEDF and PEDFR proteins in the mouse brain. Representative brain coronal sections to show the principal regions where PEDF (red dots on the left brain scheme) and PEDFR (blue dots on the right brain scheme) are detected by immunohistochemical study. An equal codistribution is observed for both proteins in the Cerebellum, Hippocampus and periventricular zone. CTX‐Layer VI, Layer VI of cerebral cortex; CTX‐Layer IV–V, Layer IV and V of cerebral cortex; CTX‐Layer I‐III: Layer I, II, and III of Cerebral Cortex; Layer CA1 HYP: layer CA1 of Hippocampus; Layer CA2‐3 HIP: Layer Ca2 and CA3 of hippocampus; SM, medial septum; DBN, Banda diagonal nuclei, and CEREB‐Purk, Purkinje layer of cerebellum.


    Abstract

    Pigment epithelium‐derived factor (PEDF) is a multifunctional protein which was initially described in the retina, although it is also present in other tissues. It functions as an antioxidant agent promoting neuronal survival. Recently, a PEDF receptor has shown an elevated binding affinity for PEDF. There are no relevant data regarding the distribution of both proteins in the brain, therefore the main goal of this work was to investigate the spatiotemporal presence of PEDF and PEDFR in the adult mouse brain, and to determine the PEDF blood level in mouse and human. The localization of both proteins was analyzed by different experimental methods such as immunohistochemistry, western‐blotting, and also by enzyme‐linked immunosorbent assay. Differential expression was found in some telencephalic structures and positive signals for both proteins were detected in the cerebellum. The magnitude of the PEDFR labeling pattern was higher than PEDF and included some cortical and subventricular areas. Age‐dependent changes in intensity of both protein immunoreactions were found in the cortical and hippocampal areas with greater reactivity between 4 and 8 months of age, whilst others, like the subventricular zones, these differences were more evident for PEDFR. Although ubiquitous presence was not found in the brain for these two proteins, their relevant functions must not be underestimated. It has been described that PEDF plays an important role in neuroprotection and data provided in the present work represents the first extensive study to understand the relevance of these two proteins in specific brain areas.

    in Journal of Comparative Neurology on June 02, 2020 04:01 PM.

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    Characterization of a cell bridge variant connecting the nodose and superior cervical ganglia in the mouse: Prevalence, anatomical features, and practical implications

    Characterization of a cell bridge variant connecting the nodose and superior cervical ganglia in the mouse: Prevalence, anatomical features, and practical implications

    This study describes the anatomy of a cell bridge (CB) variant consisting of the fusion of the mouse nodose ganglion (NG) and the superior cervical ganglion (SCG). This anastomosis was tubular shaped and significantly more prevalent in the ganglionic masses from males (38%) than females (21%). It contained a mixed of vagal afferents (blue, tyrosine hydroxylase [TH] positive, Hand2 negative, and isolectin B4 negative; purple, TH negative, Hand2 negative, and isolectin B4 positive; gray, TH negative, Hand2 negative, and isolectin B4 negative) and postganglionic sympathetic neurons (green, TH positive and Hand2 positive). The two populations of neurons abruptly replaced each other in the middle of the cell bridge. The practical implications of our observations are discussed with respect to studies of the mouse vagal afferents, an area of research of increasing popularity.


    Abstract

    While autonomic ganglia have been extensively studied in rats instead of mice, there is renewed interest in the anatomy of the mouse autonomic nervous system. This study examined the prevalence and anatomical features of a cell bridge linking two autonomic ganglia of the neck, namely, the nodose ganglion (NG) and the superior cervical ganglion (SCG) in a cohort of C57BL/6J mice. We identified a cell bridge between the NG and the cranial pole of the SCG. This cell bridge was tubular shaped with an average length and width of 700 and 240 μm, respectively. The cell bridge was frequently unilateral and significantly more prevalent in the ganglionic masses from males (38%) than females (21%). On each of its extremities, it contained a mixed of vagal afferents and postganglionic sympathetic neurons. The two populations of neurons abruptly replaced each other in the middle of the cell bridge. We examined the mRNA expression for selected autonomic markers in samples of the NG with or without cell bridge. Our results indicated that the cell bridge was enriched in both markers of postganglionic sympathetic and vagal afferents neurons. Lastly, using FluoroGold microinjection into the NG, we found that the existence of a cell bridge may occasionally lead to the inadvertent contamination of the SCG. In summary, this study describes the anatomy of a cell bridge variant consisting of the fusion of the mouse NG and SCG. The practical implications of our observations are discussed with respect to studies of the mouse vagal afferents, an area of research of increasing popularity.

    in Journal of Comparative Neurology on June 02, 2020 03:58 PM.

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    Effect of cell geometry in the evaluation of erythrocyte viscoelastic properties

    Author(s): Fran Gómez, Leandro S. Silva, Glauber Ribeiro de Sousa Araújo, Susana Frases, Ana Acacia S. Pinheiro, Ubirajara Agero, Bruno Pontes, and Nathan Bessa Viana

    The red blood cell membrane-cytoskeleton is a complex structure mainly responsible for giving the cell rigidity and shape. It also provides the erythrocyte with the ability to pass through narrow capillaries of the vertebrate blood circulatory system. Although the red blood cell viscoelastic propert...


    [Phys. Rev. E 101, 062403] Published Tue Jun 02, 2020

    in Physical Review E: Biological physics on June 02, 2020 10:00 AM.

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    Reproducibility of animal research in light of biological variation

    Nature Reviews Neuroscience, Published online: 02 June 2020; doi:10.1038/s41583-020-0313-3

    In this Perspective, Hanno Würbel and colleagues argue that a disregard for incorporating biological variation in study design is an important cause of poor reproducibility in animal research. They put the case for the use of systematic heterogenization of study samples and conditions in studies to improve reproducibility.

    in Nature Reviews on June 02, 2020 12:00 AM.

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    Stable isotopes show that earthquakes enhance permeability and release water from mountains

    Nature Communications, Published online: 02 June 2020; doi:10.1038/s41467-020-16604-y

    The authors investigate the groundwater table changes in the Kumamoto region (Japan) following the 2016 Mw 7.0 Kumamoto earthquake. Through detailed isotope analysis the study shows how earthquakes can rupture the crust and generate new pathways for aquifers.

    in Nature Communications on June 02, 2020 12:00 AM.

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    Modeling mitigation of influenza epidemics by baloxavir

    Nature Communications, Published online: 02 June 2020; doi:10.1038/s41467-020-16585-y

    Here, the authors implement a mathematical model that describes how Baloxavir antiviral-induced inhibition of influenza virus replication in infected individuals affects the spread of the virus during epidemics, suggesting that both the scaling up and acceleration of treatment would avert substantial influenza morbidity and mortality every year.

    in Nature Communications on June 02, 2020 12:00 AM.

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    The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture

    Nature Communications, Published online: 02 June 2020; doi:10.1038/s41467-020-16583-0

    Conventional co-culture systems often lack physiological complexity of the tumor microenvironment. Here, the authors report an organotypic skin melanoma culture and use this model to investigate the tumor induced suppression on dendritic cells.

    in Nature Communications on June 02, 2020 12:00 AM.

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    Type I interferon sensing unlocks dormant adipocyte inflammatory potential

    Nature Communications, Published online: 02 June 2020; doi:10.1038/s41467-020-16571-4

    White adipose inflammation can occur in obesity and is at least in part mediated by inflammatory immune cells. Here the authors show that the Type I Interferon/Interferon alpha-beta receptor axis promotes an inflammatory, glycolysis associated adipocyte phenotype.

    in Nature Communications on June 02, 2020 12:00 AM.

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    The impact of climate and antigenic evolution on seasonal influenza virus epidemics in Australia

    Nature Communications, Published online: 02 June 2020; doi:10.1038/s41467-020-16545-6

    Seasonal influenza epidemics vary in timing and size, but the causes of the variation remain unclear. Here, the authors analyse a 15-year city-level data set, and find that fluctuations in climatic factors do not predict onset timing, and that while antigenic change does not have a consistent effect on epidemic size, the timing of onset and heterosubtypic competition do.

    in Nature Communications on June 02, 2020 12:00 AM.

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    AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2

    Nature Communications, Published online: 02 June 2020; doi:10.1038/s41467-020-16533-w

    3′ end of microRNAs binds to the PAZ domain of Argonaute (AGO) proteins. Here the authors show that terminal nucleotidyltransferases TUT4/7 and exonuclease DIS3L2 induce tailing and decay of 3’ end exposed-microRNAs in AGO PAZ mutant expressing- or cancer cells.

    in Nature Communications on June 02, 2020 12:00 AM.

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    Correction: Collective forces of tumor spheroids in three-dimensional biopolymer networks

    in eLife on June 02, 2020 12:00 AM.

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    Dithranol targets keratinocytes, their crosstalk with neutrophils and inhibits the IL-36 inflammatory loop in psoriasis

    Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. IL36RN) but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, SERPINB7 and SERPINB13), antimicrobial peptides (e.g. ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), chemotactic factors for neutrophils (e.g. CXCL5, CXCL8) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs.

    in eLife on June 02, 2020 12:00 AM.

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    Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung at single cell resolution

    At birth, the lungs rapidly transition from a pathogen-free, hypoxic environment to a pathogen-rich, rhythmically distended air-liquid interface. Although many studies have focused on the adult lung, the perinatal lung remains unexplored. Here, we present an atlas of the murine lung immune compartment during early postnatal development. We show that the late embryonic lung is dominated by specialized proliferative macrophages with a surprising physical interaction with the developing vasculature. These macrophages disappear after birth and are replaced by a dynamic mixture of macrophage subtypes, dendritic cells, granulocytes, and lymphocytes. Detailed characterization of macrophage diversity revealed an orchestration of distinct subpopulations across postnatal development to fill context-specific functions in tissue remodeling, angiogenesis, and immunity. These data both broaden the putative roles for immune cells in the developing lung and provide a framework for understanding how external insults alter immune cell phenotype during a period of rapid lung growth and heightened vulnerability.

    in eLife on June 02, 2020 12:00 AM.

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    Hyperalignment: Modeling shared information encoded in idiosyncratic cortical topographies

    Information that is shared across brains is encoded in idiosyncratic fine-scale functional topographies. Hyperalignment captures shared information by projecting pattern vectors for neural responses and connectivities into a common, high-dimensional information space, rather than by aligning topographies in a canonical anatomical space. Individual transformation matrices project information from individual anatomical spaces into the common model information space, preserving the geometry of pairwise dissimilarities between pattern vectors, and model cortical topography as mixtures of overlapping, individual-specific topographic basis functions, rather than as contiguous functional areas. The fundamental property of brain function that is preserved across brains is information content, rather than the functional properties of local features that support that content. In this Perspective, we present the conceptual framework that motivates hyperalignment, its computational underpinnings for joint modeling of a common information space and idiosyncratic cortical topographies, and discuss implications for understanding the structure of cortical functional architecture.

    in eLife on June 02, 2020 12:00 AM.

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    Dynamic metastable long-living droplets formed by sticker-spacer proteins

    Multivalent biopolymers phase separate into membrane-less organelles (MLOs) which exhibit liquid-like behavior. Here, we explore formation of prototypical MOs from multivalent proteins on various time and length scales and show that the kinetically arrested metastable multi-droplet state is a dynamic outcome of the interplay between two competing processes: a diffusion-limited encounter between proteins, and the exhaustion of available valencies within smaller clusters. Clusters with satisfied valencies cannot coalesce readily, resulting in metastable, long-living droplets. In the regime of dense clusters akin to phase-separation, we observe co-existing assemblies, in contrast to the single, large equilibrium-like cluster. A system-spanning network encompassing all multivalent proteins was only observed at high concentrations and large interaction valencies. In the regime favoring large clusters, we observe a slow-down in the dynamics of the condensed phase, potentially resulting in loss of function. Therefore, metastability could be a hallmark of dynamic functional droplets formed by sticker-spacer proteins.

    in eLife on June 02, 2020 12:00 AM.

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    Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

    Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.

    in eLife on June 02, 2020 12:00 AM.

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    Temperature compensation in a small rhythmic circuit

    Temperature affects the conductances and kinetics of the ionic channels that underlie neuronal activity. Each membrane conductance has a different characteristic temperature sensitivity, which raises the question of how neurons and neuronal circuits can operate robustly over wide temperature ranges. To address this, we employed computational models of the pyloric network of crabs and lobsters. We produced multiple different models that exhibit a triphasic pyloric rhythm over a range of temperatures and explored the dynamics of their currents and how they change with temperature. Temperature can produce smooth changes in the relative contributions of the currents to neural activity so that neurons and networks undergo graceful transitions in the mechanisms that give rise to their activity patterns. Moreover, responses of the models to deletions of a current can be different at high and low temperatures, indicating that even a well-defined genetic or pharmacological manipulation may produce qualitatively distinct effects depending on the temperature.

    in eLife on June 02, 2020 12:00 AM.

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    MARCH5 mediates NOXA-dependent MCL1 degradation driven by kinase inhibitors and integrated stress response activation

    MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by kinase inhibitor activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss.

    in eLife on June 02, 2020 12:00 AM.

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    TMEM95 is a sperm membrane protein essential for mammalian fertilization

    The fusion of gamete membranes during fertilization is an essential process for sexual reproduction. Despite its importance, only three proteins are known to be indispensable for sperm-egg membrane fusion: the sperm proteins IZUMO1 and SPACA6, and the egg protein JUNO. Here we demonstrate that another sperm protein, TMEM95, is necessary for sperm-egg interaction. TMEM95 ablation in mice caused complete male-specific infertility. Sperm lacking this protein were morphologically normal exhibited normal motility, and could penetrate the zona pellucida and bind to the oolemma. However, once bound to the oolemma, TMEM95-deficient sperm were unable to fuse with the egg membrane or penetrate into the ooplasm, and fertilization could only be achieved by mechanical injection of one sperm into the ooplasm, thereby bypassing membrane fusion. These data demonstrate that TMEM95 is essential for mammalian fertilization.

    in eLife on June 02, 2020 12:00 AM.

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    Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making

    Involvement of dopamine in regulating exploration during decision-making has long been hypothesized, but direct causal evidence in humans is still lacking. Here, we use a combination of computational modeling, pharmacological intervention and functional magnetic resonance imaging to address this issue. Thirty-one healthy male participants performed a restless four-armed bandit task in a within-subjects design under three drug conditions: 150 mg of the dopamine precursor L-dopa, 2 mg of the D2 receptor antagonist haloperidol, and placebo. Choices were best explained by an extension of an established Bayesian learning model accounting for perseveration, directed exploration and random exploration. Modeling revealed attenuated directed exploration under L-dopa, while neural signatures of exploration, exploitation and prediction error were unaffected. Instead, L-dopa attenuated neural representations of overall uncertainty in insula and dorsal anterior cingulate cortex. Our results highlight the computational role of these regions in exploration and suggest that dopamine modulates how this circuit tracks accumulating uncertainty during decision-making.

    in eLife on June 02, 2020 12:00 AM.

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    Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation

    Vandael et al. report that natural activity patterns induce post-tetanic potentiation (PTP) at hippocampal mossy fiber synapses. PTP is primarily caused by an increase in the readily releasable vesicle pool. PTP is associated with an increase in the docked vesicle pool, revealing a structural correlate of presynaptic plasticity.

    in Neuron: In press on June 02, 2020 12:00 AM.

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    The Number of Transcription Factors at an Enhancer Determines Switch-like Gene Expression

    Super enhancers (SEs) are associated with a higher fold change and a threshold target gene response. Michida et al. show that these quantitative transcription properties are induced by anti-IgM stimulation of B cells through longer DNA and the pre-existence of PU.1 and NF-κB in SEs.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Cas12a Base Editors Induce Efficient and Specific Editing with Low DNA Damage Response

    Wang et al. develop a BEACON base-editing system by combining dCas12a with human APOBEC3A and its engineered versions. BEACON induces efficient editing in cells and mouse embryos with basal levels of DNA damage response, RNA off-target mutations, and unintended side products.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Inferring Active Metabolic Pathways from Proteomics and Essentiality Data

    Montero-Blay et al. identify active metabolic pathways in bacteria by integrating gene essentiality data and quantitative proteomics. Predictions agree with experimental information and show substantial differences in usage and directionality of metabolic pathways in bacteria with high degree of gene similarity.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Inactivation of Rho GTPases by Burkholderia cenocepacia Induces a WASH-Mediated Actin Polymerization that Delays Phagosome Maturation

    Despite causing profound inhibition of host cell Rho GTPases, Burkholderia cenocepacia induces F-actin polymerization near endomembranes, particularly around phagosomes. Walpole et al. show that WASH, an Arp2/3 activator, is required for this de novo F-actin polymerization. The F-actin clusters formed around phagosomes delay their maturation, preventing their fusion with lysosomes.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity

    The transcription factor Eomes is important for early natural killer (NK) cell development. Wagner et al. utilize an inducible, type 1 ILC-specific cre model to demonstrate a stage-specific role for Eomes in NK cell survival and homeostasis as well as a persistent requirement for Eomes in promoting NK cell cytotoxicity.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing

    Enlarged endosomes are an early cytopathology of Alzheimer’s disease (AD). Knupp et al. deplete the AD risk gene SORL1, a sorting receptor, in hiPSCs and report endosome enlargement in differentiated neurons but not microglia. Endosome enlargement is not dependent on amyloidogenic processing of APP but affects its trafficking within neurons.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Functional Divergence of the Arabidopsis Florigen-Interacting bZIP Transcription Factors FD and FDP

    Florigen activating complex facilitates the response to day length in higher plants and contains a specific class of bZIP transcription factor. Romera-Branchat et al. analyze the two factors of this class in Arabidopsis and find they play distinct functions in flowering control and participate in ABA signaling in early development.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts

    Huckins et al. apply transcriptomic imputation to the PGC-PTSD GWAS to reveal tissue-gene associations. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Results—especially the predicted downregulation of SNRNP35 in dorsolateral prefrontal cortex—are validated by findings in humans, cell culture, and mice.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Critical Roles of Translation Initiation and RNA Uridylation in Endogenous Retroviral Expression and Neural Differentiation in Pluripotent Stem Cells

    Takahashi et al. show that NAT1 is crucial for the self-renewal and neural differentiation of primed PSCs. Loss of NAT1 induced significant increase of HERV-H transcripts. NAT1 promotes the translation of TUT7, which controls HERV-H expression. Taken together, the NAT1/TUT7/HERV-H axis plays important roles in neural differentiation of PSCs.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Assembly and Function of a Bioengineered Human Liver for Transplantation Generated Solely from Induced Pluripotent Stem Cells

    Takeishi et al. biofabricate human livers for transplantation using human hepatocytes, biliary epithelial cells, and vascular endothelial cells. All originate from induced pluripotent stem cells, human mesenchymal cells, and fibroblasts. The organ-like microenvironment further matures some liver functions and produces tissue structures similar to those found in human livers.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Anandamide Metabolites Protect against Seizures through the TRP Channel Water Witch in Drosophila melanogaster

    Jacobs and Sehgal demonstrate that the endocannabinoids anandamide and 2-arachidonoylglycerol are anticonvulsant in Drosophila melanogaster and that seizure protection by anandamide is mediated by metabolites acting on the TRP channel Water witch.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    HMCES Maintains Replication Fork Progression and Prevents Double-Strand Breaks in Response to APOBEC Deamination and Abasic Site Formation

    Mehta et al. use APOBEC3A to demonstrate that HMCES responds to ssDNA abasic sites in cells and prevents replication fork collapse. APOBEC3A-induced abasic sites slow both leading and lagging strand polymerization, and HMCES engagement prevents further fork slowing because of the action of TLS polymerases zeta (Polζ) and kappa (Polκ).

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    TMEM163 Regulates ATP-Gated P2X Receptor and Behavior

    Fast purinergic signaling is mediated by ATP-gated P2X receptors. Salm et al. perform functional screening with a genome-wide ORF collection and identify TMEM163, which modulates the channel properties and pharmacology of P2XRs and ATP-evoked behavior. They propose TMEM163 as a critical modulator of fast purinergic signaling.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum

    Alternative splicing contributes to all steps of brain development. Farini et al. show that maturation of the cerebellum involves a dynamic splicing program that mainly affects synaptic genes. Precocious dysregulation of this program by Sam68 ablation alters cerebellar neuronal connectivity and results in defective motor coordination and social behavior.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Regional Variation in Epidermal Susceptibility to UV-Induced Carcinogenesis Reflects Proliferative Activity of Epidermal Progenitors

    Roy et al. aim to understand the field carcinogenesis mechanism in the skin. Using a multicolor fate-tracing and ultraviolet-B irradiation-inducible murine BCC model, they observe that ultraviolet-B results in epidermal proliferation around hair follicles, resulting in susceptibility to skin carcinogenesis.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer

    Becker et al. demonstrate that CAFs present with a pro-glycolytic phenotype, which helps to fuel the metabolism of breast cancer cells and promotes tumor growth. Chronic hypoxia induces the metabolic rewiring of normal fibroblasts toward a CAF-like, pro-glycolytic phenotype. These microenvironmental changes enabled the epigenetic alterations and expression of key glycolytic enzymes in CAFs.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors

    CTTNBP2, an autism-associated cytoskeleton regulator, controls dendritic spine formation and maintenance. Using mouse genetic models, Shih et al. show that Cttnbp2 deficiency impairs the synaptic targeting of a set of zinc-regulated autism-associated genes and results in autism-like behaviors. Zinc supplementation and D-cycloserine ameliorate neuronal and behavioral defects of Cttnbp2 mutant mice.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Radiation Triggers a Dynamic Sequence of Transient Microglial Alterations in Juvenile Brain

    Osman et al. show that microglia undergo transient changes after radiation, displaying a series of temporally distinct molecular signatures with a trajectory toward baseline within one week and suggesting a narrow time window for any therapeutic interventions specifically targeting early microglial activation after irradiation.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells

    Wesely et al. report that AML-iPSC-derived hematopoietic cells are hierarchically organized and contain cells with hallmark features of LSCs (iLSCs). Through integrative genomic studies of bulk and single-cell transcriptomes and chromatin accessibility, they derive a LSC gene signature and identify RUNX1 as an AML LSC dependency with therapeutic implications.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions

    den Brave et al. show that the Hsp40 chaperone Apj1 promotes Hsp70-dependent disaggregation of intra-nuclear protein aggregates. This Hsp104-independent disaggregation activity promotes proteolytic turnover and competes with substrate refolding. Co-ordinated disaggregation with turnover protects against potential toxicity of solubilized proteins.

    in Cell Reports: Current Issue on June 02, 2020 12:00 AM.

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    Realistic modeling of mesoscopic ephaptic coupling in the human brain

    by Giulio Ruffini, Ricardo Salvador, Ehsan Tadayon, Roser Sanchez-Todo, Alvaro Pascual-Leone, Emiliano Santarnecchi

    Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and proposed as a substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to model mesoscopic ephaptic activity in the human brain and explore its trajectory during aging by characterizing the electric field generated by cortical dipoles using realistic finite element modeling. Extrapolating from electrophysiological measurements, we first observe that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant self-generated fields and to those produced by noninvasive transcranial brain stimulation, and therefore possibly able to modulate neuronal activity. Then, to evaluate the role of these fields in the human cortex in large MRI databases, we adapt an interaction approximation that considers the relative orientation of neuron and field to estimate the membrane potential perturbation in pyramidal cells. We use this approximation to define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from healthy subjects aged 16–83. Results reveal that ephaptic coupling, in the simplified mesoscopic modeling approach used here, significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. This study suggests that by providing the means for fast and direct interaction between neurons, ephaptic modulation may contribute to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology.

    in PLoS Computational Biology on June 01, 2020 09:00 PM.

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    Two-step mechanism of J-domain action in driving Hsp70 function

    by Bartlomiej Tomiczek, Wojciech Delewski, Lukasz Nierzwicki, Milena Stolarska, Igor Grochowina, Brenda Schilke, Rafal Dutkiewicz, Marta A. Uzarska, Szymon J. Ciesielski, Jacek Czub, Elizabeth A. Craig, Jaroslaw Marszalek

    J-domain proteins (JDPs), obligatory Hsp70 cochaperones, play critical roles in protein homeostasis. They promote key allosteric transitions that stabilize Hsp70 interaction with substrate polypeptides upon hydrolysis of its bound ATP. Although a recent crystal structure revealed the physical mode of interaction between a J-domain and an Hsp70, the structural and dynamic consequences of J-domain action once bound and how Hsp70s discriminate among its multiple JDP partners remain enigmatic. We combined free energy simulations, biochemical assays and evolutionary analyses to address these issues. Our results indicate that the invariant aspartate of the J-domain perturbs a conserved intramolecular Hsp70 network of contacts that crosses domains. This perturbation leads to destabilization of the domain-domain interface—thereby promoting the allosteric transition that triggers ATP hydrolysis. While this mechanistic step is driven by conserved residues, evolutionarily variable residues are key to initial JDP/Hsp70 recognition—via electrostatic interactions between oppositely charged surfaces. We speculate that these variable residues allow an Hsp70 to discriminate amongst JDP partners, as many of them have coevolved. Together, our data points to a two-step mode of J-domain action, a recognition stage followed by a mechanistic stage.

    in PLoS Computational Biology on June 01, 2020 09:00 PM.

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    Modelling the effects of ephaptic coupling on selectivity and response patterns during artificial stimulation of peripheral nerves

    by Miguel Capllonch-Juan, Francisco Sepulveda

    Artificial electrical stimulation of peripheral nerves for sensory feedback restoration can greatly benefit from computational models for simulation-based neural implant design in order to reduce the trial-and-error approach usually taken, thus potentially significantly reducing research and development costs and time. To this end, we built a computational model of a peripheral nerve trunk in which the interstitial space between the fibers and the tissues was modelled using a resistor network, thus enabling distance-dependent ephaptic coupling between myelinated axons and between fascicles as well. We used the model to simulate a) the stimulation of a nerve trunk model with a cuff electrode, and b) the propagation of action potentials along the axons. Results were used to investigate the effect of ephaptic interactions on recruitment and selectivity stemming from artificial (i.e., neural implant) stimulation and on the relative timing between action potentials during propagation. Ephaptic coupling was found to increase the number of fibers that are activated by artificial stimulation, thus reducing the artificial currents required for axonal recruitment, and it was found to reduce and shift the range of optimal stimulation amplitudes for maximum inter-fascicular selectivity. During propagation, while fibers of similar diameters tended to lock their action potentials and reduce their conduction velocities, as expected from previous knowledge on bundles of identical axons, the presence of many other fibers of different diameters was found to make their interactions weaker and unstable.

    in PLoS Computational Biology on June 01, 2020 09:00 PM.

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    Stochastic dynamics of <i>Francisella tularensis</i> infection and replication

    by Jonathan Carruthers, Grant Lythe, Martín López-García, Joseph Gillard, Thomas R. Laws, Roman Lukaszewski, Carmen Molina-París

    We study the pathogenesis of Francisella tularensis infection with an experimental mouse model, agent-based computation and mathematical analysis. Following inhalational exposure to Francisella tularensis SCHU S4, a small initial number of bacteria enter lung host cells and proliferate inside them, eventually destroying the host cell and releasing numerous copies that infect other cells. Our analysis of disease progression is based on a stochastic model of a population of infectious agents inside one host cell, extending the birth-and-death process by the occurrence of catastrophes: cell rupture events that affect all bacteria in a cell simultaneously. Closed expressions are obtained for the survival function of an infected cell, the number of bacteria released as a function of time after infection, and the total bacterial load. We compare our mathematical analysis with the results of agent-based computation and, making use of approximate Bayesian statistical inference, with experimental measurements carried out after murine aerosol infection with the virulent SCHU S4 strain of the bacterium Francisella tularensis, that infects alveolar macrophages. The posterior distribution of the rate of replication of intracellular bacteria is consistent with the estimate that the time between rounds of bacterial division is less than 6 hours in vivo.

    in PLoS Computational Biology on June 01, 2020 09:00 PM.

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    Linking skeletal muscle aging with osteoporosis by lamin A/C deficiency

    by Lei Xiong, Kai Zhao, Yu Cao, Hao-Han Guo, Jin-Xiu Pan, Xiao Yang, Xiao Ren, Lin Mei, Wen-Cheng Xiong

    The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging–like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C–deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C–deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C–KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-β-gal), p16Ink4a, and p53 in lamin A/C–deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.

    in PLoS Biology on June 01, 2020 09:00 PM.

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    Ten tips for a text-mining-ready article: How to improve automated discoverability and interpretability

    by Robert Leaman, Chih-Hsuan Wei, Alexis Allot, Zhiyong Lu

    Data-driven research in biomedical science requires structured, computable data. Increasingly, these data are created with support from automated text mining. Text-mining tools have rapidly matured: although not perfect, they now frequently provide outstanding results. We describe 10 straightforward writing tips—and a web tool, PubReCheck—guiding authors to help address the most common cases that remain difficult for text-mining tools. We anticipate these guides will help authors’ work be found more readily and used more widely, ultimately increasing the impact of their work and the overall benefit to both authors and readers. PubReCheck is available at http://www.ncbi.nlm.nih.gov/research/pubrecheck.

    in PLoS Biology on June 01, 2020 09:00 PM.

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    Chemogenetic manipulation of the bed nucleus of the stria terminalis counteracts social behavioral deficits induced by early life stress in C57BL/6J mice

    Chemogenetic manipulation of the bed nucleus of the stria terminalis counteracts social behavioral deficits induced by early life stress in C57BL/6J mice

    Early life stress (ELS) induces long‐lasting social behavior deficits. We used chemogenetics to manipulate activity in the bed nucleus of the stria terminalis (BNST), which undergoes maturation during the early postnatal period. Altering BNST activity in adulthood produced divergent effects on social behavior that were dependent upon history of ELS.


    Abstract

    Trauma during critical periods of development can induce long‐lasting adverse effects. To study neural aberrations resulting from early life stress (ELS), many studies utilize rodent maternal separation, whereby pups are intermittently deprived of maternal care necessary for proper development. This can produce adulthood behavioral deficits related to anxiety, reward, and social behavior. The bed nucleus of the stria terminalis (BNST) encodes aspects of anxiety‐like and social behaviors, and also undergoes developmental maturation during the early postnatal period, rendering it vulnerable to effects of ELS. Mice underwent maternal separation (separation 4 hr/day during postnatal day (PD)2–5 and 8 hr/day on PD6‐16) with early weaning on PD17, which induced behavioral deficits in adulthood performance on two‐part social interaction task designed to test social motivation (choice between a same‐sex novel conspecific or an empty cup) and social novelty preference (choice between the original‐novel conspecific vs. a new‐novel conspecific). We used chemogenetics to non‐selectively silence or activate neurons in the BNST to examine its role in social motivation and social novelty preference, in mice with or without the history of ELS. Manipulation of BNST produced differing social behavior effects in non‐stressed versus ELS mice; social motivation was decreased in non‐stressed mice following BNST activation, but unchanged following BNST silencing, while ELS mice showed no change in social behavior after BNST activation, but exhibited enhancement of social motivation—for which they were deficient prior—following BNST silencing. Findings emphasize the BNST as a potential therapeutic target for social anxiety disorders instigated by childhood trauma.

    in Journal of Neuroscience Research on June 01, 2020 07:01 PM.

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    Multimodal cross‐registration and quantification of metric distortions in marmoset whole brain histology using diffeomorphic mappings

    Multimodal cross‐registration and quantification of metric distortions in marmoset whole brain histology using diffeomorphic mappings

    Graphical Abstract

    In this article, we present methods for guided volume reconstruction of serial section animal brain histology with an evaluation of registration accuracy. Using methods derived from diffeomorphometry, we quantify the 3D distortion caused by two steps in the histology tissue processing pipeline: (a) reassembly of tape‐transfer assisted histology sections and (b) tissue perfusion and fixation.


    Abstract

    Whole brain neuroanatomy using tera‐voxel light‐microscopic data sets is of much current interest. A fundamental problem in this field is the mapping of individual brain data sets to a reference space. Previous work has not rigorously quantified in‐vivo to ex‐vivo distortions in brain geometry from tissue processing. Further, existing approaches focus on registering unimodal volumetric data; however, given the increasing interest in the marmoset model for neuroscience research and the importance of addressing individual brain architecture variations, new algorithms are necessary to cross‐register multimodal data sets including MRIs and multiple histological series. Here we present a computational approach for same‐subject multimodal MRI‐guided reconstruction of a series of consecutive histological sections, jointly with diffeomorphic mapping to a reference atlas. We quantify the scale change during different stages of brain histological processing using the Jacobian determinant of the diffeomorphic transformations involved. By mapping the final image stacks to the ex‐vivo post‐fixation MRI, we show that (a) tape‐transfer assisted histological sections can be reassembled accurately into 3D volumes with a local scale change of 2.0 ± 0.4% per axis dimension; in contrast, (b) tissue perfusion/fixation as assessed by mapping the in‐vivo MRIs to the ex‐vivo post fixation MRIs shows a larger median absolute scale change of 6.9 ± 2.1% per axis dimension. This is the first systematic quantification of local metric distortions associated with whole‐brain histological processing, and we expect that the results will generalize to other species. These local scale changes will be important for computing local properties to create reference brain maps.

    in Journal of Comparative Neurology on June 01, 2020 07:00 PM.

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    Perceptual rivalry across animal species

    Perceptual rivalry across animal species

    This review in memoriam of Jack Pettigrew provides an overview of research into the phenomenon of perceptual rivalry, across a wide variety of species including insects, fish, reptiles, and primates. Perceptual rivalry is characterized by spontaneous alternations in perceptual state in response to ambiguous or conflicting sensory input. We highlight several interesting commonalities across species and use a comparative approach to better understand how the brain suppresses opposing sensory signals and generates alternations in perceptual dominance.


    Abstract

    This review in memoriam of Jack Pettigrew provides an overview of past and current research into the phenomenon of multistable perception across multiple animal species. Multistable perception is characterized by two or more perceptual interpretations spontaneously alternating, or rivaling, when animals are exposed to stimuli with inherent sensory ambiguity. There is a wide array of ambiguous stimuli across sensory modalities, ranging from the configural changes observed in simple line drawings, such as the famous Necker cube, to the alternating perception of entire visual scenes that can be instigated by interocular conflict. The latter phenomenon, called binocular rivalry, in particular caught the attention of the late Jack Pettigrew, who combined his interest in the neuronal basis of perception with a unique comparative biological approach that considered ambiguous sensation as a fundamental problem of sensory systems that has shaped the brain throughout evolution. Here, we examine the research findings on visual perceptual alternation and suppression in a wide variety of species including insects, fish, reptiles, and primates. We highlight several interesting commonalities across species and behavioral indicators of perceptual alternation. In addition, we show how the comparative approach provides new avenues for understanding how the brain suppresses opposing sensory signals and generates alternations in perceptual dominance.

    in Journal of Comparative Neurology on June 01, 2020 07:00 PM.

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    Projections between visual cortex and pulvinar in the rat

    Projections between visual cortex and pulvinar in the rat

    Graphical Abstract

    Unlike the geniculocortical pathway which interconnects only between the lateral geniculate nucleus and primary visual cortex (V1), the pulvinar has long been known to interconnect with most if not all of visual cortex. Here we show that pulvinar interconnectivity is actually more dominant with higher visual cortex (V2) than with V1. Thus, the pulvinocortical pathway does not likely play as big a role in directly modulating V1 activity as previously thought.


    Abstract

    The extrageniculate visual pathway, which carries visual information from the retina through the superficial layers of the superior colliculus and the pulvinar, is poorly understood. The pulvinar is thought to modulate information flow between cortical areas, and has been implicated in cognitive tasks like directing visually guided actions. In order to better understand the underlying circuitry, we performed retrograde injections of modified rabies virus in the visual cortex and pulvinar of the Long‐Evans rat. We found a relatively small population of cells projecting to primary visual cortex (V1), compared to a much larger population projecting to higher visual cortex. Reciprocal corticothalamic projections showed a similar result, implying that pulvinar does not play as big a role in directly modulating rodent V1 activity as previously thought.

    in Journal of Comparative Neurology on June 01, 2020 04:04 PM.

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    Altered spontaneous activity and effective connectivity of the anterior cingulate cortex in obsessive–compulsive disorder

    Altered spontaneous activity and effective connectivity of the anterior cingulate cortex in obsessive–compulsive disorder

    In the resting‐state functional magnetic resonance imaging study, we used a Granger causality analysis (GCA) to identify direction of information flow and whether the impact of that flow was excitatory or inhibitory of the anterior cingulate cortex (ACC) in patients with obsessive‐compulsive disorder (OCD). Results showed decreased amplitude of low‐frequency fluctuation in left pregenual ACC (pACC) in patients than controls. There was significantly decreased excitatory output from the left pACC to both right dorsal superior frontal gyrus (dSFG) and left precuneus in patients compared with controls. Patients also had decreased inhibitory input to left pACC from left ventral SFG and left thalamus and caudate relative to controls. In patients, path coefficients of GCA from left pACC to right dSFG showed significant negative correlations with obsession and anxiety ratings. Decreased spontaneous neural activity and altered effective connectivity of pACC with widely distributed cortical circuitry, and associations with clinical ratings highlight the importance of pACC functional alteration in OCD.


    Abstract

    Obsessive–compulsive disorder (OCD) is a disabling neuropsychiatric disorder whose neurobiological basis remains unclear. Magnetic resonance imaging (MRI) studies have reported functional and structural alterations of the anterior cingulate cortex (ACC) in OCD. In this study, we explored the functional activity of subregions of the ACC and effective connectivity (EC) between ACC subregions and the whole brain in OCD. We used a Granger causality analysis (GCA) to identify the direction of information flow and whether the impact of that flow was excitatory or inhibitory. We performed resting‐state functional MRI in 31 patients with OCD and 36 healthy controls and analyzed the amplitude of low‐frequency fluctuation (ALFF) and coefficient‐based GCA. The left pregenual ACC (pACC) in patients with OCD showed decreased ALFF relative to controls. There was significantly decreased excitatory output from the left pACC to both right dorsal superior frontal gyrus (dSFG) and left precuneus in patients compared with controls. Patients also had decreased inhibitory input to left pACC from left ventral SFG and left thalamus and caudate relative to controls. Results were similar in drug‐naive patients and those with prior but not current psychopharmacological treatment. In patients, path coefficients of GCA from left pACC to right dSFG showed significant negative correlations with obsession and anxiety ratings. Decreased spontaneous neural activity and altered EC of pACC with widely distributed cortical circuitry, and associations with clinical ratings highlight the importance of pACC functional alteration in OCD.

    in Journal of Comparative Neurology on June 01, 2020 03:57 PM.

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    Vertebral artery fenestration mimicking acute dissection

    in Annals of Neurology on June 01, 2020 02:59 PM.

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    Optimal trapping stability of Escherichia coli in oscillating optical tweezers

    Author(s): Amarjeet Yadav, Anindita Dutta, Pramod Kumar, Yuval Dahan, Alexander Aranovich, and Mario Feingold

    Single-beam oscillating optical tweezers can be used to trap rod-shaped bacterial cells and align them with their long axis lying within the focal plane. While such configuration is useful for imaging applications, the corresponding imaging resolution is limited by the fluctuations of the trapped ce...


    [Phys. Rev. E 101, 062402] Published Mon Jun 01, 2020

    in Physical Review E: Biological physics on June 01, 2020 10:00 AM.

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    Limitations on electromagnetic communication by vibrational resonances in biological systems

    Author(s): Kyle A. Thackston, Dimitri D. Deheyn, and Daniel F. Sievenpiper

    Previous research in biology and physics speculates that high-frequency electromagnetic fields may be an unexplored method of cellular and subcellular communication. The predominant theory for generating electric fields in the cell is mechanical vibration of charged or polar biomolecules such as cel...


    [Phys. Rev. E 101, 062401] Published Mon Jun 01, 2020

    in Physical Review E: Biological physics on June 01, 2020 10:00 AM.

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    Interactions with PDZ proteins diversify voltage‐gated calcium channel signaling

    Abstract

    Voltage‐gated Ca2+ (CaV) channels are crucial for neuronal excitability and synaptic transmission upon depolarization. Their properties in vivo are modulated by their interaction with a variety of scaffolding proteins. Such interactions can influence the function and localization of CaV channels, as well as their coupling to intracellular second messengers and regulatory pathways, thus amplifying their signaling potential. Among these scaffolding proteins, a subset of PDZ (postsynaptic density‐95, Drosophila discs‐large, and zona occludens)‐domain containing proteins play diverse roles in modulating CaV channel properties. At the presynaptic terminal, PDZ proteins enrich CaV channels in the active zone, enabling neurotransmitter release by maintaining a tight and vital link between channels and vesicles. In the postsynaptic density, these interactions are essential in regulating dendritic spine morphology and postsynaptic signaling cascades. In this review, we highlight the studies that demonstrate dynamic regulations of neuronal CaV channels by PDZ proteins. We discuss the role of PDZ proteins in controlling channel activity, regulating channel cell surface density, and influencing channel‐mediated downstream signaling events. We highlight the importance of PDZ protein regulations of CaV channels and evaluate the link between this regulatory effect and human disease.

    in Journal of Neuroscience Research on June 01, 2020 08:45 AM.

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    Localizing the seizure onset zone by comparing patient postictal hypoperfusion to healthy controls

    Localizing the seizure onset zone by comparing patient postictal hypoperfusion to healthy controls

    We compared post‐ictal hypoperfusion ASL MRI data in epilepsy patients to healthy controls to determine the location of the seizure onset zone (SOZ). This comparison identified the clinically suspected SOZ in 59% of patients. These findings matched our previous subtraction ASL MRI study (Gaxiola‐Valdez et al., 2017).


    Abstract

    Arterial spin labeling (ASL) MRI can provide seizure onset zone (SOZ) localizing information in up to 80% of patients. Clinical implementation of this technique is limited by the need to obtain two scans per patient: a postictal scan that is subtracted from an interictal scan. We aimed to determine whether it is possible to limit the number of ASL scans to one per patient by comparing patient postictal ASL scans to baseline scans of 100 healthy controls. Eighteen patients aged 20–55 years underwent ASL MRI <90 min after a seizure and during the interictal period. Each postictal cerebral blood flow (CBF) map was statistically compared to average baseline CBF maps from 100 healthy controls (pvcASL; patient postictal CBF vs. control baseline CBF). The pvcASL maps were compared to subtraction ASL maps (sASL; patient baseline CBF minus patient postictal CBF). Postictal CBF reductions from pvcASL and sASL maps were seen in 17 of 18 (94.4%) and 14 of 18 (77.8%) patients, respectively. Maximal postictal hypoperfusion seen in pvcASL and sASL maps was concordant with the SOZ in 10 of 17 (59%) and 12 of 14 (86%) patients, respectively. In seven patients, both pvcASL and sASL maps showed similar results. In two patients, sASL showed no significant hypoperfusion, while pvcASL showed significant hypoperfusion concordant with the SOZ. We conclude that pvcASL is clinically useful and although it may have a lower overall concordance rate than sASL, pvcASL does provide localizing or lateralizing information for specific cases that would be otherwise missed through sASL.

    in Journal of Neuroscience Research on June 01, 2020 08:37 AM.

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    A circadian rhythm-gated subcortical pathway for nighttime-light-induced depressive-like behaviors in mice

    Nature Neuroscience, Published online: 01 June 2020; doi:10.1038/s41593-020-0640-8

    An et al. discovered a new brain pathway in mice that conveys light signals from the retina to mood-relevant subcortical nuclei under circadian gating and thereby mediates depressive-like behaviors induced by abnormal nighttime light exposure.

    in Nature Neuroscience on June 01, 2020 12:00 AM.

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    Aggregating transcript-level analyses for single-cell differential gene expression

    Nature Methods, Published online: 01 June 2020; doi:10.1038/s41592-020-0854-4

    Aggregating transcript-level analyses for single-cell differential gene expression

    in Nature Methods on June 01, 2020 12:00 AM.

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    Real-time 3D movement correction for two-photon imaging in behaving animals

    Nature Methods, Published online: 01 June 2020; doi:10.1038/s41592-020-0851-7

    Real-time 3D movement correction by tracking a fluorescent bead in the field of view enables functional imaging with 3D two-photon random-access microscopy in behaving mice and zebrafish.

    in Nature Methods on June 01, 2020 12:00 AM.

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    Macromolecular modeling and design in Rosetta: recent methods and frameworks

    Nature Methods, Published online: 01 June 2020; doi:10.1038/s41592-020-0848-2

    This Perspective reviews tools developed over the past five years in the macromolecular modeling, docking and design software Rosetta.

    in Nature Methods on June 01, 2020 12:00 AM.

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    Targeted Perturb-seq enables genome-scale genetic screens in single cells

    Nature Methods, Published online: 01 June 2020; doi:10.1038/s41592-020-0837-5

    Targeted sequencing of perturbation effects offers a sensitive approach to capture genes of interest in CRISPR-mediated screens, enabling genome-scale screens at higher scale and lower cost than whole-transcriptome Perturb-seq.

    in Nature Methods on June 01, 2020 12:00 AM.

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    Independent superconductors and correlated insulators in twisted bilayer graphene

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0928-3

    Here, it is shown that superconductivity can exist without correlated insulating states in twisted bilayer graphene devices a little away from the magic angle. This indicates the two phases compete with each other, in contrast to previous claims.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Generalized bulk–boundary correspondence in non-Hermitian topolectrical circuits

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0922-9

    Boundary-localized bulk eigenstates given by the non-Hermitian skin effect are observed in a non-reciprocal topological circuit. A fundamental revision of the bulk–boundary correspondence in an open system is required to understand the underlying physics.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Atomic superheterodyne receiver based on microwave-dressed Rydberg spectroscopy

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0918-5

    The Rydberg-atom superhet, based on microwave-dressed Rydberg atoms and a tailored electromagnetically induced transparency spectrum, allows SI-traceable measurements of microwave electric fields with unprecedented sensitivity.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Repulsive photons in a quantum nonlinear medium

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0917-6

    Repulsive photons in a quantum nonlinear medium

    in Nature Physics on June 01, 2020 12:00 AM.

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    Evidence for quark-matter cores in massive neutron stars

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0914-9

    The cores of neutron stars could be made of hadronic matter or quark matter. By combining first-principles calculations with observational data, evidence for the presence of quark matter in neutron star cores is found.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Growth of concomitant laser-driven collisionless and resistive electron filamentation instabilities over large spatiotemporal scales

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0913-x

    In the interaction of ultraintense, short laser pulses with solid targets, the collisionless Weibel instability is observed. For a sufficiently high resistivity of the target, an additional resistive instability appears.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Cosmology at the end of the world

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0909-6

    Braneworld cosmologies describe our universe as a four-dimensional membrane embedded in a bulk five-dimensional anti-de Sitter spacetime. In a possible holographic realization, observers on the brane experience cosmology, and gravity is localized.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Emergence of criticality through a cascade of delocalization transitions in quasiperiodic chains

    Nature Physics, Published online: 01 June 2020; doi:10.1038/s41567-020-0908-7

    The localization properties of waves in the quasiperiodic chains described by the Aubry–André model and Fibonacci model are investigated. Passing from one model to the other, the system develops a cascade of delocalization transitions.

    in Nature Physics on June 01, 2020 12:00 AM.

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    Strong mid-infrared photoresponse in small-twist-angle bilayer graphene

    Nature Photonics, Published online: 01 June 2020; doi:10.1038/s41566-020-0644-7

    Owing to the superlattice-induced bandgap and superlattice-enhanced density of states, small-twist-angled (<2°) bilayer graphene exhibits a strong gate-tunable photoresponse in the mid-infrared regime of 5 to 12 μm, reaching an extrinsic peak responsivity of 26 mA W−1 at 12 μm.

    in Nature Photomics on June 01, 2020 12:00 AM.

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    Unidirectional luminescence from InGaN/GaN quantum-well metasurfaces

    Nature Photonics, Published online: 01 June 2020; doi:10.1038/s41566-020-0641-x

    Exploiting two-dimensional metamaterials, the direction of emission from InGaN/GaN quantum wells is engineered while simultaneously improving quantum efficiency.

    in Nature Photomics on June 01, 2020 12:00 AM.

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    Harmonic optical tomography of nonlinear structures

    Nature Photonics, Published online: 01 June 2020; doi:10.1038/s41566-020-0638-5

    A tomographiac approach to second-harmonic-generation imaging on nonlinear structures is demonstrated, with experiments and three-dimensional reconstructions on a beta-barium borate crystal and various biological specimens performed.

    in Nature Photomics on June 01, 2020 12:00 AM.

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    The Absence of Serotonin in the Brain Alters Acute Stress Responsiveness by Interfering With the Genomic Function of the Glucocorticoid Receptors

    Alterations in serotonergic transmission have been related to a major predisposition to develop psychiatric pathologies, such as depression. We took advantage of tryptophan hydroxylase (TPH) 2 deficient rats, characterized by a complete absence of serotonin in the brain, to evaluate whether a vulnerable genotype may influence the reaction to an acute stressor. In this context, we investigated if the glucocorticoid receptor (GR) genomic pathway activation was altered by the lack of serotonin in the central nervous system. Moreover, we analyzed the transcription pattern of the clock genes that can be affected by acute stressors. Adult wild type (TPH2+/+) and TPH2-deficient (TPH2−/−) male rats were sacrificed after exposure to one single session of acute restraint stress. Protein and gene expression analyses were conducted in the prefrontal cortex (PFC). The acute stress enhanced the translocation of GRs in the nucleus of TPH2+/+ animals. This effect was blunted in TPH2−/− rats, suggesting an impairment of the GR genomic mechanism. This alteration was mirrored in the expression of GR-responsive genes: acute stress led to the up-regulation of GR-target gene expression in TPH2+/+, but not in TPH2−/− animals. Finally, clock genes were differently modulated in the two genotypes after the acute restraint stress. Overall our findings suggest that the absence of serotonin within the brain interferes with the ability of the HPA axis to correctly modulate the response to acute stress, by altering the nuclear mechanisms of the GR and modulation of clock genes expression.

    in Frontiers in Cellular Neuroscience on June 01, 2020 12:00 AM.

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    Increased Connexin36 Phosphorylation in AII Amacrine Cell Coupling of the Mouse Myopic Retina

    Myopia is a substantial public health problem worldwide. In the myopic retina, distant images are focused in front of the photoreceptors. The cells and mechanisms for retinal signaling that account either for emmetropization (i.e., normal refraction) or for refractive errors have remained elusive. Gap junctions play a key component in enhancement of signal transmission in visual pathways. AII amacrine cells (ACs), coupled by connexin36, segregate signals into ON and OFF pathways. Coupling between AII ACs is actively modulated through phosphorylation at serine 293 via dopamine in the mouse retina. In this study, form deprivation mouse myopia models were used to evaluate the expression patterns of connexin36-positive plaques (structural assay) and the state of connexin36 phosphorylation (functional assay) in AII ACs, which was green fluorescent protein-expressing in the Fam81a mouse line. Single-cell RNA sequencing showed dopaminergic synapse and gap junction pathways of AII ACs were downregulated in the myopic retina, although Gjd2 mRNA expression remained the same. Compared with the normal refractive eye, phosphorylation of connexin36 was increased in the myopic retina, but expression of connexin36 remained unchanged. This increased phosphorylation of Cx36 could indicate increased functional gap junction coupling of AII ACs in the myopic retina, a possible adaptation to adjust to the altered noisy signaling status.

    in Frontiers in Cellular Neuroscience on June 01, 2020 12:00 AM.

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    Subscription and Copyright Information

    in Trends in Neurosciences: Current Issue on June 01, 2020 12:00 AM.

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    Advisory Board and Contents

    in Trends in Neurosciences: Current Issue on June 01, 2020 12:00 AM.

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    The Evolution-Driven Signature of Parkinson’s Disease

    In this review, we approach Parkinson’s disease (PD) in the context of an evolutionary mismatch of central nervous system functions. The neurons at risk have hyperbranched axons, extensive transmitter release sites, display spontaneous spiking, and elevated mitochondrial stress. They function in networks largely unchanged throughout vertebrate evolution, but now connecting to the expanded human cortex. Their breakdown is favoured by longevity. At the cellular level, mitochondrial dysfunction starts at the synapses, then involves axons and cell bodies.

    in Trends in Neurosciences: In press on June 01, 2020 12:00 AM.

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    CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes

    Barbar et al. identify CD49f as a novel surface marker expressed by human astrocytes that can purify hiPSC-astrocytes and primary fetal astrocytes. CD49f+ hiPSC-astrocytes respond to pro-inflammatory stimuli and become A1 reactive astrocytes, which are dysfunctional and secrete neurotoxic factors that induce apoptosis in human and rodent neurons.

    in Neuron: In press on June 01, 2020 12:00 AM.

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    Anodal transcranial direct current stimulation reduces motor slowing in athletes and non-athletes

    Motor fatigability describes a phenomenon that occurs when exhaustive exercise or physically demanding tasks are executed over an extended period of time. Concerning fast repetitive movements, it is noticeable...

    in BMC Neuroscience on June 01, 2020 12:00 AM.

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    The role of pituitary adenylyl cyclase activating polypeptide in affective signs of nicotine withdrawal

    The role of pituitary adenylyl cyclase activating polypeptide in affective signs of nicotine withdrawal

    Mice were tested for baseline place preference on day 1 (D1), conditioned on days 2–7 (D2‐7) with saline in both conditioning chambers (Saline Group) or saline in one and nicotine in the other (Nicotine Group) once daily for 6 days and tested 24 hr later on day 8 (D8). Mice received additional conditioning and tested again for place preference on day 13 (D13). Four days later, mice were challenged with mecamylamine and 30 min later tested for anxiety‐like behaviors in the elevated plus maze. Two hours later, mice were exposed to forced swim test for 15 min and tested for immobility time the next day. Our results showed that male mice lacking PACAP showed reduced anxiety‐like and depression‐like behaviors following withdrawal.


    Abstract

    Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine‐induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex‐related differences in these responses. Male and female mice lacking PACAP and their wild‐type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine‐induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety‐like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression‐like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild‐type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety‐ and depression‐like behaviors compared to their wild‐type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex‐related difference in this response.

    in Journal of Neuroscience Research on May 31, 2020 06:20 PM.

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    Mining the jewels of the cortex’s crowning mystery

    Publication date: August 2020

    Source: Current Opinion in Neurobiology, Volume 63

    Author(s): Leena A Ibrahim, Ben Schuman, Rachel Bandler, Bernardo Rudy, Gord Fishell

    in Current Opinion in Neurobiology on May 31, 2020 06:00 PM.

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    Author Correction: Kethoxal-assisted single-stranded DNA sequencing captures global transcription dynamics and enhancer activity in situ

    Nature Methods, Published online: 31 May 2020; doi:10.1038/s41592-020-0881-1

    Author Correction: Kethoxal-assisted single-stranded DNA sequencing captures global transcription dynamics and enhancer activity in situ

    in Nature Methods on May 31, 2020 12:00 AM.

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    No cognitive processing in the unconscious, Anesthetic‐Like, state of sleep

    No cognitive processing in the unconscious, Anesthetic‐Like, state of sleep

    Locations of waking/arousal‐related cell groups of the brainstem and caudal diencephalon at which general anesthetics exert anesthetic actions. They include the pontomesencephalic reticular formation (PRF), locus coeruleus (LC), parabrachial nucleus (PB), tuberomammillary nucleus (TMN) and orexin‐containing cells of the lateral hypothalamus. General anesthetics have been shown to suppress the activity of each of these structures to induce anesthesia whereas their activation (e.g., by electrical stimulation) hastens the recovery from anesthesia.


    Abstract

    We review evidence challenging the hypothesis that memories are processed or consolidated in sleep. We argue that the brain is in an unconscious state in sleep, akin to general anesthesia, and hence is incapable of meaningful cognitive processing – the sole purview of waking consciousness. At minimum, the encoding of memories in sleep would require that waking events are faithfully transferred to and reproduced in sleep. Remarkably, however, this has never been demonstrated, as waking experiences are never truly replicated in sleep but rather appear in very altered or distorted forms. General anesthetics (GAs) exert their effects through endogenous sleep‐wake control systems and accordingly GAs and sleep share several common features: sensory blockade, immobility, amnesia and lack of awareness (unconsciousness). The loss of consciousness in non‐REM (NREM) sleep or to GAs is characterized by: (1) delta oscillations throughout the cortex; (2) marked reductions in neural activity (from waking) over widespread regions of the cortex, most pronounced in frontal and parietal cortices; and (3) a significant disruption of the functional connectivity of thalamocortical and corticocortical networks, particularly those involved in “higher order” cognitive functions. Several (experimental) reports in animals and humans have shown that disrupting the activity of the cortex, particularly the orbitofrontal cortex, severely impairs higher order cognitive and executive functions. The profound and widespread deactivation of the cortex in the unconscious states of NREM sleep or GA would be expected to produce an equivalent, or undoubtedly a much greater, disruptive effect on mnemonic and cognitive functions. In conclusion, we contend that the unconscious, severely altered state of the brain in NREM sleep would negate any possibility of cognitive processing in NREM sleep.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on May 30, 2020 07:30 PM.

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    Comparison of core features in four Developmental Encephalopathies in the Rett Natural History Study

    Objective

    Rett Syndrome, CDKL5 ‐Deficiency Disorder, FOXG1 Disorder, and MECP2 Duplication Disorder are Developmental Encephalopathies with shared and distinct features. Though historically linked, no direct comparison has been performed. The first head‐to‐head comparison of clinical features in these conditions is presented.

    Methods

    Comprehensive clinical information was collected from 793 individuals enrolled in the Rett Syndrome and Related Disorders Natural History Study. Clinical features including clinical severity, regression, and seizures were cross‐sectionally compared between diagnoses to test the hypothesis that these are 4 distinct disorders.

    Results

    Distinct patterns of clinical severity, seizure onset age, and regression were present. Individuals with CDKL5 ‐Deficency Disorder were the most severely affected and had the youngest age of seizure onset (2 months) whereas children with MECP2 ‐duplication syndrome had the oldest median age of seizure onset (64 months) and lowest severity scores. Rett syndrome and FOGX1 were intermediate in both features. Smaller head circumference correlates with increased severity in all disorders and earlier age of seizure onset in MECP2‐duplication syndrome. Developmental regression occurred in all Rett syndrome participants (median 18 months) but only 23–34% of the other disorders. Seizure incidence prior to the baseline visit was highest for CDKL5 ‐Deficency Disorder (96.2%) and lowest for Rett syndrome (47.5%). Other clinical features including seizure types and frequency differed amongst groups.

    Interpretation

    While these Developmental Encephalopathies share many clinical features, clear differences in severity, regression, and seizures warrant considering them as unique disorders. These results will aid in the development of disease specific severity scales, precise therapeutics, and future clinical trials.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on May 30, 2020 01:58 PM.

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    Characterization of recessive Parkinson's disease in a large multicenter study

    Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene‐targeting approaches for Parkinson's disease have reached the clinical trial stage. We evaluated the frequencies of PRKN , PINK1 , and DJ‐1 mutations in a cohort of 1587 cases. Mutations were found in 14.1% of patients: 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians whereas PINK1 mutations predominated in Arab‐Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa‐induced motor complications, dysautonomia, and dementia than those without mutations.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on May 30, 2020 01:43 PM.

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    Structural and biochemical characterization of nsp12-nsp7-nsp8 core polymerase complex from SARS-CoV-2

    Viral polymerase plays a central role in the virus life cycle and is an important antiviral drug target. Peng et al. report the cryo-EM structure of the SARS-CoV-2 core polymerase complex, finding it has less efficient activity for RNA synthesis and lower thermostability of individual subunits as compared to SARS-CoV.

    in Cell Reports: In press on May 30, 2020 12:00 AM.

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    Phenotypic delay in the evolution of bacterial antibiotic resistance: Mechanistic models and their implications

    by Martín Carballo-Pacheco, Michael D. Nicholson, Elin E. Lilja, Rosalind J. Allen, Bartlomiej Waclaw

    Phenotypic delay—the time delay between genetic mutation and expression of the corresponding phenotype—is generally neglected in evolutionary models, yet recent work suggests that it may be more common than previously assumed. Here, we use computer simulations and theory to investigate the significance of phenotypic delay for the evolution of bacterial resistance to antibiotics. We consider three mechanisms which could potentially cause phenotypic delay: effective polyploidy, dilution of antibiotic-sensitive molecules and accumulation of resistance-enhancing molecules. We find that the accumulation of resistant molecules is relevant only within a narrow parameter range, but both the dilution of sensitive molecules and effective polyploidy can cause phenotypic delay over a wide range of parameters. We further investigate whether these mechanisms could affect population survival under drug treatment and thereby explain observed discrepancies in mutation rates estimated by Luria-Delbrück fluctuation tests. While the effective polyploidy mechanism does not affect population survival, the dilution of sensitive molecules leads both to decreased probability of survival under drug treatment and underestimation of mutation rates in fluctuation tests. The dilution mechanism also changes the shape of the Luria-Delbrück distribution of mutant numbers, and we show that this modified distribution provides an improved fit to previously published experimental data.

    in PLoS Computational Biology on May 29, 2020 09:00 PM.

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    Compositional Lotka-Volterra describes microbial dynamics in the simplex

    by Tyler A. Joseph, Liat Shenhav, Joao B. Xavier, Eran Halperin, Itsik Pe’er

    Dynamic changes in microbial communities play an important role in human health and disease. Specifically, deciphering how microbial species in a community interact with each other and their environment can elucidate mechanisms of disease, a problem typically investigated using tools from community ecology. Yet, such methods require measurements of absolute densities, whereas typical datasets only provide estimates of relative abundances. Here, we systematically investigate models of microbial dynamics in the simplex of relative abundances. We derive a new nonlinear dynamical system for microbial dynamics, termed “compositional” Lotka-Volterra (cLV), unifying approaches using generalized Lotka-Volterra (gLV) equations from community ecology and compositional data analysis. On three real datasets, we demonstrate that cLV recapitulates interactions between relative abundances implied by gLV. Moreover, we show that cLV is as accurate as gLV in forecasting microbial trajectories in terms of relative abundances. We further compare cLV to two other models of relative abundance dynamics motivated by common assumptions in the literature—a linear model in a log-ratio transformed space, and a linear model in the space of relative abundances—and provide evidence that cLV more accurately describes community trajectories over time. Finally, we investigate when information about direct effects can be recovered from relative data that naively provide information about only indirect effects. Our results suggest that strong effects may be recoverable from relative data, but more subtle effects are challenging to identify.

    in PLoS Computational Biology on May 29, 2020 09:00 PM.

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    Ranbow: A fast and accurate method for polyploid haplotype reconstruction

    by M-Hossein Moeinzadeh, Jun Yang, Evgeny Muzychenko, Giuseppe Gallone, David Heller, Knut Reinert, Stefan Haas, Martin Vingron

    Reconstructing haplotypes from sequencing data is one of the major challenges in genetics. Haplotypes play a crucial role in many analyses, including genome-wide association studies and population genetics. Haplotype reconstruction becomes more difficult for higher numbers of homologous chromosomes, as it is often the case for polyploid plants. This complexity is compounded further by higher heterozygosity, which denotes the frequent presence of variants between haplotypes. We have designed Ranbow, a new tool for haplotype reconstruction of polyploid genome from short read sequencing data. Ranbow integrates all types of small variants in bi- and multi-allelic sites to reconstruct haplotypes. To evaluate Ranbow and currently available competing methods on real data, we have created and released a real gold standard dataset from sweet potato sequencing data. Our evaluations on real and simulated data clearly show Ranbow’s superior performance in terms of accuracy, haplotype length, memory usage, and running time. Specifically, Ranbow is one order of magnitude faster than the next best method. The efficiency and accuracy of Ranbow makes whole genome haplotype reconstruction of complex genome with higher ploidy feasible.

    in PLoS Computational Biology on May 29, 2020 09:00 PM.

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    Early warning signals in motion inference

    by Yuval Hart, Maryam Vaziri-Pashkam, L. Mahadevan

    The ability to infer intention lies at the basis of many social interactions played out via motor actions. We consider a simple paradigm of this ability in humans using data from experiments simulating an antagonistic game between an Attacker and a Blocker. Evidence shows early inference of an Attacker move by as much as 100ms but the nature of the informational cues signaling the impending move remains unknown. We show that the transition to action has the hallmark of a critical transition that is accompanied by early warning signals. These early warning signals occur as much as 130 ms before motion ensues—showing a sharp rise in motion autocorrelation at lag-1 and a sharp rise in the autocorrelation decay time. The early warning signals further correlate strongly with Blocker response times. We analyze the variance of the motion near the point of transition and find that it diverges in a manner consistent with the dynamics of a fold-transition. To test if humans can recognize and act upon these early warning signals, we simulate the dynamics of fold-transition events and ask people to recognize the onset of directional motion: participants react faster to fold-transition dynamics than to its uncorrelated counterpart. Together, our findings suggest that people can recognize the intent and onset of motion by inferring its early warning signals.

    in PLoS Computational Biology on May 29, 2020 09:00 PM.

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    Sex‐linked roles of the CRF1 and the CRF2 receptor in social behavior

    Sex‐linked roles of the CRF1 and the CRF2 receptor in social behavior

    Corticotropin‐releasing factor (CRF) signaling is mediated by two receptor types, CRF1 and CRF2. Herein, we demonstrate that genetic CRF2 receptor deficiency (CRF2−/−) reduces sociability in female mice but increases it in male mice. Moreover, the CRF1 receptor‐preferring antagonist antalarmin reverses sociability in both female and male wild‐type (CRF2+/+) and CRF2−/− mice.


    Abstract

    Dysfunctional social behavior is a major clinical feature of mood, anxiety, autism spectrum, and substance‐related disorders, and may dramatically contribute to the poor outcome of these diseases. Nevertheless, the mechanisms underlying social behavior deficits are still largely unknown. The corticotropin‐releasing factor (CRF) system, a major coordinator of the stress response, has been hypothesized to modulate social behavior. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2. Using the three‐chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object), this study demonstrates that CRF2 receptor null mutation (CRF2−/−) reduces sociability in female mice but increases it in male mice. Both female and male CRF2−/− mice display a preference for social odor cues over neutral cues, indicating that sex‐ and CRF2 receptor‐dependent sociability is not due to altered olfaction or impaired social cues discrimination. Moreover, treatment with the CRF1 receptor‐preferring antagonist, antalarmin, consistently induces sociability in non‐social mice but disrupts it in social mice, independently of CRF2 receptor deficiency. Sex, CRF2 receptor deficiency, or antalarmin affect locomotor activity during the three‐chamber test. However, throughout the study CRF1 and CRF2 receptor‐linked sociability is independent of locomotor activity. The present findings highlight major functions for the CRF system in the regulation of social behavior. Moreover, they provide initial evidence of sex‐linked roles for the CRF1 and the CRF2 receptor, emphasizing the importance of sex as a major biological variable to be taken into consideration in preclinical and clinical studies.

    in Journal of Neuroscience Research on May 29, 2020 07:55 PM.

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    Categorical face perception in fish: How a fish brain warps reality to dissociate “same” from “different”

    Categorical face perception in fish: How a fish brain warps reality to dissociate “same” from “different”

    Many animals, just like humans, are able to categorize objects based on physical appearance. In humans, training improves performance in such tasks by distorting perceived similarity at the category boundary, a nonlinear effect termed categorical perception (CP). Here we sought evidence for a comparable effect in a lower vertebrate. Based on stimuli generated using a novel image morphing technique, we describe a series of visual discrimination experiments demonstrating CP of facial patterns in a reef fish, providing insight into the evolutionary origins and neural bases of this ability.


    Abstract

    Categorical perception (CP) is the phenomenon by which a smoothly varying stimulus property undergoes a nonlinear transformation during processing in the brain. Consequently, the stimuli are perceived as belonging to distinct categories separated by a sharp boundary. Originally thought to be largely innate, the discovery of CP in tasks such as novel image discrimination has piqued the interest of cognitive scientists because it provides compelling evidence that learning can shape a category's perceptual boundaries. CP has been particularly closely studied in human face perception. In nonprimates, there is evidence for CP for sound and color discrimination, but not for image or face discrimination. Here, we investigate the potential for learned CP in a lower vertebrate, the damselfish Pomacentrus amboinensis. Specifically, we tested whether the ability of these fish to discriminate complex facial patterns tracked categorical rather than metric differences in the stimuli. We first trained the fish to discriminate sets of two facial patterns. Next, we morphed between these patterns and determined the just noticeable difference (JND) between a morph and original image. Finally, we tested for CP by analyzing the discrimination ability of the fish for pairs of JND stimuli along the spectrum of morphs between two original images. Discrimination performance was significant for the image pair straddling the boundary between categories, and chance for equivalent stimulus pairs on either side, thus producing the classic “category boundary” effect. Our results reveal how perception can be influenced in a top‐down manner even in the absence of a visual cortex.

    in Journal of Comparative Neurology on May 29, 2020 07:00 PM.

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    Group visualization of class-discriminative features

    Publication date: September 2020

    Source: Neural Networks, Volume 129

    Author(s): Rui Shi, Tianxing Li, Yasushi Yamaguchi

    in Neural Networks on May 29, 2020 06:00 PM.

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    Interpretable and lightweight convolutional neural network for EEG decoding: Application to movement execution and imagination

    Publication date: September 2020

    Source: Neural Networks, Volume 129

    Author(s): Davide Borra, Silvia Fantozzi, Elisa Magosso

    in Neural Networks on May 29, 2020 06:00 PM.

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    Network dynamics underlie learning and performance of birdsong

    Publication date: October 2020

    Source: Current Opinion in Neurobiology, Volume 64

    Author(s): Richard Bertram, Richard L Hyson, Amanda J Brunick, Diana Flores, Frank Johnson

    in Current Opinion in Neurobiology on May 29, 2020 06:00 PM.

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    A Model for Structured Information Representation in Neural Networks of the Brain

    Abstract

    Humans can reason at an abstract level and structure information into abstract categories, but the underlying neural processes have remained unknown. Recent experimental data provide the hint that this is likely to involve specific subareas of the brain from which structural information can be decoded. Based on this data, we introduce the concept of assembly projections, a general principle for attaching structural information to content in generic networks of spiking neurons. According to the assembly projections principle, structure-encoding assemblies emerge and are dynamically attached to content representations through Hebbian plasticity mechanisms. This model provides the basis for explaining a number of experimental data and provides a basis for modeling abstract computational operations of the brain.

    in eNeuro on May 29, 2020 04:30 PM.

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    A Single Intraventricular Injection of VEGF Leads to Long-Term Neurotrophic Effects in Axotomized Motoneurons

    Abstract

    Vascular endothelial growth factor (VEGF) has been recently demonstrated to induce neuroprotective and synaptotrophic effects on lesioned neurons. Hitherto, the administration of VEGF in different animal models of lesion or disease has been conducted following a chronic protocol of administration. We questioned whether a single dose of VEGF, administered intraventricularly, could induce long-term neurotrophic effects on injured motoneurons. For this purpose, we performed in cats the axotomy of abducens motoneurons and the injection of VEGF into the fourth ventricle in the same surgical session and investigated the discharge characteristics of axotomized and treated motoneurons by single-unit extracellular recordings in the chronic alert preparation. We found that injured motoneurons treated with a single VEGF application discharged with normal characteristics, showing neuronal eye position (EP) and velocity sensitivities similar to control, thereby preventing the axotomy-induced alterations. These effects were present for a prolonged period of time (50 d) after VEGF administration. By confocal immunofluorescence we also showed that the synaptic stripping that ensues lesion was not present, rather motoneurons showed a normal synaptic coverage. Moreover, we demonstrated that VEGF did not lead to any angiogenic response pointing to a direct action of the factor on neurons. In summary, a single dose of VEFG administered just after motoneuron axotomy is able to prevent for a long time the axotomy-induced firing and synaptic alterations without any associated vascular sprouting. We consider that these data are of great relevance due to the potentiality of VEGF as a therapeutic agent in neuronal lesions and diseases.

    in eNeuro on May 29, 2020 04:30 PM.

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    Targeting Morphine-Responsive Neurons: Generation of a Knock-In Mouse Line Expressing Cre Recombinase from the Mu-Opioid Receptor Gene Locus

    Abstract

    The mu-opioid receptor (MOR) modulates nociceptive pathways and reward processing, and mediates the strong analgesic and addictive properties of both medicinal as well as abused opioid drugs. MOR function has been extensively studied, and tools to manipulate or visualize the receptor protein are available. However, circuit mechanisms underlying MOR-mediated effects are less known, because genetic access to MOR-expressing neurons is lacking. Here we report the generation of a knock-in Oprm1-Cre mouse line, which allows targeting and manipulating MOR opioid-responsive neurons. A cDNA encoding a T2A cleavable peptide and Cre recombinase fused to enhanced green fluorescent protein (EGFP/Cre) was inserted downstream of the Oprm1 gene sequence. The resulting Oprm1-Cre line shows intact Oprm1 gene transcription. MOR and EGFP/Cre proteins are coexpressed in the same neurons, and localized in cytoplasmic and nuclear compartments, respectively. MOR signaling is unaltered, demonstrated by maintained DAMGO-induced G-protein activation, and in vivo MOR function is preserved as indicated by normal morphine-induced analgesia, hyperlocomotion, and sensitization. The Cre recombinase efficiently drives the expression of Cre-dependent reporter genes, shown by local virally mediated expression in the medial habenula and brain-wide fluorescence on breeding with tdTomato reporter mice, the latter showing a distribution patterns typical of MOR expression. Finally, we demonstrate that optogenetic activation of MOR neurons in the ventral tegmental area of Oprm1-Cre mice evokes strong avoidance behavior, as anticipated from the literature. The Oprm1-Cre line is therefore an excellent tool for both mapping and functional studies of MOR-positive neurons, and will be of broad interest for opioid, pain, and addiction research.

    in eNeuro on May 29, 2020 04:30 PM.

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    Human Face-Selective Cortex Does Not Distinguish between Members of a Racial Outgroup

    Abstract

    People often fail to individuate members of social outgroups, a phenomenon known as the outgroup homogeneity effect. Here, we used functional magnetic resonance imaging (fMRI) repetition suppression to investigate the neural representation underlying this effect. In a preregistered study, White human perceivers (N = 29) responded to pairs of faces depicting White or Black targets. In each pair, the second face depicted either the same target as the first face, a different target from the same race, or a scrambled face outline. We localized face-selective neural regions via an independent task, and demonstrated that neural activity in the fusiform face area (FFA) distinguished different faces only when targets belonged to the perceivers’ racial ingroup (White). By contrast, face-selective cortex did not discriminate between other-race individuals. Moreover, across two studies (total N = 67) perceivers were slower to discriminate between different outgroup members and remembered them to a lesser extent. Together, these results suggest that the outgroup homogeneity effect arises when early-to-mid-level visual processing results in an erroneous overlap of representations of outgroup members.

    in eNeuro on May 29, 2020 04:30 PM.

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    Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain

    Abstract

    Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy, and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca2+-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the preexisting pathologic pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV1+ afferents in neuropathic pain are controversial, we recently demonstrated that TRPV1 and TRPV1+ afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage (TRPV1-LN) afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal in vivo two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of TNP.

    in eNeuro on May 29, 2020 04:30 PM.

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    Muscarinic-Dependent miR-182 and QR2 Expression Regulation in the Anterior Insula Enables Novel Taste Learning

    Abstract

    In a similar manner to other learning paradigms, intact muscarinic acetylcholine receptor (mAChR) neurotransmission or protein synthesis regulation in the anterior insular cortex (aIC) is necessary for appetitive taste learning. Here we describe a parallel local molecular pathway, where GABAA receptor control of mAChR activation causes upregulation of miRNA-182 and quinone reductase 2 (QR2) mRNA destabilization in the rodent aIC. Damage to long-term memory by prevention of this process, with the use of mAChR antagonist scopolamine before novel taste learning, can be rescued by local QR2 inhibition, demonstrating that QR2 acts downstream of local muscarinic activation. Furthermore, we prove for the first time the presence of endogenous QR2 cofactors in the brain, establishing QR2 as a functional reductase there. In turn, we show that QR2 activity causes the generation of reactive oxygen species, leading to modulation in Kv2.1 redox state. QR2 expression reduction therefore is a previously unaccounted mode of mAChR-mediated inflammation reduction, and thus adds QR2 to the cadre of redox modulators in the brain. The concomitant reduction in QR2 activity during memory consolidation suggests a complementary mechanism to the well established molecular processes of this phase, by which the cortex gleans important information from general sensory stimuli. This places QR2 as a promising new target to tackle neurodegenerative inflammation and the associated impediment of novel memory formation in diseases such as Alzheimer’s disease.

    in eNeuro on May 29, 2020 04:30 PM.

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    Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti–N‐Methyl‐D‐Aspartate Receptor Encephalitis

    Objective

    To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti–N‐methyl‐D‐aspartate receptor encephalitis (NMDARE) patients.

    Methods

    We studied 38 children with NMDARE (median age = 12.9 years, range =1–18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed‐effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity.

    Results

    Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid‐attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed‐effect models and z score transformation showed failure of age‐expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31–9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51–17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68–24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47–9.82, p = 0.031) as independent predictors of poor clinical outcome.

    Interpretation

    Children with NMDARE exhibit significant brain volume loss and failure of age‐expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020

    in Annals of Neurology on May 29, 2020 02:10 PM.

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    Ears of the Lynx Magnetic Resonance Imaging Sign

    in Annals of Neurology on May 29, 2020 02:09 PM.

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    Shining a light on COVID-19

    Nature Photonics, Published online: 29 May 2020; doi:10.1038/s41566-020-0650-9

    Research activities in the areas of X-ray imaging and ultraviolet sterilization illustrate how photonics is helping to combat the threat of COVID-19.

    in Nature Photomics on May 29, 2020 12:00 AM.

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    Cross-nanowire detectors

    Nature Photonics, Published online: 29 May 2020; doi:10.1038/s41566-020-0646-5

    Cross-nanowire detectors

    in Nature Photomics on May 29, 2020 12:00 AM.

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    Optically sensing neural activity without imaging

    Nature Photonics, Published online: 29 May 2020; doi:10.1038/s41566-020-0642-9

    Advanced computational imaging techniques have the potential to extract neural activity patterns from scattered data without reconstructing images.

    in Nature Photomics on May 29, 2020 12:00 AM.

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    Low-loss nonlinear optical isolators in silicon

    Nature Photonics, Published online: 29 May 2020; doi:10.1038/s41566-020-0640-y

    Asymmetric forward and backward transmission through photonic structures can be achieved via optical nonlinearities, but existing systems have typically used slow thermo-optic effects. A new resonator design has now enabled low-loss, non-reciprocal pulse routing based on the Kerr nonlinearity in integrated silicon waveguides.

    in Nature Photomics on May 29, 2020 12:00 AM.

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    On-chip Earth spin detection

    Nature Photonics, Published online: 29 May 2020; doi:10.1038/s41566-020-0626-9

    A monolithic chip-scale ring laser gyroscope based on both Brillouin and Sagnac effects provides a sensitivity sufficient to measure sinusoidal rotations with an amplitude as small as 5 degrees per hour, thus enabling the first on-chip Earth rotation measurement.

    in Nature Photomics on May 29, 2020 12:00 AM.

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    Prolonged Continuous Theta Burst Stimulation of the Motor Cortex Modulates Cortical Excitability But not Pain Perception

    Over the past decade, theta-burst stimulation (TBS) has become a focus of interest in neurostimulatory research. Compared to conventional repetitive transcranial magnetic stimulation (rTMS), TBS produces more robust changes in cortical excitability (CE). There is also some evidence of an analgesic effect of the method. Previously published studies have suggested that different TBS parameters elicit opposite effects of TBS on CE. While intermittent TBS (iTBS) facilitates CE, continuous TBS (cTBS) attenuates it. However, prolonged TBS (pTBS) with twice the number of stimuli produces the opposite effect. In a double-blind, placebo-controlled, cross-over study with healthy subjects (n = 24), we investigated the effects of various pTBS (cTBS, iTBS, and placebo TBS) over the right motor cortex on CE and pain perception. Changes in resting motor thresholds (RMTs) and absolute motor-evoked potential (MEP) amplitudes were assessed before and at two time-points (0–5 min; 40–45 min) after pTBS. Tactile and thermal pain thresholds were measured before and 5 min after application. Compared to the placebo, prolonged cTBS (pcTBS) transiently increased MEP amplitudes, while no significant changes were found after prolonged iTBS. However, the facilitation of CE after pcTBS did not induce a parallel analgesic effect. We confirmed that pcTBS with twice the duration converts the conventional inhibitory effect into a facilitatory one. Despite the short-term boost of CE following pcTBS, a corresponding analgesic effect was not demonstrated. Therefore, the results indicate a more complex regulation of pain, which cannot be explained entirely by the modulation of excitability.

    in Frontiers in Systems Neuroscience on May 29, 2020 12:00 AM.

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    Brain Derived Exosomes Are a Double-Edged Sword in Alzheimer’s Disease

    Brain derived exosomes (BDEs) are extracellular nanovesicles that are collectively released by all cell lineages of the central nervous system and contain cargo from their original cells. They are emerging as key mediators of communication and waste management among neurons, glial cells and connective tissue during both physiological and pathological conditions in the brain. We review the rapidly growing frontier of BDEs biology in recent years including the involvement of exosomes in neuronal development, maintenance and communication through their multiple signaling functions. Particularly, we highlight the important role of exosomes in Alzheimer’s disease (AD), both as a pathogenic agent and as a disease biomarker. Our understanding of such unique nanovesicles may offer not only answers about the (patho) physiological course in AD and associated neurodegenerative diseases but also ideal methods to develop these vesicles as vehicles for drug delivery or as tools to monitor brain diseases in a non-invasive manner because crossing the blood brain barrier is an inherent capability of exosomes. BDEs have potential as biomarkers and as therapeutic tools for AD and related brain disorders in the near future.

    in Frontiers in Molecular Neuroscience on May 29, 2020 12:00 AM.

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    Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis

    Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have revealed a strong association between mutations in genes encoding many RNA-binding proteins (RBPs), including TARDBP, FUS, hnRNPA1, hnRNPA2B1, MATR3, ATXN2, TAF15, TIA-1, and EWSR1, and disease onset/progression. RBPs are a group of evolutionally conserved proteins that participate in multiple steps of RNA metabolism, including splicing, polyadenylation, mRNA stability, localization, and translation. Dysregulation of RBPs, as a consequence of gene mutations, impaired nucleocytoplasmic trafficking, posttranslational modification (PTM), aggregation, and sequestration by abnormal RNA foci, has been shown to be involved in neurodegeneration and the development of ALS. While the exact mechanism by which dysregulated RBPs contribute to ALS remains elusive, emerging evidence supports the notion that both a loss of function and/or a gain of toxic function of these ALS-linked RBPs play a significant role in disease pathogenesis through facilitating abnormal protein interaction, causing aberrant RNA metabolism, and by disturbing ribonucleoprotein granule dynamics and phase transition. In this review article, we summarize the current knowledge on the molecular mechanism by which RBPs are dysregulated and the influence of defective RBPs on cellular homeostasis during the development of ALS. The strategies of ongoing clinical trials targeting RBPs and/or relevant processes are also discussed in the present review.

    in Frontiers in Molecular Neuroscience on May 29, 2020 12:00 AM.

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    Visual Feedback of Object Motion Direction Influences the Timing of Grip Force Modulation During Object Manipulation

    During manipulation, object slipping is prevented by modulating the grip force (GF) in synchrony with motion-related inertial forces, i.e., load force (LF). However, due to conduction delays of the sensory system, GF must be modulated in advance based on predictions of LF changes. It has been proposed that such predictive force control relies on internal representations, i.e., internal models, of the relation between the dynamic of the environment and movement kinematics. Somatosensory and visual feedback plays a primary role in building these internal representations. For instance, it has been shown that manipulation-dependent somatosensory signals contribute to building internal representations of gravity in normal and altered gravitational contexts. Furthermore, delaying the timing of visual feedback of object displacement has been shown to affect GF. Here, we explored whether and the extent to which spatial features of visual feedback movement, such as motion direction, may contribute to GF control. If this were the case, a spatial mismatch between actual (somatosensory) and visual feedback of object motion would elicit changes in GF modulation. We tested this hypothesis by asking participants to generate vertical object movements while visual feedback of object position was congruent (0° rotation) or incongruent (180° or 90°) with the actual object displacement. The role of vision on GF control was quantified by the temporal shift of GF modulation as a function of visual feedback orientation and actual object motion direction. GF control was affected by visual feedback when this was incongruent in the vertical (180°), but not horizontal dimension. Importantly, 180° visual feedback rotation delayed and anticipated GF modulation during upward and downward actual movements, respectively. Our findings suggest that during manipulation, spatial features of visual feedback motion are used to predict upcoming LF changes. Furthermore, the present study provides evidence that an internal model of gravity contributes to GF control by influencing sensory reweighting processes during object manipulation.

    in Frontiers in Human Neuroscience on May 29, 2020 12:00 AM.

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    Transcranial Alternating Current Stimulation With the Theta-Band Portion of the Temporally-Aligned Speech Envelope Improves Speech-in-Noise Comprehension

    Transcranial alternating current stimulation with the speech envelope can modulate the comprehension of speech in noise. The modulation stems from the theta- but not the delta-band portion of the speech envelope, and likely reflects the entrainment of neural activity in the theta frequency band, which may aid the parsing of the speech stream. The influence of the current stimulation on speech comprehension can vary with the time delay between the current waveform and the audio signal. While this effect has been investigated for current stimulation based on the entire speech envelope, it has not yet been measured when the current waveform follows the theta-band portion of the speech envelope. Here, we show that transcranial current stimulation with the speech envelope filtered in the theta frequency band improves speech comprehension as compared to a sham stimulus. The improvement occurs when there is no time delay between the current and the speech stimulus, as well as when the temporal delay is comparatively short, 90 ms. In contrast, longer delays, as well as negative delays, do not impact speech-in-noise comprehension. Moreover, we find that the improvement of speech comprehension at no or small delays of the current stimulation is consistent across participants. Our findings suggest that cortical entrainment to speech is most influenced through current stimulation that follows the speech envelope with at most a small delay. They also open a path to enhancing the perception of speech in noise, an issue that is particularly important for people with hearing impairment.

    in Frontiers in Human Neuroscience on May 29, 2020 12:00 AM.

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    Metabolic Interaction Between Schwann Cells and Axons Under Physiological and Disease Conditions

    Recent research into axon-glial interactions in the nervous system has made a compelling case that glial cells have a relevant role in the metabolic support of axons, and that, in the case of myelinating cells, this role is independent of myelination itself. In this mini-review article, we summarize some of those observations and focus on Schwann cells (SC), drawing parallels between glia of the central and peripheral nervous systems (PNS), pointing out limitations in current knowledge, and discussing its potential clinical relevance. First, we introduce SC, their development and main roles, and follow with an evolutionary perspective of glial metabolic function. Then we provide evidence of the myelin-independent aspects of axonal support and their coupling to neuronal metabolism. Finally, we address the opportunity to use SC-axon metabolic interactions as therapeutic targets to treat peripheral neuropathies.

    in Frontiers in Cellular Neuroscience on May 29, 2020 12:00 AM.

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    Neuronal Replacement as a Tool for Basal Ganglia Circuitry Repair: 40 Years in Perspective

    The ability of new neurons to promote repair of brain circuitry depends on their capacity to re-establish afferent and efferent connections with the host. In this review article, we give an overview of past and current efforts to restore damaged connectivity in the adult mammalian brain using implants of fetal neuroblasts or stem cell-derived neuronal precursors, with a focus on strategies aimed to repair damaged basal ganglia circuitry induced by lesions that mimic the pathology seen in humans affected by Parkinson’s or Huntington’s disease. Early work performed in rodents showed that neuroblasts obtained from striatal primordia or fetal ventral mesencephalon can become anatomically and functionally integrated into lesioned striatal and nigral circuitry, establish afferent and efferent connections with the lesioned host, and reverse the lesion-induced behavioral impairments. Recent progress in the generation of striatal and nigral progenitors from pluripotent stem cells have provided compelling evidence that they can survive and mature in the lesioned brain and re-establish afferent and efferent axonal connectivity with a remarkable degree of specificity. The studies of cell-based circuitry repair are now entering a new phase. The introduction of genetic and virus-based techniques for brain connectomics has opened entirely new possibilities for studies of graft-host integration and connectivity, and the access to more refined experimental techniques, such as chemo- and optogenetics, has provided new powerful tools to study the capacity of grafted neurons to impact the function of the host brain. Progress in this field will help to guide the efforts to develop therapeutic strategies for cell-based repair in Huntington’s and Parkinson’s disease and other neurodegenerative conditions involving damage to basal ganglia circuitry.

    in Frontiers in Cellular Neuroscience on May 29, 2020 12:00 AM.

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    Capgras Delusion in Posterior Cortical Atrophy–A Quantitative Multimodal Imaging Single Case Study

    Although Alzheimer’s disease presents homogeneous histopathology, it causes several clinical phenotypes depending on brain regions involved. Beside the most abundant memory variant, several atypical variants exist. Among them posterior cortical atrophy (PCA) is associated with severe visuospatial/visuoperceptual deficits in the absence of significant primary ocular disease. Here, we report for the first time a case of Capgras delusion—a delusional misidentification syndrome, where patients think that familiar persons are replaced by identical “doubles” or an impostor—in a patient with PCA. The 57-year-old female patient was diagnosed with PCA and developed Capgras delusion 8 years after first symptoms. The patient did not recognize her husband, misidentified him as a stranger, and perceived him as a threat. Such misidentifications did not happen for other persons. Events could be interrupted by reassuring the husband’s identity by the patient’s female friend or children. We applied in-depth multimodal neuroimaging phenotyping and used single-subject voxel-based morphometry to identify atrophy changes specifically related to the development of the Capgras delusion. The latter, based on structural T1 magnetic resonance imaging, revealed progressive gray matter volume decline in occipital and temporoparietal areas, involving more the right than the left hemisphere, especially at the beginning. Correspondingly, the right fusiform gyrus was already affected by atrophy at baseline, whereas the left fusiform gyrus became involved in the further disease course. At baseline, glucose hypometabolism as measured by positron emission tomography (PET) with F18-fluorodesoxyglucose (FDG-PET) was evident in the parietooccipital cortex, more pronounced right-sided, and in the right frontotemporal cortex. Amyloid accumulation as assessed by PET with F18-florbetaben was found in the gray matter of the neocortex indicating underlying Alzheimer’s disease. Appearance of the Capgras delusion was related to atrophy in the right posterior cingulate gyrus/precuneus, as well as right middle frontal gyrus/frontal eye field, supporting right frontal areas as particularly relevant for Capgras delusion. Atrophy in these regions respectively might affect the default mode and dorsal attention networks as shown by meta-analytical co-activation and resting state functional connectivity analyses. This case elucidates the brain-behavior relationship in PCA and Capgras delusion.

    in Frontiers in Ageing Neuroscience on May 29, 2020 12:00 AM.

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    Fitness Level Influences White Matter Microstructure in Postmenopausal Women

    Aerobic exercise has both neuroprotective and neurorehabilitative benefits. However, the underlying mechanisms are not fully understood and need to be investigated, especially in postmenopausal women, who are at increased risk of age-related disorders such as Alzheimer’s disease and stroke. To advance our understanding of the potential neurological benefits of aerobic exercise in aging women, we examined anatomical and functional responses that may differentiate women of varying cardiorespiratory fitness using neuroimaging and neurophysiology. A total of 35 healthy postmenopausal women were recruited (59 ± 3 years) and cardiorespiratory fitness estimated (22–70 mL/kg/min). Transcranial magnetic stimulation was used to assess -aminobutyric acid (GABA) and glutamate (Glu) receptor function in the primary motor cortex (M1), and magnetic resonance spectroscopy (MRS) was used to quantify GABA and Glu concentrations in M1. Magnetic resonance imaging was used to assess mean cortical thickness (MCT) of sensorimotor and frontal regions, while the microstructure of sensorimotor and other white matter tracts was evaluated through diffusion tensor imaging. Regression analysis revealed that higher fitness levels were associated with improved microstructure in pre-motor and sensory tracts, and the hippocampal cingulum. Fitness level was not associated with MCT, MRS, or neurophysiology measures. These data indicate that, in postmenopausal women, higher cardiorespiratory fitness is linked with preserved selective white matter microstructure, particularly in areas that influence sensorimotor control and memory.

    in Frontiers in Ageing Neuroscience on May 29, 2020 12:00 AM.

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    The Temporal Association Cortex Plays a Key Role in Auditory-Driven Maternal Plasticity

    Tasaka et al. show that the temporal association cortex (TeA) receives monosynaptic inputs from widespread cortical and subcortical regions. TeA shows strong functional connectivity to the primary auditory cortex. In the context of motherhood, TeA plays an important role in encoding and perceiving pup ultrasonic vocalizations by mothers.

    in Neuron: In press on May 29, 2020 12:00 AM.

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    Fovea-like Photoreceptor Specializations Underlie Single UV Cone Driven Prey-Capture Behavior in Zebrafish

    Yoshimatsu et al. show that larval zebrafish rely on single UV cones at a time to support visual prey capture. For this, zebrafish combine molecular, cellular, and circuit tuning to regionally boost detectability of prey in their acute zone. The mechanisms of this specialization tally with those of the primate fovea.

    in Neuron: In press on May 29, 2020 12:00 AM.

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    Dl-3-n-Butylphthalide promotes neovascularization and neurological recovery in a rat model of intracerebral hemorrhage

    Cerebral stroke occurs following ischemic and hemorrhagic lesions in the brain. Survival and recovery of stroke patients depend on the severity of the initial injury but also the therapeutic approaches applied...

    in BMC Neuroscience on May 29, 2020 12:00 AM.

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    Repeated social defeat promotes persistent inflammatory changes in splenic myeloid cells; decreased expression of β-arrestin-2 (ARRB2) and increased expression of interleukin-6 (IL-6)

    Previous studies suggest that persistent exposure to social stress in mammals may be associated with multiple physiological effects. Here, we examine the effects of social stress in rats, i.e. repeated social ...

    in BMC Neuroscience on May 29, 2020 12:00 AM.

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    Alexithymia and automatic processing of facial emotions: behavioral and neural findings

    Alexithymia is a personality trait characterized by difficulties identifying and describing feelings, an externally oriented style of thinking, and a reduced inclination to imagination. Previous research has s...

    in BMC Neuroscience on May 29, 2020 12:00 AM.

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    <i>In silico</i> analysis of hypoxia activated prodrugs in combination with anti angiogenic therapy through nanocell delivery

    by Cameron Meaney, Sander Rhebergen, Mohammad Kohandel

    Tumour hypoxia is a well-studied phenomenon with implications in cancer progression, treatment resistance, and patient survival. While a clear adverse prognosticator, hypoxia is also a theoretically ideal target for guided drug delivery. This idea has lead to the development of hypoxia-activated prodrugs (HAPs): a class of chemotherapeutics which remain inactive in the body until metabolized within hypoxic regions. In theory, these drugs have the potential for increased tumour selectivity and have therefore been the focus of numerous preclinical studies. Unfortunately, HAPs have had mixed results in clinical trials, necessitating further study in order to harness their therapeutic potential. One possible avenue for the improvement of HAPs is through the selective application of anti angiogenic agents (AAs) to improve drug delivery. Such techniques have been used in combination with other conventional chemotherapeutics to great effect in many studies. A further benefit is theoretically achieved through nanocell administration of the combination, though this idea has not been the subject of any experimental or mathematical studies to date. In the following, a mathematical model is outlined and used to compare the predicted efficacies of separate vs. nanocell administration for AAs and HAPs in tumours. The model is experimentally motivated, both in mathematical form and parameter values. Preliminary results of the model are highlighted throughout which qualitatively agree with existing experimental evidence. The novel prediction of our model is an improvement in the efficacy of AA/HAP combination therapies when administered through nanocells as opposed to separately. While this study specifically models treatment on glioblastoma, similar analyses could be performed for other vascularized tumours, making the results potentially applicable to a range of tumour types.

    in PLoS Computational Biology on May 28, 2020 09:00 PM.

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    Dilp-2–mediated PI3-kinase activation coordinates reactivation of quiescent neuroblasts with growth of their glial stem cell niche

    by Xin Yuan, Conor W. Sipe, Miyuki Suzawa, Michelle L. Bland, Sarah E. Siegrist

    Dietary nutrients provide macromolecules necessary for organism growth and development. In response to animal feeding, evolutionarily conserved growth signaling pathways are activated, leading to increased rates of cell proliferation and tissue growth. It remains unclear how different cell types within developing tissues coordinate growth in response to dietary nutrients and whether coordinated growth of different cell types is necessary for proper tissue function. Here, we report that Drosophila neural stem cells, known as neuroblasts, reactivate from developmental quiescence in a dietary-nutrient–dependent manner. Neuroblast reactivation in the brain requires nonautonomous activation of phosphoinositide 3-kinase (PI3-kinase) signaling from cortex glia and tracheal processes, both of which are closely associated with neuroblasts. Furthermore, PI3-kinase activation in neuroblasts is required nonautonomously for glial membrane expansion and robust neuroblast–glial contact. Finally, PI3-kinase is required cell autonomously for nutrient-dependent growth of neuroblasts, glia, and trachea. Of the 7 Drosophila insulin-like peptides (Dilps), we find that Dilp-2 is required for PI3-kinase activation and growth coordination between neuroblasts and glia in the brain. Dilp-2 induces brain cortex glia to initiate membrane growth and make first contact with quiescent neuroblasts. After contact, neuroblasts increase in size and reenter S-phase. Once reactivated from quiescence, neuroblasts promote growth of cortex glia, which, in turn, form a selective membrane barrier around neuroblasts and their newborn progeny. Our results highlight the importance of bidirectional growth signaling between neural stem cells and surrounding cell types in the brain in response to nutrition and demonstrate how coordinated growth among different cell types drives tissue morphogenesis and function.

    in PLoS Biology on May 28, 2020 09:00 PM.

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    The haemodynamics of the human placenta in utero

    by Neele S. Dellschaft, George Hutchinson, Simon Shah, Nia W. Jones, Chris Bradley, Lopa Leach, Craig Platt, Richard Bowtell, Penny A. Gowland

    We have used magnetic resonance imaging (MRI) to provide important new insights into the function of the human placenta in utero. We have measured slow net flow and high net oxygenation in the placenta in vivo, which are consistent with efficient delivery of oxygen from mother to fetus. Our experimental evidence substantiates previous hypotheses on the effects of spiral artery remodelling in utero and also indicates rapid venous drainage from the placenta, which is important because this outflow has been largely neglected in the past. Furthermore, beyond Braxton Hicks contractions, which involve the entire uterus, we have identified a new physiological phenomenon, the ‘utero-placental pump’, by which the placenta and underlying uterine wall contract independently of the rest of the uterus, expelling maternal blood from the intervillous space.

    in PLoS Biology on May 28, 2020 09:00 PM.

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    Hemovasculogenic origin of blood vessels in the developing mouse brain

    Hemovasculogenic origin of blood vessels in the developing mouse brain

    The brain vasculature develops by angiogenesis from preformed blood vessels in the cephalic mesenchyme. Here we show that in addition, avascular cells expressing primitive erythroid, hemangioblast, and endothelial makers exist in the developing cephalic mesenchyme and neuroepithelium where they generate angiogenic, vasculogenic, and hemogenic foci. From E10.5 to E13.5, the neuroepithelial vasculogenic foci were an additional source of blood vessel formation in the developing brain. Thus, the brain vasculature develops in part by hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously.


    Abstract

    Vascular structures in the developing brain are thought to form via angiogenesis from preformed blood vessels in the cephalic mesenchyme. Immunohistochemical studies of developing mouse brain from E10.5 to E13.5 revealed the presence of avascular blood islands of primitive erythroid cells expressing hemangioblast markers (Flk1, Tal1/Scl1, platelet endothelial cell adhesion molecule 1, vascular endothelial‐cadherin, and CD34) and an endothelial marker recognized by Griffonia simplicifolia isolectin B4 (IB4) in the cephalic mesenchyme. These cells formed a perineural vascular plexus from which angiogenic sprouts originated and penetrated the neuroepithelium. In addition, avascular isolated cells expressing primitive erythroid, hemangioblast and endothelial makers were visible in the neuroepithelium where they generated vasculogenic and hemogenic foci. From E10.5 to E13.5, these vasculogenic foci were a source of new blood vessel formation in the developing brain. In vitro, cultured E13.5 brain endothelial cells contained hemogenic endothelial cells capable of generating erythroid cells. Similar cells were present in primary cultures of dissociated cells from E10.5 embryonic head. Our results provide new evidence that the brain vasculature, like that of the yolk sac and the eye choriocapillaris and hyaloid vascular systems, develops at least in part via hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously.

    in Journal of Comparative Neurology on May 28, 2020 07:13 PM.

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    Retrospectively assessed subjective effects of initial opioid use differ between opioid misusers with opioid use disorder (OUD) and those who never progressed to OUD: Data from a pilot and a replication sample

    Retrospectively assessed subjective effects of initial opioid use differ between opioid misusers with opioid use disorder (OUD) and those who never progressed to OUD: Data from a pilot and a replication sample

    Subjective effects of initial opioid misuse were assessed in two samples of opioid misusers that included low‐level users who never met criteria for opioid use disorder (OUD) and heavier users with OUD. In both samples, OUD+ individuals reported greater euphoria, activation, pruritus, and internalizing symptoms (replication sample data are displayed).


    Abstract

    Attempts to identify opioid users with increased risk of escalating to opioid use disorder (OUD) have had limited success. Retrospectively assessed subjective effects of initial opioid misuse were compared in a pilot sample of opioid misusers (nonmedical use ≤60 times lifetime) who had never met criteria for OUD (N  = 14) and heroin‐addicted individuals in treatment for OUD (N  = 15). Relative to opioid misusers without a lifetime OUD diagnosis, individuals with OUD reported greater euphoria and other positive emotions, activation, pruritus, and internalizing symptoms. Consistent with these findings, proxy Addiction Research Center Inventory (ARCI) Amphetamine Group, and Morphine Benzedrine Group scale mean item scores were significantly higher in those with OUD. Replication was attempted in opioid misusers with (N  = 25) and without OUD (N  = 25) who were assessed as part of an ongoing genetic study. We observed similar significant between‐group differences in individual subjective effect items and ARCI scale mean item scores in the replication sample. We, thus confirm findings from prior reports that retrospectively assessed subjective responses to initial opioid exposure differ significantly between opioid users who do, and do not, progress to OUD. Our report extends these findings in comparisons limited to opioid misusers. Additional research will be necessary to examine prospectively whether the assessment of subjective effects after initial use has predictive utility in the identification of individuals more likely to progress to OUD.

    in Journal of Neuroscience Research on May 28, 2020 05:54 PM.

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    Is RBD a risk factor for impulse control disorder in Parkinson’s disease?

    Objective

    To assess the association between REM sleep behavior disorder (RBD) and other determinants and incident impulse control disorder behaviors (ICBs) in patients with early Parkinson’s disease (PD) using longitudinal data from the Parkinson's Progression Markers Initiative (PPMI).

    Methods

    401 newly‐diagnosed PD patients were prospectively evaluated at baseline (BL), month 6, and annually for 5 years. Probable RBD (pRBD) was assessed with the RBD Screening Questionnaire and dichotomized using a cut‐off value ≥6. The association of BL and time‐dependent (TD) pRBD and other covariates with the development of ICB symptoms, was evaluated using Cox proportional hazards regression and general estimating equations logistic regression. Models considered adjustment for age, sex, MDS‐UPDRS III, Geriatric Depression Scale (GDS‐15), RBD medication use, total levodopa equivalent daily dose (LEDD), and dopamine agonist (DA) and antidepressant medication use.

    Results

    Both baseline pRBD and TD pRBD were not associated with an increased risk for incident ICB symptoms after adjustment for covariates (adjusted HR=1.17, p=0.458 and HR=1.27, p=0.257 respectively). In a modified‐TD pRBD model (i.e., considering subjects as pRBD onward from the first time point with RBDSQ score ≥6), the risk for incident ICB symptoms was higher in pRBD in unadjusted (HR=1.48, p=0.038), but not adjusted (HR=1.29, p=0.202) models. TD DA use (HR=1.64, p=0.039), TD GDS‐15 score (HR=1.12, p<0.001), and male sex (year 3: HR=2.10,p=0.009; year 4: HR=3.04,p=0.006; year 5: HR=4.40,p=0.007) were associated with increased ICB symptom risk.

    Interpretation

    pRBD is not clearly associated with ICB symptom development in early PD, in contrast to DA use, depression, and male sex.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on May 28, 2020 05:30 PM.

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    Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy

    Objective

    Cognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE), but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface‐shape patterns to verbal and visual learning.

    Methods

    We analyzed hippocampal surface shapes on high‐resolution magnetic resonance images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients, and 39 age‐ and sex‐matched healthy volunteers.

    Results

    Both left TLE (LTLE) and right TLE (RTLE) patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8, RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8, visual 39 ± 6; p  < 0.001). Verbal learning was more impaired the greater the atrophy of the left superolateral hippocampal head. In contrast, visual memory was worse with greater bilateral inferomedial hippocampal atrophy. Postsurgical verbal memory decline was more common in LTLE than in RTLE (reliable change index in LTLE 27% vs RTLE 7%, p = 0.006), whereas there were no differences in postsurgical visual memory decline between those groups. Preoperative atrophy of the left hippocampal tail predicted postsurgical verbal memory decline.

    Interpretation

    Memory deficits in TLE are associated with specific morphological alterations of the hippocampus, which could help stratify TLE patients into those at high versus low risk of presurgical or postsurgical memory deficits. This knowledge could improve planning and prognosis of selective epilepsy surgery and neuropsychological counseling in TLE. ANN NEUROL 2020

    in Annals of Neurology on May 28, 2020 05:25 PM.

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    Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

    The amyloid precursor protein (APP) has been extensively studied as the precursor of the β-amyloid (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer’s disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain. It resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell-cell interaction and/or activation of intracellular signaling pathways. In this respect, the APP intracellular domain (AICD) was reported to act as a transcriptional regulator. Here, we used a transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and on maturation of primary cortical neurons. Surprisingly, the overall transcriptional changes were subtle, but a more detailed analysis pointed to genes clustered in neuronal-activity dependent pathways. In particular, we observed a decreased transcription of neuronal PAS domain protein 4 (NPAS4) in APP–/– neurons. NPAS4 is an inducible transcription factor (ITF) regulated by neuronal depolarization. The downregulation of NPAS4 co-occurs with an increased production of the inhibitory neurotransmitter GABA and a reduced expression of the GABAA receptors α1. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Patch-clamp investigation did not reveal any functional decrease of GABAA receptors activity, but long-term potentiation (LTP) measurement supported an increased GABA component in synaptic transmission of APP–/– mice. Together, NPAS4 appears to be a downstream target involved in APP-dependent regulation of inhibitory synaptic transmission.

    in eNeuro on May 28, 2020 04:26 PM.

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    Increased Tau Expression Correlates with Neuronal Maturation in the Developing Human Cerebral Cortex

    Although best known for its role in Alzheimer’s disease (AD), tau is expressed throughout brain development, although it remains unclear when and which cell types this expression occurs and how it affects disease states in both fetal and neonatal periods. We thus sought to map tau mRNA and protein expression in the developing human brain at the cellular level using a combination of existing single-cell RNA sequencing (sc-RNAseq) data, RNA in situ hybridization (RNAscope), and immunohistochemistry (IHC). Using sc-RNAseq, we found that tau mRNA expression begins in radial glia but increases dramatically as migrating neuronal precursors mature. Specifically, TBR1+ maturing neurons and SYN+ mature neurons showed significantly higher mRNA expression than GFAP+/NES+ radial glia or TBR2+ intermediate progenitors. By RNAscope, we found low levels of tau mRNA in subventricular zone (SVZ) radial glia and deep white matter intermediate progenitors, with an increase in more superficially located maturing and mature neurons. By total-tau IHC, the germinal matrix and SVZ showed little protein expression, although both RNAscope and sc-RNAseq showed mRNA, and Western blotting revealed significantly less protein in those areas compared with more mature regions. Induced pluripotent stem cell (iPSC)-derived cortical organoids showed a similar tau expression pattern by sc-RNAseq and RNAscope. Our results indicate that tau increases with neuronal maturation in both the developing fetal brain and iPSC-derived organoids and forms a basis for future research on regulatory mechanisms triggering the onset of tau gene transcription and translation, which may represent potential therapeutic targets for neurodegenerative tauopathies and neurodevelopmental disorders.

    in eNeuro on May 28, 2020 04:26 PM.

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    Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

    Objective

    Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease.

    Methods

    This single‐center, phase 2, randomized, double‐blind, placebo‐controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks.

    Results

    Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well‐tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho‐tau‐181 was reduced at 6 months and 12 months in the nilotinib group.

    Interpretation

    Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020

    in Annals of Neurology on May 28, 2020 04:10 PM.

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    Cover Image, Volume 528, Issue 11

    Cover Image, Volume 528, Issue 11

    The cover image is based on the Original Article The brain of a nocturnal migratory insect, the Australian Bogong moth by Andrea Adden, Keram Pfeiffer, Eric J. Warrant et al., https://doi.org/10.1002/cne.24866.


    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    The Journal of Comparative Neurology, Table of Content, Vol. 528, No. 11, July 15, 2020

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Cover Image, Volume 528, Issue 11

    Cover Image, Volume 528, Issue 11

    The cover image is based on the Original Article Distributions of hypothalamic neuron populations coexpressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse by Melissa J. Chee, Gabor Wittmann, Mikayla Payant et al., https://doi.org/10.1002/cne.24857.


    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    The brain of a nocturnal migratory insect, the Australian Bogong moth

    The brain of a nocturnal migratory insect, the Australian Bogong moth

    Every year, millions of Australian Bogong moths (Agrotis infusa ) migrate over 1,000 km from their breeding grounds to the alpine regions of the Snowy Mountains, where they endure the hot summer in the cool climate of alpine caves. In autumn, the moths return to their breeding grounds, where they reproduce and die. The following year, their offspring repeat the same journey. Although it was shown that the moths are guided by nocturnal visual as well as geomagnetic cues, the neural processing that underlies their migratory behavior remains unknown. Here, we provide a detailed description of the Bogong moth's brain to generate an access point for future functional studies. We describe the overall layout as well as the fine structure of all major neuropils, focusing on regions that have previously been implicated in compass‐based navigation. Our results show that the Bogong moth brain follows the typical lepidopteran ground pattern, and we find no major specializations that reflect their migratory lifestyle. These findings suggest that migratory behavior may be achievable by small changes of neural circuitry in key brain areas, rather than requiring structural modifications on a gross morphological level. Locating these subtle adjustments will be a challenging task for the future, for which our study provides an essential anatomical framework.


    Abstract

    Every year, millions of Australian Bogong moths (Agrotis infusa ) complete an astonishing journey: In Spring, they migrate over 1,000 km from their breeding grounds to the alpine regions of the Snowy Mountains, where they endure the hot summer in the cool climate of alpine caves. In autumn, the moths return to their breeding grounds, where they mate, lay eggs and die. These moths can use visual cues in combination with the geomagnetic field to guide their flight, but how these cues are processed and integrated into the brain to drive migratory behavior is unknown. To generate an access point for functional studies, we provide a detailed description of the Bogong moth's brain. Based on immunohistochemical stainings against synapsin and serotonin (5HT), we describe the overall layout as well as the fine structure of all major neuropils, including the regions that have previously been implicated in compass‐based navigation. The resulting average brain atlas consists of 3D reconstructions of 25 separate neuropils, comprising the most detailed account of a moth brain to date. Our results show that the Bogong moth brain follows the typical lepidopteran ground pattern, with no major specializations that can be attributed to their spectacular migratory lifestyle. These findings suggest that migratory behavior does not require widespread modifications of brain structure, but might be achievable via small adjustments of neural circuitry in key brain areas. Locating these subtle changes will be a challenging task for the future, for which our study provides an essential anatomical framework.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Cross‐modal modulation of cell activity by sound in first‐order visual thalamic nucleus

    Cross‐modal modulation of cell activity by sound in first‐order visual thalamic nucleus

    Sound stimulation modulated cell activities in the dorsal lateral geniculate nucleus of anesthetized rats with regard to response magnitude, latency, jitter and burst spiking of onset and late visual responses evoked by single or double flashlight stimulation. Suppression predominated in modulation but de novo cell activity was also induced. Modulation was observed in cells morphologically comparable to X‐, Y‐, and W‐like projection cells and interneurons. Auditory influence is considered incorporated into parallel channels of visual processing in the first‐order thalamic nucleus.


    Abstract

    Cross‐modal auditory influence on cell activity in the primary visual cortex emerging at short latencies raises the possibility that the first‐order visual thalamic nucleus, which is considered dedicated to unimodal visual processing, could contribute to cross‐modal sensory processing, as has been indicated in the auditory and somatosensory systems. To test this hypothesis, the effects of sound stimulation on visual cell activity in the dorsal lateral geniculate nucleus were examined in anesthetized rats, using juxta‐cellular recording and labeling techniques. Visual responses evoked by light (white LED) were modulated by sound (noise burst) given simultaneously or 50–400 ms after the light, even though sound stimuli alone did not evoke cell activity. Alterations of visual response were observed in 71% of cells (57/80) with regard to response magnitude, latency, and/or burst spiking. Suppression predominated in response magnitude modulation, but de novo responses were also induced by combined stimulation. Sound affected not only onset responses but also late responses. Late responses were modulated by sound given before or after onset responses. Further, visual responses evoked by the second light stimulation of a double flash with a 150–700 ms interval were also modulated by sound given together with the first light stimulation. In morphological analysis of labeled cells projection cells comparable to X‐, Y‐, and W‐like cells and interneurons were all susceptible to auditory influence. These findings suggest that the first‐order visual thalamic nucleus incorporates auditory influence into parallel and complex thalamic visual processing for cross‐modal modulation of visual attention and perception.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing

    Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing

    The marrow cavity, trabecular bone, and the periosteum are all innervated by myelinated spinal afferent nerve endings, and both peptidergic and nonpeptidergic unmyelinated spinal afferent nerve endings, and there is heterogeneity with respect to their morphology. This approach to selective anterograde labeling of nerve terminal endings will help better identify how different sub‐populations of sensory neurons interact with bone.


    Abstract

    While sensory and sympathetic neurons are known to innervate bone, previous studies have found it difficult to unequivocally identify and characterize only those that are of sensory origin. In this study, we have utilized an in vivo anterograde tracing technique to selectively label spinal afferent (sensory) nerve endings that innervate the periosteum and marrow cavity of murine long bones. Unilateral injections of dextran–biotin (anterograde tracer; 20% in saline, 50–100 nl) were made into L3–L5 dorsal root ganglia. After a 10‐day recovery period to allow sufficient time for selective anterograde transport of the tracer to nerve terminal endings in bone, the periosteum (whole‐mount) and underlying bone were collected, processed to reveal anterograde labeling, and immuno‐labeled with antibodies directed against protein gene product (pan‐neuronal marker; PGP9.5), tyrosine hydroxylase (sympathetic neuron marker; TH), calcitonin gene‐related protein (peptidergic nociceptor marker; CGRP), and/or neurofilament 200 (myelinated axon marker; NF200). Anterograde‐labeled nerve endings were dispersed throughout the periosteum and marrow cavity and could be identified in close apposition to blood vessels and at sites distant from them. The periosteum and the marrow cavity were each innervated by myelinated (NF200+) sensory neurons, and unmyelinated (NF200‑) sensory neurons that were either peptidergic (CGRP+) or nonpeptidergic (CGRP‑). Spinal afferent nerve endings did not express TH, and lacked the cylindrical morphology around blood vessels characteristic of sympathetic innervation. This approach to selective labeling of sensory nerve terminal endings will help to better identify how different sub‐populations of sensory neurons, and their peripheral nerve terminal endings, interact with bone.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Visual pathways in the brain of the jumping spider Marpissa muscosa

    Visual pathways in the brain of the jumping spider Marpissa muscosa

    Most spider species possess eight eyes, of which two (the principal eyes) are used for object discrimination, whereas the other three pairs (secondary eyes) detect movement. Jumping spiders are particularly renowned for their visual abilities and we studied the neural substrate for visual processing in the jumping spider Marpissa muscosa . We show that the principal eye pathway involves two subsequent visual neuropils and the arcuate body. Among the secondary eyes, the anterior lateral and the posterior lateral eyes are connected to two subsequent visual neuropils (AL1, PL1, and AL2/PL2) and the mushroom body (MBp). They also share an additional second‐order visual neuropil (L2), which might serve as integration center. The small posterior median eye is connected via a single visual neuropil (PM1) with the arcuate body and might thus not detect movement. Additional data on the visual pathways in the ctenid spider Cupiennius salei are provided and differences to M. muscosa are discussed.


    Abstract

    Some animals have evolved task differentiation among their eyes. A particular example is spiders, where most species have eight eyes, of which two (the principal eyes) are used for object discrimination, whereas the other three pairs (secondary eyes) detect movement. In the ctenid spider Cupiennius salei , these two eye types correspond to two visual pathways in the brain. Each eye is associated with its own first‐ and second‐order visual neuropil. The second‐order neuropils of the principal eyes are connected to the arcuate body, whereas the second‐order neuropils of the secondary eyes are linked to the mushroom body. We explored the principal‐ and secondary eye visual pathways of the jumping spider Marpissa muscosa , in which size and visual fields of the two eye types are considerably different. We found that the connectivity of the principal eye pathway is the same as in C. salei , while there are differences in the secondary eye pathways. In M. muscosa , all secondary eyes are connected to their own first‐order visual neuropils. The first‐order visual neuropils of the anterior lateral and posterior lateral eyes are connected with a second‐order visual neuropil each and an additional shared one (L2). In the posterior median eyes, the axons of their first‐order visual neuropils project directly to the arcuate body, suggesting that the posterior median eyes do not detect movement. The L2 might function as an upstream integration center enabling faster movement decisions.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    What is a multisensory cortex? A laminar, connectional, and functional study of a ferret temporal cortical multisensory area

    What is a multisensory cortex? A laminar, connectional, and functional study of a ferret temporal cortical multisensory area

    Multisensory processing occurs across the neocortex, but what makes an area multisensory? Multisensory processing in ferret lateral rostral suprasylvian (LRSS) area was examined using tract tracing and multichannel neuronal recording and compared with other cortical areas. Inputs from lower level auditory and somatosensory cortices converged in the LRSS, where the majority of neurons were auditory‐somatosensory multisensory and multisensory activity was the dominant output signal. Comparison with similarly studied cortical areas indicates that areas dominated by multisensory activity are appropriately designated as multisensory.


    Abstract

    Now that examples of multisensory neurons have been observed across the neocortex, this has led to some confusion about the features that actually designate a region as “multisensory.” While the documentation of multisensory effects within many different cortical areas is clear, often little information is available about their proportions or net functional effects. To assess the compositional and functional features that contribute to the multisensory nature of a region, the present investigation used multichannel neuronal recording and tract tracing methods to examine the ferret temporal region: the lateral rostral suprasylvian sulcal area. Here, auditory‐tactile multisensory neurons were predominant and constituted the majority of neurons across all cortical layers whose responses dominated the net spiking activity of the area. These results were then compared with a literature review of cortical multisensory data and were found to closely resemble multisensory features of other, higher‐order sensory areas. Collectively, these observations argue that multisensory processing presents itself in hierarchical and area‐specific ways, from regions that exhibit few multisensory features to those whose composition and processes are dominated by multisensory activity. It seems logical that the former exhibit some multisensory features (among many others), while the latter are legitimately designated as “multisensory.”

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Structural brain network development in children following prenatal methamphetamine exposure

    Structural brain network development in children following prenatal methamphetamine exposure

    Prenatal methamphetamine exposure (PME) may alter brain structure of children, but no longitudinal studies have investigated structural connectivity during the formative school years. Graph theoretical analysis was used to investigate changes in structural connectivity at age 6 and 8 years in children with and without PME. While controls showed increased connectivity in frontal and limbic hubs (i.e., regions directing brain function) over time, children with PME showed increased connectivity in the superior parietal cortex and striatum. Those with PME also had less change in segregation of structural networks over time. These findings are consistent with previous work on regions implicated in children with PME, but they additionally demonstrate alterations in structural connectivity between regions that underlie primary cognitive, behavioral, and emotional development. Understanding patterns of network development during critical periods in at‐risk children may inform supportive strategies in these developmental tasks important for lifelong brain health and development.


    Abstract

    Brain imaging studies in children with prenatal methamphetamine exposure (PME) suggest structural and functional alterations of striatal, frontal, parietal, and limbic regions. However, no longitudinal studies have investigated changes in structural connectivity during the first 2 years of formal schooling. The aim of this study was to explore the effects of PME on structural connectivity of brain networks in children over the critical first 2 years of formal schooling when foundational learning takes place. Networks are expected to gradually increase in global connectedness while segregating into defined systems. Graph theoretical analysis was used to investigate changes in structural connectivity at age 6 and 8 years in children with and without PME. While healthy control children showed increased connectivity in frontal and limbic hubs over time, children with PME showed increased connectivity in the superior parietal cortex and striatum in their global network. Furthermore, compared to control children, those with PME were characterized by less change in segregation of structural networks over time. These findings are consistent with previous work on regions implicated in children with PME, but they additionally demonstrate alterations in structural connectivity between regions that underlie primary cognitive, behavioral, and emotional development. Understanding patterns of network development during critical periods in at‐risk children may inform strategies for supporting this group of children in these developmental tasks important for lifelong brain health and development.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Distributions of hypothalamic neuron populations coexpressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse

    Distributions of hypothalamic neuron populations coexpressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse

    Nissl‐based maps of the distribution of tyrosine hydroxylase immunoreactivity in hypothalamic neurons that coexpress the vesicular GABA transporter revealed striking colocalization within the zona incerta. These neurons also express dopamine immunoreactivity but not dopamine beta‐hydroxylase; thus, dopamine is the likely terminal catecholamine produced by these cells.


    Abstract

    The hypothalamus contains catecholaminergic neurons marked by the expression of tyrosine hydroxylase (TH). As multiple chemical messengers coexist in each neuron, we determined if hypothalamic TH‐immunoreactive (ir) neurons express vesicular glutamate or GABA transporters. We used Cre/loxP recombination to express enhanced GFP (EGFP) in neurons expressing the vesicular glutamate (vGLUT2) or GABA transporter (vGAT), then determined whether TH‐ir neurons colocalized with native EGFP Vglut2 ‐ or EGFP Vgat ‐fluorescence, respectively. EGFP Vglut2 neurons were not TH‐ir. However, discrete TH‐ir signals colocalized with EGFP Vgat neurons, which we validated by in situ hybridization for Vgat mRNA. To contextualize the observed pattern of colocalization between TH‐ir and EGFP Vgat , we first performed Nissl‐based parcellation and plane‐of‐section analysis, and then mapped the distribution of TH‐ir EGFP Vgat neurons onto atlas templates from the Allen Reference Atlas (ARA ) for the mouse brain. TH‐ir EGFP Vgat neurons were distributed throughout the rostrocaudal extent of the hypothalamus. Within the ARA ontology of gray matter regions, TH‐ir neurons localized primarily to the periventricular hypothalamic zone, periventricular hypothalamic region, and lateral hypothalamic zone. There was a strong presence of EGFP Vgat fluorescence in TH‐ir neurons across all brain regions, but the most striking colocalization was found in a circumscribed portion of the zona incerta (ZI)—a region assigned to the hypothalamus in the ARA —where every TH‐ir neuron expressed EGFP Vgat . Neurochemical characterization of these ZI neurons revealed that they display immunoreactivity for dopamine but not dopamine β‐hydroxylase. Collectively, these findings indicate the existence of a novel mouse hypothalamic population that may signal through the release of GABA and/or dopamine.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    The role of PDLIM1, a PDZ‐LIM domain protein, at the ribbon synapses in the chicken retina

    The role of PDLIM1, a PDZ‐LIM domain protein, at the ribbon synapses in the chicken retina

    We report that a protein belonged to the PDLIM family is associated to the retinal periactive zone in cones of the chicken retina. PDLIM1, is a cytoskeletal protein that acts as an adapter that allows the trafficking of other proteins, like kinases, to the cytoskeleton and plays a role in controlling neurite outgrowth. The data in this work demonstrated that PDLIM1 delineates the cone's terminals and intermingles between the ribbons of the synapses. The localization of PDLIM1 could be of importance not only for understanding the molecular anatomy of the terminal ending in cones, but also to knowledge the fine mechanisms of the process of neurotransmission.


    Abstract

    PDLIM's protein family is involved in the rearrangement of the actin cytoskeleton. In the present study, we describe the localization of PDLIM1 in chicken photoreceptors. This study provides evidence that this protein is present at the cone pedicles, as well as in other synapses of the chicken retina. Here, we demonstrate the expression pattern of PDLIM1 through immunofluorescence staining, immunoblots, subcellular fractionation, and immunoprecipitation experiments. Also, we consider the possibility that PDLIM1 may be involved in the synaptic vesicle endocytosis and/or the presynaptic trafficking of synaptic vesicles back to the nonready releasable pool. This endocytotic/exocytotic coupling requires a tight link between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. In turn, photoreceptor ribbon synaptic structure depends on the cytoskeleton arrangement, both at the active zone‐related with exocytosis—as well as at the endocytic zone—periactive zone. To our knowledge, the PDLIM1 protein has not been observed in the pre synapses of the retina. Thus, the present study describes the expression and subcellular localization of PDLIM1 for the first time, as well as its modulation by visual environment in the chicken retina.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice

    Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice

    Retrograde transsynaptic virus (a) allowed to trace (two to three synapses) projections onto the main olfactory bulb (b). Monosynaptic cholera toxin b (a) was a control to differentiate direct and indirect projections. The MOB mainly receives indirect projections from hypothalamic nuclei (c) and reward‐related regions (c1), underlining the role of olfaction in feeding (d).


    Abstract

    A wide range of evidence indicates that olfactory perception is strongly involved in food intake. However, the polysynaptic circuitry linking the brain areas involved in feeding behavior to the olfactory regions is not well known. The aim of this article was to examine such circuits. Thus, we described, using hodological tools such as transsynaptic viruses (PRV152) transported in a retrograde manner, the long‐distance indirect projections (two to three synapses) onto the main olfactory bulb (MOB). The ß‐subunit of the cholera toxin which is a monosynaptic retrograde tracer was used as a control to be able to differentiate between direct and indirect projections. Our tracing experiments showed that the arcuate nucleus of the hypothalamus, as a major site for regulation of food intake, sends only very indirect projections onto the MOB. Indirect projections to MOB also originate from the solitary nucleus which is involved in energy homeostasis. Other indirect projections have been evidenced in areas of the reward circuit such as VTA and accumbens nucleus. In contrast, direct projections to the MOB arise from melanin‐concentrating hormone and orexin neurons in the lateral hypothalamus. Functional significances of these projections are discussed in relation to the role of food odors in feeding and reward‐related behavior.

    in Journal of Comparative Neurology on May 28, 2020 12:22 PM.

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    Three-dimensional pore network characterization of reconstructed extracellular matrix

    Author(s): Seongjin Park, Seongjin Lim, Pan Siriviriyakul, and Jessie S. Jeon

    The extracellular matrix (ECM) has a fiber network that provides physical scaffolds to cells and plays important roles by regulating cellular functions. Some previous works characterized the mechanical and geometrical properties of the ECM fiber network using reconstituted collagen-I. However, the c...


    [Phys. Rev. E 101, 052414] Published Thu May 28, 2020

    in Physical Review E: Biological physics on May 28, 2020 10:00 AM.

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    Collective intracellular cargo transport by multiple kinesins on multiple microtubules

    Author(s): Kejie Chen, Woochul Nam, and Bogdan I. Epureanu

    The transport of intracellular organelles is accomplished by groups of molecular motors, such as kinesin, myosin, and dynein. Previous studies have demonstrated that the cooperation between kinesins on a track is beneficial for long transport. However, within crowded three-dimensional (3D) cytoskele...


    [Phys. Rev. E 101, 052413] Published Thu May 28, 2020

    in Physical Review E: Biological physics on May 28, 2020 10:00 AM.

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    Consequences of Dale's law on the stability-complexity relationship of random neural networks

    Author(s): J. R. Ipsen and A. D. H. Peterson

    In the study of randomly connected neural network dynamics there is a phase transition from a simple state with few equilibria to a complex state characterized by the number of equilibria growing exponentially with the neuron population. Such phase transitions are often used to describe pathological...


    [Phys. Rev. E 101, 052412] Published Thu May 28, 2020

    in Physical Review E: Biological physics on May 28, 2020 10:00 AM.

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    Extrinsic noise of the target gene governs abundance pattern of feed-forward loop motifs

    Author(s): Md Sorique Aziz Momin and Ayan Biswas

    Feed-forward loop (FFL) is found to be a recurrent structure in bacterial and yeast gene transcription regulatory networks. In a generic FFL, transcription factor (TF) S regulates production of another TF X while both of these TFs regulate production of final gene-product Y. Depending upon the regul...


    [Phys. Rev. E 101, 052411] Published Thu May 28, 2020

    in Physical Review E: Biological physics on May 28, 2020 10:00 AM.

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    Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

    Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre- and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. In a complex NMJ organization centering on MuSK: (1) the Wnt non-canonical pathway through the Wnt-Lrp4-MuSK cysteine-rich domain (CRD)-Dishevelled (Dvl, scaffold protein) signaling acts to form AChR prepatterning with axonal guidance; (2) the neural agrin-Lrp4-MuSK (Ig1/2 domains) signaling acts to form rapsyn-anchored AChR clusters at the innervated stage of muscle; (3) adaptor protein Dok-7 acts on MuSK activation for AChR clustering from “inside” and also on cytoskeleton to stabilize AChR clusters by the downstream effector Sorbs1/2; (4) the trans-synaptic retrograde signaling contributes to the presynaptic organization via: (i) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 pathway; (ii) Lrp4; and (iii) laminins. The presynaptic Ca2+ homeostasis conditioning ACh release is modified by autoreceptors such as M1-type muscarinic AChR and A2A adenosine receptors. The post-synaptic structure is stabilized by: (i) laminin-network including the muscle-derived agrin; (ii) the extracellular matrix proteins (including collagen Q/perlecan and biglycan which link to MuSK Ig1 domain and CRD); and (iii) the dystrophin-associated glycoprotein complex. The study on MuSK ectodomains (Ig1/2 domains and CRD) recognized by antibodies suggested that the MuSK antibodies were pathologically heterogeneous due to their binding to multiple functional domains. Focussing one of the matrix proteins, biglycan which functions in the manner similar to collagen Q, our antibody assay showed the negative result in MG patients. However, the synaptic stability may be impaired by antibodies against MuSK ectodomains because of the linkage of biglycan with MuSK Ig1 domain and CRD. The pathogenic diversity of MG is discussed based on NMJ signaling molecules.

    in Frontiers in Molecular Neuroscience on May 28, 2020 12:00 AM.

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    Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research

    Rett syndrome is a debilitating neurodevelopmental disorder for which no disease-modifying treatment is available. Fortunately, advances in our understanding of the genetics and pathophysiology of Rett syndrome has led to the development of promising new therapeutics for the condition. Several of these therapeutics are currently being tested in clinical trials with others likely to progress to clinical trials in the coming years. The failure of recent clinical trials for Rett syndrome and other neurodevelopmental disorders has highlighted the need for electrophysiological or other objective biological markers of treatment response to support the success of clinical trials moving forward. The purpose of this review is to describe the existing studies of electroencephalography (EEG) and evoked potentials (EPs) in Rett syndrome and discuss the open questions that must be addressed before the field can adopt these measures as surrogate endpoints in clinical trials. In addition to summarizing the human work on Rett syndrome, we also describe relevant studies with animal models and the limited research that has been carried out on Rett-related disorders, particularly methyl-CpG binding protein 2 (MECP2) duplication syndrome, CDKL5 deficiency disorder, and FOXG1 disorder.

    in Frontiers in Integrative Neuroscience on May 28, 2020 12:00 AM.

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    Distinct Insular Functional Connectivity Changes Related to Mood and Fatigue Improvements in Major Depressive Disorder Following Tai Chi Training: A Pilot Study

    Objective: Tai chi (TC), a contemplative practice combining slow movements and deep breathing, has been shown to be clinically effective in alleviating depressive symptoms. Feelings of fatigue or low vitality often accompany major depressive disorder (MDD) though they are commonly overlooked and not well understood neurologically. By using resting state functional connectivity (rs-FC) using the insula as the seed, this study examines the relationship between mood and vitality symptoms in MDD and how they are impacted by TC training.

    Methods: Patients (N = 16) with MDD participated in a 10-week TC intervention. Self-report scores of vitality (using the SF-36 scale) and depressed mood (using the Beck Depression Inventory) as well as rs-fMRI were collected pre- and post-intervention. A seed-to-voxel approach was used to test whether changes in insular rs-FC were related to therapeutic improvement in MDD-related symptoms resulting from TC practice.

    Results: We found decreased self-reported depressed mood and increased vitality following the TC intervention. Furthermore, decreases in depressed mood were associated with increased rs-FC between the right anterior insula (AIC) and superior temporal gyrus and caudate (cluster-corrected p < 0.05). Increased vitality was associated with increased rs-FC between the right posterior insula (PIC) and regions associated with sensorimotor processes (cluster-corrected p < 0.05).

    Conclusion: These results provide support for differential changes in insula connectivity as neural correlates of symptom improvement in MDD.

    in Frontiers in Integrative Neuroscience on May 28, 2020 12:00 AM.

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    Understanding Cortical Dysfunction in Schizophrenia With TMS/EEG

    In schizophrenia and related disorders, a deeper mechanistic understanding of neocortical dysfunction will be essential to developing new diagnostic and therapeutic techniques. To this end, combined transcranial magnetic stimulation and electroencephalography (TMS/EEG) provides a non-invasive tool to simultaneously perturb and measure neurophysiological correlates of cortical function, including oscillatory activity, cortical inhibition, connectivity, and synchronization. In this review, we summarize the findings from a variety of studies that apply TMS/EEG to understand the fundamental features of cortical dysfunction in schizophrenia. These results lend to future applications of TMS/EEG in understanding the pathophysiological mechanisms underlying cognitive deficits in schizophrenia.

    in Frontiers in Neuroscience: Brain Imaging Methods on May 28, 2020 12:00 AM.

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    A New Statistical Framework for Corpus Callosum Sub-Region Characterization Based on LBP Texture in Patients With Parkinsonian Disorders: A Pilot Study

    Purpose

    The study is conducted to identify the best corpus callosum (CC) sub-region that corresponds to highest callosal tissue alteration occurred due to Parkinsonism. In this regard the efficacy of local binary pattern (LBP) based texture analysis (TA) of CC is performed to quantify the changes in topographical distribution of callosal fiber connected to different regions of cortex. The extent of highest texture alteration in CC is used for differential diagnosis.

    Materials and Methods

    Study included subjects with Parkinson’s disease (PD) (n = 20), and atypical Parkinsonian disorders – multiple system atrophy (MSA) (n = 20), Progressive supranuclear palsy (PSP) (n = 20), and healthy controls (n = 20). For each subject, we have automated the ROI extraction within mid-sagittal CC, followed by LBP TA. Two-class support vector machine (SVM) classification for each disorder as against HC is performed using extracted LBP features like energy and entropy. Correct classification ratio (CCR) is computed as the fraction of correctly classified ROIs at each of the CC sub-regions based on well-known Witelson and Hofer schemes. Based on CCR values, the “Scatter Index (SI)” is proposed to capture how localized (closer to 0) or scattered (closer to 1) the textural changes are among the CC sub-regions, across all subjects per class. The CCR values are further utilized to classify the disease groups.

    Results

    Highest alteration of texture is observed in mid-body of CC. The consistency of this finding is quantified using SI for all subjects in a specific class that results more localized textural changes in PSP (15%) and MSA (25%), in comparison to PD (47%). Classification among disease groups results maximum classification accuracy of 90% in classifying PSP from PD-NC.

    Conclusion

    Our result demonstrates the efficacy of proposed methodology in analyzing tissue alteration in MRI of Parkinsonian disorders and thus has potential to become valuable tool in computer aided differential diagnosis.

    in Frontiers in Neuroscience: Neurodegeneration on May 28, 2020 12:00 AM.

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    Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish

    Besides several endogenous elements, exogenous factors, including exposure to pesticides, have been recognized as putative factors contributing to the onset and development of neurodegenerative diseases, including Parkinson’s disease (PD). Considering the availability, success rate, and limitations associated with the current arsenals to fight PD, there is an unmet need for novel therapeutic interventions. Therefore, based on the previously reported beneficial functions of the L1 cell adhesion molecule, we hypothesized that L1 mimetic compounds may serve to neutralize neurotoxicity triggered by the pesticide paraquat (PQ). In this study, we attempt to use PQ for inducing PD-like pathology and the L1 mimetic compounds phenelzine sulfate (PS) and tacrine (TC) as potential candidates for the amelioration of PD symptoms using zebrafish as a model system. Administration of PQ together with the L1 mimetic compounds PS or TC (250 nM) improved survival of zebrafish larvae, protected them from locomotor deficits, and increased their sensorimotor reflexes. Moreover, application of PQ together with PS (500 nM) or TC (1000 nM) in adult zebrafish counteracted PQ-induced toxicity, maintaining normal locomotor functions and spatial memory in an open field and T-maze task, respectively. Both L1 mimetic compounds prevented reduction in tyrosine hydroxylase and dopamine levels, reduced reactive oxygen species (ROS) generation, protected against impairment of mitochondrial viability, improved the antioxidant enzyme system, and prevented a decrease in ATP levels. Altogether, our findings highlight the beneficial functions of the agonistic L1 mimetics PS and TC by improving several vital cell functions against PQ-triggered neurotoxicity.

    in Frontiers in Neuroscience: Neurodegeneration on May 28, 2020 12:00 AM.

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    Sammba-MRI: A Library for Processing SmAll-MaMmal BrAin MRI Data in Python

    Small-mammal neuroimaging offers incredible opportunities to investigate structural and functional aspects of the brain. Many tools have been developed in the last decade to analyse small animal data, but current softwares are less mature than the available tools that process human brain data. The Python package Sammba-MRI (SmAll-MaMmal BrAin MRI in Python; http://sammba-mri.github.io) allows flexible and efficient use of existing methods and enables fluent scriptable analysis workflows, from raw data conversion to multimodal processing.

    in Frontiers in Neuroinformatics on May 28, 2020 12:00 AM.

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    Theta-Nested Gamma Oscillations in Next Generation Neural Mass Models

    Theta-nested gamma oscillations have been reported in many areas of the brain and are believed to represent a fundamental mechanism to transfer information across spatial and temporal scales. In a series of recent experiments in vitro it has been possible to replicate with an optogenetic theta frequency stimulation several features of cross-frequency coupling (CFC) among theta and gamma rhythms observed in behaving animals. In order to reproduce the main findings of these experiments we have considered a new class of neural mass models able to reproduce exactly the macroscopic dynamics of spiking neural networks. In this framework, we have examined two set-ups able to support collective gamma oscillations: namely, the pyramidal interneuronal network gamma (PING) and the interneuronal network gamma (ING). In both set-ups we observe the emergence of theta-nested gamma oscillations by driving the system with a sinusoidal theta-forcing in proximity of a Hopf bifurcation. These mixed rhythms always display phase amplitude coupling. However, two different types of nested oscillations can be identified: one characterized by a perfect phase locking between theta and gamma rhythms, corresponding to an overall periodic behavior; another one where the locking is imperfect and the dynamics is quasi-periodic or even chaotic. From our analysis it emerges that the locked states are more frequent in the ING set-up. In agreement with the experiments, we find theta-nested gamma oscillations for forcing frequencies in the range [1:10] Hz, whose amplitudes grow proportionally to the forcing intensity and which are clearly modulated by the theta phase. Furthermore, analogously to the experiments, the gamma power and the frequency of the gamma-power peak increase with the forcing amplitude. At variance with experimental findings, the gamma-power peak does not shift to higher frequencies by increasing the theta frequency. This effect can be obtained, in our model, only by incrementing, at the same time, also the stimulation power. An effect achieved by increasing the amplitude either of the noise or of the forcing term proportionally to the theta frequency. On the basis of our analysis both the PING and the ING mechanism give rise to theta-nested gamma oscillations with almost identical features.

    in Frontiers in Computational Neuroscience on May 28, 2020 12:00 AM.

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    Stress-Related Neuronal Clusters in Sublenticular Extended Amygdala of Basal Forebrain Show Individual Differences of Positions

    To understand functional neuronal circuits for emotion in the basal forebrain, patterns of neuronal activation were examined in mice by immunohistochemistry of immediate-early gene products (Zif268/Egr1 and c-Fos). In all mice examined, clusters of 30–50 neurons expressing Zif268 were found on both sides in the area between the extended amygdala (EA) and globus pallidus (GP), generally designated as sublenticular extended amygdala (SLEA). The clusters consisted of 79.9 ± 3.0% of GABAergic neurons in GAD65-mCherry mice. The expression of the cholinergic marker choline acetyltransferase and the GP markers parvalbumin, proenkephalin, and FoxP2 indicated that these neurons were different from known types of neurons in the EA and GP; therefore, we named them the sublenticular extended amygdalar Zif268/Egr1-expressing neuronal cluster (SLEA-zNC). Sublenticular extended amygdalar Zif268/Egr1-expressing neuronal clusters participated in stress processing because increasing numbers of cells were observed in SLEA-zNCs after exposure to restraint stress (RS), the induction of which was suppressed by diazepam treatment. Mapping SLEA-zNCs showed that their positions and arrangement varied individually; SLEA-zNCs were distributed asymmetrically and tended to be situated mainly in the middle region between the anterior commissure (AC) and posterior end of the GP. However, the total cell number in SLEA-zNCs was compatible between the right and left hemispheres after activation by RS. Therefore, SLEA-zNCs were distributed asymmetrically but were not lateralized. Because time courses of activation differed between the Zif268 and c-Fos, the sequential dual treatment of RSs enabled us to differentiate SLEA-zNCs activated by the first and second RS. The results supported that the same SLEA-zNCs responded to both the first and second RS, and this also applied for all SLEA-zNCs. Thus, we concluded that the cluster positions were invariable under RS in each mouse but were distributed differently between individual mice. We name these newly identified neuronal clusters as stress-related neuronal clusters, SLEA-zNCs, which are considered to be novel functional units of “islands of activation.” Moreover, SLEA-zNCs were situated at different positions in all mice examined, showing individual differences in their positions.

    in Frontiers in Neural Circuits on May 28, 2020 12:00 AM.

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    Stimulus Contrast Information Modulates Sensorimotor Decision Making in Goldfish

    Animal survival relies on environmental information gathered by their sensory systems. We found that contrast information of a looming stimulus biases the type of defensive behavior that goldfish (Carassius auratus) perform. Low-contrast looms only evoke subtle alarm reactions whose probability is independent of contrast. As looming contrast increases, the probability of eliciting a fast escape maneuver, the C-start response, increases dramatically. Contrast information also modulates the decision of when to escape. Although response latency is known to depend on looming retinal size, we found that contrast acts as an additional parameter influencing this decision. When presenting progressively higher contrast stimuli, animals need shorter periods of stimulus processing to initiate the response. Our results comply with the notion that the decision to escape is a flexible process initiated with stimulus detection and followed by assessment of the perceived risk posed by the stimulus. Highly disruptive behaviors as the C-start are only observed when a multifactorial threshold that includes stimulus contrast is surpassed.

    in Frontiers in Neural Circuits on May 28, 2020 12:00 AM.

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    Red Photoactivatable Genetic Optical-Indicators

    Emerging genetically-encoded Ca2+-indicators (GECIs) are intensiometric reporters that increase in fluorescence when bound to Ca2+; highly suited for studying calcium-signaling in many cell types, notably neurons. Today, major efforts are devoted toward optimizing red-emitting [red fluorescent protein (RFP)-based] GECIs (R-GECI), as these provide several advantages over GFP-based reporters, for instance, increased imaging depth, reduced photodamage by longer imaging wavelengths and, in principle, are better suited for use with prevalent blue-absorbing optogenetic tools (e.g., channelrhodopsin). However, excessive fluorescence from intersecting neighboring cells in very dense tissues, notably the brain, hinders the ability to collect signals from single cells and their processes. This challenge can be addressed by photoactivatable (PA) fluorescent proteins that can be rendered fluorescent on demand by user-defined targeted light. This allows activation and, thereby, collection of fluorescent signals exclusively from desired cells and their processes, while leaving all neighboring cells in the dark (i.e., non-fluorescent). Nevertheless, there are no PA R-GECIs. Here, we sought to develop PA-R-GECIs. To do so, we initially explored a recently discovered phenomenon of Ca2+-independent increases in fluorescence (i.e., artifacts) in an emerging R-GECI, which has led us to rationally engineer several functional PA-R-GECIs. We also take advantage of our findings to quickly engineer a novel PA-RFP, namely, PA-mRuby3.

    in Frontiers in Cellular Neuroscience on May 28, 2020 12:00 AM.

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    Antennal Lobe Atlas of an Emerging Corn Pest, Athetis dissimilis

    Moths develop sophisticated olfactory systems to sense the airborne chemical cues from the environment. Understanding the structural basis in the neuronal center is a fundamental neuroethological step. Little is known about the emerging crop pest Athetis dissimilis with regard to its morphology or its neuronal organizations. Through antibody staining and digital 3D modeling, we re-constructed the primary olfactory center—the antennal lobe of A. dissimilis. In the antennal lobes 68.8 ± 3.1 male glomeruli and 70.8 ± 1.0 female glomeruli were identified with obvious sexual dimorphism. In particular, male adults of A. dissimilis contain a macroglomerular complex (MGC) that consists of three subunits, while the female lobe has four relatively enlarged glomeruli at the entrance of the antennal nerve. Glomeruli were later clustered with deviation and variance, and referring to reported olfactory related receptor family genes in seven different moth species, we found that glomerular counts of these insects are better related to the sum of odorant receptor and ionotropic receptor numbers, suggesting olfactory receptors and ionotropic receptors may both involved in olfaction of Noctuidae moths.

    in Frontiers in Neuroanatomy on May 28, 2020 12:00 AM.

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    Vestibular impact of Friedreich ataxia in early onset patients

    Friedreich ataxia (FRDA) is the most frequent form of inherited ataxias. Vestibular and auditory assessments are not commonly part of the check up for these patients despite hearing and balance complaints. Scr...

    in Cerebellum and Ataxias on May 28, 2020 12:00 AM.

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    Afferent and efferent connections of the nucleus prethalamicus in the yellowfin goby Acanthogobius flavimanus

    Afferent and efferent connections of the nucleus prethalamicus in the yellowfin goby Acanthogobius flavimanus

    The nucleus prethalamicus of the yellowfin goby relays visual information from the optic tectum to as many as 13 regions of the telencephalon that is amazingly well compartmentalized in the goby. The goby is a promising model fish for studying telencephalic circuitries involved in the processing of visual information.


    Abstract

    The nucleus prethalamicus (PTh) receives fibers from the optic tectum and then projects to the dorsal telencephalon in the yellowfin goby Acanthogobius flavimanus . However, it remained unclear whether the PTh is a visual relay nucleus, because the optic tectum receives not only visual but also other sensory modalities. Furthermore, precise telencephalic regions receiving prethalamic input remained unknown in the goby. We therefore investigated the full set of afferent and efferent connections of the PTh by direct tracer injections into the nucleus. Injections into the PTh labeled cells in the optic tectum, ventromedial thalamic nucleus, central and medial parts of the dorsal telencephalon, and caudal lobe of the cerebellum. We found that the somata of most tecto‐prethalamic neurons are present in the stratum periventriculare. Their dendrites ascend to reach the major retinorecipient layers of the tectum. The PTh is composed of two subnuclei (medial and lateral) and topographic organization was appreciated only for tectal projections to the lateral subnucleus (PTh‐l), which also receives sparse retinal projections. In contrast, the medial subnucleus receives fibers only from the medial tectum. We found that the PTh projects to nine subregions in the dorsal telencephalon and four in the ventral telencephalon. Furthermore, cerebellar injections revealed that cerebello‐prethalamic fibers cross the midline twice to innervate the PTh‐l on both sides. The present study is the first detailed report on the full set of the connections of PTh, which suggests that the PTh relays visual information from the optic tectum to the telencephalon.

    in Journal of Comparative Neurology on May 27, 2020 07:00 PM.

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    Antagonism of peripheral opioid receptors by methylnaltrexone does not prevent morphine tolerance in rats

    Antagonism of peripheral opioid receptors by methylnaltrexone does not prevent morphine tolerance in rats

    Blockade of peripheral opioid receptors with the peripherally restricted antagonist, methylnaltrexone (MNTX), had no effect on acute morphine antinociception or development of tolerance. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.


    Abstract

    Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague‐Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5–30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail‐flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography‐tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.

    in Journal of Neuroscience Research on May 27, 2020 11:10 AM.

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    Clinical and basic research investigations into the long‐term effects of prenatal opioid exposure on brain development

    Abstract

    Coincident with the opioid epidemic in the United States has been a dramatic increase in the number of children born with neonatal abstinence syndrome (NAS), a form of withdrawal resulting from opioid exposure during pregnancy. Many research efforts on NAS have focused on short‐term care, including acute symptom treatment and weaning of the infants off their drug dependency prior to authorizing their release. However, investigations into the long‐term effects of prenatal opioid exposure (POE) on brain development, from the cellular to the behavioral level, have not been as frequent. Given the importance of the perinatal period for human brain development, opioid‐induced disturbances in the formation and function of nascent synaptic networks and glia have the potential to impact brain connectivity and cognition long after the drug supply is cutoff shortly after birth. In this review, we will summarize the current state of NAS research, bringing together findings from human studies and preclinical animal models to highlight what is known about how POE can induce significant, prolonged deficits in brain structure and function. With rates of NAS continuing to rise, particularly in regions that already face substantial socioeconomic challenges, we speculate as to the most promising avenues for future research to alleviate this growing multigenerational threat.

    in Journal of Neuroscience Research on May 27, 2020 10:44 AM.

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    Adhesion-stabilizing long-distance transport of cells on tissue surface

    Author(s): Katsuyoshi Matsushita

    The stable transport of migrating eukaryotic cells is essential in organ development and repair processes. However, the mechanism that preserves transport stability over long distances in organs is not fully understood. As the driving mechanism of cell migration, the expressions of heterophilic cell...


    [Phys. Rev. E 101, 052410] Published Wed May 27, 2020

    in Physical Review E: Biological physics on May 27, 2020 10:00 AM.

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    Dysregulation of the Retromer Complex System in Down Syndrome

    Objective

    Most of the patients with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by age 40. Although this increased susceptibility to AD in DS is thought to be primarily due to triplication of the amyloid precursor protein located on chromosome 21, the precise molecular mechanisms are not well understood. Recent evidence has implicated defective protein sorting and trafficking secondary to deficiencies in retromer complex proteins in AD pathogenesis. Thus, the objective of the present study is to assess the retromer complex system in DS.

    Methods

    Human postmortem brain tissue and fibroblasts from subjects with DS and healthy controls were examined for the various retromer protein components using Western blot analysis and reverse transcription quantitative polymerase chain reaction (RT‐qPCR).

    Results

    Retromer recognition core proteins were significantly decreased in DS fibroblasts, and in both the hippocampi and cortices of young (age 15–40 years old) and aged (40–65 years old) subjects with DS compared with controls. Correlation analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of Aβ 1–40 and 1–42 in both hippocampus (n = 33, Spearman = −0.59 to −0.38, p  ≤ 0.03 for VPS35, VPS26, VPS29, and VPS26B) and cortex tissue (n = 57, Spearman = −0.46 to −0.27, p  ≤ 0.04 for VPS35, VPS26, and VPS29) of the same patients.

    Interpretation

    We conclude that dysregulation of the retromer complex system is an early event in the development of the AD‐like pathology and cognitive decline in DS, and for this reason the system could represent a novel potential therapeutic target for DS. ANN NEUROL 2020

    in Annals of Neurology on May 27, 2020 09:22 AM.

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    A-to-Z interactions in fear extinction

    Nature Reviews Neuroscience, Published online: 27 May 2020; doi:10.1038/s41583-020-0321-3

    A-to-Z interactions in fear extinction

    in Nature Reviews on May 27, 2020 12:00 AM.

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    Action pictures

    Nature Reviews Neuroscience, Published online: 27 May 2020; doi:10.1038/s41583-020-0320-4

    Action pictures

    in Nature Reviews on May 27, 2020 12:00 AM.

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    Audition for a speaking role

    Nature Reviews Neuroscience, Published online: 27 May 2020; doi:10.1038/s41583-020-0319-x

    Audition for a speaking role

    in Nature Reviews on May 27, 2020 12:00 AM.

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    Figuring out body integrity dysphoria

    Nature Reviews Neuroscience, Published online: 27 May 2020; doi:10.1038/s41583-020-0318-y

    Figuring out body integrity dysphoria

    in Nature Reviews on May 27, 2020 12:00 AM.

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    Physical Exercise May Increase Plasma Concentration of High-Density Lipoprotein-Cholesterol in Patients With Alzheimer’s Disease

    Lifestyle factors have been shown to increase the risk of developing Alzheimer’s disease (AD) later in life. Specifically, an unfavorable cholesterol profile, and insulin resistance are associated with increased risk of developing AD. One way to non-pharmacologically affect the levels of plasma lipids is by exercise, which has been shown to be beneficial in cognitively healthy individuals. In this randomized controlled trial y, we therefore aimed to clarify the effect of physical exercise on the lipid profile, insulin and glucose in patients with AD. In addition, we investigated the effect of apolipoproteinE genotype on total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein–cholesterol (LDL-C), and triglycerides (TG) in plasma from patients with AD. Plasma samples from 172 patients who underwent 16 weeks of moderate-to-high intensity exercise (n = 90) or treatment as usual (n = 82) were analyzed change from baseline for the levels of total cholesterol, LDL-C, HDL-C, TG, glucose, and insulin. In addition, we analyzed those from the exercise group who adhered to the protocol with an attendance of 2/3 or more of the exercise session and who followed the protocol of an intensity of 70% of the maximum heart rate. We found a significant increase in plasma HDL-C levels between the “high exercise sub-group” compared to control group. After intervention HDL-C was increased by 4.3% in the high-exercise group, and decreased by 0.7% in the control group, after adjustment for statin use. In conclusion, short term physical activity may be beneficial on the cholesterol profile in patients with AD.

    in Frontiers in Neuroscience: Neurodegeneration on May 27, 2020 12:00 AM.

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    Functional Segregation of the Middle Temporal Visual Motion Area Revealed With Coactivation-Based Parcellation

    Traditionally, the visual motion area (MT) is considered as a brain region specialized for visual motion perception. However, accumulating evidence showed that MT is also related to various functions, suggesting that it is a complex functional area and different functional subregions might exist in this area. To delineate functional subregions of this area, left and right masks of MT were defined using meta-analysis in the BrainMap database, and coactivation-based parcellation was then performed on these two masks. Two dorsal subregions (Cl1 and Cl2) and one ventral subregion (Cl3) of left MT, as well as two dorsal-anterior subregions (Cl1 and Cl2), one ventral-anterior subregion (Cl3), and an additional posterior subregion (Cl4) of right MT were identified. In addition to vision motion, distinct and specific functions were identified in different subregions characterized by task-dependent functional connectivity mapping and forward/reverse inference on associated functions. These results not only were in accordance with the previous findings of a hemispheric asymmetry of MT, but also strongly confirmed the existence of subregions in this region with distinct and specific functions. Furthermore, our results extend the special role of visual motion perception on this area and might facilitate future cognitive study.

    in Frontiers in Neuroscience: Brain Imaging Methods on May 27, 2020 12:00 AM.

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    Editorial: Reproducibility and Rigour in Computational Neuroscience

    in Frontiers in Neuroinformatics on May 27, 2020 12:00 AM.

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    Pre-stimulus EEG Microstates Correlate With Anticipatory Alpha Desynchronization

    In the last decades, several electrophysiological markers have been investigated to better understand how humans precede a signaled event. Among others, the pre-stimulus microstates’ topography, representing the whole brain activity, has been proposed as a promising index of the anticipatory period in several cognitive tasks. However, to date, a clear relationship between the metrics of the pre-stimulus microstates [i.e., the global explained variance (GEV) and the frequency of occurrence (FOO)] and well-known electroencephalography marker of the anticipation (i.e., the alpha power reduction) has not been investigated. Here, after extracting the microstates during the expectancy of the semantic memory task, we investigate the correlations between the microstate features and the anticipatory alpha (8–12 Hz) power reduction (i.e., the event-related de-synchronization of the alpha rhythms; ERD) that is widely interpreted as a functional correlate of brain activation. We report a positive correlation between the occurrence of the dominant, but not non-dominant, microstate and both the mean amplitude of high-alpha ERD and the magnitude of the alpha ERD peak so that the stronger the decrease (percentage) in the alpha power, the higher the FOO of the dominant microstate. Moreover, we find a positive correlation between the occurrence of the dominant microstate and the latency of the alpha ERD peak, suggesting that subjects with higher FOO present the stronger alpha ERD closely to the target. These correlations are not significant between the GEV and all anticipatory alpha ERD indices. Our results suggest that only the occurrence of the dominant, but not non-dominant, microstate should be considered as a useful electrophysiological correlate of the cortical activation.

    in Frontiers in Human Neuroscience on May 27, 2020 12:00 AM.

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    Reaching and Grasping Training Improves Functional Recovery After Chronic Cervical Spinal Cord Injury

    Previous studies suggest locomotion training could be an effective non-invasive therapy after spinal cord injury (SCI) using primarily acute thoracic injuries. However, the majority of SCI patients have chronic cervical injuries. Regaining hand function could significantly increase their quality of life. In this study, we used a clinically relevant chronic cervical contusion to study the therapeutic efficacy of rehabilitation in forelimb functional recovery. Nude rats received a moderate C5 unilateral contusive injury and were then divided into two groups with or without Modified Montoya Staircase (MMS) rehabilitation. For the rehabilitation group, rats were trained 5 days a week starting at 8 weeks post-injury (PI) for 6 weeks. All rats were assessed for skilled forelimb functions with MMS test weekly and for untrained gross forelimb locomotion with grooming and horizontal ladder (HL) tests biweekly. Our results showed that MMS rehabilitation significantly increased the number of pellets taken at 13 and 14 weeks PI and the accuracy rates at 12 to 14 weeks PI. However, there were no significant differences in the grooming scores or the percentage of HL missteps at any time point. Histological analyses revealed that MMS rehabilitation significantly increased the number of serotonergic fibers and the amount of presynaptic terminals around motor neurons in the cervical ventral horns caudal to the injury and reduced glial fibrillary acidic protein (GFAP)-immunoreactive astrogliosis in spinal cords caudal to the lesion. This study shows that MMS rehabilitation can modify the injury environment, promote axonal sprouting and synaptic plasticity, and importantly, improve reaching and grasping functions in the forelimb, supporting the therapeutic potential of task-specific rehabilitation for functional recovery after chronic SCI.

    in Frontiers in Cellular Neuroscience on May 27, 2020 12:00 AM.

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    Involvement of Frontal Functions in Pain Tolerance in Aging: Evidence From Neuropsychological Assessments and Gamma-Band Oscillations

    Reduced pain tolerance may be one of the possible explanations for high prevalence of chronic pain among older people. We hypothesized that age-related alterations in pain tolerance are associated with functioning deterioration of the frontal cortex during normal aging. Twenty-one young and 41 elderly healthy participants underwent a tonic heat pain test, during which cerebral activity was recorded using electroencephalography (EEG). Elderly participants were divided into two subgroups according to their scores on executive tests, high performers (HPs; n = 21) and low performers (LPs; n = 20). Pain measures [exposure times (ETs) and perceived pain ratings] and cerebral activity were compared among the three groups. ETs were significantly lower in elderly LPs than in young participants and elderly HPs. Electroencephalographic analyses showed that gamma-band oscillations (GBOs) were significantly increased in pain state for all subjects, especially in the frontal sites. Source analysis showed that GBO increase in elderly LPs was contributed not only by frontal but also by central, parietal, and occipital regions. These findings suggest that better preservation of frontal functions may result in better pain tolerance by elderly subjects.

    in Frontiers in Ageing Neuroscience on May 27, 2020 12:00 AM.

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    Rapid 3D Enhanced Resolution Microscopy Reveals Diversity in Dendritic Spinule Dynamics, Regulation, and Function

    Enhanced resolution 3D microscopy reveals the dynamics of thin dendritic spine protrusions, termed spinules, which are uniquely regulated by local Ca2+ and the Rac1-GEF kalirin-7. The majority are small, short-lived, dynamic, and recurrent, whereas an elongated subset is activity-induced, stabilized by distal presynaptic terminals, and can form connectivity-altering secondary synapses.

    in Neuron: In press on May 27, 2020 12:00 AM.

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    Microbial communities display alternative stable states in a fluctuating environment

    by Clare I. Abreu, Vilhelm L. Andersen Woltz, Jonathan Friedman, Jeff Gore

    The effect of environmental fluctuations is a major question in ecology. While it is widely accepted that fluctuations and other types of disturbances can increase biodiversity, there are fewer examples of other types of outcomes in a fluctuating environment. Here we explore this question with laboratory microcosms, using cocultures of two bacterial species, P. putida and P. veronii. At low dilution rates we observe competitive exclusion of P. veronii, whereas at high dilution rates we observe competitive exclusion of P. putida. When the dilution rate alternates between high and low, we do not observe coexistence between the species, but rather alternative stable states, in which only one species survives and initial species’ fractions determine the identity of the surviving species. The Lotka-Volterra model with a fluctuating mortality rate predicts that this outcome is independent of the timing of the fluctuations, and that the time-averaged mortality would also lead to alternative stable states, a prediction that we confirm experimentally. Other pairs of species can coexist in a fluctuating environment, and again consistent with the model we observe coexistence in the time-averaged dilution rate. We find a similar time-averaging result holds in a three-species community, highlighting that simple linear models can in some cases provide powerful insight into how communities will respond to environmental fluctuations.

    in PLoS Computational Biology on May 26, 2020 09:00 PM.

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    Chloride dynamics alter the input-output properties of neurons

    by Christopher B. Currin, Andrew J. Trevelyan, Colin J. Akerman, Joseph V. Raimondo

    Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.

    in PLoS Computational Biology on May 26, 2020 09:00 PM.

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    Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites

    by Agata P. Perlinska, Adam Stasiulewicz, Ewa K. Nawrocka, Krzysztof Kazimierczuk, Piotr Setny, Joanna I. Sulkowska

    S-adenosylmethionine (SAM) is one of the most important enzyme substrates. It is vital for the function of various proteins, including large group of methyltransferases (MTs). Intriguingly, some bacterial and eukaryotic MTs, while catalysing the same reaction, possess significantly different topologies, with the former being a knotted one. Here, we conducted a comprehensive analysis of SAM conformational space and factors that affect its vastness. We investigated SAM in two forms: free in water (via NMR studies and explicit solvent simulations) and bound to proteins (based on all data available in the PDB and on all-atom molecular dynamics simulations in water). We identified structural descriptors—angles which show the major differences in SAM conformation between unknotted and knotted methyltransferases. Moreover, we report that this is caused mainly by a characteristic for knotted MTs compact binding site formed by the knot and the presence of adenine-binding loop. Additionally, we elucidate conformational restrictions imposed on SAM molecules by other protein groups in comparison to conformational space in water.

    in