• #### Controller design for finite-time and fixed-time stabilization of fractional-order memristive complex-valued BAM neural networks with uncertain parameters and time-varying delays

Publication date: Available online 3 July 2020

Source: Neural Networks

Author(s): Emel Arslan, G. Narayanan, M. Syed Ali, Sabri Arik, Sumit Saroha

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

• #### Progressive Tandem Learning for Pattern Recognition with Deep Spiking Neural Networks. (arXiv:2007.01204v1 [cs.NE])

Spiking neural networks (SNNs) have shown clear advantages over traditional artificial neural networks (ANNs) for low latency and high computational efficiency, due to their event-driven nature and sparse communication. However, the training of deep SNNs is not straightforward. In this paper, we propose a novel ANN-to-SNN conversion and layer-wise learning framework for rapid and efficient pattern recognition, which is referred to as progressive tandem learning of deep SNNs. By studying the equivalence between ANNs and SNNs in the discrete representation space, a primitive network conversion method is introduced that takes full advantage of spike count to approximate the activation value of analog neurons. To compensate for the approximation errors arising from the primitive network conversion, we further introduce a layer-wise learning method with an adaptive training scheduler to fine-tune the network weights. The progressive tandem learning framework also allows hardware constraints, such as limited weight precision and fan-in connections, to be progressively imposed during training. The SNNs thus trained have demonstrated remarkable classification and regression capabilities on large-scale object recognition, image reconstruction, and speech separation tasks, while requiring at least an order of magnitude reduced inference time and synaptic operations than other state-of-the-art SNN implementations. It, therefore, opens up a myriad of opportunities for pervasive mobile and embedded devices with a limited power budget.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### Multiclass Classification with an Ensemble of Binary Classification Deep Networks. (arXiv:2007.01192v1 [cs.CV])

Deep neural network classifiers have been used frequently and are efficient. In multiclass deep network classifiers, the burden of classifying samples of different classes is put on a single classifier. As shown in this paper, the classification capability of deep networks can be further increased by using an ensemble of binary classification deep networks. In the proposed approach, a single (one-versus-all) deep network binary classifier is dedicated to each category classification. Subsequently, binary classification deep network ensembles have been investigated. Every network in an ensemble has been trained by a one-versus-all binary training technique using the Stochastic Gradient Descent with Momentum Algorithm. For classification of the test sample, the sample is presented to each network in the ensemble. After softmax-layer score voting, the network with the largest score is assumed to have classified the sample. Digit image recognition has been used for experimentation. Three datasets have been used for experimentation viz. the MATLAB Digit Image Dataset, the USPS+ Digit Image Dataset, and the MNIST Digit Image Dataset. The experiments demonstrate that given sufficient training, a Binary Classification Convolutional Neural Network (BCCNN) ensemble can outperform a conventional Multi-class Convolutional Neural Network (MCNN). In one of the experiments, it was noted that after training and testing of a BCCNN ensemble and an MCNN respectively on a subset of the MNIST Digit Image Dataset, the BCCNN ensemble gave a higher accuracy of 98.03% as compared to the MCNN which gave an accuracy of 97.90%. The architecture of the BCCNNs in an ensemble has also been modified in order to increase their recognition accuracy. On a large subset of the MNIST Digit Image Dataset, the modified BCCNN ensemble gave a higher accuracy of 98.50%, while as the MCNN gave an accuracy of 98.4875%.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### Are there any 'object detectors' in the hidden layers of CNNs trained to identify objects or scenes?. (arXiv:2007.01062v1 [cs.CV])

Various methods of measuring unit selectivity have been developed with the aim of better understanding how neural networks work. But the different measures provide divergent estimates of selectivity, and this has led to different conclusions regarding the conditions in which selective object representations are learned and the functional relevance of these representations. In an attempt to better characterize object selectivity, we undertake a comparison of various selectivity measures on a large set of units in AlexNet, including localist selectivity, precision, class-conditional mean activity selectivity (CCMAS), network dissection,the human interpretation of activation maximization (AM) images, and standard signal-detection measures. We find that the different measures provide different estimates of object selectivity, with precision and CCMAS measures providing misleadingly high estimates. Indeed, the most selective units had a poor hit-rate or a high false-alarm rate (or both) in object classification, making them poor object detectors. We fail to find any units that are even remotely as selective as the 'grandmother cell' units reported in recurrent neural networks. In order to generalize these results, we compared selectivity measures on units in VGG-16 and GoogLeNet trained on the ImageNet or Places-365 datasets that have been described as 'object detectors'. Again, we find poor hit-rates and high false-alarm rates for object classification. We conclude that signal-detection measures provide a better assessment of single-unit selectivity compared to common alternative approaches, and that deep convolutional networks of image classification do not learn object detectors in their hidden layers.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### A Novel DNN Training Framework via Data Sampling and Multi-Task Optimization. (arXiv:2007.01016v1 [cs.NE])

Conventional DNN training paradigms typically rely on one training set and one validation set, obtained by partitioning an annotated dataset used for training, namely gross training set, in a certain way. The training set is used for training the model while the validation set is used to estimate the generalization performance of the trained model as the training proceeds to avoid over-fitting. There exist two major issues in this paradigm. Firstly, the validation set may hardly guarantee an unbiased estimate of generalization performance due to potential mismatching with test data. Secondly, training a DNN corresponds to solve a complex optimization problem, which is prone to getting trapped into inferior local optima and thus leads to undesired training results. To address these issues, we propose a novel DNN training framework. It generates multiple pairs of training and validation sets from the gross training set via random splitting, trains a DNN model of a pre-specified structure on each pair while making the useful knowledge (e.g., promising network parameters) obtained from one model training process to be transferred to other model training processes via multi-task optimization, and outputs the best, among all trained models, which has the overall best performance across the validation sets from all pairs. The knowledge transfer mechanism featured in this new framework can not only enhance training effectiveness by helping the model training process to escape from local optima but also improve on generalization performance via implicit regularization imposed on one model training process from other model training processes. We implement the proposed framework, parallelize the implementation on a GPU cluster, and apply it to train several widely used DNN models. Experimental results demonstrate the superiority of the proposed framework over the conventional training paradigm.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### PGD-UNet: A Position-Guided Deformable Network for Simultaneous Segmentation of Organs and Tumors. (arXiv:2007.01001v1 [eess.IV])

Precise segmentation of organs and tumors plays a crucial role in clinical applications. It is a challenging task due to the irregular shapes and various sizes of organs and tumors as well as the significant class imbalance between the anatomy of interest (AOI) and the background region. In addition, in most situation tumors and normal organs often overlap in medical images, but current approaches fail to delineate both tumors and organs accurately. To tackle such challenges, we propose a position-guided deformable UNet, namely PGD-UNet, which exploits the spatial deformation capabilities of deformable convolution to deal with the geometric transformation of both organs and tumors. Position information is explicitly encoded into the network to enhance the capabilities of deformation. Meanwhile, we introduce a new pooling module to preserve position information lost in conventional max-pooling operation. Besides, due to unclear boundaries between different structures as well as the subjectivity of annotations, labels are not necessarily accurate for medical image segmentation tasks. It may cause the overfitting of the trained network due to label noise. To address this issue, we formulate a novel loss function to suppress the influence of potential label noise on the training process. Our method was evaluated on two challenging segmentation tasks and achieved very promising segmentation accuracy in both tasks.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### MPLP: Learning a Message Passing Learning Protocol. (arXiv:2007.00970v1 [cs.LG])

We present a novel method for learning the weights of an artificial neural network - a Message Passing Learning Protocol (MPLP). In MPLP, we abstract every operations occurring in ANNs as independent agents. Each agent is responsible for ingesting incoming multidimensional messages from other agents, updating its internal state, and generating multidimensional messages to be passed on to neighbouring agents. We demonstrate the viability of MPLP as opposed to traditional gradient-based approaches on simple feed-forward neural networks, and present a framework capable of generalizing to non-traditional neural network architectures. MPLP is meta learned using end-to-end gradient-based meta-optimisation. We further discuss the observed properties of MPLP and hypothesize its applicability on various fields of deep learning.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### High Dimensional Bayesian Optimization Assisted by Principal Component Analysis. (arXiv:2007.00925v1 [cs.NE])

Bayesian Optimization (BO) is a surrogate-assisted global optimization technique that has been successfully applied in various fields, e.g., automated machine learning and design optimization. Built upon a so-called infill-criterion and Gaussian Process regression (GPR), the BO technique suffers from a substantial computational complexity and hampered convergence rate as the dimension of the search spaces increases. Scaling up BO for high-dimensional optimization problems remains a challenging task. In this paper, we propose to tackle the scalability of BO by hybridizing it with a Principal Component Analysis (PCA), resulting in a novel PCA-assisted BO (PCA-BO) algorithm. Specifically, the PCA procedure learns a linear transformation from all the evaluated points during the run and selects dimensions in the transformed space according to the variability of evaluated points. We then construct the GPR model, and the infill-criterion in the space spanned by the selected dimensions. We assess the performance of our PCA-BO in terms of the empirical convergence rate and CPU time on multi-modal problems from the COCO benchmark framework. The experimental results show that PCA-BO can effectively reduce the CPU time incurred on high-dimensional problems, and maintains the convergence rate on problems with an adequate global structure. PCA-BO therefore provides a satisfactory trade-off between the convergence rate and computational efficiency opening new ways to benefit from the strength of BO approaches in high dimensional numerical optimization.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### Modelling Drosophila Motion Vision Pathways for Decoding the Direction of Translating Objects Against Cluttered Moving Backgrounds. (arXiv:2007.00886v1 [q-bio.NC])

Decoding the direction of translating objects in front of cluttered moving backgrounds, accurately and efficiently, is still a challenging problem. In nature, lightweight and low-powered flying insects apply motion vision to detect a moving target in highly variable environments during flight, which are excellent paradigms to learn motion perception strategies. This paper investigates the fruit fly \textit{Drosophila} motion vision pathways and presents computational modelling based on cutting-edge physiological researches. The proposed visual system model features bio-plausible ON and OFF pathways, wide-field horizontal-sensitive (HS) and vertical-sensitive (VS) systems. The main contributions of this research are on two aspects: 1) the proposed model articulates the forming of both direction-selective (DS) and direction-opponent (DO) responses, revealed as principal features of motion perception neural circuits, in a feed-forward manner; 2) it also shows robust direction selectivity to translating objects in front of cluttered moving backgrounds, via the modelling of spatiotemporal dynamics including combination of motion pre-filtering mechanisms and ensembles of local correlators inside both the ON and OFF pathways, which works effectively to suppress irrelevant background motion or distractors, and to improve the dynamic response. Accordingly, the direction of translating objects is decoded as global responses of both the HS and VS systems with positive or negative output indicating preferred-direction (PD) or null-direction (ND) translation. The experiments have verified the effectiveness of the proposed neural system model, and demonstrated its responsive preference to faster-moving, higher-contrast and larger-size targets embedded in cluttered moving backgrounds.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### Hardware Acceleration of Sparse and Irregular Tensor Computations of ML Models: A Survey and Insights. (arXiv:2007.00864v1 [cs.AR])

Machine learning (ML) models are widely used in many domains including media processing and generation, computer vision, medical diagnosis, embedded systems, high-performance and scientific computing, and recommendation systems. For efficiently processing these computational- and memory-intensive applications, tensors of these over-parameterized models are compressed by leveraging sparsity, size reduction, and quantization of tensors. Unstructured sparsity and tensors with varying dimensions yield irregular-shaped computation, communication, and memory access patterns; processing them on hardware accelerators in a conventional manner does not inherently leverage acceleration opportunities. This paper provides a comprehensive survey on how to efficiently execute sparse and irregular tensor computations of ML models on hardware accelerators. In particular, it discusses additional enhancement modules in architecture design and software support; categorizes different hardware designs and acceleration techniques and analyzes them in terms of hardware and execution costs; highlights further opportunities in terms of hardware/software/algorithm co-design optimizations and joint optimizations among described hardware and software enhancement modules. The takeaways from this paper include: understanding the key challenges in accelerating sparse, irregular-shaped, and quantized tensors; understanding enhancements in acceleration systems for supporting their efficient computations; analyzing trade-offs in opting for a specific type of design enhancement; understanding how to map and compile models with sparse tensors on the accelerators; understanding recent design trends for efficient accelerations and further opportunities.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### Adversarial Neural Pruning with Latent Vulnerability Suppression. (arXiv:1908.04355v4 [cs.LG] UPDATED)

Despite the remarkable performance of deep neural networks on various computer vision tasks, they are known to be susceptible to adversarial perturbations, which makes it challenging to deploy them in real-world safety-critical applications. In this paper, we conjecture that the leading cause of adversarial vulnerability is the distortion in the latent feature space, and provide methods to suppress them effectively. Explicitly, we define \emph{vulnerability} for each latent feature and then propose a new loss for adversarial learning, \emph{Vulnerability Suppression (VS)} loss, that aims to minimize the feature-level vulnerability during training. We further propose a Bayesian framework to prune features with high vulnerability to reduce both vulnerability and loss on adversarial samples. We validate our \emph{Adversarial Neural Pruning with Vulnerability Suppression (ANP-VS)} method on multiple benchmark datasets, on which it not only obtains state-of-the-art adversarial robustness but also improves the performance on clean examples, using only a fraction of the parameters used by the full network. Further qualitative analysis suggests that the improvements come from the suppression of feature-level vulnerability.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### A Survey on Bayesian Deep Learning. (arXiv:1604.01662v3 [stat.ML] UPDATED)

A comprehensive artificial intelligence system needs to not only perceive the environment with different senses' (e.g., seeing and hearing) but also infer the world's conditional (or even causal) relations and corresponding uncertainty. The past decade has seen major advances in many perception tasks such as visual object recognition and speech recognition using deep learning models. For higher-level inference, however, probabilistic graphical models with their Bayesian nature are still more powerful and flexible. In recent years, Bayesian deep learning has emerged as a unified probabilistic framework to tightly integrate deep learning and Bayesian models. In this general framework, the perception of text or images using deep learning can boost the performance of higher-level inference and in turn, the feedback from the inference process is able to enhance the perception of text or images. This survey provides a comprehensive introduction to Bayesian deep learning and reviews its recent applications on recommender systems, topic models, control, etc. Besides, we also discuss the relationship and differences between Bayesian deep learning and other related topics such as Bayesian treatment of neural networks.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 03, 2020 01:30 AM.

• #### Wnt-controlled sphingolipids modulate Anthrax Toxin Receptor palmitoylation to regulate oriented mitosis in zebrafish

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17196-3

During development, oriented cell division is important to proper body axis extension. Here, the authors show that sphingolipids are required to direct spindle rotation and oriented mitosis via Anthrax receptor palmitoylation in zebrafish gastrulation.

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

• #### The Seminavis robusta genome provides insights into the evolutionary adaptations of benthic diatoms

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17191-8

Available genomics studies have mostly focused on planktonic centric diatom. Here, the authors report the genome assembly of the marine biofilm-forming diatom Seminavis robusta and the resequencing data of a panel of accessions to reveal their evolutionary adaptations.

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

• #### The RNA quality control pathway nonsense-mediated mRNA decay targets cellular and viral RNAs to restrict KSHV

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17151-2

Cellular nonsense-mediated mRNA decay (NMD) has been shown to play a role in defense against RNA viruses. Here, Zhao et al. show that NMD restricts the DNA virus Kaposi sarcoma-associated herpesvirus (KSHV) via targeting both cellular and viral transcripts leading to inhibition of KSHV lytic reactivation.

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

• #### Fast three-color single-molecule FRET using statistical inference

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17149-w

Three-colour FRET is a powerful tool to study macromolecular conformational dynamics, but is temporally limited due to the experimental complexity. Here the authors develop experimental and analytical methods for probing submillisecond-time scale dynamics using single continuous-wave excitation.

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

• #### De novo design of Au36(SR)24 nanoclusters

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17132-5

The discovery of atomically precise metal nanoclusters is generally unpredictable, and there are few examples of their rational synthesis. Here, the authors report the de novo design of Au36(SR)24 nanoclusters, from theoretical prediction to experimental synthesis and characterization of physicochemical properties.

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

• #### Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17109-4

In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B.

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

• #### The induction and function of the anti-inflammatory fate of TH17 cells

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17097-5

CD4+ T helper cells producing IL-17A (TH17 cells) can take on pathogenic or anti-inflammatory functions in context-specific manners. Here the authors show that the anti-inflammatory fate of TH17 cells contributes, via TGF-β signaling and induction of IL-10, to host immune tolerance, but also simultaneously dampens protective immunity against S. aureus.

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

• #### Anomalous 3D nanoscale photoconduction in hybrid perovskite semiconductors revealed by tomographic atomic force microscopy

Nature Communications, Published online: 03 July 2020; doi:10.1038/s41467-020-17012-y

The role of grain boundaries (GBs) in halide perovskite is an interesting topic but existing investigations are limited to the top surface. Here Song et al. employ tomographic AFM to study the buried features of grains and GBs, revealing coexistence of interconnected conducting and inert GBs.

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

• #### Daily briefing: Cosmologists are mapping invisible magnetic fields that pervade the Universe

Nature, Published online: 03 July 2020; doi:10.1038/d41586-020-02022-z

Curved magnetic fields could have arisen in the first instants after the Big Bang. Plus: the best evidence yet for the existence of particle-like anyons, and how sewage surveillance could be used to track coronavirus outbreaks.

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

• #### Coronapod: Lessons from pandemic ‘war-game’ simulations

Nature, Published online: 03 July 2020; doi:10.1038/d41586-020-02020-1

Biosecurity experts use military-style exercises to plan for biological threats. Have their warnings been heeded?

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

• #### A guide to R — the pandemic’s misunderstood metric

Nature, Published online: 03 July 2020; doi:10.1038/d41586-020-02009-w

What the reproduction number can and can’t tell us about managing COVID-19.

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

• #### Six months of coronavirus: the mysteries scientists are still racing to solve

Nature, Published online: 03 July 2020; doi:10.1038/d41586-020-01989-z

From immunity to the role of genetics, Nature looks at five pressing questions about COVID-19 that researchers are tackling.

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

• #### Welcome anyons! Physicists find best evidence yet for long-sought 2D structures

Nature, Published online: 03 July 2020; doi:10.1038/d41586-020-01988-0

The ‘quasiparticles’ defy the categories of ordinary particles and herald a potential way to build quantum computers.

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

• #### Goodbye, Pluto’s atmosphere

Nature, Published online: 03 July 2020; doi:10.1038/d41586-020-01985-3

The gases that envelop the distant dwarf planet might finally be freezing out and falling to the surface.

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

• #### A Pilot Adaptive Neurofeedback Investigation of the Neural Mechanisms of Implicit Emotion Regulation Among Women With PTSD

Posttraumatic stress disorder (PTSD) is widely associated with deficits in implicit emotion regulation. Recently, adaptive fMRI neurofeedback (A-NF) has been developed as a methodology that offers a unique probe of brain networks that mediate implicit emotion regulation and their impairment in PTSD. We designed an A-NF paradigm in which difficulty of an emotional conflict task (i.e., embedding trauma distractors onto a neutral target stimulus) was controlled by a whole-brain classifier trained to differentiate attention to the trauma distractor vs. target. We exploited this methodology to test whether PTSD was associated with: (1) an altered brain state that differentiates attention towards vs. away from trauma cues; and (2) an altered ability to use concurrent feedback about brain states during an implicit emotion regulation task. Adult women with a current diagnosis of PTSD (n = 10) and healthy control (n = 9) women participated in this task during 3T fMRI. During two initial non-feedback runs used to train a whole-brain classifier, we observed: (1) poorer attention performance in PTSD; and (2) a linear relationship between brain state discrimination and attention performance, which was significantly attenuated among the PTSD group when the task contained trauma cues. During the A-NF phase, the PTSD group demonstrated poorer ability to regulate brain states as per attention instructions, and this poorer ability was related to PTSD symptom severity. Further, PTSD was associated with the heightened encoding of feedback in the insula and hippocampus. These results suggest a novel understanding of whole-brain states and their regulation that underlie emotion regulation deficits in PTSD.

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

• #### Targeting Catecholaminergic Systems in Transgenic Rats With a CAV-2 Vector Harboring a Cre-Dependent DREADD Cassette

Techniques that allow the manipulation of specific neural circuits have greatly increased in the past few years. DREADDs (Designer receptors exclusively activated by designer drugs) provide an elegant way to manipulate individual brain structures and/or neural circuits, including neuromodulatory pathways. Considerable efforts have been made to increase cell-type specificity of DREADD expression while decreasing possible limitations due to multiple viral vectors injections. In line with this, a retrograde canine adenovirus type 2 (CAV-2) vector carrying a Cre-dependent DREADD cassette has been recently developed. In combination with Cre-driver transgenic animals, the vector allows one to target neuromodulatory pathways with cell-type specificity. In the present study, we specifically targeted catecholaminergic pathways by injecting the vector in knock-in rat line containing Cre recombinase cassette under the control of the tyrosine hydroxylase promoter. We assessed the efficacy of infection of the nigrostriatal pathway and the catecholaminergic pathways ascending to the orbitofrontal cortex (OFC) and found cell-type-specific DREADD expression.

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

• #### Reciprocal Interplay Between Astrocytes and CD4+ Cells Affects Blood-Brain Barrier and Neuronal Function in Response to β Amyloid

Background: In Alzheimer’s disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. However, the role of T cells, once they migrate into the CNS, is not well defined. CD4+ cells interact with astrocytes able to release several factors and cytokines that can modulate T cell polarization; similarly, astrocytic properties are modulated after interaction with T cells.

Methods: In in vitro models, astrocytes were primed with β-amyloid (Aβ; 2.5 μM, 5 h) and then co-cultured with magnetically isolated CD4+ cells. Cytokines expression was evaluated both in co-cultured CD4+ cells and astrocytes. The effects of this crosstalk were further evaluated by co-culturing CD4+ cells with the neuronal-like SH-SY5Y cell line and astrocytes with endothelial cells.

Results: The pattern of cytokines and trophic factors expressed by CD4+ cells were strongly modulated in the presence of Aβ-primed astrocytes. Specifically, the percentage of IL-4+ and IFNγ+ CD4+ cells was significantly increased and reduced, respectively. Further, increased BDNF mRNA levels were observed in CD4+ cells. When SH-SY5Y cells were co-cultured with astrocyte-conditioned CD4+ cells and exposed to Aβ, the reduction of the presynaptic protein synaptophysin was prevented with a BDNF-dependent mechanism. In astrocytes co-cultured with CD4+ cells, reduced mRNA levels of inflammatory cytokines and VEGF were observed. This was paralleled by the prevention of the reduction of claudin-5 when astrocytes were co-cultured with endothelial cells.

Conclusion: Following Aβ exposure, there exists reciprocal crosstalk between infiltrating peripheral cells and astrocytes that in turn affects not only endothelial function and thus BBB properties, but also neuronal behavior. Since astrocytes are the first cells that lymphocytes interact with and are among the principal players in neuroinflammation occurring in AD, understanding this crosstalk may disclose new potential targets of intervention in the treatment of neurodegeneration.

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

• #### A History of Concussion Affects Relevancy-Based Modulation of Cortical Responses to Tactile Stimuli

Modulating cortical excitability based on a stimulus’ relevance to the task at hand is a component of sensory gating, and serves to protect higher cortical centers from being overwhelmed with irrelevant information (McIlroy et al., 2003; Kumar et al., 2005; Wasaka et al., 2005). This study examined relevancy-based modulation of cortical excitability, and corresponding behavioral responses, in the face of distracting stimuli in participants with and without a history of concussion (mean age 22 ± 3 SD years; most recent concussion 39.1 ± 30 SD months). Participants were required to make a scaled motor response to the amplitudes of visual and tactile stimuli presented individually or concurrently. Task relevance was manipulated, and stimuli were occasionally presented with irrelevant distractors. Electroencephalography (EEG) and task accuracy data were collected from participants with and without a history of concussion. The somatosensory-evoked N70 event-related potential (ERP) was significantly modulated by task relevance in the control group but not in those with a history of concussion, and there was a significantly greater cost to task accuracy in the concussion history group when relevant stimuli were presented with an irrelevant distractor. This study demonstrated that relevancy-based modulation of electrophysiological responses and behavioral correlates of sensory gating differ in people with and without a history of concussion, even after patients were symptom-free and considered recovered from their injuries.

in Frontiers in Integrative Neuroscience on July 03, 2020 12:00 AM.

• #### In vivo Retinal Fluorescence Imaging With Curcumin in an Alzheimer Mouse Model

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques in the brain detectable by highly invasive in vivo brain imaging or in post-mortem tissues. A non-invasive and inexpensive screening method is needed for early diagnosis of asymptomatic AD patients. The shared developmental origin and similarities with the brain make the retina a suitable surrogate tissue to assess Aβ load in AD. Using curcumin, a FluoroProbe that binds to Aβ, we labeled and measured the retinal fluorescence in vivo and compared with the immunohistochemical measurements of the brain and retinal Aβ load in the APP/PS1 mouse model. In vivo retinal images were acquired every 2 months using custom fluorescence scanning laser ophthalmoscopy (fSLO) after tail vein injections of curcumin in individual mice followed longitudinally from ages 5 to 19 months. At the same time points, 1–2 mice from the same cohort were sacrificed and immunohistochemistry was performed on their brain and retinal tissues. Results demonstrated cortical and retinal Aβ immunoreactivity were significantly greater in Tg than WT groups. Age-related increase in retinal Aβ immunoreactivity was greater in Tg than WT groups. Retinal Aβ immunoreactivity was present in the inner retinal layers and consisted of small speck-like extracellular deposits and intracellular labeling in the cytoplasm of a subset of retinal ganglion cells. In vivo retinal fluorescence with curcumin injection was significantly greater in older mice (11–19 months) than younger mice (5–9 months) in both Tg and WT groups. In vivo retinal fluorescence with curcumin injection was significantly greater in Tg than WT in older mice (ages 11–19 months). Finally, and most importantly, the correlation between in vivo retinal fluorescence with curcumin injection and Aβ immunoreactivity in the cortex was stronger in Tg compared to WT groups. Our data reveal that retina and brain of APP/PS1 Tg mice increasingly express Aβ with age. In vivo retinal fluorescence with curcumin correlated strongly with cortical Aβ immunohistochemistry in Tg mice. These findings suggest that using in vivo fSLO imaging of AD-susceptible retina may be a useful, non-invasive method of detecting Aβ in the retina as a surrogate indicator of Aβ load in the brain.

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

• #### Functional Analysis of Continuous, High-Resolution Measures in Aging Research: A Demonstration Using Cerebral Oxygenation Data From the Irish Longitudinal Study on Aging

Background: A shift towards the dynamic measurement of physiologic resilience and improved technology incorporated into experimental paradigms in aging research is producing high-resolution data. Identifying the most appropriate analysis method for this type of data is a challenge. In this work, the functional principal component analysis (fPCA) was employed to demonstrate a data-driven approach to the analysis of high-resolution data in aging research.

Methods: Cerebral oxygenation during standing was measured in a large cohort [The Irish Longitudinal Study on Aging (TILDA)]. FPCA was performed on tissue saturation index (TSI) data. A regression analysis was then conducted with the functional principal component (fPC) scores as the explanatory variables and transition time as the response.

Results: The mean ± SD age of the analysis sample was 64 ± 8 years. Females made up 54% of the sample and overall, 43% had tertiary education. The first PC explained 96% of the variance in cerebral oxygenation upon standing and was related to a baseline shift. Subsequent components described the recovery to before-stand levels (fPC2), drop magnitude and initial recovery (fPC3 and fPC4) as well as a temporal shift in the location of the minimum TSI value (fPC5). Transition time was associated with components describing the magnitude and timing of the nadir.

Conclusions: Application of fPCA showed utility in reducing a large amount of data to a small number of parameters which summarize the inter-participant variation in TSI upon standing. A demonstration of principal component regression was provided to allow for continued use and development of data-driven approaches to high-resolution data analysis in aging research.

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

• #### The Acquisition of Survey Knowledge by Individuals With Down Syndrome

People with Down syndrome often exhibit deficiencies in wayfinding activities, particularly route learning (e.g., Courbois et al., 2013; Davis et al., 2014; Farran et al., 2015). Evidence concerning more sophisticated survey learning has been sparse. In the research reported here, two experiments are reported that evaluated survey learning of youth with DS and typically developing children (TD) matched on mental age. In Experiment 1, participants learned two overlapping routes consisting of three turns each through a virtual environment depicting 9 square city blocks. Following acquisition, they were tested on multiple measures of survey knowledge: finding a shortcut, identifying the direction of landmarks not currently visible from their location in the environment, and recognizing a bird’s-eye representation of the overall environment. Under these conditions, which should provide relatively optimal opportunities for survey learning, the participants with DS performed comparably to TD participants matched on non-verbal ability on all of our measures of survey learning. Hence, we concluded that people with DS can acquire some survey knowledge when tasked with learning a small environment and given the opportunity to do so. In Experiment 2, the experimenter navigated participants through a large, relatively complex, virtual environment along a circuitous path, beginning and ending at a target landmark. Then, the participants were placed at a pre-specified location in the environment that they had viewed previously and instructed to navigate to the same target (a door) using the shortest possible path from their current location. They completed the task three times: once after being shown the environment one time, once after three exposures, and once after five exposures. Results indicated that the participants with DS exhibited significantly less skill at identifying the shortcut than did the TD participants, with differences emerging as the number of exposures increased. Participants with DS were also less able to recall landmarks at the end of the experiment. Overall, however, the performance of both groups was relatively poor in both experiments – with the performance of participants with DS being worse as conditions became less optimal. These results were discussed in terms of underlying mechanisms that may account for variations in survey learning as environmental complexity increases.

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

• #### Predicting Cognitive Load and Operational Performance in a Simulated Marksmanship Task

Modern operational environments can place significant demands on a service member's cognitive resources, increasing the risk of errors or mishaps due to overburden. The ability to monitor cognitive burden and associated performance within operational environments is critical to improving mission readiness. As a key step toward a field-ready system, we developed a simulated marksmanship scenario with an embedded working memory task in an immersive virtual reality environment. As participants performed the marksmanship task, they were instructed to remember numbered targets and recall the sequence of those targets at the end of the trial. Low and high cognitive load conditions were defined as the recall of three- and six-digit strings, respectively. Physiological and behavioral signals recorded included speech, heart rate, breathing rate, and body movement. These features were input into a random forest classifier that significantly discriminated between the low- and high-cognitive load conditions (AUC = 0.94). Behavioral features of gait were the most informative, followed by features of speech. We also showed the capability to predict performance on the digit recall (AUC = 0.71) and marksmanship (AUC = 0.58) tasks. The experimental framework can be leveraged in future studies to quantify the interaction of other types of stressors and their impact on operational cognitive and physical performance.

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

• #### Role of Single Low Pulse Intensity of Transcranial Magnetic Stimulation Over the Frontal Cortex for Cognitive Function

Background: The principal aim of this study was to measure the effect of online single-pulse transcranial magnetic stimulation (TMS) over the right dorsolateral prefrontal cortex (DLPFC) on cognition via the Cambridge Neuropsychological Test Automated Battery (CANTAB) in healthy individuals.

Methods: In a single-blind, sham-controlled study, we assessed both 50% and 60% of the resting motor threshold (RMT) over the right DLPFC in healthy right-handed (n = 42) adults using cognitive function, such as attention and memory, as a measure via CANTAB.

Results: We observed an improvement in the cognitive function level during the use of online low intensities of 50% and 60% RMT active stimulation of the DLPFC compared to the sham stimulation.

Conclusions: The results showed that low-intensity TMS can indeed effectively modulate cognitive function in DLPFC. Future research is, however, necessary to investigate the potential effects of low-intensity TMS on different brain areas to increase confidence in the observed results.

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

• #### Mesoscopic Mapping of Stimulus-Selective Response Plasticity in the Visual Pathways Modulated by the Cholinergic System

The cholinergic potentiation of visual conditioning enhances visual acuity and discrimination of the trained stimulus. To determine if this also induces long-term plastic changes on cortical maps and connectivity in the visual cortex and higher associative areas, mesoscopic calcium imaging was performed in head-fixed awake GCaMP6s adult mice before and after conditioning. The conditioned stimulus (0.03 cpd, 30°, 100% contrast, 1 Hz-drifting gratings) was presented 10 min daily for a week. Saline or Donepezil (DPZ, 0.3 mg/kg, s.c.), a cholinesterase inhibitor that potentiates cholinergic transmission, were injected prior to each conditioning session and compared to a sham-conditioned group. Cortical maps of resting state and evoked response to the monocular presentation of conditioned or non-conditioned stimulus (30°, 50 and 75% contrast; 90°, 50, 75, and 100% contrast) were established. Amplitude, duration, and latency of the peak response, as well as size of activation were measured in the primary visual cortex (V1), secondary visual areas (AL, A, AM, PM, LM, RL), retrosplenial cortex (RSC), and higher cortical areas. Visual stimulation increased calcium signaling in all primary and secondary visual areas, the RSC, but no other cortices. There were no significant effects of sham-conditioning or conditioning alone, but DPZ treatment during conditioning significantly decreased the integrated neuronal activity of superficial layers evoked by the conditioned stimulus in V1, AL, PM, and LM. The activity of downstream cortical areas was not changed. The size of the activated area was decreased in V1 and PM, and the signal-to-noise ratio was decreased in AL and PM. Interestingly, signal correlation was seen only between V1, the ventral visual pathway, and the RSC, and was decreased by DPZ administration. The resting state activity was slightly correlated and rarely affected by treatments, except between binocular and monocular V1 in both hemispheres. In conclusion, cholinergic potentiation of visual conditioning induced change in visual processing in the superficial cortical layers. This effect might be a key mechanism in the establishment of the fine cortical tuning in response to the conditioned visual stimulus.

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

• #### Antigen-Dependent T Cell Response to Neural Peptides After Human Ischemic Stroke

Ischemic stroke causes brain tissue damage and may release central nervous system (CNS)-specific peptides to the periphery. Neural antigen presentation in the lymphoid tissue could prime immune cells and result in adaptive immune response. However, autoimmune responses against neural antigens are not commonly uncovered after stroke. We studied the brain tissue of nine fatal stroke cases and the blood of a cohort of 13 patients and 11 controls. Flow cytometry carried out in three of the brain samples showed CD8 and CD4 T cells in the cerebrospinal fluid (CSF) of the ventricles in the patient deceased 1 day poststroke, T cells with an activated phenotype in the CSF of the patient that died at day 6, and T cells in the ischemic brain tissue in the patient deceased 140 days after stroke onset. Immunohistochemistry showed higher T cell numbers in the core of the lesion of the patient deceased 18 days post-stroke than in the patients deceased from 1 to 5 days post-stroke. In blood samples, we studied whether lymphocytes were primed in the periphery against neural antigens at sequential times (on admission, day 5, and day 90) after stroke. T lymphocytes of stroke patients produced IFN-γ and TNF-α and responded to MBP peptides by increasing their production of TNF-α and IL-10 at admission, but not at later time points. In contrast, IL-4 producing T cells showed progressive increases. Higher percentages of TNF-α producing T lymphocytes at admission were independently associated with poorer outcomes at 90 days. However, we did not detect T cell responses to neural-antigen stimulation 90 days post-stroke. Altogether the results suggest acute T cell priming in the periphery in acute stroke, T cell trafficking from the CSF to the ischemic brain tissue, and the existence of active mechanisms preventing autoreactivity.

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

• #### IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model

Aging is a major risk factor for Alzheimer’s disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ1–40/42 concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9–10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ1–40/42. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.

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

• #### Mechanisms of Axon Elongation Following CNS Injury: What Is Happening at the Axon Tip?

After an injury to the central nervous system (CNS), functional recovery is limited by the inability of severed axons to regenerate and form functional connections with appropriate target neurons beyond the injury. Despite tremendous advances in our understanding of the mechanisms of axon growth, and of the inhibitory factors in the injured CNS that prevent it, disappointingly little progress has been made in restoring function to human patients with CNS injuries, such as spinal cord injury (SCI), through regenerative therapies. Clearly, the large number of overlapping neuron-intrinsic and -extrinsic growth-inhibitory factors attenuates the benefit of neutralizing any one target. More daunting is the distances human axons would have to regenerate to reach some threshold number of target neurons, e.g., those that occupy one complete spinal segment, compared to the distances required in most experimental models, such as mice and rats. However, the difficulties inherent in studying mechanisms of axon regeneration in the mature CNS in vivo have caused researchers to rely heavily on extrapolation from studies of axon regeneration in peripheral nerve, or of growth cone-mediated axon development in vitro and in vivo. Unfortunately, evidence from several animal models, including the transected lamprey spinal cord, has suggested important differences between regeneration of mature CNS axons and growth of axons in peripheral nerve, or during embryonic development. Specifically, long-distance regeneration of severed axons may not involve the actin-myosin molecular motors that guide embryonic growth cones in developing axons. Rather, non-growth cone-mediated axon elongation may be required to propel injured axons in the mature CNS. If so, it may be necessary to use other experimental models to promote regeneration that is sufficient to contact a critical number of target neurons distal to a CNS lesion. This review examines the cytoskeletal underpinnings of axon growth, focusing on the elongating axon tip, to gain insights into how CNS axons respond to injury, and how this might affect the development of regenerative therapies for SCI and other CNS injuries.

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

• #### Convolutional Neural Networks Can Predict Retinal Differentiation in Retinal Organoids

We have developed a deep learning-based computer algorithm to recognize and predict retinal differentiation in stem cell-derived organoids based on bright-field imaging. The three-dimensional “organoid” approach for the differentiation of pluripotent stem cells (PSC) into retinal and other neural tissues has become a major in vitro strategy to recapitulate development. We decided to develop a universal, robust, and non-invasive method to assess retinal differentiation that would not require chemical probes or reporter gene expression. We hypothesized that basic-contrast bright-field (BF) images contain sufficient information on tissue specification, and it is possible to extract this data using convolutional neural networks (CNNs). Retina-specific Rx-green fluorescent protein mouse embryonic reporter stem cells have been used for all of the differentiation experiments in this work. The BF images of organoids have been taken on day 5 and fluorescent on day 9. To train the CNN, we utilized a transfer learning approach: ImageNet pre-trained ResNet50v2, VGG19, Xception, and DenseNet121 CNNs had been trained on labeled BF images of the organoids, divided into two categories (retina and non-retina), based on the fluorescent reporter gene expression. The best-performing classifier with ResNet50v2 architecture showed a receiver operating characteristic-area under the curve score of 0.91 on a test dataset. A comparison of the best-performing CNN with the human-based classifier showed that the CNN algorithm performs better than the expert in predicting organoid fate (84% vs. 67 ± 6% of correct predictions, respectively), confirming our original hypothesis. Overall, we have demonstrated that the computer algorithm can successfully recognize and predict retinal differentiation in organoids before the onset of reporter gene expression. This is the first demonstration of CNN’s ability to classify stem cell-derived tissue in vitro.

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

• #### Differences in Hypothalamic Lipid Profiles of Young and Aged Male Rats With Impaired and Unimpaired Spatial Cognitive Abilities and Memory

Lipids play a major role for several brain functions, including cognition and memory. There is a series of work on individual lipids showing involvement in memory mechanisms, a concise lipidome was not reported so far. Moreover, there is no evidence for age-related memory decline and there is only work on brain of young vs. aging animals. Aging animals, however, are not a homogeneous group with respect to memory impairments, thus animals with impaired and unimpaired memory can be discriminated. Following recent studies of hippocampal lipid profiles and hypothalamus controlled hormone profiles, the aim of this study was to compare hypothalamic, lipidomic changes in male Sprague-Dawley rats between young (YM), old impaired (OMI) and old unimpaired (OMU) males. Grouping criterions for aged rats were evaluated by testing them in a spatial memory task, the hole-board. YMs were also tested. Subsequently brains were removed, dissected and hypothalami were kept at −80°C until sample preparation and analysis on liquid chromatography / mass spectrometry (LC-MS). Significant differences in the amounts of a series of lipids from several classes could be detected between young and aged and between OMI and OMU. A large number of lipids were increased in OMI and a smaller number in OMU as compared to young rats. Differences of lipid ratios (log2 of ratio) between OMI and OMU consisted of glycerophosphocholines (aPC 36:2 and 36:3; PC 34:0, 36:1, 36:3 and 40:2); Glycerophosphoethanolamines (aPE 34:2, 38:5 and 40:5; LPE 18:1, 20:1, 20:4, 22:4 and 22:6; PE36:1 and 38:4); glycerophosphoserines (PS 36:1, 40:4, and 40:6); triacylglycerol TG 52:4; ceramide Cer 17:2 and sphingomyelin SM 20:0. Thus, hypothalamic lipid profiles across different lipid classes discriminate aged male animals into OMU and OMI. The underlying mechanisms may be related to different functional networks of lipids in memory mechanisms and differences in metabolic processes. The study underlines the importance of lipidomics in the pathophysiology of age-related cognitive decline. The necessity of evaluating the cognitive status of aged subjects by behavioral tests results in more specific detection of critical lipids in memory decline, on which now can be focused in subsequent memory studies in animals and humans.

in Frontiers in Ageing Neuroscience on July 03, 2020 12:00 AM.

• #### Functional Disorganization of Small-World Brain Networks in Patients With Ischemic Leukoaraiosis

Cognitive impairment is a key clinical feature of ischemic leukoaraiosis (ILA); however, the underlying neurobiological mechanism is still unclear. ILA has been associated with widespread gray and white matter (WM) damage mainly located in cortical-cortical and cortico-subcortical pathways. A total of 36 patients with ILA (Fazekas rating score ≥2) and 31 healthy controls (HCs) underwent comprehensive neuropsychological assessments (covering four cognitive domains, i.e., information processing speed, episodic memory, executive and visuospatial function) and resting-state functional MRI scans. Graph theory-based analyses were employed to explore the topological organization of the brain connectome in ILA patients, and we further sought to explore the associations of connectome-based metrics and neuropsychological performances. An efficient small-world architecture in the functional brain connectome was observed in the ILA and control groups. Moreover, compared with the HCs, the ILA patients showed increased path length and decreased network efficiency (i.e., global and local efficiency) in their functional brain networks. Further network-based statistic (NBS) analysis revealed a functional-disconnected network in ILA, which is comprised of functional connections linking different brain modules (i.e., default mode, frontoparietal, ventral attention and limbic systems) and connections within single modules (i.e., ventral attention and limbic systems). Intriguingly, the abnormal network metrics correlated with cognitive deficits in ILA patients. Therefore, our findings provide further evidence to support the concept that ILA pathologies could disrupt brain connections, impairing network functioning, and cognition via a “disconnection syndrome.”

in Frontiers in Ageing Neuroscience on July 03, 2020 12:00 AM.

• #### Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration

N-myristoylation is a ubiquitous class of protein lipidation across eukaryotes and N-myristoyl transferase (NMT) has been proposed as an attractive drug target in several pathogens. Myristoylation often primes for subsequent palmitoylation and stable membrane attachment, however, growing evidence suggests additional regulatory roles for myristoylation on proteins. Here we describe the myristoylated proteome of Toxoplasma gondii using chemoproteomic methods and show that a small-molecule NMT inhibitor developed against related Plasmodium spp. is also functional in Toxoplasma. We identify myristoylation on a transmembrane protein, the microneme protein 7 (MIC7), which enters the secretory pathway in an unconventional fashion with the myristoylated N-terminus facing the lumen of the micronemes. MIC7 and its myristoylation play a crucial role in the initial steps of invasion, likely during the interaction with and penetration of the host cell. Myristoylation of secreted eukaryotic proteins represents a substantial expansion of the functional repertoire of this co-translational modification.

in eLife on July 03, 2020 12:00 AM.

• #### Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.

in eLife on July 03, 2020 12:00 AM.

• #### Temporal selectivity declines in the aging human auditory cortex

Current models successfully describe the auditory cortical response to natural sounds with a set of spectro-temporal features. However, these models have hardly been linked to the ill-understood neurobiological changes that occur in the aging auditory cortex. Modelling the hemodynamic response to a rich natural sound mixture in N=64 listeners of varying age, we here show that in older listeners' auditory cortex, the key feature of temporal rate is represented with a markedly broader tuning. This loss of temporal selectivity is most prominent in primary auditory cortex and planum temporale, with no such changes in adjacent auditory or other brain areas. Amongst older listeners, we observe a direct relationship between chronological age and temporal-rate tuning, unconfounded by auditory acuity or model goodness of fit. In line with senescent neural dedifferentiation more generally, our results highlight decreased selectivity to temporal information as a hallmark of the aging auditory cortex.

in eLife on July 03, 2020 12:00 AM.

• #### Vestigial auriculomotor activity indicates the direction of auditory attention in humans

Unlike dogs and cats, people do not point their ears as they focus attention on novel, salient, or task-relevant stimuli. Our species may nevertheless have retained a vestigial pinna-orienting system that has persisted as a 'neural fossil’ within in the brain for about 25 million years. Consistent with this hypothesis, we demonstrate that the direction of auditory attention is reflected in sustained electrical activity of muscles within the vestigial auriculomotor system. Surface electromyograms (EMGs) were taken from muscles that either move the pinna or alter its shape. To assess reflexive, stimulus-driven attention we presented novel sounds from speakers at four different lateral locations while the participants silently read a boring text in front of them. To test voluntary, goal-directed attention we instructed participants to listen to a short story coming from one of these speakers, while ignoring a competing story from the corresponding speaker on the opposite side. In both experiments, EMG recordings showed larger activity at the ear on the side of the attended stimulus, but with slightly different patterns. Upward movement (perking) differed according to the lateral focus of attention only during voluntary orienting; rearward folding of the pinna’s upper-lateral edge exhibited such differences only during reflexive orienting. The existence of a pinna-orienting system in humans, one that is experimentally accessible, offers opportunities for basic as well as applied science.

in eLife on July 03, 2020 12:00 AM.

• #### Preparatory Suppression and Facilitation of Voluntary and Involuntary Responses to Loud Acoustic Stimuli in an Anticipatory Timing Task.

In this study, we sought to characterise the effects of intense sensory stimulation at different stages of preparation for an anticipated action on voluntary and involuntary behaviours. In our experiment, we presented unexpected loud acoustic stimuli (LAS) at four critical times during movement preparation (Baseline, -1192 ms, -392 ms, and 0 ms relative to expected movement onset) to probe the state of the nervous system, and measured their effect on voluntary (finger-press) and involuntary (eye-blink startle reflex) motor actions. Voluntary responses were largely facilitated by the LAS, leading to earlier and more forceful responses compared to Control (without LAS) and Baseline conditions. Notably, voluntary responses were significantly facilitated on trials where the LAS was presented early during preparation (-1192 ms). Eye-blink reflexes elicited by the LAS at -392 ms were significantly reduced and delayed compared to other time-points, indicating suppression of sub-cortical excitability. Despite being in a suppressive state, voluntary responses on these trials were still facilitated by the LAS. The results provide insight into the mechanisms involved in preparing anticipatory actions. Induced activation can persist in the nervous system and can modulate subsequent actions for a longer time period than previously thought, highlighting that movement preparation is a continuously evolving process that is susceptible to external influence throughout the preparation period. Suppression of sub-cortical excitability shortly before movement onset is consistent with previous work showing corticospinal suppression which may be a necessary step before the execution of any voluntary response.

in bioRxiv: Neuroscience on July 03, 2020 12:00 AM.

• #### Deep learning-based classification of resting-state fMRI independent-component analysis

Functional connectivity analyses of fMRI data have shown that the activity of the brain at rest is spatially organized into resting-state networks (RSNs). RSNs appear as groups of anatomically distant but functionally tightly connected brain regions. Inter-RSN intrinsic connectivity analyses may provide an optimal spatial level of integration to analyze the variability of the functional connectome. Here, we propose a deep learning approach to enable the automated classification of individual independent-component (IC) decompositions into a set of predefined RSNs. Two databases were used in this work, BIL&GIN and MRi-Share, with 427 and 1811 participants respectively. We trained a multi-layer perceptron (MLP) to classify each IC as one of 45 RSNs, using the IC classification of 282 participants in BIL&GIN for training and a 5-dimensional parameter grid search for hyperparameter optimization. It reached an accuracy of 92%. Predictions on the remaining individuals in BIL&GIN were tested against the original classification and demonstrated good spatial overlap between the cortical RSNs. As a first application, we created an RSN atlas based on MRi-Share. This atlas defined a brain parcellation in 29 RSNs covering 96% of the gray matter. Second, we proposed an individual-based analysis of the subdivision of the default-mode network into 4 networks. Minimal overlap between RSNs was found except in the angular gyrus and potentially in the precuneus. We thus provide the community with an individual IC classifier that can be used to analyze one dataset or to statistically compare different datasets for RSN spatial definitions.

in bioRxiv: Neuroscience on July 03, 2020 12:00 AM.

• #### Estimation of country-level basic reproductive ratios for novel Coronavirus (SARS-CoV-2/COVID-19) using synthetic contact matrices

by Joe Hilton, Matt J. Keeling

The 2019-2020 pandemic of atypical pneumonia (COVID-19) caused by the virus SARS-CoV-2 has spread globally and has the potential to infect large numbers of people in every country. Estimating the country-specific basic reproductive ratio is a vital first step in public-health planning. The basic reproductive ratio (R0) is determined by both the nature of pathogen and the network of human contacts through which the disease can spread, which is itself dependent on population age structure and household composition. Here we introduce a transmission model combining age-stratified contact frequencies with age-dependent susceptibility, probability of clinical symptoms, and transmission from asymptomatic (or mild) cases, which we use to estimate the country-specific basic reproductive ratio of COVID-19 for 152 countries. Using early outbreak data from China and a synthetic contact matrix, we estimate an age-stratified transmission structure which can then be extrapolated to 151 other countries for which synthetic contact matrices also exist. This defines a set of country-specific transmission structures from which we can calculate the basic reproductive ratio for each country. Our predicted R0 is critically sensitive to the intensity of transmission from asymptomatic cases; with low asymptomatic transmission the highest values are predicted across Eastern Europe and Japan and the lowest across Africa, Central America and South-Western Asia. This pattern is largely driven by the ratio of children to older adults in each country and the observed propensity of clinical cases in the elderly. If asymptomatic cases have comparable transmission to detected cases, the pattern is reversed. Our results demonstrate the importance of age-specific heterogeneities going beyond contact structure to the spread of COVID-19. These heterogeneities give COVID-19 the capacity to spread particularly quickly in countries with older populations, and that intensive control measures are likely to be necessary to impede its progress in these countries.

in PLoS Computational Biology on July 02, 2020 09:00 PM.

• #### Brain-optimized extraction of complex sound features that drive continuous auditory perception

by Julia Berezutskaya, Zachary V. Freudenburg, Umut Güçlü, Marcel A. J. van Gerven, Nick F. Ramsey

Understanding how the human brain processes auditory input remains a challenge. Traditionally, a distinction between lower- and higher-level sound features is made, but their definition depends on a specific theoretical framework and might not match the neural representation of sound. Here, we postulate that constructing a data-driven neural model of auditory perception, with a minimum of theoretical assumptions about the relevant sound features, could provide an alternative approach and possibly a better match to the neural responses. We collected electrocorticography recordings from six patients who watched a long-duration feature film. The raw movie soundtrack was used to train an artificial neural network model to predict the associated neural responses. The model achieved high prediction accuracy and generalized well to a second dataset, where new participants watched a different film. The extracted bottom-up features captured acoustic properties that were specific to the type of sound and were associated with various response latency profiles and distinct cortical distributions. Specifically, several features encoded speech-related acoustic properties with some features exhibiting shorter latency profiles (associated with responses in posterior perisylvian cortex) and others exhibiting longer latency profiles (associated with responses in anterior perisylvian cortex). Our results support and extend the current view on speech perception by demonstrating the presence of temporal hierarchies in the perisylvian cortex and involvement of cortical sites outside of this region during audiovisual speech perception.

in PLoS Computational Biology on July 02, 2020 09:00 PM.

• #### A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms

by August George, Paola Bisignano, John M. Rosenberg, Michael Grabe, Daniel M. Zuckerman

Motivated by growing evidence for pathway heterogeneity and alternative functions of molecular machines, we demonstrate a computational approach for investigating two questions: (1) Are there multiple mechanisms (state-space pathways) by which a machine can perform a given function, such as cotransport across a membrane? (2) How can additional functionality, such as proofreading/error-correction, be built into machine function using standard biochemical processes? Answers to these questions will aid both the understanding of molecular-scale cell biology and the design of synthetic machines. Focusing on transport in this initial study, we sample a variety of mechanisms by employing Metropolis Markov chain Monte Carlo. Trial moves adjust transition rates among an automatically generated set of conformational and binding states while maintaining fidelity to thermodynamic principles and a user-supplied fitness/functionality goal. Each accepted move generates a new model. The simulations yield both single and mixed reaction pathways for cotransport in a simple environment with a single substrate along with a driving ion. In a “competitive” environment including an additional decoy substrate, several qualitatively distinct reaction pathways are found which are capable of extremely high discrimination coupled to a leak of the driving ion, akin to proofreading. The array of functional models would be difficult to find by intuition alone in the complex state-spaces of interest.

in PLoS Computational Biology on July 02, 2020 09:00 PM.

• #### Computational models to improve surveillance for cassava brown streak disease and minimize yield loss

by Alex C. Ferris, Richard O. J. H. Stutt, David Godding, Christopher A. Gilligan

Cassava brown streak disease (CBSD) is a rapidly spreading viral disease that affects a major food security crop in sub-Saharan Africa. Currently, there are several proposed management interventions to minimize loss in infected fields. Field-scale data comparing the effectiveness of these interventions individually and in combination are limited and expensive to collect. Using a stochastic epidemiological model for the spread and management of CBSD in individual fields, we simulate the effectiveness of a range of management interventions. Specifically we compare the removal of diseased plants by roguing, preferential selection of planting material, deployment of virus-free ‘clean seed’ and pesticide on crop yield and disease status of individual fields with varying levels of whitefly density crops under low and high disease pressure. We examine management interventions for sustainable production of planting material in clean seed systems and how to improve survey protocols to identify the presence of CBSD in a field or quantify the within-field prevalence of CBSD. We also propose guidelines for practical, actionable recommendations for the deployment of management strategies in regions of sub-Saharan Africa under different disease and whitefly pressure.

in PLoS Computational Biology on July 02, 2020 09:00 PM.

• #### A kinetic mechanism for enhanced selectivity of membrane transport

by Paola Bisignano, Michael A. Lee, August George, Daniel M. Zuckerman, Michael Grabe, John M. Rosenberg

Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intracellular matrix of the organelles (only in eukaryotes). In recent years, a number of high resolution structures have supported this general framework for a wide class of transport molecules, although additional states along the transport pathway are emerging as critically important. Given that substrate binding is often weak in order to enhance overall transport rates, there exists the distinct possibility that transporters may transport the incorrect substrate. This is certainly the case for many pharmaceutical compounds that are absorbed in the gut or cross the blood brain barrier through endogenous transporters. Docking studies on the bacterial sugar transporter vSGLT reveal that many highly toxic compounds are compatible with binding to the orthosteric site, further motivating the selective pressure for additional modes of selectivity. Motivated by recent work in which we observed failed substrate delivery in a molecular dynamics simulation where the energized ion still goes down its concentration gradient, we hypothesize that some transporters evolved to harness this ‘slip’ mechanism to increase substrate selectivity and reduce the uptake of toxic molecules. Here, we test this idea by constructing and exploring a kinetic transport model that includes a slip pathway. While slip reduces the overall productive flux, when coupled with a second toxic molecule that is more prone to slippage, the overall substrate selectivity dramatically increases, suppressing the accumulation of the incorrect compound. We show that the mathematical framework for increased substrate selectivity in our model is analogous to the classic proofreading mechanism originally proposed for tRNA synthase; however, because the transport cycle is reversible we identified conditions in which the selectivity is essentially infinite and incorrect substrates are exported from the cell in a ‘detoxification’ mode. The cellular consequences of proofreading and membrane slippage are discussed as well as the impact on future drug development.

in PLoS Computational Biology on July 02, 2020 09:00 PM.

• #### Resting-state brain and spinal cord networks in humans are functionally integrated

by Shahabeddin Vahdat, Ali Khatibi, Ovidiu Lungu, Jürgen Finsterbusch, Christian Büchel, Julien Cohen-Adad, Veronique Marchand-Pauvert, Julien Doyon

In the absence of any task, both the brain and spinal cord exhibit spontaneous intrinsic activity organised in a set of functionally relevant neural networks. However, whether such resting-state networks (RSNs) are interconnected across the brain and spinal cord is unclear. Here, we used a unique scanning protocol to acquire functional images of both brain and cervical spinal cord (CSC) simultaneously and examined their spatiotemporal correspondence in humans. We show that the brain and spinal cord activities are strongly correlated during rest periods, and specific spinal cord regions are functionally linked to consistently reported brain sensorimotor RSNs. The functional organisation of these networks follows well-established anatomical principles, including the contralateral correspondence between the spinal hemicords and brain hemispheres as well as sensory versus motor segregation of neural pathways along the brain–spinal cord axis. Thus, our findings reveal a unified functional organisation of sensorimotor networks in the entire central nervous system (CNS) at rest.

in PLoS Biology on July 02, 2020 09:00 PM.

• #### The President, Past President, Executive Director, and the Board of the Child Neurology Society Denounce Racism and Inequality

in Annals of Neurology on July 02, 2020 02:49 PM.

## Objective

We analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.

## Methods

Amyloid‐β 1 to 42 (Aβ42), total tau (t‐tau) and phosphorylated tau (p‐tau) at the threonine 181 position were measured using the high‐precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear‐mixed effects models.

## Results

We found patients with PD had lower CSF t‐tau (median = 157.7 pg/mL; range = 80.9–467.0); p‐tau (median = 13.4 pg/mL; range = 8.0–40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8–3,707.0) than HCs at baseline (CSF t‐tau median = 173.5 pg/mL; range = 82.0–580.8; p‐tau median = 15.4 pg/mL; range = 8.1–73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1–3,297.0; p < 0.05–0.001) and a moderate‐to‐strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50–0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ42 at baseline and these patients with PD had lower p‐tau levels (median = 10.8 pg/mL; range = 8.0–32.8) compared with 27.7% of HCs with pathologically low CSF Aβ42 (CSF p‐tau median = 12.8 pg/mL; range 8.2–73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ42 (mean difference = −41.83 pg/mL; p = 0.03) and CSF p‐tau (mean difference = −0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.

## Interpretation

Our data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3‐year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020

in Annals of Neurology on July 02, 2020 02:36 PM.

• #### Benchmarking for Metaheuristic Black-Box Optimization: Perspectives and Open Challenges. (arXiv:2007.00541v1 [cs.NE])

Research on new optimization algorithms is often funded based on the motivation that such algorithms might improve the capabilities to deal with real-world and industrially relevant optimization challenges. Besides a huge variety of different evolutionary and metaheuristic optimization algorithms, also a large number of test problems and benchmark suites have been developed and used for comparative assessments of algorithms, in the context of global, continuous, and black-box optimization. For many of the commonly used synthetic benchmark problems or artificial fitness landscapes, there are however, no methods available, to relate the resulting algorithm performance assessments to technologically relevant real-world optimization problems, or vice versa. Also, from a theoretical perspective, many of the commonly used benchmark problems and approaches have little to no generalization value. Based on a mini-review of publications with critical comments, advice, and new approaches, this communication aims to give a constructive perspective on several open challenges and prospective research directions related to systematic and generalizable benchmarking for black-box optimization.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 02, 2020 01:30 AM.

• #### On the precision of neural computation with interaural time differences in the medial superior olive. (arXiv:2007.00524v1 [q-bio.NC])

Incoming sound is in cochlea and auditory nerve encoded into spike trains. At the third neuron of the auditory pathway, spike trains of the left and right sides are processed in brainstem nuclei to yield sound localization information. Two different localization encoding mechanisms are employed in two centers for low and high sound frequencies in the brainstem. The centers are superior olivary nuclei, medial and lateral. This paper contains analytical estimates of parameters needed in description of auditory coding in sound localization neural circuit. Our model spike trains are based on electro-physiological recordings. We arrive to best estimates for neuronal signaling with the use of just noticeable difference of the ideal observer. We describe spike timing jitter and its role in the spike train processing. All parameters are accompanied with detailed estimates of their values and variability. Intervals bounding all the parameter from lower and higher values are discussed.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### Few-shots Parameter Tuning via Co-evolution. (arXiv:2007.00501v1 [cs.NE])

Generalization, i.e., the ability of addressing problem instances that are not available during the system design and development phase, is a critical goal for intelligent systems. A typical way to achieve good generalization is to exploit vast data to train a model. In the context of heuristic search, such a paradigm is termed parameter tuning or algorithm configuration, i.e., configuring the parameters of a search method based on a set of "training" problem instances. However, compared to its counterpart in machine learning, parameter tuning could more often suffer from the lack of training instances, and the obtained configuration may fail to generalize. This paper suggests competitive co-evolution as a remedy to this challenge and proposes a framework named Co-Evolution of Parameterized Search (CEPS). By alternately evolving a configuration population and an instance population, CEPS is capable of obtaining generalizable configurations with few training instances. The advantage of CEPS in improving generalization is analytically shown. Two concrete instantiations, namely CEPS-TSP and CEPS-VRPSPDTW, are also presented for the Traveling Salesman Problem (TSP) and the Vehicle Routing Problem with Simultaneous Pickup-Delivery and Time Windows (VRPSPDTW), respectively. Computational results on the two problems confirm the advantages of CEPS over state-of-the-art parameter tuning methods.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 02, 2020 01:30 AM.

• #### Continual Learning: Tackling Catastrophic Forgetting in Deep Neural Networks with Replay Processes. (arXiv:2007.00487v1 [cs.LG])

Humans learn all their life long. They accumulate knowledge from a sequence of learning experiences and remember the essential concepts without forgetting what they have learned previously. Artificial neural networks struggle to learn similarly. They often rely on data rigorously preprocessed to learn solutions to specific problems such as classification or regression. In particular, they forget their past learning experiences if trained on new ones. Therefore, artificial neural networks are often inept to deal with real-life settings such as an autonomous-robot that has to learn on-line to adapt to new situations and overcome new problems without forgetting its past learning-experiences. Continual learning (CL) is a branch of machine learning addressing this type of problem. Continual algorithms are designed to accumulate and improve knowledge in a curriculum of learning-experiences without forgetting. In this thesis, we propose to explore continual algorithms with replay processes. Replay processes gather together rehearsal methods and generative replay methods. Generative Replay consists of regenerating past learning experiences with a generative model to remember them. Rehearsal consists of saving a core-set of samples from past learning experiences to rehearse them later. The replay processes make possible a compromise between optimizing the current learning objective and the past ones enabling learning without forgetting in sequences of tasks settings. We show that they are very promising methods for continual learning. Notably, they enable the re-evaluation of past data with new knowledge and the confrontation of data from different learning-experiences. We demonstrate their ability to learn continually through unsupervised learning, supervised learning and reinforcement learning tasks.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 02, 2020 01:30 AM.

• #### Review on Biophysical Modelling and Simulation Studies for Transcranial Magnetic Stimulation. (arXiv:2007.00469v1 [q-bio.NC])

Transcranial magnetic stimulation (TMS) is a technique for noninvasively stimulating a brain area for therapeutic, rehabilitation treatments and neuroscience research. Despite our understanding of the physical principles and experimental developments pertaining to TMS, it is difficult to identify the exact brain target as the generated dosage exhibits a non-uniform distribution owing to the complicated and subject-dependent brain anatomy and the lack of biomarkers that can quantify the effects of TMS in most cortical areas. Computational dosimetry has progressed significantly and enables TMS assessment by computation of the induced electric field (the primary physical agent known to activate the brain neurons) in a digital representation of the human head. In this review, TMS dosimetry studies are summarised, clarifying the importance of the anatomical and human biophysical parameters and computational methods. This review shows that there is a high consensus on the importance of a detailed cortical folding representation and an accurate modelling of the surrounding cerebrospinal fluid. Recent studies have also enabled the prediction of individually optimised stimulation based on magnetic resonance imaging of the patient/subject and have attempted to understand the temporal effects of TMS at the cellular level by incorporating neural modelling. These efforts, together with the fast deployment of personalised TMS computations, will permit the adoption of TMS dosimetry as a standard procedure in clinical procedures.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### Multi-objective Optimal Control of Dynamic Integrated Model of Climate and Economy: Evolution in Action. (arXiv:2007.00449v1 [econ.GN])

One of the widely used models for studying economics of climate change is the Dynamic Integrated model of Climate and Economy (DICE), which has been developed by Professor William Nordhaus, one of the laureates of the 2018 Nobel Memorial Prize in Economic Sciences. Originally a single-objective optimal control problem has been defined on DICE dynamics, which is aimed to maximize the social welfare. In this paper, a bi-objective optimal control problem defined on DICE model, objectives of which are maximizing social welfare and minimizing the temperature deviation of atmosphere. This multi-objective optimal control problem solved using Non-Dominated Sorting Genetic Algorithm II (NSGA-II) also it is compared to previous works on single-objective version of the problem. The resulting Pareto front rediscovers the previous results and generalizes to a wide range of non-dominant solutions to minimize the global temperature deviation while optimizing the economic welfare. The previously used single-objective approach is unable to create such a variety of possibilities, hence, its offered solution is limited in vision and reachable performance. Beside this, resulting Pareto-optimal set reveals the fact that temperature deviation cannot go below a certain lower limit, unless we have significant technology advancement or positive change in global conditions.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 02, 2020 01:30 AM.

• #### Structural diverseness of neurons between brain areas and between cases. (arXiv:2007.00212v1 [q-bio.NC])

The cerebral cortex is composed of multiple cortical areas that exert a wide variety of brain functions. Although human brain neurons are genetically and areally mosaic, the three-dimensional structural differences between neurons in different brain areas or between the neurons of different individuals have not been delineated. Here, we report a nanometer-scale geometric analysis of brain tissues of the superior temporal gyrus of 4 schizophrenia and 4 control cases by using synchrotron radiation nanotomography. The results of the analysis and a comparison with results for the anterior cingulate cortex indicated that 1) neuron structures are dissimilar between brain areas and that 2) the dissimilarity varies from case to case. The structural diverseness was mainly observed in terms of the neurite curvature that inversely correlates with the diameters of the neurites and spines. The analysis also revealed the geometric differences between the neurons of the schizophrenia and control cases, suggesting that neuron structure is associated with brain function. The area dependency of the neuron structure and its diverseness between individuals should represent the individuality of brain functions.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### Functional MRI applications for psychiatric disease subtyping: a review. (arXiv:2007.00126v1 [q-bio.NC])

Psychiatric disorders have historically been classified using symptom information alone. With the advent of new technologies that allowed researchers to investigate brain mechanisms more directly, interest in the mechanistic rationale behind defined pathologies and aetiology redefinition has greatly increased. This is particularly appealing for the field of personalised medicine, which searches for data-driven approaches to improve individual diagnosis, prognosis and treatment selection. Here we intend to systematically analyse the usage of functional MRI on both the elucidation of psychiatric disease biotypes and the interpretation of subtypes obtained via unsupervised learning applied to symptom or biomarker data. We searched the existing literature for functional MRI applications to the obtention or interpretation of psychiatric disease subtypes. The PRISMA guidelines were applied to filter the retrieved studies, and the active learning framework ASReviews was applied for article prioritization. From the 20 studies that met the inclusion criteria, 5 used functional MRI data to interpret symptom-derived disease clusters, 4 used it for the interpretation of clusters derived from biomarker data other than fMRI itself, and 11 applied clustering to fMRI directly. Major depression disorder and schizophrenia were the two most studied pathologies, followed by ADHD, psychosis, autism disorder, and early violence. No trans-diagnostic studies were retrieved. While interest in personalised medicine and data-driven disease subtyping is on the rise and psychiatry is not the exception, unsupervised analyses of functional MRI data are inconsistent to date, and much remains to be done in terms of gathering and centralising data, standardising pipelines and model validation, and method refinement. The usage of fMRI in the field of trans-diagnostic psychiatry remains vastly unexplored.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### Normalized Connectomes Show Increased Synchronizability with Age Through Their Second Largest Eigenvalue. (arXiv:2007.00079v1 [q-bio.NC])

The synchronization of different brain regions is widely observed under both normal and pathological conditions such as epilepsy. However, the relationship between the dynamics of these brain regions, the connectivity between them, and the ability to synchronize remains an open question. We investigated the problem of inter-region synchronization in networks of Wilson-Cowan/Neural field equations with homeostatic plasticity, each of which acts as a model for an isolated brain region. We considered arbitrary connection profiles with only one constraint: the rows of the connection matrices are all identically normalized. We found that these systems often synchronize to the solution obtained from a single, self-coupled neural region. We analyze the stability of this solution through a straightforward modification of the Master Stability Function (MSF) approach and found that synchronized solutions lose stability for connectivity matrices when the second largest positive eigenvalue is sufficiently large, for values of the global coupling parameter that are not too large. This result was numerically confirmed for ring systems and lattices and was also robust to small amounts of heterogeneity in the homeostatic set points in each node. Finally, we tested this result on connectomes obtained from 196 subjects over a broad age range (4-85 years) from the Human Connectome Project. We found that the second largest eigenvalue tended to decrease with age, indicating an increase in synchronizability that may be related to the increased prevalence of epilepsy with old age.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### Bringing Anatomical Information into Neuronal Network Models. (arXiv:2007.00031v1 [q-bio.NC])

For constructing neuronal network models computational neuroscientists have access to a wealth of anatomical data that nevertheless tend to cover only a fraction of the parameters to be determined. Finding and interpreting the most relevant data, estimating missing values, and combining the data and estimates from various sources into a coherent whole is a daunting task. With this chapter we aim to give modelers a helping hand by describing the main types of anatomical data that may be useful for informing neuronal network models, aspects of the underlying experimental techniques relevant to their interpretation, particularly comprehensive datasets, and methods for filling in the gaps in the data. Estimating connectivity where the data are lacking generally relies on statistical relationships with known quantities and may be referred to as predictive connectomics'. In addition, we touch upon the most prominent features of brain organization that are likely to influence predicted neuronal network dynamics, with a focus on mammalian cerebral cortex. Given the still existing need for modelers to navigate a complex data landscape full of holes and stumbling blocks, it is vital that the field of neuroanatomy is moving toward increasingly systematic data collection, representation, and publication.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### Conscious Intelligence Requires Lifelong Autonomous Programming For General Purposes. (arXiv:2007.00001v1 [q-bio.NC])

Universal Turing Machines [29, 10, 18] are well known in computer science but they are about manual programming for general purposes. Although human children perform conscious learning (i.e., learning while being conscious) from infancy [24, 23, 14, 4], it is unknown that Universal Turing Machiness can facilitate not only our understanding of Autonomous Programming For General Purposes (APFGP) by machines, but also enable early-age conscious learning. This work reports a new kind of AI---conscious learning AI from a machine's "baby" time. Instead of arguing what static tasks a conscious machine should be able to do during its "adulthood", this work suggests that APFGP is a computationally clearer and necessary criterion for us to judge whether a machine is capable of conscious learning so that it can autonomously acquire skills along its "career path". The results here report new concepts and experimental studies for early vision, audition, natural language understanding, and emotion, with conscious learning capabilities that are absent from traditional AI systems.

in arXiv: Quantitative Biology: Neurons and Cognition on July 02, 2020 01:30 AM.

• #### XtarNet: Learning to Extract Task-Adaptive Representation for Incremental Few-Shot Learning. (arXiv:2003.08561v2 [cs.LG] UPDATED)

Learning novel concepts while preserving prior knowledge is a long-standing challenge in machine learning. The challenge gets greater when a novel task is given with only a few labeled examples, a problem known as incremental few-shot learning. We propose XtarNet, which learns to extract task-adaptive representation (TAR) for facilitating incremental few-shot learning. The method utilizes a backbone network pretrained on a set of base categories while also employing additional modules that are meta-trained across episodes. Given a new task, the novel feature extracted from the meta-trained modules is mixed with the base feature obtained from the pretrained model. The process of combining two different features provides TAR and is also controlled by meta-trained modules. The TAR contains effective information for classifying both novel and base categories. The base and novel classifiers quickly adapt to a given task by utilizing the TAR. Experiments on standard image datasets indicate that XtarNet achieves state-of-the-art incremental few-shot learning performance. The concept of TAR can also be used in conjunction with existing incremental few-shot learning methods; extensive simulation results in fact show that applying TAR enhances the known methods significantly.

in arXiv: Computer Science: Neural and Evolutionary Computing on July 02, 2020 01:30 AM.

• #### Why Black lives matter in science

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0908-7

Systemic racism has held back under-represented minorities, especially Black people, in scientific research. We’re committed in our roles as journal editors to help correct this inequality.

in Nature Methods on July 02, 2020 12:00 AM.

• #### A clearer view of mitophagy

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0903-z

A clearer view of mitophagy

in Nature Methods on July 02, 2020 12:00 AM.

• #### GemSpot allows modeling of ligands in cryo-EM maps

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0900-2

GemSpot allows modeling of ligands in cryo-EM maps

in Nature Methods on July 02, 2020 12:00 AM.

• #### Expanding worms

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0898-5

Expanding worms

in Nature Methods on July 02, 2020 12:00 AM.

• #### Selective cell-surface N-glycan editing

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0896-7

A two-step chemoenzymatic method for N-glycan subtype-selective editing.

in Nature Methods on July 02, 2020 12:00 AM.

• #### Contamination in sequence databases

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0895-8

A fast algorithm detects unexpected contamination events in public databases.

in Nature Methods on July 02, 2020 12:00 AM.

• #### Sugar-coating dendritic cells

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0892-y

In situ labeling with azido sugars enables in vivo immunomodulation of dendritic cells.

in Nature Methods on July 02, 2020 12:00 AM.

• #### A new way to see RNAs

Nature Methods, Published online: 02 July 2020; doi:10.1038/s41592-020-0888-7

Producing reliable atomic- or close-to-atomic-resolution structures of RNA-only molecules has been a formidable task. Ribosolve can solve sub-nanometer-resolution cryo-EM structures of unbound RNA molecules with unprecedented accuracy and speed.

in Nature Methods on July 02, 2020 12:00 AM.

• #### Author Correction: Tunable correlated states and spin-polarized phases in twisted bilayer–bilayer graphene

Nature, Published online: 02 July 2020; doi:10.1038/s41586-020-2393-7

Author Correction: Tunable correlated states and spin-polarized phases in twisted bilayer–bilayer graphene

in Nature on July 02, 2020 12:00 AM.

• #### A channel for degeneration

Nature Reviews Neuroscience, Published online: 02 July 2020; doi:10.1038/s41583-020-0343-x

In flies, mutant TRPV4 causes mitochondrial transport deficits, axonal degeneration and neuronal dysfunction.

in Nature Reviews on July 02, 2020 12:00 AM.

• #### Driving toward hot new phases

Nature Physics, Published online: 02 July 2020; doi:10.1038/s41567-020-0963-0

Novel non-equilibrium phases of matter have recently become the focus of intense interest. The realization of topological phases which cannot exist under the constraints of thermodynamic equilibrium is a key aim.

in Nature Physics on July 02, 2020 12:00 AM.

• #### Author Correction: A strong and ductile medium-entropy alloy resists hydrogen embrittlement and corrosion

Nature Communications, Published online: 02 July 2020; doi:10.1038/s41467-020-17295-1

Author Correction: A strong and ductile medium-entropy alloy resists hydrogen embrittlement and corrosion

in Nature Communications on July 02, 2020 12:00 AM.

• #### Daily briefing: Australian archaeological sites discovered on the seabed

Nature, Published online: 02 July 2020; doi:10.1038/d41586-020-02010-3

Divers found stone tools belonging to people that lived more than 7,000 years ago. Plus: an image library with offensive tags has been pulled offline, and a fire has destroyed important specimens at a museum in Brazil.

in Nature on July 02, 2020 12:00 AM.

• #### Former Harvard researcher who sexually harassed postdoc sparks turmoil at Italian institute

Nature, Published online: 02 July 2020; doi:10.1038/d41586-020-01987-1

A research institute that appointed Pier Paolo Pandolfi as its scientific director has reversed its decision after internal protests.

in Nature on July 02, 2020 12:00 AM.

• #### Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

Oxidative stress (OS) plays a critical role in the pathophysiology of several brain-related disorders, including neurodegenerative diseases and ischemic stroke, which are the major causes of dementia. The Nrf2-ARE (nuclear factor erythroid 2-related factor 2/antioxidant responsive element antioxidant) system, the primary cellular defense against OS, plays an essential role in neuroprotection by regulating the expressions of antioxidant molecules and enzymes. However, simultaneous events resulting in the overproduction of reactive oxygen species (ROS) and deregulation of the Nrf2-ARE system damage essential cell components and cause loss of neuron structural and functional integrity. On the other hand, TrkB (tropomyosin-related kinase B) signaling, a classical neurotrophin signaling pathway, regulates neuronal survival and synaptic plasticity, which play pivotal roles in memory and cognition. Also, TrkB signaling, specifically the TrkB/PI3K/Akt (TrkB/phosphatidylinositol 3 kinase/protein kinase B) pathway promotes the activation and nuclear translocation of Nrf2, and thus, confers neuroprotection against OS. However, the TrkB signaling pathway is also known to be downregulated in brain disorders due to lack of neurotrophin support. Therefore, activations of TrkB and the Nrf2-ARE signaling system offer a potential approach to the design of novel therapeutic agents for brain disorders. Here, we briefly overview the development of OS and the association between OS and the pathogenesis of neurodegenerative diseases and brain injury. We propose the cellular antioxidant defense and TrkB signaling-mediated cell survival systems be considered pharmacological targets for the treatment of neurodegenerative diseases, and review the literature on the neuroprotective effects of phytochemicals that can co-activate these neuronal defense systems.

in Frontiers in Molecular Neuroscience on July 02, 2020 12:00 AM.

• #### Functional MRI Signal Complexity Analysis Using Sample Entropy

Resting-state functional magnetic resonance imaging (rs-fMRI) is an immensely powerful method in neuroscience that uses the blood oxygenation level-dependent (BOLD) signal to record and analyze neural activity in the brain. We examined the complexity of brain activity acquired by rs-fMRI to determine whether it exhibits variation across brain regions. In this study the complexity of regional brain activity was analyzed by calculating the sample entropy of 200 whole-brain BOLD volumes as well as of distinct brain networks, cortical regions, and subcortical regions of these brain volumes. It can be seen that different brain regions and networks exhibit distinctly different levels of entropy/complexity, and that entropy in the brain significantly differs between brains at rest and during task performance.

in Frontiers in Neuroscience: Brain Imaging Methods on July 02, 2020 12:00 AM.

• #### Periodontitis Induced by P. gingivalis-LPS Is Associated With Neuroinflammation and Learning and Memory Impairment in Sprague-Dawley Rats

Background

Periodontitis is one of the most common oral diseases and is a potential risk factor for systemic diseases. In this study, we aimed to investigate the association between periodontitis and learning and memory impairment.

Methods

We established a periodontitis model by topical application of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) into the palatal gingival sulcus of the maxillary first molars of 10-week-old male rats for a 10-week period. We assessed alveolar bone resorption using micro–computed tomography analysis and learning and memory ability using the Morris water maze test. We determined the levels of cytokines [interleukin (IL)-1β, IL-6, IL-8, and IL-21] and LPS in the peripheral blood and cortex, as well as toll-like receptor 4 (TLR4)/NF-κB signaling pathway activation, using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot. We determined activation of microglia and astrocytes, expression of Aβ1-42, APP and Tau by immunohistochemistry. Finally, we measured the expression of amyloid precursor protein (APP) and its key secretases, as well as the Aβ1-40/1-42 ratio, by RT-PCR, western blot, and ELISA.

Results

We found that periodontitis induced learning and memory impairment in the rats. Further, we observed that it induced significant alveolar bone resorption. There was an increase in the levels of inflammatory cytokines and LPS. Moreover, we confirmed TLR4/NF-κB signaling pathway activation. We also observed activated microglia and astrocytes with enlarged cell bodies and irregular protrusions. Finally, we observed the promotion of β- and γ-secretases APP processing.

Conclusion

Our findings indicated that periodontitis was associated with learning and memory impairment, probably induced by neuroinflammation via activating the TLR4/NF-κB signaling pathway. Furthermore, abnormal APP processing could be involved in this progress.

in Frontiers in Neuroscience: Neurodegeneration on July 02, 2020 12:00 AM.

• #### Weighted Brain Network Metrics for Decoding Action Intention Understanding Based on EEG

Background: Understanding the action intentions of others is important for social and human-robot interactions. Recently, many state-of-the-art approaches have been proposed for decoding action intention understanding. Although these methods have some advantages, it is still necessary to design other tools that can more efficiently classify the action intention understanding signals.

New Method: Based on EEG, we first applied phase lag index (PLI) and weighted phase lag index (WPLI) to construct functional connectivity matrices in five frequency bands and 63 micro-time windows, then calculated nine graph metrics from these matrices and subsequently used the network metrics as features to classify different brain signals related to action intention understanding.

Results: Compared with the single methods (PLI or WPLI), the combination method (PLI+WPLI) demonstrates some overwhelming victories. Most of the average classification accuracies exceed 70%, and some of them approach 80%. In statistical tests of brain network, many significantly different edges appear in the frontal, occipital, parietal, and temporal regions.

Conclusions: Weighted brain networks can effectively retain data information. The integrated method proposed in this study is extremely effective for investigating action intention understanding. Both the mirror neuron and mentalizing systems participate as collaborators in the process of action intention understanding.

in Frontiers in Human Neuroscience on July 02, 2020 12:00 AM.

• #### Temporal-Sequential Learning With a Brain-Inspired Spiking Neural Network and Its Application to Musical Memory

Sequence learning is a fundamental cognitive function of the brain. However, the ways in which sequential information is represented and memorized are not dealt with satisfactorily by existing models. To overcome this deficiency, this paper introduces a spiking neural network based on psychological and neurobiological findings at multiple scales. Compared with existing methods, our model has four novel features: (1) It contains several collaborative subnetworks similar to those in brain regions with different cognitive functions. The individual building blocks of the simulated areas are neural functional minicolumns composed of biologically plausible neurons. Both excitatory and inhibitory connections between neurons are modulated dynamically using a spike-timing-dependent plasticity learning rule. (2) Inspired by the mechanisms of the brain's cortical-striatal loop, a dependent timing module is constructed to encode temporal information, which is essential in sequence learning but has not been processed well by traditional algorithms. (3) Goal-based and episodic retrievals can be achieved at different time scales. (4) Musical memory is used as an application to validate the model. Experiments show that the model can store a huge amount of data on melodies and recall them with high accuracy. In addition, it can remember the entirety of a melody given only an episode or the melody played at different paces.

in Frontiers in Computational Neuroscience on July 02, 2020 12:00 AM.

• #### Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.

in Frontiers in Cellular Neuroscience on July 02, 2020 12:00 AM.

• #### MicroRNA-124 Overexpression in Schwann Cells Promotes Schwann Cell-Astrocyte Integration and Inhibits Glial Scar Formation Ability

Schwann cell (SC) transplantation is a promising approach for the treatment of spinal cord injury (SCI); however, SC grafts show a low migratory capacity within the astrocytic environment, which inevitably hampers their therapeutic efficacy. The purpose of this study was to explore mechanisms to modify the characteristics of SCs and astrocytes (ASs), as well as to adjust the SC-AS interface to break the SC-AS boundary, thus improving the benefits of SCI treatment. We observed that the expression levels of miR-124 in SCs and ASs were significantly lower than those in the normal spinal cord. Furthermore, overexpressing miR-124 in SCs (miR-124-SCs) significantly inhibited gene and protein expression levels of SC-specific markers, such as GFAP and Krox20. The expression of neurotrophic factors, Bdnf and Nt-3, was up-regulated in miR-124-SCs without affecting their proliferation. Further, the boundary assay showed an increased number of miR-124-SCs that had actively migrated and entered the astrocytic region to intermingle with ASs, compared with normal SCs. In addition, although Krox20 protein expression was down-regulated in miR-124-SCs, the luciferase assay showed that Krox20 is not a direct target of miR-124. RNA sequencing of miR-124-SCs revealed seven upregulated and eleven downregulated genes involved in cell migration and motility. Based on KEGG pathway and KOG functional analyses, changes in these genes corresponded to the activation of Hippo, FoxO, and TGF-beta signaling pathways, cytokine-cytokine receptor interactions, and the cell cycle. Finally, co-culturing of miR-124-SCs and ASs in a transwell system revealed that GFAP and p-STAT3 protein expression in ASs was significantly reduced. Collectively, these results show that overexpression of miR-124 in SCs promotes SC-AS integration in vitro and may attenuate the capacity of ASs to form glial scars. Thus, this study provides novel insights into modifying SCs by overexpressing miR-124 to improve their therapeutic potential in SCI.

in Frontiers in Cellular Neuroscience on July 02, 2020 12:00 AM.

• #### Response: Commentary: Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model

in Frontiers in Ageing Neuroscience on July 02, 2020 12:00 AM.

• #### Structural Covariance Network Disruption and Functional Compensation in Parkinson’s Disease

Purpose: To investigate the structural covariance network disruption in Parkinson’s disease (PD), and explore the functional alterations of disrupted structural covariance network.

Methods: A cohort of 100 PD patients and 70 healthy participants underwent structural and functional magnetic resonance scanning. Independent component analysis (ICA) was applied separately to both deformation-based morphometry (DBM) maps and functional maps with the same calculating parameters (both decomposed into 20 independent components (ICs) and computed 20 times the Infomax algorithm in ICASSO). Disrupted structural covariance network in PD patients was identified, and then, we performed goodness of fit analysis to obtain the functional network that showed the highest spatial overlap with it. We investigated the relationship between structural covariance network and functional network alterations. Finally, to further understand the structural and functional alterations over time, we performed a longitudinal subgroup analysis (51 patients were followed up for 2 years) with the same procedures.

Results: In a cross-sectional analysis, PD patients showed decreased structural covariance between anterior and posterior cingulate subnetworks. The functional components showed best overlap with anterior and posterior cingulate structural subnetworks were selected as anterior and posterior cingulate functional subnetworks. The functional connectivity between them was significantly increased [assessed by Functional Network Connectivity (FNC) toolbox]; and the increased functional connectivity was negatively correlated with cingulate structural covariance network integrity. Longitudinal subgroup analysis showed cingulate structural covariance network disruption was worse at follow-up, while the functional connectivity between anterior and posterior cingulate network was increased at baseline and decreased at follow-up.

Conclusion: This study indicated that the cingulate structural covariance network displayed a high susceptibility in PD patients. This study indicated that the cingulate structural covariance network displayed a high susceptibility in PD patients. Considering that disrupted structural covariance network coexisted with enhanced/remained functional activity during disease development, enhanced functional activity underlying the disrupted cingulate structural covariance network might represent a temporal compensation for maintaining clinical performance.

in Frontiers in Ageing Neuroscience on July 02, 2020 12:00 AM.

• #### Assessment of Alzheimer’s Disease Based on Texture Analysis of the Entorhinal Cortex

Alzheimer’s disease (AD) brain magnetic resonance imaging (MRI) biomarkers based on larger-scale tissue neurodegeneration changes, such as atrophy, are currently widely used. Texture analysis evaluates the statistical properties of the tissue image quantitatively; therefore, it could detect smaller-scale changes of neurodegeneration. Entorhinal cortex is the first region affected, and no study has investigated texture analysis on this region before. This study aims to differentiate AD patients from Normal Control (NC) and Mild Cognitive Impairment (MCI) subjects using entorhinal cortex texture features. Furthermore, it was evaluated whether texture has association to MCI beyond that of volume, to evaluate if atrophy development may precede. Texture features were extracted from 194 NC, 200 MCI, 84 MCI who converted to AD (MCIc), and 130 AD subjects. Receiving operating characteristic curves determined the performance of the various features in discriminating the groups, and a predictive model was used to predict conversion of MCIc subjects to AD. An area under the curve (AUC) of 0.872, 0.710, 0.730, and 0.764 was seen between NC vs. AD, NC vs. MCI, MCI vs. MCIc, and MCI vs. AD subjects, respectively. Including entorhinal cortex volume improved the AUCs to 0.914, 0.740, 0.756, and 0.780, respectively. For the disease prediction, binary logistic regression was applied on five randomly selected test groups and achieved on average AUC’s of 0.760 and 0.764 on the training and validation cohorts, respectively. Entorhinal cortex texture features were significantly different between the four groups and in many cases provided better results compared to other methods such as volumetry.

in Frontiers in Ageing Neuroscience on July 02, 2020 12:00 AM.

• #### Drum Communication Program Intervention in Older Adults With Cognitive Impairment and Dementia at Nursing Home: Preliminary Evidence From Pilot Randomized Controlled Trial

Introduction: Inactivity and consequent deterioration of cognitive and physical function is a major concern among older adults with the limited walking ability and need a high level of care in nursing homes. We aimed to test whether a drumming communication program (DCP) that uses the rhythmic response function of the elderly with cognitive impairment, dementia, and other debilitating disorders would improve their cognitive and physical function.

Methods: We conducted a Randomized Controlled Trial (RCT) to investigate the effects of the DCP in 46 nursing home residents who needed high levels of nursing care. The participants were randomly assigned to an intervention and control group. The intervention group attended 30 min of the DCP thrice a week for 3 months. Cognitive function was measured using the Mini-Mental State Examination-Japanese (MMSE-J) and Frontal Assessment Battery (FAB). Physical function was measured using grip strength and active upper limb range of motion with the dominant hand. Body composition was measured using bioelectrical impedance analysis (BIA). These measures were analyzed before and after the DCP intervention period, and data for the two groups were compared thereafter.

Results: Initially, the participants had low scores on the MMSE-J, and 84.78% of them used wheelchairs. Following the DCP intervention, the MMSE-J and FAB scores of the DCP group improved significantly. In terms of motor function, the active range of motion of the wrist palmar and the shoulder flexion improved in the intervention group. Regarding body composition, the skeletal muscle mass index, total body protein, and the dominant hand muscle mass that was adding physical load decreased.

Conclusions: The DCP provided the participants with an opportunity to engage in continued exercise for 3 months. The intervention group exhibited improved cognitive function and upper limb motion range, and changes in body composition. The results suggest that DCP can be used as an intervention method to promote exercise and improve various health and cognitive functions.

Trial Registration: This trial was registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN000024714) on 4 November 2016. The URL is available at https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028399.

in Frontiers in Ageing Neuroscience on July 02, 2020 12:00 AM.

• #### Cortical ChAT+ neurons co-transmit acetylcholine and GABA in a target-and brain-region specific manner

The mouse cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT+ neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT+ neurons in mice are specialized VIP+ interneurons that release GABA strongly onto other inhibitory interneurons and acetylcholine sparsely onto layer 1 interneurons and other VIP+/ChAT+ interneurons. This differential transmission of ACh and GABA based on the postsynaptic target neuron is reflected in VIP+/ChAT+ interneuron pre-synaptic terminals, as quantitative molecular analysis shows that only a subset of these are specialized to release acetylcholine. In addition, we identify a separate, sparse population of non-VIP ChAT+ neurons in the medial prefrontal cortex with a distinct developmental origin that robustly release acetylcholine in layer 1. These results demonstrate both cortex-region heterogeneity in cortical ChAT+ interneurons and target-specific co-release of acetylcholine and GABA.

in eLife on July 02, 2020 12:00 AM.

• #### Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling

Ubiquitin ligases (E3s) embedded in the endoplasmic reticulum (ER) membrane regulate essential cellular activities including protein quality control, calcium flux, and sterol homeostasis. At least 25 different, transmembrane domain (TMD)-containing E3s are predicted to be ER-localised, but for most their organisation and cellular roles remain poorly defined. Using a comparative proteomic workflow, we mapped over 450 protein-protein interactions for 21 stably expressed, full-length E3s. Bioinformatic analysis linked ER-E3s and their interactors to multiple homeostatic, regulatory, and metabolic pathways. Among these were four membrane-embedded interactors of RNF26, a polytopic E3 whose abundance is auto-regulated by ubiquitin-proteasome dependent degradation. RNF26 co-assembles with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. This RNF26 complex represents a new modulatory axis of STING and innate immune signalling at the ER membrane. Collectively, these data reveal the broad scope of regulation and differential functionalities mediated by ER-E3s for both membrane-tethered and cytoplasmic processes.

in eLife on July 02, 2020 12:00 AM.

• #### Evolution of a plant gene cluster in Solanaceae and emergence of metabolic diversity

Plants produce phylogenetically and spatially restricted, as well as structurally diverse specialized metabolites via multistep metabolic pathways. Hallmarks of specialized metabolic evolution include enzymatic promiscuity and recruitment of primary metabolic enzymes and examples of genomic clustering of pathway genes. Solanaceae glandular trichomes produce defensive acylsugars, with sidechains that vary in length across the family. We describe a tomato gene cluster on chromosome 7 involved in medium chain acylsugar accumulation due to trichome specific acyl-CoA synthetase and enoyl-CoA hydratase genes. This cluster co-localizes with a tomato steroidal alkaloid gene cluster and is syntenic to a chromosome 12 region containing another acylsugar pathway gene. We reconstructed the evolutionary events leading to this gene cluster and found that its phylogenetic distribution correlates with medium chain acylsugar accumulation across the Solanaceae. This work reveals insights into the dynamics behind gene cluster evolution and cell-type specific metabolite diversity.

in eLife on July 02, 2020 12:00 AM.

• #### Receptor-driven, multimodal mapping of cortical areas in the macaque monkey intraparietal sulcus

The intraparietal sulcus (IPS) is structurally and functionally heterogeneous. We performed a quantitative cyto- and receptor architectonical analysis to provide a multimodal map of the macaque IPS. We identified 17 cortical areas, including novel areas PEipe, PEipi (external and internal subdivisions of PEip), and MIPd. Multivariate analyses of receptor densities resulted in a grouping of areas based on the degree of (dis)similarity of their receptor architecture: a cluster encompassing areas located in the posterior portion of the IPS and associated mainly with the processing of visual information, a cluster including areas found in the anterior portion of the IPS and involved in sensorimotor processing, and an 'intermediate' cluster of multimodal association areas. Thus, differences in cyto- and receptor architecture segregate the cortical ribbon within the IPS, and receptor fingerprints provide novel insights into the relationship between the structural and functional segregation of this brain region in the macaque monkey.

in eLife on July 02, 2020 12:00 AM.

• #### Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in Lyme arthritis

Pathogen specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint. Genetic differences between inbred mouse models and the outbred human population and allelic receptor variants not present in mice, however, argue for caution when directly translating these findings to the human system. By studying Borrelia burgdorferi infection in humanized mice reconstituted with human hematopoietic stem cells from donors homozygous for a functional or non-functional FcgRIIb allele, we show that the human inhibitory FcgRIIb is a critical checkpoint balancing protective and autoreactive immune responses, linking infection with induction of autoimmunity in the human immune system.

in eLife on July 02, 2020 12:00 AM.

• #### Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity

Sleep homeostasis manifests as a relative constancy of its daily amount and intensity. Theoretical descriptions define ‘Process S’, a variable with dynamics dependent on global sleep-wake history, and reflected in electroencephalogram (EEG) slow wave activity (SWA, 0.5–4 Hz) during sleep. The notion of sleep as a local, activity-dependent process suggests that activity history must be integrated to determine the dynamics of global Process S. Here, we developed novel mathematical models of Process S based on cortical activity recorded in freely behaving mice, describing local Process S as a function of the deviation of neuronal firing rates from a locally defined set-point, independent of global sleep-wake state. Averaging locally derived Processes S and their rate parameters yielded values resembling those obtained from EEG SWA and global vigilance states. We conclude that local Process S dynamics reflects neuronal activity integrated over time, and global Process S reflects local processes integrated over space.

in eLife on July 02, 2020 12:00 AM.

• #### Connectivity patterns of task-specific brain networks allow individual prediction of cognitive symptom dimension of schizophrenia and link to molecular architecture

Background: Despite the marked inter-individual variability in the clinical presentation of schizophrenia, it remains unclear the extent to which individual dimensions of psychopathology may be reflected in variability across the collective set of functional brain connections. Here, we address this question using network-based predictive modeling of individual psychopathology along four data-driven symptom dimensions. Follow-up analyses assess the molecular underpinnings of predictive networks by relating them to neurotransmitter-receptor distribution patterns. Methods: We investigated resting-state fMRI data from 147 schizophrenia patients recruited at seven sites. Individual expression along negative, positive, affective, and cognitive symptom dimensions was predicted using relevance vector machine based on functional connectivity within 17 meta-analytic task-networks following a repeated 10-fold cross-validation and leave-one-site-out analyses. Results were validated in an independent sample. Networks robustly predicting individual symptom dimensions were spatially correlated with density maps of nine receptors/transporters from prior molecular imaging in healthy populations. Results: Ten-fold and leave-one-site-out analyses revealed five predictive network-symptom associations. Connectivity within theory-of-mind, cognitive reappraisal, and mirror neuron networks predicted negative, positive, and affective symptom dimensions, respectively. Cognitive dimension was predicted by theory-of-mind and socio-affective-default networks. Importantly, these predictions generalized to the independent sample. Intriguingly, these two networks were positively associated with D1 dopamine receptor and serotonin reuptake transporter densities as well as dopamine-synthesis-capacity. Conclusions: We revealed a robust association between intrinsic functional connectivity within networks for socio-affective processes and the cognitive dimension of psychopathology. By investigating the molecular architecture, the present work links dopaminergic and serotonergic systems with the functional topography of brain networks underlying cognitive symptoms in schizophrenia.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### A multi-informatic description of neural differentiation in the Drosophila type-II neuroblast lineages

To adopt terminal neural fates, neural progenitors respond to a combination of molecular factors, the interplay between which remains difficult to untangle. In this work, we interrogated the type-II neuroblast lineages in the developing Drosophila brain using targeted single-cell mRNA sequencing. We used pseudotime analysis to group cells by their differentiation state and subsequently used marker gene analysis to identify genes that may play a role in neural fate specification. To aid the candidate gene selection process, we created MiCV, a scRNA-seq data visualization web tool that integrates results from the multifaceted analysis, displays the co-expression pattern of multiple genes, and provides an automated gene function curating feature. In situ profiling of these mRNAs further recovered the spatial information lacking in the single-cell data. Combining prior knowledge, in silico analysis, and in situ evidence, we characterize the molecular landscape of the developing Drosophila type-II neuroblast lineages and provide a roadmap for navigating the more complex brains.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Systematic comparison and automated validation of detailed models of hippocampal neurons

Anatomically and biophysically detailed data-driven neuronal models can be useful tools in understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that enable accurate neuronal modeling, there are now a large number of different models of many cell types available in the literature. These models were usually built to capture a few important or interesting properties of the given neuron type, and it is often unknown how they would behave outside their original context. This limits the re-use and further development of the existing models, and thus prevents the building of consensus "community models" that could capture an increasing proportion of the electrophysiological properties of the given cell type. We addressed this problem for the representative case of the CA1 pyramidal cell of the rat hippocampus by developing an open-source Python test suite, which makes it possible to automatically and systematically test the generalization properties of models by making quantitative comparisons between the models and electrophysiological data. The tests cover various aspects of somatic behavior, and signal propagation and integration in apical dendrites. To demonstrate the utility of our approach, we applied our validation tests to compare the behavior of several different hippocampal CA1 pyramidal cell models from the ModelDB database against electrophysiological data available in the literature, and concluded that all of these models perform well in some domains but badly in others. We also show how we employed the test suite to aid the development of models within the European Human Brain Project (HBP), and describe the integration of the tests into the validation framework developed in the HBP, with the aim of facilitating more reproducible and transparent community model building.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### 3 versus 7 Tesla Magnetic Resonance Imaging for parcellations of subcortical brain structures

7 Tesla (7T) magnetic resonance imaging holds great promise for improved visualization of the human brain for clinical purposes. To assess whether 7T is superior regarding localization procedures of small brain structures, we compared manual parcellations of the red nucleus, subthalamic nucleus, substantia nigra, globus pallidus interna and externa, created on a commonly used clinical anisotropic clinical 3T with an optimized isotropic (o)3T and standard 7T scan. While the clinical 3T MRI scan did not allow delineation of an anatomical plausible structure due to its limited spatial resolution, optimized 3T and 7T parcellations could be directly compared. We found that 7T outperformed the o3T MRI as reflected by higher Dice scores, which were used as a measurement of interrater agreement for manual parcellations on quantitative susceptibility maps. This increase in agreement was associated with higher contrast to noise ratios for smaller structures, but not for the larger globus pallidus segments. Additionally, control-analyses were performed to account for potential biases in manual parcellations by assessing semi-automatic parcellations. These results did not confirm increased Dice scores for 7T, although they revealed a higher consistency for structure volumes for 7T compared to o3T, potentially indicative of more agreement with increased field strength. Together these results indicate the importance of the use of isotropic voxels with both 3T and 7T, and the potential for clinical applications.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Effects of practice on a mechanical horse with an online feedback on performing a sitting postural coordination

The present research aims at quantifying the impact of practicing a new coordination pattern with an online visual feedback on the postural coordination performed on a mechanical horse. Forty-four voluntary participants were recruited in this study. They were randomly assigned to four practice groups based on i) with or without feedback ( i.e., group 1, control, did not receive the feedback; group 2, 3 and 4 received an online feedback during practice) and ii) the specific trunk/horse coordination to target during practice (group 1, target coordination = 180{degrees} (without feedback); group 2, target coordination = 0{degrees}; group 3, target coordination = 90{degrees}; group 4, target coordination = 180{degrees}). All participants performed pre-, practice, post- and retention sessions. The pre-, post- and retention sessions consisted of four trials, with one trial corresponding to one specific target coordination to maintain between their own oscillations and the horse oscillations (spontaneous, 0{degrees}, 90{degrees}, and 180{degrees}). The practice phase was composed of three different sessions during which participants received an online feedback about the coordination between their own oscillations and the horse oscillations. Results showed a significant change with practice in the trunk/horse coordination patterns which persisted even after one month (retention-test). However, all the groups did not show the same nature of change, evidenced by a high postural variability during post-test for 0{degrees} and 90{degrees} target coordination groups, in opposition to the 180{degrees} and spontaneous groups who showed a decrease in coordination variability for the 180{degrees} group. The coordination in anti-phase was characterized as spontaneously adopted by participants on the mechanical horse, explaining the ease of performing this coordination (compared to the 0{degrees} and 90{degrees} target coordination). The effect of online visual feedback appeared not only on the coordination pattern itself, but most importantly on its variability during practice, including concerning initially stable coordination patterns.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Perivascular pumping in the mouse brain: Realistic boundary conditions reconcile theory, simulation, and experiment

Cerebrospinal fluid (CSF) flows through the perivascular spaces surrounding cerebral arteries. Revealing the mechanisms driving its flow would bring improved understanding of brain waste transport and insights for disorders including Alzheimer's disease, stroke, and traumatic brain injury. In vivo CSF velocity measurements in mice have been used to argue that flow is driven primarily by the pulsatile motion of artery walls~--- perivascular pumping. However, fluid dynamics theory and simulation have predicted that perivascular pumping produces flows differing from in vivo observations starkly, particularly in the phase and relative amplitude of flow oscillation. Here we show that coupling theoretical and simulated flows to realistic end boundary conditions, using resistance and compliance values measured in mice, results in velocities that match observations closely in phase, relative amplitude of oscillation, and mean flow speed. This new, quantitative agreement among theory, simulation, and in vivo measurement further supports the idea that perivascular pumping is a primary CSF driver in physiological conditions.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease

Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson's disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remains largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes, generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs but LRRK2 G2019S EVs are abnormally enriched in neurites and provide only marginal neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### All hands on deck: Large-scale (re)sculpting of cortical circuits in post-resection children

Despite the relative successes in the surgical treatment of pharmacoresistant epilepsy, there is rather little research on the neural (re)organization that potentially subserves behavioral compensation. Here, we examined the post-surgical functional connectivity (FC) in children and adolescents who have undergone unilateral cortical resection and, yet, display remarkably normal behavior. Conventionally, FC has been investigated in terms of the mean correlation of the BOLD time courses extracted from different brain regions. Here, we demonstrated the value of segregating the voxel-wise relationships into mutually exclusive populations that were either positively or negatively correlated. While, relative to controls, the positive correlations were largely normal, negative correlations among networks were increased. Together, our results point to reorganization in the contralesional hemisphere, possibly suggesting competition for cortical territory due to the demand for representation of function. Conceivably, the ubiquitous negative correlations enable the differentiation of function in the reduced cortical volume following a unilateral resection.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### High-performance brain-to-text communication via imagined handwriting

Brain-computer interfaces (BCIs) can restore communication to people who have lost the ability to move or speak. To date, a major focus of BCI research has been on restoring gross motor skills, such as reaching and grasping or point-and-click typing with a 2D computer cursor. However, rapid sequences of highly dexterous behaviors, such as handwriting or touch typing, might enable faster communication rates. Here, we demonstrate an intracortical BCI that can decode imagined handwriting movements from neural activity in motor cortex and translate it to text in real-time, using a novel recurrent neural network decoding approach. With this BCI, our study participant (whose hand was paralyzed) achieved typing speeds that exceed those of any other BCI yet reported: 90 characters per minute at >99% accuracy with a general-purpose autocorrect. These speeds are comparable to able-bodied smartphone typing speeds in our participant's age group (115 characters per minute) and significantly close the gap between BCI-enabled typing and able-bodied typing rates. Finally, new theoretical considerations explain why temporally complex movements, such as handwriting, may be fundamentally easier to decode than point-to-point movements. Our results open a new approach for BCIs and demonstrate the feasibility of accurately decoding rapid, dexterous movements years after paralysis.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### An Antibody to RGMa Promotes Regeneration of Cochlear Synapses after Noise Exposure

Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### High-frequency stimulation of ventral CA1 neurons reduces amygdala activity and inhibits fear

The hippocampus can be divided into distinct segments that make unique contributions to learning and memory. The dorsal hippocampus supports cognitive processes like spatial learning and navigation while the ventral hippocampus regulates emotional behaviors related to fear, anxiety and reward. In the current study, we determined how pyramidal cells in ventral CA1 respond to spatial cues and aversive stimulation during a context fear conditioning task. We also examined the effects of high and low frequency stimulation of these neurons on defensive behaviors. Similar to previous work in the dorsal hippocampus, we found that cells in ventral CA1 expressed high-levels of c-Fos in response to a novel spatial environment. Surprisingly, however, the number of activated neurons did not increase when the environment was subsequently paired with footshock. This was true even in the subpopulation of ventral CA1 pyramidal cells that send direct projections to the amygdala. When these cells were stimulated at high-frequencies (20-Hz), we observed feedforward inhibition of basal amygdala neurons and impaired expression of context fear. In contrast, low-frequency stimulation (4-Hz) did not inhibit principal cells in the amygdala and produced a slight increase in fear generalization. Similar results have been reported in dorsal CA1. Therefore, despite the clear differences between the dorsal and ventral hippocampus, CA1 neurons in each segment appear to make similar contributions to context fear conditioning.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Spatially distributed representation of taste quality in the gustatory insular cortex of awake behaving mice

Visual, auditory and somatosensory cortices are topographically organized, with neurons responding to similar sensory features clustering in adjacent portions of the cortex. Such topography has not been observed in the piriform cortex, whose responses to odorants are sparsely distributed across the cortex. The spatial organization of taste responses in the gustatory insular cortex (GC) is currently debated, with conflicting evidence from anesthetized rodents pointing to alternative and mutually exclusive models. Here, we rely on calcium imaging to determine how taste and task-related variables are represented in the superficial layers of GC of alert, licking mice. Our data show that the various stimuli evoke sparse responses from a combination of broadly and narrowly tuned neurons. Analysis of the distribution of responses over multiple spatial scales demonstrates that taste representations are distributed across the cortex, with no sign of spatial clustering or topography. Altogether, data presented here support the idea that the representation of taste qualities in GC of alert mice is sparse and distributed, analogous to the representation of odorants in piriform cortex.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Surface-Based Connectivity Integration

There has been increasing interest in jointly studying structural connectivity (SC) and functional connectivity (FC) derived from diffusion and functional MRI. However, several fundamental problems are still not well considered when conducting such connectome integration analyses, e.g., "Which structure (e.g., gray matter, white matter, white surface or pial surface) should be used for defining SC and FC and exploring their relationships", "Which brain parcellation should be used", and "How do the SC and FC correlate with each other and how do such correlations vary in different locations of the brain?". In this work, we develop a new framework called surface-based connectivity integration (SBCI) to facilitate the integrative analysis of SC and FC with a re-thinking of these problems. We propose to use the white surface (the interface of white matter and gray matter) to build both SC and FC since diffusion signals are in the white matter while functional signals are more present in the gray matter. SBCI also represents both SC and FC in a continuous manner at very high spatial resolution on the white surface, avoiding the need of pre-specified atlases which may bias the comparison of SC and FC. Using data from the Human Connectome Project, we show that SBCI can create reproducible, high quality SC and FC, in addition to three novel imaging biomarkers reflective of the similarity between SC and FC throughout the brain, called global, local, and discrete SC-FC coupling. Further, we demonstrate the usefulness of these biomarkers in finding group effects due to biological sex throughout the brain.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### GREATER EMPATHIC ABILITIES AND THEIR CORELATION WITH RESTING STATE BRAIN CONNECTIVITY IN PSYCHOTHERAPISTS COMPARED TO NON-PSYCHOTHERAPISTS

Psychotherapists constantly regulate their own perspective and emotions to better understand the other state. We compared 52 psychotherapists with 92 non-psychotherapists to characterized psychometric constructs like, Fantasy (FS) and Perspective Taking (PT), and the emotion regulation strategy of Expressive Suppression (ES), which hampers the empathic response. Psychotherapists showed greater FS, PT and lower ES scores. In a subsample (36, 18 ea.), we did a functional connectivity (FC) study. Psychotherapists showed greater FC between the left anterior insula and the dorsomedial prefrontal cortex; and less connectivity between rostral anterior cingulate cortex and the orbito prefrontal cortex. Both associations correlated with the PT scores and suggest a cognitive regulatory effect related to the empathic response. Considering, that the psychometric differences between groups were in the cognitive domain and that the FC associations are related to cognitive processes, these results suggest that psychotherapists have a greater cognitive regulation over their empathic response.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Trk Agonist Drugs Rescue Noise-Induced Hidden Hearing Loss

TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline and 7,8- dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 h after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the ABR were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact one year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of post-exposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposure(s).

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Pinpointing the neural signatures of single-exposure visual familiarity

Memories of the images that we have seen are thought to be reflected in the reduction of neural responses in high-level visual areas such as inferotemporal (IT) cortex, a phenomenon known as repetition suppression (RS). We challenged this hypothesis with a task that required rhesus monkeys to report image familiarity while ignoring variations in contrast, a stimulus attribute that is also known to modulate the overall IT response. The monkeys' behavior was largely contrast-invariant, contrary to the predictions of the RS encoding scheme, which could not distinguish response familiarity from changes in contrast. However, the monkeys' behavioral patterns were well predicted by a linearly decodable variant in which the total spike count is corrected for contrast modulation. These results suggest that the IT neural activity pattern that best aligns with single-exposure visual familiarity behavior is not RS but rather "sensory referenced suppression (SRS)": reductions in IT population response magnitude, corrected for sensory modulation.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

Alcohol withdrawal directly impacts the brain's stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning, however the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair fear extinction learning, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Slow walking synergies reveal a functional role for arm swing asymmetry in healthy adults: a principal component analysis with relation to mechanical work.

Introduction: The purpose of this study was to reveal a functional role for arm-swing asymmetry during gait in healthy adults. The primary aim was to identify differences in propulsive and collision work between sides at either end of the double-support phase of slow-walking (WDS). The secondary aim was to identify differences between sides in propulsive and collision work done at either end of the single-support phase (WSS) and the effect of arm-swing asymmetry on this difference. It was hypothesized that differences between sides would be evident during the double-support phase and that these differences would be coherent with differences in single-support control symmetry. It was also hypothesized that left-side dominant arm-swing would reduce the collision work done on the dominant lower-limb side. Methods: A secondary analysis of slow-walking trials of 25 healthy, uninjured adults was undertaken where a principal component analysis of kinematic data was carried out to generate the movement synergies (PMk). Independent variables included the tightness of neuromuscular control (Nk) which was formulated from the first PMk and arm-swing asymmetry which was quantified using the directional Arm-swing asymmetry index (dASI). Dependent variables included the difference between double-support collision and propulsive work (WDS) and a ratio consisting of the difference between single-support collision and propulsive work of both sides (WSS). A linear mixed-effects model was utilized for aim 1 while a multiple linear regression analysis was undertaken for aim 2. Results: Healthy adult gait was accompanied by a left-side dominant arm-swing on average as seen elsewhere. For aim 1, Nk demonstrated a significant negative effect on WDS while sidedness had a direct negative effect and indirect positive effect through Nk on WDS. The most notable finding was the effect of a crossover interaction between dASI and Nk which demonstrated a highly significant positive effect on WSS. All main-effects in aim 2 were in the hypothesized direction but were insignificant. Interpretation: The aim 1 hypothesis was supported while the aim 2 hypothesis was not supported. Nk exhibited opposing signs between ipsilateral and contralateral WBAM regulation, revealing a differential control strategy while the effect of sidedness on WDS was evident. The findings from aim 2 describe a relationship between arm-swing asymmetry and the magnitude of lower-limb mechanical work asymmetry that is cohesive with the sidedness effect found in aim 1. Individuals with left-side dominant arm-swing had an increased collision work indicative of a lateralised preference for WBAM regulation. Evidence was therefore put forward that arm-swing asymmetry during gait is related to footedness. Future studies should look to formally confirm this finding. Implications for further research into dynamic balance control mechanisms are also discussed.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### What are the gray and white matter volumes of the human spinal cord?

The gray matter of the spinal cord is the seat of somata of various types of neurons devoted to the sensory and motor function of the limbs and trunk. The volume of the spinal gray matter is an indicator of the local neuronal processing and this can decrease due to atrophy associated with degenerative diseases and injury. Nevertheless, the absolute volume of the human spinal cord has rarely been reported, if ever. Here, we use high--resolution magnetic resonance imaging, with a cross--sectional resolution of 50 x 50$mathrm{mu m}^2$, to estimate the total gray and white matter volume of two post mortem human spinal cords. Segregation of gray and white matter was accomplished using deep learning image segmentation. The gray and white matter volumes were found to be 2.87 and 11.33 ml, respectively for a female and 3.55 and 19.33 ml, respectively for a male. The gray and white matter profiles along the vertebral axis were found to be strikingly similar and the volumes of the cervical, thoracic and lumbosacral sections were almost equal.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using a combination of RNA immunoprecipitations and tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified several TDP-43 dependent translational alterations including the glypican Dally like protein (Dlp), a wingless (wg/wnt) signaling component. Here we show that dlp mRNA is enriched in TDP-43 protein complexes and depleted from ribosomes in the context of TDP-43 proteinopathy. We also show that dlp mRNA is insolubilized and Dlp protein is significantly depleted from neuromuscular synapses while steady state transcript levels remain unchanged, consistent with mRNA sequestration and translation inhibition. Furthermore, we find that Dlp accumulates in cytoplasmic puncta in the Drosophila ventral cord, supporting the possibility of added axonal transport deficits, a well-established ALS phenotype. Notably, overexpression of dlp in Drosophila motor neurons is sufficient to mitigate TDP-43 dependent neurodegenerative phenotypes indicating that dlp is a physiologically relevant target of TDP-43. Finally, we show that similar to Dlp in the Drosophila ventral cord, the human ortholog GPC6 forms puncta-like structures in ALS patient spinal cords, further supporting a role for Dlp/GPC6 in TDP-43 induced neurodegeneration.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### A psychophysically tuned computational model of human primary visual cortex produces geometric optical illusions

Geometrical optical illusion (GOIs) are mismatches between physical stimuli and perception. GOIs provide an access point to study the interplay between sensation and perception, yet there is scant quantitative investigation of the extent to which different GOIs rely on similar or distinct brain mechanisms. We addressed this knowledge gap. First, 30 healthy adults reported quantitatively their perceptual biases with three GOIs, whose physical properties parametrically varied on a trial-by-trial basis. Biases observed with one GOI were unrelated to those observed with another GOI, suggestive of (partially) distinct underlying mechanisms. Next, we used these psychophysical results to tune a computational model of primary visual cortex that combines parameters of orientation, selectivity, intra-cortical connectivity, and long-range interactions. We showed that similar biases could be generated in-silico, mirroring those observed in humans. Such results provide a roadmap whereby computational modelling, informed by human psychophysics, can reveal likely mechanistic underpinnings of perception.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Ontogeny of the VIP+ interneuron sensory-motor circuit prior to active whisking

Development of the cortical circuits for sensory-motor processing require the coordinated integration of both columnar and long-range synaptic connections. To understand how this occurs at the level of individual neurons we have explored the timeline over which vasoactive intestinal peptide (VIP)-expressing interneurons integrate into mouse somatosensory cortex. We find a distinction in emergent long-range anterior-motor and columnar glutamatergic inputs onto layer (L)2 and L3 VIP+ interneurons respectively. In parallel, VIP+ interneurons form efferent connections onto both pyramidal cells and interneurons in the immediate column in an inside-out manner. Cell-autonomous deletion of the fate-determinant transcription factor, Prox1, spares long-range anterior-motor inputs onto VIP+ interneurons, but leads to deficits in local connectivity. This imbalance in the somatosensory circuit results in altered spontaneous and sensory-evoked cortical activity in vivo. This identifies a critical role for VIP+ interneurons, and more broadly interneuron heterogeneity, in formative circuits of neocortex.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### A chronic photocapacitor implant for noninvasive neurostimulation with deep red light

Implantable clinical neuroelectronic devices are limited by a lack of reliable, safe, and minimally invasive methods to wirelessly modulate neural tissue. Here, we address this challenge by using organic electrolytic photocapacitors (OEPCs) to perform chronic peripheral nerve stimulation via transduction of tissue-penetrating deep-red light into electrical signals. The operating principle of the OEPC relies on efficient charge generation by nanoscale organic semiconductors comprising nontoxic commercial pigments. OEPCs integrated on an ultrathin cuff are implanted, and light impulses at wavelengths in the tissue transparency window are used to stimulate from outside of the body. Typical stimulation parameters involve irradiation with pulses of 50-1000 microsecond length (638 or 660 nm), capable of actuating the implant about 10 mm below the skin. We detail how to benchmark performance parameters of OEPCs first ex vivo, and in vivo using a rat sciatic nerve. Incorporation of a microfabricated zip-tie mechanism enabled stable, long-term nerve implantation of OEPC devices in rats, with sustained ability to non-invasively mediate neurostimulation over 100 days. OEPC devices introduce a high performance, ultralow volume (0.1 mm3), biocompatible approach to wireless neuromodulation, with potential applicability to an array of clinical bioelectronics.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Trial-by-trial variability in cortical responses exhibits scaling in spatial correlations predicted from critical dynamics

Simple sensory stimuli or motor outputs engage large populations of neurons in the mammalian cortex. When stimuli or outputs repeat, the robust population response contrasts with fluctuating responses of individual neurons, known as trial-by-trial variability. To understand this apparent discrepancy, a detailed identification of the underlying spatiotemporal correlations is required. Here, we analyze spatial correlations in the instantaneous fluctuations between neurons relative to the neuronal population. Using 2-photon imaging of visual and auditory responses in primary cortices of awake mice, we show that these correlations grow linearly with the size of the observed cortical area. We extend these observations to the cortical mesoscale by analyzing local field potentials in behaving nonhuman primates. In network simulations, we demonstrate this linear growth in spatial correlation to emerge at criticality. Our findings suggest that trial-by-trial variability is a signature of critical dynamics in cortex maintaining robust, long-range spatial correlations among neurons.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Is there a neuropathic-like component to endometriosis-associated pain? Results from a large cohort questionnaire study

Background: Pain is one of the primary symptoms of endometriosis, a chronic inflammatory condition characterised by the presence of endometrial tissue outside the uterus. Endometriosis-associated pain is commonly considered as nociceptive in nature but its clinical presentation suggests that it might have neuropathic-like properties in a subgroup of patients. Methods: This is a cross sectional study using an online survey. The survey was distributed by patient support websites. The survey was composed of validated questionnaires assessing pain symptoms, psychological measures and questions about number of surgeries. Main results and the role of chance: We had 1417 responses which met the inclusion criteria. Using standard painDETECT cut-off scores, we found that pain was classified as neuropathic in 40% of patients and as mixed neuropathic/nociceptive in a further 35%. In line with observations in other neuropathic conditions, the neuropathic subgroup reported higher pain intensities, greater psychological distress and cognitive impairment. Neuropathic pain was also more likely in those with more surgeries to the abdomen and a longer history of pain. As revealed by a cluster analysis, those with a neuropathic pain component could further be divided into two subgroups based on their sensory profile. Conclusions: The data presented here indicate that endometriosis-associated pain includes a neuropathic-like component in a substantial proportion of women. Although further investigation is required, our finding challenges the current conceptualisation of endometriosis-associated pain as nociceptive and advocates for a new perspective on this type of pain, which is so debilitating to a large number of women.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Spatial cueing effects do not always index attentional capture: Evidence for a Priority Accumulation Framework

In visual search, improved performance when a target appears at a recently cued location is taken as strong evidence that attention was shifted to this cue. Here, we provide evidence challenging the canonical interpretation of spatial-cueing (or cue-validity) effects and supporting the Priority Accumulation Framework (PAF). According to PAF, attentional priority accumulates over time at each location until the search context triggers selection of the highest-priority location. Spatial-cueing effects reflect how long it takes to resolve the competition and can thus be observed even when attention was never shifted to the cue. Here, we used a spatial-cueing paradigm with abruptly onset cues and search displays varying in target-distractor similarity. We show search performance on valid-cue trials deteriorated the more difficult the search, a finding that is incompatible with the standard interpretation of spatial-cueing effects. By using brief displays (Experiment 1) and by examining the effect of search difficulty on the fastest trials (Experiment 2), we invalidate alternative accounts invoking post-perceptual verification processes (Experiment 1) or occasional failures of the onset cue to capture attention (Experiment 2). In Experiment 3, we used a combination of the spatial-cueing and dot-probe paradigms. We show that the events that occurred in both the cue and search displays affected attentional distribution, and that the relative attentional priority weight that accumulated at the target location determined how easily the competition was resolved. These findings fully support PAFs predictions.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Recalled parental bonding interacts with oxytocin receptor gene polymorphism in modulating anxiety and avoidance in adult relationships

Early interactions with parents affect subsequent social experience throughout the course of a lifetime, as a repeated and prolonged perception of different levels of care, independence or control influences the modulation of emotional regulatory processes. As many factors play a role in shaping the expectations and features of social interaction, in this study we consider the influence of reported parental bonding and allelic variation of oxytocin receptor gene polymorphism (rs53576) over relationship levels of experienced anxiety and avoidance in 309 young adults belonging to two different cultural contexts, namely Italy and Singapore. Results highlight a major effect of maternal characteristics, care and overprotection, with differences between the two cultural groups. Additionally, the interaction between rs53576 and maternal overprotection suggest different environmental susceptibility in the Italian sample and the Singaporean one. Implication in clinical work and future steps are described in the conclusion.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Brain-wide electrical dynamics encode an appetitive socioemotional state

Many cortical and subcortical regions contribute to complex social behavior; nevertheless, the network level architecture whereby the brain integrates this information to encode appetitive socioemotional behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover an explainable brain network that encodes the extent to which mice chose to engage another mouse. This socioemotional network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on ventral tegmental area, and network activity is synchronized with brain-wide cellular firing. The network generalizes, on a mouse-by-mouse basis, to encode socioemotional behaviors in healthy animals, but fails to encode an appetitive socioemotional state in a high confidence genetic mouse model of autism. Thus, our findings reveal the architecture whereby the brain integrates spatially distributed activity across timescales to encode an appetitive socioemotional brain state in health and disease.

in bioRxiv: Neuroscience on July 02, 2020 12:00 AM.

• #### Extracellular loops of BtuB facilitate transport of vitamin B<sub>12</sub> through the outer membrane of <i>E. coli</i>

by Tomasz Pieńko, Joanna Trylska

Vitamin B12 (or cobalamin) is an enzymatic cofactor essential both for mammals and bacteria. However, cobalamin can be synthesized only by few microorganisms so most bacteria need to take it up from the environment through the TonB-dependent transport system. The first stage of cobalamin import to E. coli cells occurs through the outer-membrane receptor called BtuB. Vitamin B12 binds with high affinity to the extracellular side of the BtuB protein. BtuB forms a β-barrel with inner luminal domain and extracellular loops. To mechanically allow for cobalamin passage, the luminal domain needs to partially unfold with the help of the inner-membrane TonB protein. However, the mechanism of cobalamin permeation is unknown. Using all-atom molecular dynamics, we simulated the transport of cobalamin through the BtuB receptor embedded in an asymmetric and heterogeneous E. coli outer membrane. To enhance conformational sampling of the BtuB loops, we developed the Gaussian force-simulated annealing method (GF-SA) and coupled it with umbrella sampling. We found that cobalamin needs to rotate in order to permeate through BtuB. We showed that the mobility of BtuB extracellular loops is crucial for cobalamin binding and transport and resembles an induced fit mechanism. Loop mobility depends not only on the position of cobalamin but also on the extension of luminal domain. We provided atomistic details of cobalamin transport through the BtuB receptor showing the essential role of the mobility of BtuB extracellular loops. A similar TonB-dependent transport system is used also by many other compounds, such as haem and siderophores, and importantly, can be hijacked by natural antibiotics. Our work could have implications for future delivery of antibiotics to bacteria using this transport system.

in PLoS Computational Biology on July 01, 2020 09:00 PM.

• #### Using information theory to optimise epidemic models for real-time prediction and estimation

by Kris V. Parag, Christl A. Donnelly

The effective reproduction number, Rt, is a key time-varying prognostic for the growth rate of any infectious disease epidemic. Significant changes in Rt can forewarn about new transmissions within a population or predict the efficacy of interventions. Inferring Rt reliably and in real-time from observed time-series of infected (demographic) data is an important problem in population dynamics. The renewal or branching process model is a popular solution that has been applied to Ebola and Zika virus disease outbreaks, among others, and is currently being used to investigate the ongoing COVID-19 pandemic. This model estimates Rt using a heuristically chosen piecewise function. While this facilitates real-time detection of statistically significant Rt changes, inference is highly sensitive to the function choice. Improperly chosen piecewise models might ignore meaningful changes or over-interpret noise-induced ones, yet produce visually reasonable estimates. No principled piecewise selection scheme exists. We develop a practical yet rigorous scheme using the accumulated prediction error (APE) metric from information theory, which deems the model capable of describing the observed data using the fewest bits as most justified. We derive exact posterior prediction distributions for infected population size and integrate these within an APE framework to obtain an exact and reliable method for identifying the piecewise function best supported by available epidemic data. We find that this choice optimises short-term prediction accuracy and can rapidly detect salient fluctuations in Rt, and hence the infected population growth rate, in real-time over the course of an unfolding epidemic. Moreover, we emphasise the need for formal selection by exposing how common heuristic choices, which seem sensible, can be misleading. Our APE-based method is easily computed and broadly applicable to statistically similar models found in phylogenetics and macroevolution, for example. Our results explore the relationships among estimate precision, forecast reliability and model complexity.

in PLoS Computational Biology on July 01, 2020 09:00 PM.

• #### A simple model for learning in volatile environments

by Payam Piray, Nathaniel D. Daw

Sound principles of statistical inference dictate that uncertainty shapes learning. In this work, we revisit the question of learning in volatile environments, in which both the first and second-order statistics of observations dynamically evolve over time. We propose a new model, the volatile Kalman filter (VKF), which is based on a tractable state-space model of uncertainty and extends the Kalman filter algorithm to volatile environments. The proposed model is algorithmically simple and encompasses the Kalman filter as a special case. Specifically, in addition to the error-correcting rule of Kalman filter for learning observations, the VKF learns volatility according to a second error-correcting rule. These dual updates echo and contextualize classical psychological models of learning, in particular hybrid accounts of Pearce-Hall and Rescorla-Wagner. At the computational level, compared with existing models, the VKF gives up some flexibility in the generative model to enable a more faithful approximation to exact inference. When fit to empirical data, the VKF is better behaved than alternatives and better captures human choice data in two independent datasets of probabilistic learning tasks. The proposed model provides a coherent account of learning in stable or volatile environments and has implications for decision neuroscience research.

in PLoS Computational Biology on July 01, 2020 09:00 PM.

• #### Intact Brain Network Function in an Unresponsive Patient with COVID‐19

Many patients with severe coronavirus disease 2019 (COVID‐19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID‐19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID‐19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness.

in Annals of Neurology on July 01, 2020 04:04 PM.

• #### Ingrained Injustice: The ANA Responds

in Annals of Neurology on July 01, 2020 03:41 PM.

• #### Spontaneous Multilevel Cerebrospinal Fluid Leak in Marfan Syndrome

in Annals of Neurology on July 01, 2020 03:34 PM.

• #### A Young Generalized Dystonia Patient with Globus‐Pallidus‐Specific Lesion

in Annals of Neurology on July 01, 2020 02:11 PM.

• #### 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 magnetic resonance imaging (MRI) of muscle may offer this opportunity, as it is noninvasive 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. ANN NEUROL 2020

in Annals of Neurology on July 01, 2020 02:09 PM.

## Objective

The aim was to investigate whether intensive blood pressure treatment is associated with less hematoma growth and better outcome in intracerebral hemorrhage (ICH) patients who received intravenous nicardipine treatment ≤2 hours after onset of symptoms.

## Methods

A post‐hoc exploratory analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH‐2) trial was performed. This was a multicenter, international, open‐label, randomized clinical trial, in which patients with primary ICH were allocated to intensive versus standard blood pressure treatment with nicardipine ≤4.5 hours after onset of symptoms. We have included 913 patients with complete imaging and follow‐up data in the present analysis.

## Results

Among the 913 included patients, 354 (38.7%) had intravenous nicardipine treatment initiated within 2 hours. In this subgroup of patients treated within 2 hours, the frequency of ICH expansion was significantly lower in the intensive blood pressure reduction group compared with the standard treatment group (p = 0.02). Multivariable analysis showed that ultra‐early intensive blood pressure treatment was associated with a decreased risk of hematoma growth (odds ratio, 0.56; 95% confidence interval [CI], 0.34–0.92; p = 0.02), higher rate of functional independence (odds ratio, 2.17; 95% CI, 1.28–3.68; p = 0.004), and good outcome (odds ratio, 1.68; 95% CI, 1.01–2.83; p = 0.048) at 90 days. Ultra‐early intensive blood pressure reduction was associated with a favorable shift in modified Rankin Scale score distribution at 3 months (p = 0.04).

## Interpretation

In a subgroup of ICH patients with elevated blood pressure given intravenous nicardipine ≤2 hours after onset of symptoms, intensive blood pressure reduction was associated with reduced hematoma growth and improved functional outcome. ANN NEUROL 2020

in Annals of Neurology on July 01, 2020 02:02 PM.

• #### Classification of Facial Expressions for Intended Display of Emotions Using Brain–Computer Interfaces

Facial expressions are important for intentional display of emotions in social interaction. For people with severe paralysis, the ability to display emotions intentionally can be impaired. Current brain–computer interfaces (BCIs) allow for linguistic communication but are cumbersome for expressing emotions. Here, we investigated the feasibility of a BCI to display emotions by decoding facial expressions. We used electrocorticographic recordings from the sensorimotor cortex of people with refractory epilepsy and classified five facial expressions, based on neural activity. The mean classification accuracy was 72%. This approach could be a promising avenue for development of BCI‐based solutions for fast communication of emotions. ANN NEUROL 2020

in Annals of Neurology on July 01, 2020 02:02 PM.

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

in Annals of Neurology on July 01, 2020 01:54 PM.

• #### QPSO-CD: Quantum-behaved Particle Swarm Optimization Algorithm with Cauchy Distribution. (arXiv:2006.16989v1 [cs.NE])

Motivated by particle swarm optimization (PSO) and quantum computing theory, we have presented a quantum variant of PSO (QPSO) mutated with Cauchy operator and natural selection mechanism (QPSO-CD) from evolutionary computations. The performance of proposed hybrid quantum-behaved particle swarm optimization with Cauchy distribution (QPSO-CD) is investigated and compared with its counterparts based on a set of benchmark problems. Moreover, QPSO-CD is employed in well-studied constrained engineering problems to investigate its applicability. Further, the correctness and time complexity of QPSO-CD are analysed and compared with the classical PSO. It has been proven that QPSO-CD handles such real-life problems efficiently and can attain superior solutions in most of the problems. The experimental results showed that QPSO associated with Cauchy distribution and natural selection strategy outperforms other variants in the context of stability and convergence.

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

• #### Learning to Combine Top-Down and Bottom-Up Signals in Recurrent Neural Networks with Attention over Modules. (arXiv:2006.16981v1 [cs.LG])

Robust perception relies on both bottom-up and top-down signals. Bottom-up signals consist of what's directly observed through sensation. Top-down signals consist of beliefs and expectations based on past experience and short-term memory, such as how the phrase `peanut butter and~...' will be completed. The optimal combination of bottom-up and top-down information remains an open question, but the manner of combination must be dynamic and both context and task dependent. To effectively utilize the wealth of potential top-down information available, and to prevent the cacophony of intermixed signals in a bidirectional architecture, mechanisms are needed to restrict information flow. We explore deep recurrent neural net architectures in which bottom-up and top-down signals are dynamically combined using attention. Modularity of the architecture further restricts the sharing and communication of information. Together, attention and modularity direct information flow, which leads to reliable performance improvements in perceptual and language tasks, and in particular improves robustness to distractions and noisy data. We demonstrate on a variety of benchmarks in language modeling, sequential image classification, video prediction and reinforcement learning that the \emph{bidirectional} information flow can improve results over strong baselines.

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

• #### Self-Supervised Learning of a Biologically-Inspired Visual Texture Model. (arXiv:2006.16976v1 [cs.CV])

We develop a model for representing visual texture in a low-dimensional feature space, along with a novel self-supervised learning objective that is used to train it on an unlabeled database of texture images. Inspired by the architecture of primate visual cortex, the model uses a first stage of oriented linear filters (corresponding to cortical area V1), consisting of both rectified units (simple cells) and pooled phase-invariant units (complex cells). These responses are processed by a second stage (analogous to cortical area V2) consisting of convolutional filters followed by half-wave rectification and pooling to generate V2 'complex cell' responses. The second stage filters are trained on a set of unlabeled homogeneous texture images, using a novel contrastive objective that maximizes the distance between the distribution of V2 responses to individual images and the distribution of responses across all images. When evaluated on texture classification, the trained model achieves substantially greater data-efficiency than a variety of deep hierarchical model architectures. Moreover, we show that the learned model exhibits stronger representational similarity to texture responses of neural populations recorded in primate V2 than pre-trained deep CNNs.

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

• #### Modeling and Uncertainty Analysis of Groundwater Level Using Six Evolutionary Optimization Algorithms Hybridized with ANFIS, SVM, and ANN. (arXiv:2006.16848v1 [eess.SP])

In the present study, six meta-heuristic schemes are hybridized with artificial neural network (ANN), adaptive neuro-fuzzy interface system (ANFIS), and support vector machine (SVM), to predict monthly groundwater level (GWL), evaluate uncertainty analysis of predictions and spatial variation analysis. The six schemes, including grasshopper optimization algorithm (GOA), cat swarm optimization (CSO), weed algorithm (WA), genetic algorithm (GA), krill algorithm (KA), and particle swarm optimization (PSO), were used to hybridize for improving the performance of ANN, SVM, and ANFIS models. Groundwater level (GWL) data of Ardebil plain (Iran) for a period of 144 months were selected to evaluate the hybrid models. The pre-processing technique of principal component analysis (PCA) was applied to reduce input combinations from monthly time series up to 12-month prediction intervals. The results showed that the ANFIS-GOA was superior to the other hybrid models for predicting GWL in the first piezometer and third piezometer in the testing stage. The performance of hybrid models with optimization algorithms was far better than that of classical ANN, ANFIS, and SVM models without hybridization. The percent of improvements in the ANFIS-GOA versus standalone ANFIS in piezometer 10 were 14.4%, 3%, 17.8%, and 181% for RMSE, MAE, NSE, and PBIAS in the training stage and 40.7%, 55%, 25%, and 132% in testing stage, respectively. The improvements for piezometer 6 in train step were 15%, 4%, 13%, and 208% and in the test step were 33%, 44.6%, 16.3%, and 173%, respectively, that clearly confirm the superiority of developed hybridization schemes in GWL modeling. Uncertainty analysis showed that ANFIS-GOA and SVM had, respectively, the best and worst performances among other models. In general, GOA enhanced the accuracy of the ANFIS, ANN, and SVM models.

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

• #### Technical Report: Auxiliary Tuning and its Application to Conditional Text Generation. (arXiv:2006.16823v1 [cs.CL])

We introduce a simple and efficient method, called Auxiliary Tuning, for adapting a pre-trained Language Model to a novel task; we demonstrate this approach on the task of conditional text generation. Our approach supplements the original pre-trained model with an auxiliary model that shifts the output distribution according to the target task. The auxiliary model is trained by adding its logits to the pre-trained model logits and maximizing the likelihood of the target task output. Our method imposes no constraints on the auxiliary architecture. In particular, the auxiliary model can ingest additional input relevant to the target task, independently from the pre-trained model's input. Furthermore, mixing the models at the logits level provides a natural probabilistic interpretation of the method. Our method achieved similar results to training from scratch for several different tasks, while using significantly fewer resources for training; we share a specific example of text generation conditioned on keywords.

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

• #### An energy efficient service composition mechanism using a hybrid meta-heuristic algorithm in a mobile cloud environment. (arXiv:2006.16771v1 [cs.NI])

By increasing mobile devices in technology and human life, using a runtime and mobile services has gotten more complex along with the composition of a large number of atomic services. Different services are provided by mobile cloud components to represent the non-functional properties as Quality of Service (QoS), which is applied by a set of standards. On the other hand, the growth of the energy-source heterogeneity in mobile clouds is an emerging challenge according to the energy-saving problem in mobile nodes. To mobile cloud service composition as an NP-Hard problem, an efficient selection method should be taken by problem using optimal energy-aware methods that can extend the deployment and interoperability of mobile cloud components. Also, an energy-aware service composition mechanism is required to preserve high energy saving scenarios for mobile cloud components. In this paper, an energy-aware mechanism is applied to optimize mobile cloud service composition using a hybrid Shuffled Frog Leaping Algorithm and Genetic Algorithm (SFGA). Experimental results capture that the proposed mechanism improves the feasibility of the service composition with minimum energy consumption, response time, and cost for mobile cloud components against some current algorithms.

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

• #### Beyond accuracy: quantifying trial-by-trial behaviour of CNNs and humans by measuring error consistency. (arXiv:2006.16736v1 [cs.CV])

A central problem in cognitive science and behavioural neuroscience as well as in machine learning and artificial intelligence research is to ascertain whether two or more decision makers (e.g. brains or algorithms) use the same strategy. Accuracy alone cannot distinguish between strategies: two systems may achieve similar accuracy with very different strategies. The need to differentiate beyond accuracy is particularly pressing if two systems are at or near ceiling performance, like Convolutional Neural Networks (CNNs) and humans on visual object recognition. Here we introduce trial-by-trial error consistency, a quantitative analysis for measuring whether two decision making systems systematically make errors on the same inputs. Making consistent errors on a trial-by-trial basis is a necessary condition if we want to ascertain similar processing strategies between decision makers. Our analysis is applicable to compare algorithms with algorithms, humans with humans, and algorithms with humans. When applying error consistency to visual object recognition we obtain three main findings: (1.) Irrespective of architecture, CNNs are remarkably consistent with one another (2.) The consistency between CNNs and human observers, however, is little above what can be expected by chance alone--indicating that humans and CNNs are likely implementing very different strategies (3.) CORnet-S, a recurrent model termed the "current best model of the primate ventral visual stream", fails to capture essential characteristics of human behavioural data and behaves essentially like a ResNet-50 in our analysis--that is, just like a standard feedforward network. Taken together, error consistency analysis suggests that the strategies used by human and machine vision are still very different--but we envision our general-purpose error consistency analysis to serve as a fruitful tool for quantifying future progress.

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

• #### Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2494-3

Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease

in Nature on July 01, 2020 12:00 AM.

• #### Structural basis of CXC chemokine receptor 2 activation and signalling

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2492-5

Structural basis of CXC chemokine receptor 2 activation and signalling

in Nature on July 01, 2020 12:00 AM.

• #### Extensive signal integration by the phytohormone protein network

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2460-0

A systems-level map of the Arabidopsis hormone signalling network, comprising more than 2,000 binary protein–protein interactions, reveals hundreds of interpathway contact points, many of which mediate crosstalk between different hormone pathways.

in Nature on July 01, 2020 12:00 AM.

• #### Wapl repression by Pax5 promotes V gene recombination by Igh loop extrusion

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2454-y

Pax5 regulates contraction of the immunoglobulin heavy chain (Igh) locus—an essential step in V(D)J recombination—by promoting chromatin loop extrusion via repression of Wapl expression.

in Nature on July 01, 2020 12:00 AM.

• #### Physiological blood–brain transport is impaired with age by a shift in transcytosis

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2453-z

Tagging and tracking the blood plasma proteome as a discovery tool reveals widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which the brain endothelium regulates this process with age.

in Nature on July 01, 2020 12:00 AM.

• #### Structure and flexibility in cortical representations of odour space

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2451-1

Both piriform cortex and its sensory inputs from the olfactory bulb represent chemical odour relationships, but cortex reshapes relational information inherited from the sensory periphery to enhance odour generalization and to reflect experience.

in Nature on July 01, 2020 12:00 AM.

• #### Cryo-EM of elongating ribosome with EF-Tu•GTP elucidates tRNA proofreading

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2447-x

Time-resolved cryogenic electron microscopy structures of a ribosome during the delivery of aminoacyl-tRNA by EF-Tu•GTP capture 33 ribosomal states, enabling visualization of the initial selection, proofreading and peptidyl transfer stages.

in Nature on July 01, 2020 12:00 AM.

• #### Systematic quantitative analysis of ribosome inventory during nutrient stress

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2446-y

During nutrient stress, ribosomal protein abundance is regulated primarily by translational and non-autophagic degradative mechanisms, but ribosome density per cell is largely maintained by reductions in cell volume and rates of cell division.

in Nature on July 01, 2020 12:00 AM.

• #### A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2444-0

Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome.

in Nature on July 01, 2020 12:00 AM.

• #### Clinical targeting of HIV capsid protein with a long-acting small molecule

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2443-1

The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

in Nature on July 01, 2020 12:00 AM.

• #### Abrupt increase in harvested forest area over Europe after 2015

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2438-y

Fine-scale satellite data are used to quantify forest harvest rates in 26 European countries, finding an increase in harvested forest area of 49% and an increase in biomass loss of 69% between 2011–2015 and 2016–2018.

in Nature on July 01, 2020 12:00 AM.

• #### Chemical gradients in human enamel crystallites

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2433-3

Hydroxylapatite crystallites in human dental enamel show gradients in chemical composition, with a layer of magnesium enrichment on each side of a core rich in sodium, fluoride and carbonate ions.

in Nature on July 01, 2020 12:00 AM.

• #### Laser picoscopy of valence electrons in solids

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2429-z

Laser-generated high-harmonic emission is used to image the valence potential and electron density in magnesium fluoride and calcium fluoride at the picometre scale, enabling direct probing of material properties.

in Nature on July 01, 2020 12:00 AM.

• #### Structural cells are key regulators of organ-specific immune responses

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2424-4

Structural cells implement a broad range of immune-regulatory functions beyond their roles as barriers and connective tissues, and they utilize an epigenetically encoded potential for immune gene activation in their rapid response to viral infection.

in Nature on July 01, 2020 12:00 AM.

• #### A remnant planetary core in the hot-Neptune desert

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2421-7

Observations of TOI-849b reveal a radius smaller than Neptune’s but a large mass of about 40 Earth masses, indicating that the planet is the remnant core of a gas giant.

in Nature on July 01, 2020 12:00 AM.

• #### Quantum correlations between light and the kilogram-mass mirrors of LIGO

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2420-8

Quantum correlations between the laser beams and the positions of the 40-kg mirrors of LIGO are confirmed experimentally, enabling high-precision measurements of both gravitational waves and macroscopic quantum states.

in Nature on July 01, 2020 12:00 AM.

• #### Reply to: Transformation of naked mole-rat cells

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2411-9

Reply to: Transformation of naked mole-rat cells

in Nature on July 01, 2020 12:00 AM.

• #### Transformation of naked mole-rat cells

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2410-x

Transformation of naked mole-rat cells

in Nature on July 01, 2020 12:00 AM.

• #### Observation of branched flow of light

Nature, Published online: 01 July 2020; doi:10.1038/s41586-020-2376-8

Branched flow of light is experimentally observed inside a thin soap membrane, where smooth variations of the membrane thickness transform the light beam into branched filaments of enhanced intensity that keep dividing as the waves propagate.

in Nature on July 01, 2020 12:00 AM.

• #### Chill out

Nature Reviews Neuroscience, Published online: 01 July 2020; doi:10.1038/s41583-020-0337-8

Two studies shed light on the neural bases of torpor and a hibernation-like state not usually observed in mice.

in Nature Reviews on July 01, 2020 12:00 AM.

• #### Publisher Correction: Glacial–interglacial Nd isotope variability of North Atlantic Deep Water modulated by North American ice sheet

Nature Communications, Published online: 01 July 2020; doi:10.1038/s41467-020-17208-2

Publisher Correction: Glacial–interglacial Nd isotope variability of North Atlantic Deep Water modulated by North American ice sheet

in Nature Communications on July 01, 2020 12:00 AM.

• #### High-altitude populations need special considerations for COVID-19

Nature Communications, Published online: 01 July 2020; doi:10.1038/s41467-020-17131-6

High-altitude populations need special considerations for COVID-19

in Nature Communications on July 01, 2020 12:00 AM.

• #### Impact of dual-layer solid-electrolyte interphase inhomogeneities on early-stage defect formation in Si electrodes

Nature Communications, Published online: 01 July 2020; doi:10.1038/s41467-020-17104-9

Severe structural deformation during (de)lithiation is the main factor limiting the stability of Si anodes in Li-ion batteries. Here, a multi-modal approach is used to visualize these deformations in their early-stage and link them to inhomogeneities in the dual-layer solid-electrolyte interphase.

in Nature Communications on July 01, 2020 12:00 AM.

• #### NSs amyloid formation is associated with the virulence of Rift Valley fever virus in mice

Nature Communications, Published online: 01 July 2020; doi:10.1038/s41467-020-17101-y

Rift Valley fever virus (RVFV) can cause severe diseases in humans, including encephalitis. Here the authors show that NSs, the major virulence factor of RVFV, is an amyloidogenic protein forming fibrils in infected mouse brains and causing increased mortality in mice.

in Nature Communications on July 01, 2020 12:00 AM.

• #### A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction

Nature Communications, Published online: 01 July 2020; doi:10.1038/s41467-020-17099-3

Osteocytes are mechanoresponsive within skeletal tissue. Here, the authors show that class IIa histone deacetylases are phosphorylated by focal adhesion kinase, suggesting that HDAC5 may propagate mechanobiological cues to regulate cell type-specific gene expression.

in Nature Communications on July 01, 2020 12:00 AM.

• #### Flexible experimental designs for valid single-cell RNA-sequencing experiments allowing batch effects correction

Nature Communications, Published online: 01 July 2020; doi:10.1038/s41467-020-16905-2

It is not clear which designs, other than completely randomized ones, are valid for scRNA-seq experiments so that batch effects can be adjusted. Here the authors show that under flexible reference panel and chain-type designs, biological variability can also be separated from batch effects, at least by BUSseq.

in Nature Communications on July 01, 2020 12:00 AM.

• #### Daily briefing: LIGO turns huge mirrors into quantum objects to break precision limit

Nature, Published online: 01 July 2020; doi:10.1038/d41586-020-01998-y

Gravitational-wave detector goes quantum to overcome the limits of the Heisenberg uncertainty principle. Plus: why it’s so hard to know when we will reach herd immunity to COVID-19, and how flying snakes glide through the air.

in Nature on July 01, 2020 12:00 AM.

• #### Second Brazilian museum fire in two years reignites calls for reform

Nature, Published online: 01 July 2020; doi:10.1038/d41586-020-01990-6

A recent fire at a natural history museum in Minas Gerais is forcing some researchers to relive the pain of losing priceless specimens and artefacts.

in Nature on July 01, 2020 12:00 AM.

• #### Exciting inhibition in primates

A new genetic marker enables precise control over a group of inhibitory neurons in monkeys.

in eLife on July 01, 2020 12:00 AM.

• #### Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers

We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.

in eLife on July 01, 2020 12:00 AM.

• #### Subscription and Copyright Information

in Trends in Neurosciences: Current Issue on July 01, 2020 12:00 AM.

• #### Advisory Board and Contents

in Trends in Neurosciences: Current Issue on July 01, 2020 12:00 AM.

• #### From Complexity to Consciousness

We thank Cecconi and colleagues for their probing questions about our opinion article ‘Are There Islands of Awareness?’ [1], and we are grateful for the opportunity to return to these important issues.

in Trends in Neurosciences: In press on July 01, 2020 12:00 AM.

• #### Islands of Awareness or Cortical Complexity?

Bayne et al. (2020) [1] envision the fascinating possibility that disconnected hemispheres (through hemispherotomy), ex cranio brains, and cerebral organoids may be islands of awareness (IOAs). They defined IOAs as systems fully disconnected from the external surrounding, both in terms of input (i.e., sensory information) and output (i.e., motor responses), yet capable of conscious experience (i.e., aware). In order to test whether these islands are effectively aware, the authors propose to use measures of human/animal consciousness that have been well validated in human/animal settings by correlation with pretheoretical measures of consciousness (e.g., behavioural reports) or subjective reports (in the case of humans).

in Trends in Neurosciences: In press on July 01, 2020 12:00 AM.

• #### The Role of Astrocytes in Remyelination

Remyelination is the regeneration of myelin sheaths following demyelination. This regenerative process is critical for the re-establishment of axonal conduction velocity and metabolic support to the axons. Successful remyelination in the CNS generally depends on the activation, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs). However, other cell types play critical roles in establishing where a lesion is conducive for regeneration. In the last few years, several studies have described beneficial and detrimental roles played by astrocytes in remyelination.

in Trends in Neurosciences: In press on July 01, 2020 12:00 AM.

• #### COVID-19 and the chemical senses: supporting players take center stage

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.

in Neuron: In press on July 01, 2020 12:00 AM.

• #### Exaggerating Harmful Drug Effects on the Brain Is Killing Black People

Exaggerations of the detrimental impact of recreational drug use on the human brain have bolstered support for draconian drug policies and have been used to justify police brutality against Black people. This situation has led to disproportionately high Black incarceration rates and countless Black deaths. Here, Hart offers solutions to remedy this multi-century maltreatment of Black people.

in Neuron: In press on July 01, 2020 12:00 AM.

• #### Human IgG neutralizing monoclonal antibodies block SARS-CoV-2 infection

Wan et al. identify 11 potent neutralizing antibodies against COVID-19 from 11 convalescent patients. These human neutralizing antibodies target 3 separate epitopes on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and epitope B antibody (553-15) can enhance the neutralizing abilities of most other antibodies.

in Cell Reports: In press on July 01, 2020 12:00 AM.

• #### Potential causes and consequences of gastrointestinal disorders during a SARS-CoV-2 infection

In this review, Trottein & Sokol present hypothetical mechanisms leading to gut symptoms in patients with COVID-19 and discuss their potential consequences on disease severity. They also discuss the role of the gut microbiota in disease and the potential interest of targeting it to improve COVID-19 pathogenesis.

in Cell Reports: In press on July 01, 2020 12:00 AM.

• #### Statistical analysis of 3D localisation microscopy images for quantification of membrane protein distributions in a platelet clot model

by Sandra Mayr, Fabian Hauser, Sujitha Puthukodan, Markus Axmann, Janett Göhring, Jaroslaw Jacak

We present the software platform 2CALM that allows for a comparative analysis of 3D localisation microscopy data representing protein distributions in two biological samples. The in-depth statistical analysis reveals differences between samples at the nanoscopic level using parameters such as cluster-density and -curvature. An automatic classification system combines multiplex and multi-level statistical approaches into one comprehensive parameter for similarity testing of the compared samples. We demonstrated the biological importance of 2CALM, comparing the protein distributions of CD41 and CD62p on activated platelets in a 3D artificial clot. Additionally, using 2CALM, we quantified the impact of the inflammatory cytokine interleukin-1β on platelet activation in clots. The platform is applicable to any other cell type and biological system and can provide new insights into biological and medical applications.

in PLoS Computational Biology on June 30, 2020 09:00 PM.

• #### Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer

by María Gutiérrez-Salmerón, José Manuel García-Martínez, Javier Martínez-Useros, María Jesús Fernández-Aceñero, Benoit Viollet, Severine Olivier, Jagat Chauhan, Silvia R. Lucena, Antonio De la Vieja, Colin R. Goding, Ana Chocarro-Calvo, Custodia García-Jiménez

Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type–specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply–demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards β-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/β-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.

in PLoS Biology on June 30, 2020 09:00 PM.

• #### Input‐output connections of LJA5 prodynorphin neurons

We identified a novel population of inhibitory prodynorphin neurons in the mouse and human brainstem which we named LJA5. LJA5 neurons selectively target lamina I of the spinal cord, and other sensory nuclei including the lateral parabrachial and periaqueductal gray. The LJA5 area receives input from sensory and stress regions.

## Abstract

Sensory information is transmitted from peripheral nerves, through the spinal cord, and up to the brain. Sensory information may be modulated by projections from the brain to the spinal cord, but the neural substrates for top‐down sensory control are incompletely understood. We identified a novel population of inhibitory neurons in the mouse brainstem, distinguished by their expression of prodynorphin, which we named LJA5. Here, we identify a similar group of pdyn+ neurons in the human brainstem, and we define the efferent and afferent projection patterns of LJA5 neurons in mouse. Using specific genetic tools, we selectively traced the projections of the pdyn ‐expressing LJA5 neurons through the brain and spinal cord. Terminal fields were densest in the lateral and ventrolateral periaqueductal grey (PAG), lateral parabrachial nucleus (LPB), caudal pressor area, and lamina I of the spinal trigeminal nucleus and all levels of the spinal cord. We then labeled cell types in the PAG, LPB, medulla, and spinal cord to better define the specific targets of LJA5 boutons. LJA5 neurons send the only known inhibitory descending projection specifically to lamina I of the spinal cord, which transmits afferent pain, temperature, and itch information up to the brain. Using retrograde tracing, we found LJA5 neurons receive inputs from sensory and stress areas such as somatosensory/insular cortex, preoptic area, paraventricular nucleus, dorsomedial nucleus and lateral hypothalamus, PAG, and LPB. This pattern of inputs and outputs suggest LJA5 neurons are uniquely positioned to be activated by sensation and stress, and in turn, inhibit pain and itch.

in Journal of Comparative Neurology on June 30, 2020 07:00 PM.

• #### Visual interaction networks: A novel bio-inspired computational model for image classification

Publication date: Available online 30 June 2020

Source: Neural Networks

Author(s): Bing Wei, Haibo He, Kuangrong Hao, Lei Gao, Xue-song Tang

in Neural Networks on June 30, 2020 06:00 PM.

## Graphical Abstract

Locations of waking/arousal‐related cell groups of the brainstem and caudal diencephalon at which GA 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. GAs 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 (GA), 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 GA 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: (a) delta oscillations throughout the cortex; (b) marked reductions in neural activity (from waking) over widespread regions of the cortex, most pronounced in frontal and parietal cortices; and (c) 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.

in Journal of Comparative Neurology on June 30, 2020 05:42 PM.

• #### Mitochondrial protein interaction landscape of SS-31 [Systems Biology]

Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects...

in PNAS on June 30, 2020 05:11 PM.

• #### Plastocyanin is the long-range electron carrier between photosystem II and photosystem I in plants [Plant Biology]

In photosynthetic electron transport, large multiprotein complexes are connected by small diffusible electron carriers, the mobility of which is challenged by macromolecular crowding. For thylakoid membranes of higher plants, a long-standing question has been which of the two mobile electron carriers, plastoquinone or plastocyanin, mediates electron transport from stacked grana...

in PNAS on June 30, 2020 05:11 PM.

• #### Dynamic measurement of cytosolic pH and [NO3-] uncovers the role of the vacuolar transporter AtCLCa in cytosolic pH homeostasis [Plant Biology]

Ion transporters are key players of cellular processes. The mechanistic properties of ion transporters have been well elucidated by biophysical methods. Meanwhile, the understanding of their exact functions in cellular homeostasis is limited by the difficulty of monitoring their activity in vivo. The development of biosensors to track subtle changes...

in PNAS on June 30, 2020 05:11 PM.

• #### Protein complex stoichiometry and expression dynamics of transcription factors modulate stem cell division [Plant Biology]

Stem cells divide and differentiate to form all of the specialized cell types in a multicellular organism. In the Arabidopsis root, stem cells are maintained in an undifferentiated state by a less mitotically active population of cells called the quiescent center (QC). Determining how the QC regulates the surrounding stem...

in PNAS on June 30, 2020 05:11 PM.

• #### Wounding-induced changes in cellular pressure and localized auxin signalling spatially coordinate restorative divisions in roots [Plant Biology]

Wound healing in plant tissues, consisting of rigid cell wall-encapsulated cells, represents a considerable challenge and occurs through largely unknown mechanisms distinct from those in animals. Owing to their inability to migrate, plant cells rely on targeted cell division and expansion to regenerate wounds. Strict coordination of these wound-induced responses...

in PNAS on June 30, 2020 05:11 PM.

• #### The 3' processing of antisense RNAs physically links to chromatin-based transcriptional control [Plant Biology]

Noncoding RNA plays essential roles in transcriptional control and chromatin silencing. At Arabidopsis thaliana FLC, antisense transcription quantitatively influences transcriptional output, but the mechanism by which this occurs is still unclear. Proximal polyadenylation of the antisense transcripts by FCA, an RNA-binding protein that physically interacts with RNA 3′ processing factors,...

in PNAS on June 30, 2020 05:11 PM.

• #### Abundant expression of maternal siRNAs is a conserved feature of seed development [Plant Biology]

Small RNAs are abundant in plant reproductive tissues, especially 24-nucleotide (nt) small interfering RNAs (siRNAs). Most 24-nt siRNAs are dependent on RNA Pol IV and RNA-DEPENDENT RNA POLYMERASE 2 (RDR2) and establish DNA methylation at thousands of genomic loci in a process called RNA-directed DNA methylation (RdDM). In Brassica rapa,...

in PNAS on June 30, 2020 05:11 PM.

• #### EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology in Drosophila [Physiology]

Organisms possess photoperiodic timing mechanisms to detect variations in day length and temperature as the seasons progress. The nature of the molecular mechanisms interpreting and signaling these environmental changes to elicit downstream neuroendocrine and physiological responses are just starting to emerge. Here, we demonstrate that, in Drosophila melanogaster, EYES ABSENT...

in PNAS on June 30, 2020 05:11 PM.

• #### Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain [Pharmacology]

Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated...

in PNAS on June 30, 2020 05:11 PM.

• #### Functional imaging evidence for task-induced deactivation and disconnection of a major default mode network hub in the mouse brain [Neuroscience]

The default mode network (DMN) has been defined in functional brain imaging studies as a set of highly connected brain areas, which are active during wakeful rest and inactivated during task-based stimulation. DMN function is characteristically impaired in major neuropsychiatric diseases, emphasizing its interest for translational research. However, in the...

in PNAS on June 30, 2020 05:11 PM.

• #### Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision [Neuroscience]

Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor β (thrb) is required for expression of long-wavelength-sensitive opsin (lws) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme,...

in PNAS on June 30, 2020 05:11 PM.

• #### Brain networks underlying vulnerability and resilience to drug addiction [Neuroscience]

Regular drug use can lead to addiction, but not everyone who takes drugs makes this transition. How exactly drugs of abuse interact with individual vulnerability is not fully understood, nor is it clear how individuals defy the risks associated with drugs or addiction vulnerability. We used resting-state functional MRI (fMRI)...

in PNAS on June 30, 2020 05:11 PM.

• #### Auditory representation of learned sound sequences in motor regions of the macaque brain [Neuroscience]

Human speech production requires the ability to couple motor actions with their auditory consequences. Nonhuman primates might not have speech because they lack this ability. To address this question, we trained macaques to perform an auditory–motor task producing sound sequences via hand presses on a newly designed device (“monkey piano”)....

in PNAS on June 30, 2020 05:11 PM.

• #### ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function [Neuroscience]

Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS UBQLN2 patients and in a transgenic P497S UBQLN2 mouse model...

in PNAS on June 30, 2020 05:11 PM.

• #### A common rule governing differentiation kinetics of mouse cortical progenitors [Neuroscience]

The balance between proliferation and differentiation of stem cells and progenitors determines the size of an adult brain region. While the molecular mechanisms regulating proliferation and differentiation of cortical progenitors have been intensively studied, an analysis of the kinetics of progenitor choice between self-renewal and differentiation in vivo is, due...

in PNAS on June 30, 2020 05:11 PM.

• #### Impact of {alpha}-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized {alpha}-synuclein rat model of PD [Neuroscience]

Preclinical assessment of the therapeutic potential of dopamine (DA) neuron replacement in Parkinson’s disease (PD) has primarily been performed in the 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect the pathological features or progressive nature of the disease. In this study,...

in PNAS on June 30, 2020 05:11 PM.

• #### The ventral striatum dissociates information expectation, reward anticipation, and reward receipt [Psychological and Cognitive Sciences]

Do dopaminergic reward structures represent the expected utility of information similarly to a reward? Optimal experimental design models from Bayesian decision theory and statistics have proposed a theoretical framework for quantifying the expected value of information that might result from a query. In particular, this formulation quantifies the value of...

in PNAS on June 30, 2020 05:11 PM.

• #### Genomic determinants of pathogenicity in SARS-CoV-2 and other human coronaviruses [Microbiology]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an immediate, major threat to public health across the globe. Here we report an in-depth molecular analysis to reconstruct the evolutionary origins of the enhanced pathogenicity of SARS-CoV-2 and other coronaviruses that are severe human pathogens. Using integrated comparative genomics and machine...

in PNAS on June 30, 2020 05:11 PM.

• #### Uncoupling DNA damage from chromatin damage to detoxify doxorubicin [Medical Sciences]

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It...

in PNAS on June 30, 2020 05:11 PM.

• #### Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted {alpha}-particle therapy [Medical Sciences]

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225–labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the...

in PNAS on June 30, 2020 05:11 PM.

• #### Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis [Immunology and Inflammation]

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages...

in PNAS on June 30, 2020 05:11 PM.

• #### Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides [Immunology and Inflammation]

The potency of adoptive T cell therapies targeting the cell surface antigen CD19 has been demonstrated in hematopoietic cancers. It has been difficult to identify appropriate targets in nonhematopoietic tumors, but one class of antigens that have shown promise is aberrant O-glycoprotein epitopes. It has long been known that dysregulated...

in PNAS on June 30, 2020 05:11 PM.

• #### Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis [Genetics]

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere...

in PNAS on June 30, 2020 05:11 PM.

• #### A high-coverage Neandertal genome from Chagyrskaya Cave [Genetics]

We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to Neandertals in western Eurasia [Prüfer et al., Science 358, 655–658 (2017); Hajdinjak et al., Nature 555,...

in PNAS on June 30, 2020 05:11 PM.

• #### The Whi2p-Psr1p/Psr2p complex regulates interference competition and expansion of cells with competitive advantage in yeast colonies [Evolution]

Yeast form complex highly organized colonies in which cells undergo spatiotemporal phenotypic differentiation in response to local gradients of nutrients, metabolites, and specific signaling molecules. Colony fitness depends on cell interactions, cooperation, and the division of labor between differentiated cell subpopulations. Here, we describe the regulation and dynamics of the...

in PNAS on June 30, 2020 05:11 PM.

• #### Wild hummingbirds discriminate nonspectral colors [Evolution]

Many animals have the potential to discriminate nonspectral colors. For humans, purple is the clearest example of a nonspectral color. It is perceived when two color cone types in the retina (blue and red) with nonadjacent spectral sensitivity curves are predominantly stimulated. Purple is considered nonspectral because no monochromatic light...

in PNAS on June 30, 2020 05:11 PM.

• #### Structure of the RECK CC domain, an evolutionary anomaly [Evolution]

Five small protein domains, the CC-domains, at the N terminus of the RECK protein, play essential roles in signaling by WNT7A and WNT7B in the context of central nervous system angiogenesis and blood–brain barrier formation and maintenance. We have determined the structure of CC domain 4 (CC4) at 1.65-Å resolution...

in PNAS on June 30, 2020 05:11 PM.

• #### Regulation of spatiotemporal limits of developmental gene expression via enhancer grammar [Developmental Biology]

The regulatory specificity of a gene is determined by the structure of its enhancers, which contain multiple transcription factor binding sites. A unique combination of transcription factor binding sites in an enhancer determines the boundary of target gene expression, and their disruption often leads to developmental defects. Despite extensive characterization...

in PNAS on June 30, 2020 05:11 PM.

• #### Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics [Developmental Biology]

Comparative transcriptomics between differentiating human pluripotent stem cells (hPSCs) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate human pluripotent stem cell-derived Purkinje cells (hPSC-PCs) that formed...

in PNAS on June 30, 2020 05:11 PM.

• #### Long-term association of a transcription factor with its chromatin binding site can stabilize gene expression and cell fate commitment [Developmental Biology]

Some lineage-determining transcription factors are overwhelmingly important in directing embryonic cells to a particular differentiation pathway, such as Ascl1 for nerve. They also have an exceptionally strong ability to force cells to change from an unrelated pathway to one preferred by their action. Transcription factors are believed to have a...

in PNAS on June 30, 2020 05:11 PM.

• #### Synaptic loss in the multiple sclerosis spinal cord

Disability in multiple sclerosis (MS) is considered primarily a result of axonal loss. However, correlation with spinal cord cross‐sectional area – a predictor of disability – is poor, questioning the unique role of axonal loss. We investigated the degree of synaptic loss in post‐mortem spinal cords (18 chronic MS, eight healthy controls) using immunohistochemistry for synaptophysin and synapsin. Substantial (58–96%) loss of synapses throughout the spinal cord was detected, along with moderate (47%) loss of anterior horn neurons, notably in demyelinating MS lesions. We conclude that synaptic loss is significant in chronic MS, likely contributing to disability accrual.

in Annals of Neurology on June 30, 2020 03:34 PM.

• #### Extra neural ensemble disrupts memory recall

Nature Neuroscience, Published online: 30 June 2020; doi:10.1038/s41593-020-0673-z

Poll and colleagues examined the historical activity of hippocampal CA1 neurons during learning and memory recall using longitudinal two-photon in vivo imaging, providing evidence that extra neural ensemble activity disrupts memory recall in a mouse model of early Alzheimer’s disease.

in Nature Neuroscience on June 30, 2020 12:00 AM.

• #### Publisher Correction: Intermittent metabolic switching, neuroplasticity and brain health

Nature Reviews Neuroscience, Published online: 30 June 2020; doi:10.1038/s41583-020-0342-y

Publisher Correction: Intermittent metabolic switching, neuroplasticity and brain health

in Nature Reviews on June 30, 2020 12:00 AM.

• #### Author Correction: Polarizing an antiferromagnet by optical engineering of the crystal field

Nature Physics, Published online: 30 June 2020; doi:10.1038/s41567-020-0977-7

Author Correction: Polarizing an antiferromagnet by optical engineering of the crystal field

in Nature Physics on June 30, 2020 12:00 AM.

• #### Author Correction: Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

Nature Communications, Published online: 30 June 2020; doi:10.1038/s41467-020-17273-7

Author Correction: Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

in Nature Communications on June 30, 2020 12:00 AM.

• #### Structural characterization of a novel human adeno-associated virus capsid with neurotropic properties

Nature Communications, Published online: 30 June 2020; doi:10.1038/s41467-020-17047-1

Adeno-associated viruses (AAVs) are vehicles for gene therapy in humans, but currently only a limited amount of AAV serotypes is available. Here, the authors identify a novel AAV, AAVv66, and demonstrate enhanced production yields, virion stability, and CNS transduction compared to the clinically approved serotype AAV2.

in Nature Communications on June 30, 2020 12:00 AM.

• #### A framework for on-implant spike sorting based on salient feature selection

Nature Communications, Published online: 30 June 2020; doi:10.1038/s41467-020-17031-9

On-implant spike sorting methods utilize static waveform features for the classification. Here, the authors propose a framework based on dynamic selection of features that is more accurate and requires less memory.

in Nature Communications on June 30, 2020 12:00 AM.

• #### The increasing likelihood of temperatures above 30 to 40 °C in the United Kingdom

Nature Communications, Published online: 30 June 2020; doi:10.1038/s41467-020-16834-0

The United Kingdom has experienced a strong heat wave in 2019 that set a new temperature record for the country of 38.7 °C. In this study the authors show that under climate change, local temperatures are increasingly likely to exceed 35 °C and 40 °C in the next decades and, hence, summers like the one of 2019 become more frequent.

in Nature Communications on June 30, 2020 12:00 AM.

• #### Chemogenetic Suppression of the Subthalamic Nucleus Induces Attentional Deficits and Impulsive Action in a Five-Choice Serial Reaction Time Task in Mice

The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, receives inputs from broad cerebral cortical areas and relays cortical activity to subcortical structures. Recent human and animal studies have suggested that executive function, which is assumed to consist of a set of different cognitive processes for controlling behavior, depends on precise information processing between the cerebral cortex and subcortical structures, leading to the idea that the STN contains neurons that transmit the information required for cognitive processing through their activity, and is involved in such cognitive control directly and dynamically. On the other hand, the STN activity also affects intracellular signal transduction and gene expression profiles influencing plasticity in other basal ganglia components. The STN may also indirectly contribute to information processing for cognitive control in other brain areas by regulating slower signaling mechanisms. However, the precise correspondence and causal relationship between the STN activity and cognitive processes are not fully understood. To address how the STN activity is involved in cognitive processes for controlling behavior, we applied Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic manipulation of neural activity to behavioral analysis using a touchscreen operant platform. We subjected mice selectively expressing DREADD receptors in the STN neurons to a five-choice serial reaction time task, which has been developed to quantitatively measure executive function. Chemogenetic suppression of the STN activity reversibly impaired attention, especially required under highly demanding conditions, and increased impulsivity but not compulsivity. These findings, taken together with the results of previous lesion studies, suggest that the STN activity, directly and indirectly, participates in cognitive processing for controlling behavior, and dynamically regulates specific types of subprocesses in cognitive control probably through fast synaptic transmission.

in Frontiers in Systems Neuroscience on June 30, 2020 12:00 AM.

• #### Long-Term Spinal Cord Stimulation After Chronic Complete Spinal Cord Injury Enables Volitional Movement in the Absence of Stimulation

Background: Chronic spinal cord injury (SCI) portends a low probability of recovery, especially in the most severe subset of motor-complete injuries. Active spinal cord stimulation with or without intensive locomotor training has been reported to restore movement after traumatic SCI. Only three cases have been reported where participants developed restored volitional movement with active stimulation turned off after a period of chronic stimulation and only after intensive rehabilitation with locomotor training. It is unknown whether restoration of movement without stimulation is possible after stimulation alone.

Objective: We describe the development of spontaneous volitional movement (SVM) without active stimulation in a subset of participants in the Epidural Stimulation After Neurologic Damage (ESTAND) trial, in which locomotor training is not prescribed as part of the study protocol, and subject’s rehabilitation therapies are not modified.

Methods: Volitional movement was evaluated with the Brain Motor Control Assessment using sEMG recordings and visual examination at baseline and at follow-up visits with and without stimulation. Additional functional assessment with a motor-assisted bicycle exercise at follow-up with and without stimulation identified generated work with and without effort.

Results: The first seven participants had ASIA Impairment Scale (AIS) A or B thoracic SCI, a mean age of 42 years, and 7.7 years post-injury on average. Four patients developed evidence of sustained volitional movement, even in the absence of active stimulation after undergoing chronic epidural spinal cord stimulation (eSCS). Significant increases in volitional power were found between those observed to spontaneously move without stimulation and those unable (p < 0.0005). The likelihood of recovery of spontaneous volitional control was correlated with spasticity scores prior to the start of eSCS therapy (p = 0.048). Volitional power progressively improved over time (p = 0.016). Additionally, cycling was possible without stimulation (p < 0.005).

Conclusion: While some SVM after eSCS has been reported in the literature, this study demonstrates sustained restoration without active stimulation after long-term eSCS stimulation in chronic and complete SCI in a subset of participants. This finding supports previous studies suggesting that “complete” SCI is likely not as common as previously believed, if it exists at all in the absence of transection and that preserved pathways are substrates for eSCS-mediated recovery in clinically motor-complete SCI.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT03026816.

in Frontiers in Systems Neuroscience on June 30, 2020 12:00 AM.

• #### Compatibility Evaluation of Clustering Algorithms for Contemporary Extracellular Neural Spike Sorting

Deciphering useful information from electrophysiological data recorded from the brain, in-vivo or in-vitro, is dependent on the capability to analyse spike patterns efficiently and accurately. The spike analysis mechanisms are heavily reliant on the clustering algorithms that enable separation of spike trends based on their spatio-temporal behaviors. Literature review report several clustering algorithms over decades focused on different applications. Although spike analysis algorithms employ only a small subset of clustering algorithms, however, not much work has been reported on the compliance and suitability of such clustering algorithms for spike analysis. In our study, we have attempted to comment on the suitability of available clustering algorithms and performance capacity when exposed to spike analysis. In this regard, the study reports a compatibility evaluation on algorithms previously employed in spike sorting as well as the algorithms yet to be investigated for application in sorting neural spikes. The performance of the algorithms is compared in terms of their accuracy, confusion matrix and accepted validation indices. Three data sets comprising of easy, difficult, and real spike similarity with known ground-truth are chosen for assessment, ensuring a uniform testbed. The procedure also employs two feature-sets, principal component analysis and wavelets. The report also presents a statistical score scheme to evaluate the performance individually and overall. The open nature of the data sets, the clustering algorithms and the evaluation criteria make the proposed evaluation framework widely accessible to the research community. We believe that the study presents a reference guide for emerging neuroscientists to select the most suitable algorithms for their spike analysis requirements.

in Frontiers in Systems Neuroscience on June 30, 2020 12:00 AM.

Protocadherins (Pcdhs) are cell adhesion molecules that belong to the cadherin superfamily, and are subdivided into clustered (cPcdhs) and non-clustered Pcdhs (ncPcdhs) in vertebrates. In this review, we summarize their discovery, expression mechanisms, and roles in neuronal development and cancer, thereby highlighting the context-dependent nature of their actions. We furthermore provide an extensive overview of current structural knowledge, and its implications concerning extracellular interactions between cPcdhs, ncPcdhs, and classical cadherins. Next, we survey the known molecular action mechanisms of Pcdhs, emphasizing the regulatory functions of proteolytic processing and domain shedding. In addition, we outline the importance of Pcdh intracellular domains in the regulation of downstream signaling cascades, and we describe putative Pcdh interactions with intracellular molecules including components of the WAVE complex, the Wnt pathway, and apoptotic cascades. Our overview combines molecular interaction data from different contexts, such as neural development and cancer. This comprehensive approach reveals potential common Pcdh signaling hubs, and points out future directions for research. Functional studies of such key factors within the context of neural development might yield innovative insights into the molecular etiology of Pcdh-related neurodevelopmental disorders.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### Poly(I:C) Challenge Alters Brain Expression of Oligodendroglia-Related Genes of Adult Progeny in a Mouse Model of Maternal Immune Activation

Background: Altered white matter connectivity, as evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia. Despite an increasing appreciation that such white matter disconnectivity is linked to social behavior deficits, virtually no etiologically meaningful myelin-related genes have been identified in oligodendrocytes, the key myelinating cells in the CNS, to furnish an account on the causes. The impact of neurodevelopmental perturbations during pregnancy such as maternal immune activation (MIA) on these genes in memory-related neural networks has not been experimentally scrutinized.

Methods: In this study, a mouse model of MIA by the viral dsRNA analog poly(I:C) was employed to mimic the effects of inflammation during pregnancy. Transcriptional expression levels of selected myelin- or oligodendroglia-related genes implicated in schizophrenia or ASD development were analyzed by in situ hybridization (ISH) and quantitative real-time PCR (qRT-PCR) with brain samples from MIA and control groups. The analysis focused on SOX-10 (SRY-related HMG-box 10), MAG (myelin-associated glycoprotein), and Tf (transferrin) expression in the hippocampus and the surrounding memory-related cortical regions in either hemisphere.

Results: Specifically, ISH reveals that in the brain of prenatal poly(I:C)-exposed mouse offspring in the MIA model (gestation day 9), mRNA expression of the genes SOX10, MAG and Tf were generally reduced in the limbic system including the hippocampus, retrosplenial cortex and parahippocampal gyrus on either side of the hemispheres. qRT-PCR further confirms the reduction of SOX10, MAG, and Tf expression in the medial prefrontal cortex, sensory cortex, amygdala, and hippocampus.

Conclusions: Our present results provide direct evidence that prenatal exposure to poly(I:C) elicits profound and long-term changes in transcript level and spatial distribution of myelin-related genes in multiple neocortical and limbic regions, notably the hippocampus and its surrounding memory-related neural networks. Our work demonstrates the potential utility of oligodendroglia-related genes as biomarkers for modeling neurodevelopmental disorders, in agreement with the hypothesis that MIA during pregnancy could lead to compromised white matter connectivity in ASD.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### LMTK1, a Novel Modulator of Endosomal Trafficking in Neurons

Neurons extend long processes known as axons and dendrites, through which they communicate with each other. The neuronal circuits formed by the axons and dendrites are the structural basis of higher brain functions. The formation and maintenance of these processes are essential for physiological brain activities. Membrane components, both lipids, and proteins, that are required for process formation are supplied by vesicle transport. Intracellular membrane trafficking is regulated by a family of Rab small GTPases. A group of Rabs regulating endosomal trafficking has been studied mainly in nonpolarized culture cell lines, and little is known about their regulation in polarized neurons with long processes. As shown in our recent study, lemur tail (former tyrosine) kinase 1 (LMTK1), an as yet uncharacterized Ser/Thr kinase associated with Rab11-positive recycling endosomes, modulates the formation of axons, dendrites, and spines in cultured primary neurons. LMTK1 knockdown or knockout (KO) or the expression of a kinase-negative mutant stimulates the transport of endosomal vesicles in neurons, leading to the overgrowth of axons, dendrites, and spines. More recently, we found that LMTK1 regulates TBC1D9B Rab11 GAP and proposed the Cdk5/p35-LMTK1-TBC1D9B-Rab11 pathway as a signaling cascade that regulates endosomal trafficking. Here, we summarize the biochemical, cell biological, and physiological properties of LMTK1.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### Inhibition of M/Kv7 Currents Contributes to Chloroquine-Induced Itch in Mice

M/Kv7 potassium channels play a key role in regulation of neuronal excitability. Modulation of neuronal excitability of primary sensory neurons determines the itch sensation induced by a variety of itch-causing substances including chloroquine (CQ). In the present study, we demonstrate that suppression of M/Kv7 channel activity contributes to generation of itch in mice. CQ enhances excitability of the primary sensory neurons through inhibiting M/Kv7 potassium currents in a Ca2+ influx-dependent manner. Specific M/Kv7 channel opener retigabine (RTG) or tannic acid (TA) not only reverses the CQ-induced enhancement of neuronal excitability but also suppresses the CQ-induced itch behavior. Systemic application of RTG or TA also significantly inhibits the itch behavior induced by a variety of pruritogens. Taken together, our findings provide novel insight into the molecular basis of CQ-induced itch sensation in mammals that can be applied to the development of strategies to mitigate itch behavior.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### LncRNA LINC00641 Sponges miR-497-5p to Ameliorate Neural Injury Induced by Anesthesia via Up-Regulating BDNF

Introduction

Ketamine, which is widely used in anesthesia, can induce cortical neurotoxicity in patients. This study aims to investigate the effects of long non-coding RNA LINC00641 on the ketamine-induced neural injury.

Materials and Methods

In this study, rat pheochromocytoma cells (PC12 cells) were used as a cell model and Sprague–Dawley postnatal day 7 rats were used for experiments in vivo. Ketamine-induced aberrant expression levels of LINC00641, miR-497-5p and brain-derived neurotrophic factor (BDNF) were examined by qRT-PCR. The effects of LINC00641 and miR-497-5p on ketamine-induced neural injury were then examined by MTT assays and TUNEL analysis. In addition, the activity of ROS and caspase-3 was measured. The regulatory relationships between LINC00641 and miR-497-5p, miR-497-5p and BDNF were detected by dual-luciferase reporter assay, respectively.

Results

Ketamine induced the apoptosis of PC12 cells, accompanied by down-regulation of LINC00641 and BDNF, and up-regulation of miR-497-5p. LINC00641 overexpression enhanced the resistance to the apoptosis of PC12 cells, while transfection of miR-497-5p had opposite effects. Furthermore, LINC00641 could bind to miR-497-5p and reduce its expression, but indirectly increase the BDNF expression, which was considered as a protective factor in neural injury and activated TrkB/PI3K/Akt pathway.

Conclusion

Collectively, LINC00641/miR-497-5p/BDNF axis was validated to be an important signaling pathway in modulating ketamine-induced neural injury.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### Integrated Metabolomics and Proteomics Analysis Reveals Plasma Lipid Metabolic Disturbance in Patients With Parkinson’s Disease

Parkinson’s disease (PD) is a common neurodegenerative disease in the elderly with a pathogenesis that remains unclear. We aimed to explore its pathogenesis through plasma integrated metabolomics and proteomics analysis. The clinical data of consecutively recruited PD patients and healthy controls were assessed. Fasting plasma samples were obtained and analyzed using metabolomics and proteomics methods. After that, differentially expressed metabolites and proteins were identified for further bioinformatics analysis. No significant difference was found in the clinical data between these two groups. Eighty-three metabolites were differentially expressed in PD patients identified by metabolomics analysis. These metabolites were predominately lipid and lipid-like molecules (63%), among which 25% were sphingolipids. The sphingolipid metabolism pathway was enriched and tended to be activated in the following KEGG pathway analysis. According to the proteomics analysis, forty proteins were identified to be differentially expressed, seven of which were apolipoproteins. Furthermore, five of the six top ranking Gene Ontology terms from cellular components and eleven of the other fourteen Gene Ontology terms from biological processes were directly associated with lipid metabolism. In KEGG pathway analysis, the five enriched pathways were also significantly related with lipid metabolism (p < 0.05). Overall, Parkinson’s disease is associated with plasma lipid metabolic disturbance, including an activated sphingolipid metabolism and decreased apolipoproteins.

in Frontiers in Molecular Neuroscience on June 30, 2020 12:00 AM.

• #### Corrigendum: Sensory Habituation as a Shared Mechanism for Sensory Over-Responsivity and Obsessive–Compulsive Symptoms

in Frontiers in Integrative Neuroscience on June 30, 2020 12:00 AM.

• #### Brain Computer Interfaces for Improving the Quality of Life of Older Adults and Elderly Patients

All people experience aging, and the related physical and health changes, including changes in memory and brain function. These changes may become debilitating leading to an increase in dependence as people get older. Many external aids and tools have been developed to allow older adults and elderly patients to continue to live normal and comfortable lives. This mini-review describes some of the recent studies on cognitive decline and motor control impairment with the goal of advancing non-invasive brain computer interface (BCI) technologies to improve health and wellness of older adults and elderly patients. First, we describe the state of the art in cognitive prosthetics for psychiatric diseases. Then, we describe the state of the art of possible assistive BCI applications for controlling an exoskeleton, a wheelchair and smart home for elderly people with motor control impairments. The basic age-related brain and body changes, the effects of age on cognitive and motor abilities, and several BCI paradigms with typical tasks and outcomes are thoroughly described. We also discuss likely future trends and technologies to assist healthy older adults and elderly patients using innovative BCI applications with minimal technical oversight.

in Frontiers in Neuroscience: Neural Technology on June 30, 2020 12:00 AM.

• #### Spectrally Tunable Neural Network-Assisted Segmentation of Microneurosurgical Anatomy

Background

Distinct tissue types are differentiated based on the surgeon’s knowledge and subjective visible information, typically assisted with white-light intraoperative imaging systems. Narrow-band imaging (NBI) assists in tissue identification and enables automated classifiers, but many anatomical details moderate computational predictions and cause bias. In particular, tissues’ light-source-dependent optical characteristics, anatomical location, and potentially hazardous microstructural changes such as peeling have been overlooked in previous literature.

Methods

Narrow-band images of five (n = 5) facial nerves (FNs) and internal carotid arteries (ICAs) were captured from freshly frozen temporal bones. The FNs were split into intracranial and intratemporal samples, and ICAs’ adventitia was peeled from the distal end. Three-dimensional (3D) spectral data were captured by a custom-built liquid crystal tunable filter (LCTF) spectral imaging (SI) system. We investigated the normal variance between the samples and utilized descriptive and machine learning analysis on the image stack hypercubes.

Results

Reflectance between intact and peeled arteries in lower-wavelength domains between 400 and 576 nm was significantly different (p < 0.05). Proximal FN could be differentiated from distal FN in a higher range, 490–720 nm (p < 0.001). ICA with intact tunica differed from proximal FN nearly thorough the VIS range, 412–592 nm (p < 0.001) and 664–720 nm (p < 0.05) as did its distal counterpart, 422–720 nm (p < 0.001). The availed U-Net algorithm classified 90.93% of the pixels correctly in comparison to tissue margins delineated by a specialist.

Conclusion

Selective NBI represents a promising method for assisting tissue identification and computational segmentation of surgical microanatomy. Further multidisciplinary research is required for its clinical applications and intraoperative integration.

in Frontiers in Neuroscience: Brain Imaging Methods on June 30, 2020 12:00 AM.

• #### Self-Tuning Deep Brain Stimulation Controller for Suppression of Beta Oscillations: Analytical Derivation and Numerical Validation

Closed-loop control strategies for deep brain stimulation (DBS) in Parkinson's disease offer the potential to provide more effective control of patient symptoms and fewer side effects than continuous stimulation, while reducing battery consumption. Most of the closed-loop methods proposed and tested to-date rely on controller parameters, such as controller gains, that remain constant over time. While the controller may operate effectively close to the operating point for which it is set, providing benefits when compared to conventional open-loop DBS, it may perform sub-optimally if the operating conditions evolve. Such changes may result from, for example, diurnal variation in symptoms, disease progression or changes in the properties of the electrode-tissue interface. In contrast, an adaptive or “self-tuning” control mechanism has the potential to accommodate slowly varying changes in system properties over a period of days, months, or years. Such an adaptive mechanism would automatically adjust the controller parameters to maintain the desired performance while limiting side effects, despite changes in the system operating point. In this paper, two neural modeling approaches are utilized to derive and test an adaptive control scheme for closed-loop DBS, whereby the gain of a feedback controller is continuously adjusted to sustain suppression of pathological beta-band oscillatory activity at a desired target level. First, the controller is derived based on a simplified firing-rate model of the reciprocally connected subthalamic nucleus (STN) and globus pallidus (GPe). Its efficacy is shown both when pathological oscillations are generated endogenously within the STN-GPe network and when they arise in response to exogenous cortical STN inputs. To account for more realistic biological features, the control scheme is then tested in a physiologically detailed model of the cortical basal ganglia network, comprised of individual conductance-based spiking neurons, and simulates the coupled DBS electric field and STN local field potential. Compared to proportional feedback methods without gain adaptation, the proposed adaptive controller was able to suppress beta-band oscillations with less power consumption, even as the properties of the controlled system evolve over time due to alterations in the target for beta suppression, beta fluctuations and variations in the electrode impedance.

in Frontiers in Neuroscience: Neural Technology on June 30, 2020 12:00 AM.

• #### Fulminant Guillain–Barré Syndrome and Spontaneous Intraventricular Hemorrhage: A Case Report and Literature Review

Guillain–Barré syndrome (GBS) is an acute, immune-mediated inflammatory peripheral polyneuropathy that is characterized by flaccid paralysis. A few cases have reported that GBS can be caused by head trauma or neurosurgery, but it has never been associated with intraventricular hemorrhage. Here, we report an uncommon case of fulminant GBS that occurred after spontaneous intraventricular hemorrhage. A 73-year-old woman was admitted to the hospital after sudden unconsciousness and vomiting. A head computed tomography (CT) scan following the incident showed a newly developed intraventricular hemorrhage, which led to an immediate ventriculostomy. After 5 days, the endotracheal tube was removed. Two days later, the external ventricular drainage tube was also removed. At this time, the patient was alert and the neurological examination was normal. However, the patient suddenly presented with acute respiratory failure and bilateral limb weakness 3 days later. An analysis of the patient’s cerebrospinal fluid (CSF) revealed that albuminocytologic dissociation was present. The patient was treated with intravenous immunoglobulin (0.4 g/kg/day) for 5 days. Despite timely medical intervention in the hospital, the patient passed away 2 months later. After a cerebral hemorrhagic injury, limb and respiratory muscle weakness can occur on occasion in the ICU. In this context, the potential involvement of GBS should not be ignored. Importantly, the pathogenic mechanism of GBS has been discussed for over a century, and it still remains a mystery. We speculate that the TLR4/NF-κB signaling pathway may be involved in the pathogenesis of GBS following intraventricular hemorrhage. The prognosis of most patients with GBS is usually good, but cerebral hemorrhage and mechanical ventilation may serve as risk factors that exacerbate the condition. This case is reported to remind clinicians to consider the possibility of GBS when patients present limb and respiratory muscle weakness after intraventricular hemorrhage, and to provide a starting point to discuss potential mechanisms of GBS after intraventricular hemorrhage.

in Frontiers in Neuroscience: Neural Technology on June 30, 2020 12:00 AM.

• #### Heart Rate and Respiration Affect the Functional Connectivity of Default Mode Network in Resting-State Functional Magnetic Resonance Imaging

A growing number of brain imaging studies show functional connectivity (FC) between regions during emotional and cognitive tasks in humans. However, emotions are accompanied by changes in physiological parameters such as heart rate and respiration. These changes may affect blood oxygen level-dependent signals, as well as connectivity between brain areas. This study aimed to clarify the effects of physiological noise on the connectivity between areas related to the default mode network using resting-state functional magnetic resonance imaging (rs-fMRI). Healthy adult volunteers (age range: 19–51 years, mean age: 26.9 ± 9.1 years, 8 males and 8 females) underwent rs-fMRI for 10 min using a clinical 3T scanner (MAGNETOM Trio A Tim System, Siemens) with simultaneously recorded respiration and cardiac output. Physiological noise signals were subsequently removed from the acquired fMRI data using the DRIFTER toolbox. Image processing and analysis of the FC between areas related to the default mode network were performed using DPARSF. Network-Based Statistic (NBS) analysis of the functional connectome of the DMN and DMN-related area was used to perform three groups of comparison: without physiological noise correction, with cardiac noise correction, and with cardiac and respiratory noise correction. NBS analysis identified 36 networks with significant differences in three conditions in FC matrices. Post hoc comparison showed no differences between the three conditions, indicating that all three had the same networks. Among the 36 networks, strength of FC of 8 networks was modified under physiological noise correction. Connectivity between left and right anterior medial frontal regions increased strength of connectivity. These areas are located on the medial cerebral hemisphere, close to the sagittal sinus and arteries in the cerebral hemispheres, suggesting that medial frontal areas may be sensitive to cardiac rhythm close to arteries. The other networks observed temporal regions and showed a decrease in their connectivity strength by removing physiological noise, indicating that physiological noise, especially respiration, may be sensitive to BOLD signal in the temporal regions during resting state. Temporal lobe was highly correlated with anxiety-related respiration changes (Masaoka and Homma, 2000), speech processing, and respiratory sensation. These factors may affect the rs-fMRI signaling sensitivity.

in Frontiers in Neuroscience: Brain Imaging Methods on June 30, 2020 12:00 AM.

• #### Understanding Graph Isomorphism Network for rs-fMRI Functional Connectivity Analysis

Graph neural networks (GNN) rely on graph operations that include neural network training for various graph related tasks. Recently, several attempts have been made to apply the GNNs to functional magnetic resonance image (fMRI) data. Despite recent progresses, a common limitation is its difficulty to explain the classification results in a neuroscientifically explainable way. Here, we develop a framework for analyzing the fMRI data using the Graph Isomorphism Network (GIN), which was recently proposed as a powerful GNN for graph classification. One of the important contributions of this paper is the observation that the GIN is a dual representation of convolutional neural network (CNN) in the graph space where the shift operation is defined using the adjacency matrix. This understanding enables us to exploit CNN-based saliency map techniques for the GNN, which we tailor to the proposed GIN with one-hot encoding, to visualize the important regions of the brain. We validate our proposed framework using large-scale resting-state fMRI (rs-fMRI) data for classifying the sex of the subject based on the graph structure of the brain. The experiment was consistent with our expectation such that the obtained saliency map show high correspondence with previous neuroimaging evidences related to sex differences.

in Frontiers in Neuroscience: Brain Imaging Methods on June 30, 2020 12:00 AM.

• #### Investigation of Electrically Evoked Auditory Brainstem Responses to Multi-Pulse Stimulation of High Frequency in Cochlear Implant Users

We investigated the effects of electric multi-pulse stimulation on electrically evoked auditory brainstem responses (eABRs). Multi-pulses with a high burst rate of 10,000 pps were assembled from pulses of 45-μs phase duration. Conditions of 1, 2, 4, 8, and 16 pulses were investigated. Psychophysical thresholds (THRs) and most comfortable levels (MCLs) in multi-pulse conditions were measured. Psychophysical temporal integration functions (slopes of THRs/MCLs as a function of number of pulses) were −1.30 and −0.93 dB/doubling of the number of pulses, which correspond to the doubling of pulse duration. A total of 15 eABR conditions with different numbers of pulses and amplitudes were measured. The morphology of eABRs to multi-pulse stimuli did not differ from those to conventional single pulses. eABR wave eV amplitudes and latencies were analyzed extensively. At a fixed stimulation amplitude, an increasing number of pulses caused increasing wave eV amplitudes up to a certain, subject-dependent number of pulses. Then, amplitudes either saturated or even decreased. This contradicted the conventional amplitude growth functions and also contradicted psychophysical results. We showed that destructive interference could be a possible reason for such a finding, where peaks and troughs of responses to the first pulses were suppressed by those of successive pulses in the train. This study provides data on psychophysical THRs and MCLs and corresponding eABR responses for stimulation with single-pulse and multi-pulse stimuli with increasing duration. Therefore, it provides insights how pulse trains integrate at the level of the brainstem.

in Frontiers in Neuroscience: Neural Technology on June 30, 2020 12:00 AM.

• #### Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism

Molecular imaging of tauopathies is complicated by the differing specificities and off-target binding properties of available radioligands for positron emission tomography (PET). [18F]-APN-1607 ([18F]-PM-PBB3) is a newly developed PET tracer with promising properties for tau imaging. We aimed to characterize the cerebral binding of [18F]-APN-1607 in Alzheimer’s disease (AD) patients compared to normal control (NC) subjects. Therefore, we obtained static late frame PET recordings with [18F]-APN-1607 and [18F]-FDG in patients with a clinical diagnosis of AD group, along with an age-matched NC group ([18F]-APN-1607 only). Using statistical parametric mapping (SPM) and volume of interest (VOI) analyses of the reference region normalized standardized uptake value ratio maps, we then tested for group differences and relationships between both PET biomarkers, as well as their associations with clinical general cognition. In the AD group, [18F]-APN-1607 binding was elevated in widespread cortical regions (P < 0.001 for VOI analysis, familywise error-corrected P < 0.01 for SPM analysis). The regional uptake in AD patients correlated negatively with Mini-Mental State Examination score (frontal lobe: R = -0.632, P = 0.004; temporal lobe: R = -0.593, P = 0.008; parietal lobe: R = -0.552, P = 0.014; insula: R = -0.650, P = 0.003; cingulum: R = -0.665, P = 0.002) except occipital lobe (R = -0.417, P = 0.076). The hypometabolism to [18F]-FDG PET in AD patients also showed negative correlations with regional [18F]-APN-1607 binding in some signature areas of AD (temporal lobe: R = -0.530, P = 0.020; parietal lobe: R = -0.637, P = 0.003; occipital lobe: R = -0.567, P = 0.011). In conclusion, our results suggested that [18F]-APN-1607 PET sensitively detected tau deposition in AD and that individual tauopathy correlated with impaired cerebral glucose metabolism and cognitive function.

in Frontiers in Neuroscience: Neurodegeneration on June 30, 2020 12:00 AM.

• #### Electrophysiological Effects of Transcranial Direct Current Stimulation on Neural Activity in the Rat Motor Cortex

Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the neuronal membrane potential. We have previously documented a sustainable increase in extracellular dopamine levels in the rat striatum of cathodal tDCS, suggesting that cathodal tDCS enhances the neuronal excitability of the cortex. In the present study, we investigated changes in neuronal activity in the cerebral cortex induced by tDCS at the point beneath the stimulus electrode in anesthetized rats in vivo. Multiunit recordings were performed to examine changes in neuronal activity before and after the application of tDCS. In the cathodal tDCS group, multiunit activity (indicating the collective firing rate of recorded neuronal populations) increased in the cerebral cortex. Both anodal and cathodal tDCS increased the firing rate of isolated single units in the cerebral cortex. Significant differences in activity were observed immediately following stimulation and persisted for more than an hour after stimulation. The primary finding of this study was that both anodal and cathodal tDCS increased in vivo neuronal activity in the rat cerebral cortex underneath the stimulus electrode.

in Frontiers in Neuroscience: Neural Technology on June 30, 2020 12:00 AM.

• #### 20 Hz Steady-State Response in Somatosensory Cortex During Induction of Tactile Perceptual Learning Through LTP-Like Sensory Stimulation

The induction of synaptic plasticity requires the presence of temporally patterned neural activity. Numerous cellular studies in animals and brain slices have demonstrated that long-term potentiation (LTP) enhances synaptic transmission, which can be evoked by high-frequency intermittent stimulation. In humans, plasticity processes underlying perceptual learning can be reliably induced by repetitive, LTP-like sensory stimulation. These protocols lead to improvement of perceptual abilities parallel to widespread remodeling of cortical processing. However, whether maintained rhythmic cortical activation induced by the LTP-like stimulation is also present during human perceptual learning experiments, remains elusive. To address this question, we here applied a 20 Hz intermittent stimulation protocol for 40 min to the index-, middle- and ring-fingers of the right hand, while continuously recording EEG over the hand representation in primary somatosensory cortex in young adult participants. We find that each train of stimulation initiates a transient series of sensory-evoked potentials which accumulate after about 500 ms into a 20 Hz steady-state response persisting over the entire period of the 2-s-train. During the inter-train interval, no consistent evoked activity can be detected. This response behavior is maintained over the whole 40 min of stimulation without any indication of habituation. However, the early stimulation evoked potentials (SEPs) and the event-related desynchronization (ERD) during the steady-state response change over the 40 min of stimulation. In a second experiment, we demonstrate in a separate cohort of participants that the here-applied pneumatic type of stimulation results in improvement of tactile acuity as typically observed for electrically applied 20 Hz intermittent stimulation. Our data demonstrate that repetitive stimulation using a 20 Hz protocol drives rhythmic activation in the hand representation of somatosensory cortex, which is sustained during the entire stimulation period. At the same time, cortical excitability increases as indicated by altered ERD and SEP amplitudes. Our results, together with previous data underlining the dependence of repetitive sensory stimulation effects on NMDA-receptor activation, support the view that repetitive sensory stimulation elicits LTP-like processes in the cortex, thereby facilitating perceptual learning processes.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Aerobic Exercise Induces Functional and Structural Reorganization of CNS Networks in Multiple Sclerosis: A Randomized Controlled Trial

Objectives: Evidence from animal studies suggests that aerobic exercise may promote neuroplasticity and could, therefore, provide therapeutic benefits for neurological diseases such as multiple sclerosis (MS). However, the effects of exercise in human CNS disorders on the topology of brain networks, which might serve as an outcome at the interface between biology and clinical performance, remain poorly understood.

Methods: We investigated functional and structural networks in patients with relapsing-remitting MS in a clinical trial of standardized aerobic exercise. Fifty-seven patients were randomly assigned to moderate-intensity exercise for 3 months or a non-exercise control group. We reconstructed functional networks based on resting-state functional magnetic resonance imaging (MRI) and used probabilistic tractography on diffusion-weighted imaging data for structural networks.

Results: At baseline, compared to 30 healthy controls, patients exhibited decreased structural connectivity that was most pronounced in hub regions of the brain. Vice versa, functional connectivity was increased in hubs. After 3 months, we observed hub independent increased functional connectivity in the exercise group while the control group presented a loss of functional hub connectivity. On a structural level, the control group remained unchanged, while the exercise group had also increased connectivity. Increased clustering of hubs indicates a better structural integration and internal connectivity at the top of the network hierarchy.

Conclusion: Increased functional connectivity of hubs contrasts a loss of structural connectivity in relapsing-remitting MS. Under an exercise condition, a further hub independent increase of functional connectivity seems to translate in higher structural connectivity of the whole brain.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Functional Near-Infrared Spectroscopy Indicates That Asymmetric Right Hemispheric Activation in Mental Rotation of a Jigsaw Puzzle Decreases With Task Difficulty

Mental rotation (MR) is a cognitive skill whose neural dynamics are still a matter of debate as previous neuroimaging studies have produced controversial results. In order to investigate the underlying neurophysiology of MR, hemodynamic responses from the prefrontal cortex of 14 healthy subjects were recorded with functional near-infrared spectroscopy (fNIRS) during a novel MR task that had three categorical difficulty levels. Hemodynamic activity strength (HAS) parameter, which reflects the ratio of brain activation during the task to the baseline activation level, was used to assess the prefrontal cortex activation localization and strength. Behavioral data indicated that the MR requiring conditions are more difficult than the condition that did not require MR. The right dorsolateral prefrontal cortex (DLPFC) was found to be active in all conditions and to be the dominant region in the easiest task while more complex tasks showed widespread bilateral prefrontal activation. A significant increase in left DLPFC activation was observed with increasing task difficulty. Significantly higher right DLPFC activation was observed when the incongruent trials were contrasted against the congruent trials, which implied the possibility of a robust error or conflict-monitoring process during the incongruent trials. Our results showed that the right DLPFC is a core region for the processing of MR tasks regardless of the task complexity and that the left DLPFC is involved to a greater extent with increasing task complexity, which is consistent with the previous neuroimaging literature.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Closed-Loop Frontal Midlineθ Neurofeedback: A Novel Approach for Training Focused-Attention Meditation

Cortical oscillations serve as an index of both sensory and cognitive processes and represent one of the most promising candidates for training and targeting the top-down mechanisms underlying executive functions. Research findings suggest that theta (θ) oscillations (3–7 Hz) recorded over frontal-midline electrodes are broadly associated with a number of higher-order cognitive processes and may serve as the mechanistic backbone for cognitive control. Frontal-midline theta (FMθ) oscillations have also been shown to inversely correlate with activity in the default mode network (DMN), a network in the brain linked to spontaneous thought processes such as mind-wandering and rumination. In line with these findings, we previously observed increased FMθ oscillations in expert meditation practitioners during reported periods of focused-attention meditation practice when compared to periods of mind-wandering. In an effort to narrow the explanatory gap by directly connecting observed neurophysiological activity in the brain to the phenomenological nature of reported experience, we designed a methodologically novel and adaptive neurofeedback protocol with the aim of modulating FMθ while having meditation novice participants implement breath-focus strategies derived from focused-attention mediation practices. Participants who received eight sessions of the adaptive FMθ-meditation neurofeedback protocol were able to significantly modulate FMθ over frontal electrodes using focused-attention meditation strategies relative to their baseline by the end of the training and demonstrated significantly faster reaction times on correct trials during the n-back working memory task assessed before and after the FMθ-meditation neurofeedback protocol. No significant differences in frontal theta activity or behavior were observed in the active control participants who received age and gender matched sham neurofeedback. These findings help lay the groundwork for the development of brain training protocols and neurofeedback applications that aim to train features of the mental states and traits associated with focused-attention meditation.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Late fMRI Response Components Are Altered in Autism Spectrum Disorder

Disrupted cortical neural inhibition has been hypothesized to be a primary contributor to the pathophysiology of autism spectrum disorder (ASD). This hypothesis predicts that ASD will be associated with an increase in neural responses. We tested this prediction by comparing fMRI response magnitudes to simultaneous visual, auditory, and motor stimulation in ASD and neurotypical (NT) individuals. No increases in the initial transient response in any brain region were observed in ASD, suggesting that there is no increase in overall cortical neural excitability. Most notably, there were widespread fMRI magnitude increases in the ASD response following stimulation offset, approximately 6–8 s after the termination of sensory and motor stimulation. In some regions, the higher fMRI offset response in ASD could be attributed to a lack of an “undershoot”—an often observed feature of fMRI responses believed to reflect inhibitory processing. Offset response magnitude was associated with reaction times (RT) in the NT group and may explain an overall reduced RT in the ASD group. Overall, our results suggest that increases in neural responsiveness are present in ASD but are confined to specific components of the neural response, are particularly strong following stimulation offset, and are linked to differences in RT.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Developmental Differences of Structural Connectivity and Effective Connectivity in Semantic Judgments of Chinese Characters

Previous studies have investigated the developmental differences of semantic processing regarding brain activation between adults and children. However, little is known about whether the patterns of structural connectivity and effective connectivity differ between adults and children during semantic processing. Functional magnetic resonance imaging (fMRI), diffusion spectrum imaging (DSI), and dynamic causal modeling (DCM) were used to study the developmental differences of brain activation, structural connectivity, and effective connectivity during semantic judgments. Twenty-six children (8- to 12-year-olds) and 26 adults were asked to indicate if character pairs were related in meaning. Compared to children, adults showed greater activation in the left ventral inferior frontal gyrus (IFG) and left middle temporal gyrus (MTG). Also, adults had significantly greater structural connectivity in the left ventral pathway (inferior frontal occipital fasciculus, IFOF) than children. Moreover, adults showed significantly stronger bottom-up effects from left fusiform gyrus (FG) to ventral IFG than children in the related condition. In conclusion, our findings suggest that age-related increases in brain activation (ventral IFG and MTG), IFOF, and effective connectivity (from FG to ventral IFG) might be associated with the bottom-up influence of orthographic representations on retrieving semantic representations for processing Chinese characters.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Temporal Combination Pattern Optimization Based on Feature Selection Method for Motor Imagery BCIs

Common spatial pattern (CSP) method is widely used for spatial filtering and brain pattern extraction from electroencephalogram (EEG) signals in motor imagery (MI)-based brain-computer interfaces (BCIs). The participant-specific time window relative to the visual cue has a significant impact on the effectiveness of the CSP. However, the time window is usually selected experientially or manually. To solve this problem, we propose a novel feature selection approach for MI-based BCIs. Specifically, multiple time segments were obtained by decomposing each EEG sample of the MI task. Furthermore, the features were extracted by CSP from each time segment and were combined to form a new feature vector. Finally, the optimal temporal combination patterns for the new feature vector were selected based on four feature selection algorithms, i.e., mutual information, least absolute shrinkage and selection operator, principal component analysis and stepwise linear discriminant analysis (denoted as MUIN, LASSO, PCA, and SWLDA, respectively), and the classification algorithm was employed to evaluate the average classification accuracy. With three BCI competition datasets, the results of the four proposed algorithms were compared with traditional CSP algorithm in classification accuracy. Experimental results show that compared with traditional algorithm, the proposed methods significantly improve performance. Specifically, the LASSO achieved the highest accuracy (88.58%) among the proposed methods. Importantly, the average classification accuracies using the proposed approaches significantly improved 10.14% (MUIN), 11.40% (LASSO), 6.08% (PCA), and 10.25% (SWLDA) compared to that using CSP. These results indicate that the proposed approach is expected to be practical in MI-based BCIs.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Current Socioeconomic Status Correlates With Brain Volumes in Healthy Children and Adolescents but Not in Children With Prenatal Alcohol Exposure

Individuals with prenatal alcohol exposure (PAE) exhibit neurological deficits associated with brain injury including smaller brain volumes. Additional risk factors such as lower socioeconomic status (SES) may also have an impact on brain development for this population. This study examined how brain volumes are related to SES in both neurotypically developing children and adolescents, and those with PAE. 3D T1-weighted MPRAGE images were acquired from 69 participants with PAE (13.0 ± 3.2 years, range 7.1–18.8 years, 49% female) and 70 neurotypical controls (12.4 ± 2.9 years, range 7.0–18.5 years, 60% female) from four scanning sites in Canada. SES scores calculated using Hollingshead’s Four-Factor Index of Social Status from current caregiver placement were not significantly different between groups, though more children with PAE had lower SES scores compared to controls. Psychometric data comprised 14 cognitive measures, including executive functioning, attention and working memory, memory, math/numerical ability, and word reading. All cognitive scores were significantly worse in children with PAE compared to controls, though SES was not correlated with cognitive scores in either group after correction for multiple comparisons. All 13 brain volumes were smaller in children with PAE compared to children in the control group. Higher SES was associated with larger hippocampus and amygdala volumes in controls, but there were no such associations in children with PAE. Direct evaluation of the interaction between SES and diagnostic group did not show a significant differential impact of SES on these structures. These findings support previous links between SES and brain volumes in neurotypically developing children, but the lack of such a relationship with SES in children with PAE may be due to the markedly smaller brain volumes resulting from the initial brain injury and postpartum brain development, regardless of later SES.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Brain Cortex Activity in Children With Anterior Open Bite: A Pilot Study

Anterior open bite (AOB) is related to functional alterations of the stomatognathic system. There are no studies concerning brain activation of the cortex comparing children with and without AOB during rest and activities such as deglutition and phonation. The aim of this study was to determine the activity of the brain cortex of children with AOB at rest and during phonation and deglutition and to evaluate the association of intelligence quotient (IQ), attention (Test of Variables of Attention, known as TOVA), beats per minute (BPM), and oxygen saturation measurement (SpO2) with brain activity in subjects with AOB. Fourteen children (seven with AOB and seven without AOB) with mixed dentition, aged 10–13 years, underwent an IQ test, TOVA, SpO2, and quantitative electroencephalography (QEEG). Electrodes were set in the scalp, according to the 10–20 protocol. Data were analyzed using statistical tests to assess comparisons between children with and without AOB. The results showed that IQ, TOVA, SpO2, or BPM did not show any statistically significant differences between the groups, except for the response time (contained in TOVA) (p = 0.03). Significant differences were found for the brain activity during rest (Condition 1) of the tongue, between children with and without AOB (p < 0.05 for alpha/theta and alpha peaks), whereas there were no differences during function (Condition 2). The findings of this investigation provide insights about the cortex activity of the brain while the tongue is in the resting position in children with AOB. This may imply an altered activity of the brain cortex, which should be considered when diagnosing and treating AOB. Other diagnostic techniques derived from investigations based on neuroscience could develop new diagnostic and therapeutic techniques to give better solutions to children with malocclusions. Treatments should be focused not only on the teeth but also on the brain cortex.

in Frontiers in Human Neuroscience on June 30, 2020 12:00 AM.

• #### Neurons as Canonical Correlation Analyzers

Normative models of neural computation offer simplified yet lucid mathematical descriptions of murky biological phenomena. Previously, online Principal Component Analysis (PCA) was used to model a network of single-compartment neurons accounting for weighted summation of upstream neural activity in the soma and Hebbian/anti-Hebbian synaptic learning rules. However, synaptic plasticity in biological neurons often depends on the integration of synaptic currents over a dendritic compartment rather than total current in the soma. Motivated by this observation, we model a pyramidal neuronal network using online Canonical Correlation Analysis (CCA). Given two related datasets represented by distal and proximal dendritic inputs, CCA projects them onto the subspace which maximizes the correlation between their projections. First, adopting a normative approach and starting from a single-channel CCA objective function, we derive an online gradient-based optimization algorithm whose steps can be interpreted as the operation of a pyramidal neuron. To model networks of pyramidal neurons, we introduce a novel multi-channel CCA objective function, and derive from it an online gradient-based optimization algorithm whose steps can be interpreted as the operation of a pyramidal neuron network including its architecture, dynamics, and synaptic learning rules. Next, we model a neuron with more than two dendritic compartments by deriving its operation from a known objective function for multi-view CCA. Finally, we confirm the functionality of our networks via numerical simulations. Overall, our work presents a simplified but informative abstraction of learning in a pyramidal neuron network, and demonstrates how such networks can integrate multiple sources of inputs.

in Frontiers in Computational Neuroscience on June 30, 2020 12:00 AM.

• #### The Nucleus Accumbens: A Common Target in the Comorbidity of Depression and Addiction

The comorbidity of depression and addiction has become a serious public health issue, and the relationship between these two disorders and their potential mechanisms has attracted extensive attention. Numerous studies have suggested that depression and addiction share common mechanisms and anatomical pathways. The nucleus accumbens (NAc) has long been considered a key brain region for regulating many behaviors, especially those related to depression and addiction. In this review article, we focus on the association between addiction and depression, highlighting the potential mediating role of the NAc in this comorbidity via the regulation of changes in the neural circuits and molecular signaling. To clarify the mechanisms underlying this association, we summarize evidence from overlapping reward neurocircuitry, the resemblance of cellular and molecular mechanisms, and common treatments. Understanding the interplay between these disorders should help guide clinical comorbidity prevention and the search for a new target for comorbidity treatment.

in Frontiers in Neural Circuits on June 30, 2020 12:00 AM.

• #### Optimal Pipette Resistance, Seal Resistance, and Zero-Current Membrane Potential for Loose Patch or Breakthrough Whole-Cell Recording in vivo

In vivo loose patch and breakthrough whole-cell recordings are useful tools for investigating the intrinsic and synaptic properties of neurons. However, the correlation among pipette resistance, seal condition, and recording time is not thoroughly clear. Presently, we investigated the recording time of different pipette resistances and seal conditions in loose patch and breakthrough whole-cell recordings. The recording time did not change with pipette resistance for loose patch recording (Rp-loose) and first increased and then decreased as seal resistance for loose patch recording (Rs-loose) increased. For a high probability of a recording time ≥30 min, the low and high cutoff values of Rs-loose were 21.5 and 36 MΩ, respectively. For neurons with Rs-loose values of 21.5–36 MΩ, the action potential (AP) amplitudes changed slightly 30 min after the seal. The recording time increased as seal resistance for whole-cell recording (Rs-tight) increased and the zero-current membrane potential for breakthrough whole-cell recording (MPzero-current) decreased. For a high probability of a recording time ≥30 min, the cutoff values of Rs-tight and MPzero-current were 2.35 GΩ and −53.5 mV, respectively. The area under the curve (AUC) of the MPzero-current receiver operating characteristic (ROC) curve was larger than that of the Rs-tight ROC curve. For neurons with MPzero-current values ≤ −53.5 mV, the inhibitory or excitatory postsynaptic current amplitudes did not show significant changes 30 min after the seal. In neurons with Rs-tight values ≥2.35 GΩ, the recording time gradually increased and then decreased as the pipette resistance for whole-cell recording (Rp-tight) increased. For the high probability of a recording time ≥30 min, the low and high cutoff values of Rp-tight were 6.15 and 6.45 MΩ, respectively. Together, we concluded that the optimal Rs-loose range is 21.5–36 MΩ, the optimal Rp-tight range is 6.15–6.45 MΩ, and the optimal Rs-tight and MPzero-current values are ≥2.35 GΩ and ≤ −53.5 mV, respectively. Compared with Rs-tight, the MPzero-current value can more accurately discriminate recording times ≥30 min and <30 min.

in Frontiers in Neural Circuits on June 30, 2020 12:00 AM.

• #### Spinal Cord Injury in Myelomeningocele: Prospects for Therapy

Myelomeningocele (MMC) is the most common congenital defect of the central nervous system and results in devastating and lifelong disability. In MMC, the initial failure of neural tube closure early in gestation is followed by a progressive prenatal injury to the exposed spinal cord, which contributes to the deterioration of neurological function in fetuses. Prenatal strategies to control the spinal cord injury offer an appealing therapeutic approach to improve neurological function, although the definitive pathophysiological mechanisms of injury remain to be fully elucidated. A better understanding of these mechanisms at the cellular and molecular level is of paramount importance for the development of targeted prenatal MMC therapies to minimize or eliminate the effects of the injury and improve neurological function. In this review article, we discuss the pathological development of MMC with a focus on in utero injury to the exposed spinal cord. We emphasize the need for a better understanding of the causative factors in MMC spinal cord injury, pathophysiological alterations associated with the injury, and cellular and molecular mechanisms by which these alterations are induced.

in Frontiers in Cellular Neuroscience on June 30, 2020 12:00 AM.

• #### Ceftriaxone Relieves Trigeminal Neuropathic Pain Through Suppression of Spatiotemporal Synaptic Plasticity via Restoration of Glutamate Transporter 1 in the Medullary Dorsal Horn

Using a rat model of trigeminal neuropathic pain (TNP) produced by chronic compression of the infraorbital nerve (CCI-ION), we investigated the analgesic effect and the underlying mechanisms of ceftriaxone (Cef), a β-lactam antibiotic, that is thought to be a potent stimulator of glutamate transporter 1 (GLT-1). First, repeated intraperitoneal (i.p.) injections of Cef (200 mg/kg) for 5-days since Day 1 of CCI-ION could significantly relieve both mechanical and thermal pain hypersensitivity from day 10 after drug administration. Western blot and immunofluorescent results demonstrated that 5-days administration of Cef resulted in the restoration of GLT-1 expression to a level equivalent to the sham control which was dramatically lost under the TNP condition. Moreover, multi-electrode (8 × 8) array recordings of network field excitatory postsynaptic potentials (fEPSPs) were performed on the acutely dissociated medullary dorsal horn slice evoked by electrical stimulation of the trigeminal spinal tract. The results showed that the increased number of fEPSPs, induction rate, and maintenance of long-term potentiation caused by CCI-ION were significantly suppressed by 5-days administration of Cef. Taken together, the results indicate that Cef can relieve TNP through suppression of spatiotemporal synaptic plasticity via GLT-1 restoration in the medullary dorsal horn of the trigeminal nerve.

in Frontiers in Cellular Neuroscience on June 30, 2020 12:00 AM.

• #### Aging, Cellular Senescence, and Progressive Multiple Sclerosis

Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.

in Frontiers in Cellular Neuroscience on June 30, 2020 12:00 AM.

• #### Distribution of Molecules Related to Neurotransmission in the Nervous System of the Mussel Crenomytilus grayanus

In bivalves neurotransmitters are involved in a variety of behaviors, but their diversity and distribution in the nervous system of these organisms remains somewhat unclear. Here, we first examined immunohistochemically the distributions of neurons containing different neurotransmitters, neuropeptides, and related enzymes, as well as the proliferative status of neurons in the ganglia of the mussel Crenomytilus grayanus. H-Phe-Met-Arg-Phe-NH2 (FMRFamide), choline acetyltransferase (ChAT), γ-aminobutyric acid (GABA) and tyrosine hydroxylase (TH) were found to be expressed by neurons in all the ganglia, whereas serotonin (5-HT) neurons were found only in the cerebropleural and pedal, but not visceral ganglia. Moreover, incubation of living mussels in the presence of a 5-HT precursor (5-HTP) confirmed the absence of 5-HT-containing neurons from the visceral ganglia, indicating that the “serotonin center” of the visceral nervous system is located in the cerebral ganglia. Furthermore, immunostaining of molecules related to neurotransmission together with α-acetylated tubulin demonstrated that this cytoskeletal protein may be a potential pan-neuronal marker in bivalves. Adult mussel neurons do not proliferate, but a population of proliferating PCNA-LIP cells which do not express any of the neurotransmitters examined, perhaps glia cells, was detected in the ganglia. These novel findings suggest that the nervous system of bivalves contains a broad variety of signal molecules most likely involved in the regulation of different physiological and behavioral processes. In addition, proliferating cells may maintain and renew glial cells and neurons throughout the lives of bivalves.

in Frontiers in Neuroanatomy on June 30, 2020 12:00 AM.

• #### Impact of Age on tDCS Effects on Pain Threshold and Working Memory: Results of a Proof of Concept Cross-Over Randomized Controlled Study

Background: Age is an important factor that impacts the variability of tDCS effects.

Objective/Hypothesis: To compare effects of anodal (a)-tDCS over the left dorsolateral prefrontal cortex (DLPFC), and primary motor cortex (M1) in adolescents, adults, and elderly on heat pain threshold (HPT; primary outcome) and the working memory (WM; secondary outcome). We hypothesized that the effect of tDCS on HPT and WM performance would be the largest in adolescents because their pre-frontal cortex is more prone to neuroplasticity.

Methods: We included 30 healthy women within the age ranges of 15–16 (adolescents, n = 10), 30–40 (adults, n = 10), and 60–70 (elderly, n = 10) years. In this crossover single-blinded study, participants received three interventions applied over the DLPF and M1. The active stimulation intensity was two mA for 30 min. From 20 min of stimulation onset, the tDCS session was coupled with an online n-back task. The a-tDCS and sham were applied in a random sequence, with a washout time of a minimum 7 days between each trial. HPT was evaluated before and after stimulation. The WM performance with an n-back task was assessed after the tDCS session.

Results: A Generalized Estimating Equation (GEE) model revealed a significant effect of the a-tDCS over the left DLPFC to reduce the HPT in adolescents compared with sham. It increased the pain perception significantly [a large effect size (ES) of 1.09)]. In the adults, a-tDCS over M1 enhanced the HPT significantly (a large ES of 1.25) compared to sham. No significant effect for HPT was found in the elderly. Response time for hits was reduced for a-tDCS over the DLPFC in adolescents, as compared to the other two age groups.

Conclusions: These findings suggest that a-tDCS modulates pain perception and WM differentially according to age and target area of stimulation. In adolescents, anodal stimulation over the DLPFC increased the pain perception, while in adults, the stimulation over the M1 increased the pain threshold. Thus, they elucidate the impact of tDCS for different age groups and can help to define what is the appropriate intervention according to age in further clinical trials.

Clinical Trial Registration:www.ClinicalTrials.gov, Identifier: NCT04328545.

in Frontiers in Ageing Neuroscience on June 30, 2020 12:00 AM.

• #### Default Mode Network Analysis of APOE Genotype in Cognitively Unimpaired Subjects Based on Persistent Homology

Current researches on default mode network (DMN) in normal elderly have mainly focused on finding some dysfunctional areas with decreased or increased connectivity. The global network dynamics of apolipoprotein E (APOE) e4 allele group is rarely studied. In our previous brain network study, we have demonstrated the advantage of persistent homology. It can distinguish robust and noisy topological features over multiscale nested networks, and the derived properties are more stable. In this study, for the first time we applied persistent homology to analyze APOE-related effects on whole-brain functional network. In our experiments, the risk allele group exhibited lower network radius and modularity in whole brain DMN based on graph theory, suggesting the abnormal organization structure. Moreover, two suggested measures from persistent homology detected significant differences between groups within the left hemisphere and in the whole brain in two datasets. They were more statistically sensitive to APOE genotypic differences than standard graph-based measures. In summary, we provide evidence that the e4 genotype leads to distinct DMN functional alterations in the early phases of Alzheimer’s disease using persistent homology approach. Our study offers a novel insight to explore potential biomarkers in healthy elderly populations carrying APOE e4 allele.

in Frontiers in Ageing Neuroscience on June 30, 2020 12:00 AM.

• #### Effects of an APOE Promoter Polymorphism on Fronto-Parietal Functional Connectivity During Nondemented Aging

Background: The rs405509 polymorphism ofthe apolipoprotein E (APOE) promoter is related to Alzheimer’sdisease (AD). The T/T allele of rs405509 is known to decrease the transcription of the APOE gene and lead to impairments in specific brain structural networks with aging; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects brain functional connectivity (FC) in aging.

Methods: We investigated the effect of the rs405509 genotype (T/T vs. G-allele) on age-related brain FC using functional magnetic resonance imaging. Forty-five elderly TT carriers and 45 elderly G-allele carriers were scanned during a working memory (WM) task.

Results: We found that TT carriers showed an accelerated age-related increase in functional activation in the left postcentral gyrus compared with G-allele carriers. Furthermore, the FC between the left postcentral gyrus and some key regions during WM performance, including the right caudal and superior frontal sulcus (SFS), was differentially modulated by age across rs405509 genotype groups.

Conclusions: These results demonstrate that the rs405509 T/T allele of APOE causes an age-related brain functional decline in nondemented elderly people, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis.

in Frontiers in Ageing Neuroscience on June 30, 2020 12:00 AM.

• #### Correction: Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure

in eLife on June 30, 2020 12:00 AM.

• #### Correction: Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure

in eLife on June 30, 2020 12:00 AM.

• #### Structure of MlaFB uncovers novel mechanisms of ABC transporter regulation

ABC transporters facilitate the movement of diverse molecules across cellular membranes, but how their activity is regulated post-translationally is not well understood. Here we report the crystal structure of MlaFB from E. coli, the cytoplasmic portion of the larger MlaFEDB ABC transporter complex, which drives phospholipid trafficking across the bacterial envelope to maintain outer membrane integrity. MlaB, a STAS domain protein, binds the ABC nucleotide binding domain, MlaF, and is required for its stability. Our structure also implicates a unique C-terminal tail of MlaF in self-dimerization. Both the C-terminal tail of MlaF and the interaction with MlaB are required for the proper assembly of the MlaFEDB complex and its function in cells. This work leads to a new model for how an important bacterial lipid transporter may be regulated by small proteins, and raises the possibility that similar regulatory mechanisms may exist more broadly across the ABC transporter family.

in eLife on June 30, 2020 12:00 AM.

• #### Genomics against gonorrhoea

Surveillance strategies based on whole genome sequencing could help with the early identification and detection of new forms of drug-resistant gonorrhoea.

in eLife on June 30, 2020 12:00 AM.

• #### An atlas for hemocytes in an insect

Single-cell RNA sequencing has revealed distinct subpopulations of hemocytes in fruit fly larvae.

in eLife on June 30, 2020 12:00 AM.

• #### Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes

The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I.

in eLife on June 30, 2020 12:00 AM.

• #### Transient role of the middle ear as a lower jaw support across mammals

Mammals articulate their jaws using a novel joint between the dentary and squamosal bones. In eutherian mammals, this joint forms in the embryo, supporting feeding and vocalisation from birth. In contrast, marsupials and monotremes exhibit extreme altriciality and are born before the bones of the novel mammalian jaw joint form. These mammals need to rely on other mechanisms to allow them to feed. Here we show that this vital function is carried out by the earlier developing, cartilaginous incus of the middle ear, abutting the cranial base to form a cranio-mandibular articulation. The nature of this articulation varies between monotremes and marsupials, with juvenile monotremes retaining a double articulation, similar to that of the fossil mammaliaform Morganucodon, while marsupials use a versican-rich matrix to stabilise the jaw against the cranial base. These findings provide novel insight into the evolution of mammals and the changing relationship between the jaw and ear.

in eLife on June 30, 2020 12:00 AM.

• #### Divergent sensory investment mirrors potential speciation via niche partitioning across Drosophila

The examination of phylogenetic and phenotypic characteristics of the nervous system, such as behavior and neuroanatomy, can be utilized as a means to assess speciation. Recent studies have proposed a fundamental tradeoff between two sensory organs, the eye and the antenna. However, the identification of ecological mechanisms for this observed tradeoff have not been firmly established. Our current study examines several monophyletic species within the obscura group, and asserts that despite their close relatedness and overlapping ecology, they deviate strongly in both visual and olfactory investment. We contend that both courtship and microhabitat preferences support the observed inverse variation in these sensory traits. Here, this variation in visual and olfactory investment seems to provide relaxed competition, a process by which similar species can use a shared environment differently and in ways that help them coexist. Moreover, that behavioral separation according to light gradients occurs first, and subsequently, courtship deviations arise.

in eLife on June 30, 2020 12:00 AM.

• #### Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants

Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance variants, but efficient strategies to do so remain undefined. We evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting antibiotic resistance and diagnostic escape variants in Neisseria gonorrhoeae, a pathogen associated with a high burden of disease and antibiotic resistance and the development of genotype-based diagnostics. We show that patient characteristic-informed sampling is not a reliable strategy for efficient variant detection. In contrast, sampling informed by pathogen characteristics, such as genomic diversity and genomic background, is significantly more efficient than random sampling in identifying genetic variants associated with resistance and diagnostic escape.

in eLife on June 30, 2020 12:00 AM.

• #### HA stabilization promotes replication and transmission of swine H1N1 gamma influenza viruses in ferrets

Pandemic influenza A viruses can emerge from swine, an intermediate host that supports adaptation of human-preferred receptor-binding specificity by the hemagglutinin (HA) surface antigen. Other HA traits necessary for pandemic potential are poorly understood. For swine influenza viruses isolated in 2009–2016, gamma-clade viruses had less stable HA proteins (activation pH 5.5–5.9) than pandemic clade (pH 5.0–5.5). Gamma-clade viruses replicated to higher levels in mammalian cells than pandemic clade. In ferrets, a model for human adaptation, a relatively stable HA protein (pH 5.5–5.6) was necessary for efficient replication and airborne transmission. The overall airborne transmission frequency in ferrets for four isolates tested was 42%, and isolate G15 airborne transmitted 100% after selection of a variant with a stabilized HA. The results suggest swine influenza viruses containing both a stabilized HA and alpha-2,6 receptor binding in tandem pose greater pandemic risk. Increasing evidence supports adding HA stability to pre-pandemic risk assessment algorithms.

in eLife on June 30, 2020 12:00 AM.

• #### Alcids ‘fly’ at efficient Strouhal numbers in both air and water but vary stroke velocity and angle

Birds that use their wings for ‘flight’ in both air and water are expected to fly poorly in each fluid relative to single-fluid specialists; that is, these jacks-of-all-trades should be the masters of none. Alcids exhibit exceptional dive performance while retaining aerial flight. We hypothesized that alcids maintain efficient Strouhal numbers and stroke velocities across air and water, allowing them to mitigate the costs of their ‘fluid generalism’. We show that alcids cruise at Strouhal numbers between 0.10 and 0.40 – on par with single-fluid specialists – in both air and water but flap their wings ~ 50% slower in water. Thus, these species either contract their muscles at inefficient velocities or maintain a two-geared muscle system, highlighting a clear cost to using the same morphology for locomotion in two fluids. Additionally, alcids varied stroke-plane angle between air and water and chord angle during aquatic flight, expanding their performance envelope.

in eLife on June 30, 2020 12:00 AM.

• #### Generation of inner ear hair cells by direct lineage conversion of primary somatic cells

The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.

in eLife on June 30, 2020 12:00 AM.

• #### Parvalbumin interneurons provide spillover to newborn and mature dentate granule cells

Parvalbumin-expressing interneurons (PVs) in the dentate gyrus provide activity-dependent regulation of adult neurogenesis as well as maintain inhibitory control of mature neurons. In mature neurons, PVs evoke GABAA postsynaptic currents (GPSCs) with fast rise and decay phases that allow precise control of spike timing, yet synaptic currents with fast kinetics do not appear in adult-born neurons until several weeks after cell birth. Here we used mouse hippocampal slices to address how PVs signal to newborn neurons prior to the appearance of fast GPSCs. Whereas PV-evoked currents in mature neurons exhibit hallmark fast rise and decay phases, newborn neurons display slow GPSCs with characteristics of spillover signaling. We also unmasked slow spillover currents in mature neurons in the absence of fast GPSCs. Our results suggest that PVs mediate slow spillover signaling in addition to conventional fast synaptic signaling, and that spillover transmission mediates activity-dependent regulation of early events in adult neurogenesis.

in eLife on June 30, 2020 12:00 AM.

• #### An Emerging Role for Prolactin in Female-Selective Pain

Women experience many pain conditions more frequently when compared with men, but the biological mechanisms underlying sex differences in pain remain poorly understood. In particular, little is known about possible sex differences in peripheral nociceptors, the fundamental building blocks of pain transmission. Emerging evidence reveals that prolactin (PRL) signaling at its cognate prolactin receptor (PRLR) in primary afferents promotes nociceptor sensitization and pain in a female-selective fashion.

in Trends in Neurosciences: In press on June 30, 2020 12:00 AM.

• #### VTA Glutamate Neuron Activity Drives Positive Reinforcement Absent Dopamine Co-release

Activation of VTA glutamate neurons leads to dopamine co-release in nucleus accumbens. Zell et al. genetically block this dopamine signal to show that VTA glutamate projections to nucleus accumbens can reinforce behaviors independently. These findings establish a parallel dopamine-independent mesolimbic pathway capable of supporting positive reinforcement.

in Neuron: In press on June 30, 2020 12:00 AM.

• #### Defining the Homo- and Heterodimerization Propensities of Metabotropic Glutamate Receptors

(Cell Reports 31, 107605-1–107605-15.e1–e5; May 5, 2020)

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Plasma Cell Fate Is Orchestrated by Elaborate Changes in Genome Compartmentalization and Inter-chromosomal Hubs

(Cell Reports 31, 107470-1–107470-15.e1–e6; April 7, 2020)

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Visual Experience Influences Dendritic Orientation but Is Not Required for Asymmetric Wiring of the Retinal Direction Selective Circuit

El-Quessny et al. investigate the structure-function relationship of a ventrally-tuned directionally-selective ganglion cell (vDSGC), which has ventrally oriented dendrites during adulthood. They find that visual experience orients the vDSGC dendrites ventrally, affecting dendritic mechanisms, while sparing circuit mechanisms, for direction computations.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation

Gene expression analysis of human AD microglia has been limited by technical challenges. Srinivasan et al. use RNA-seq to profile FACS-purified microglia from frozen AD and control brains, revealing that human AD microglia exhibit accelerated aging, as well as age-independent changes, like upregulation of APOE.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Small-Molecule Control of Super-Mendelian Inheritance in Gene Drives

Gene drives offer potential solutions to fight vector-borne diseases but raise concerns around their safe experimentation. Lopez Del Amo et al. describe a modified Cas9-based gene drive that can be controlled by the addition of a small molecule to the fruit fly diet, adding a layer of safety for laboratory studies.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone

Yan et al. show how N-glycosylation transforms a chaperone from a folding to a scaffolding protein that remodels protein connectivity, with the end result of proteome-wide dysfunction. This specific modification, exploited by cancer cells for enhanced fitness, is an actionable target in disease.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer’s Disease

Park et al. show that inhibition of amyloid precursor protein (APP) C terminus cleavage by D664A mutation prevents Aβ-induced local caspase activation, leading to localized synaptic injury.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits

Targeted ablation of the ATRX intellectual disability gene in forebrain excitatory neurons of mice causes male-specific deficits in long-term spatial memory. Tamming et al. establish that ATRX suppresses miR-137 to regulate an ensemble of genes required to maintain synaptic integrity in the hippocampus.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery

Guardia et al. report a high-resolution cryo-EM structure of human ATG9A, the only transmembrane protein of the core autophagy machinery. The structure shows that ATG9A is a domain-swapped homotrimer with a complex network of internal cavities. Structure-based computational simulations predict that ATG9A has membrane-bending properties.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Promiscuous Binding of Microprotein Mozart1 to γ-Tubulin Complex Mediates Specific Subcellular Targeting to Control Microtubule Array Formation

Huang et al. demonstrate that the microprotein Mzt1 adopts an intercalative binding mode to tightly associate with N-terminal domains of multiple γ-TuRC subunits. Furthermore, they show that promiscuous binding of Mzt1 in γ-TuRC regulates γ-TuRC assembly and targeting, controlling subcellular localizations of γ-TuRC and modulating microtubule formation in fission yeast.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Vcp Overexpression and Leucine Supplementation Increase Protein Synthesis and Improve Fear Memory and Social Interaction of Nf1 Mutant Mice

Shih et al. show that neurofibromin (NF1 protein) acts through valosin-containing protein (VCP)/p97 to regulate endoplasmic reticulum formation and protein synthesis. It consequently controls dendritic spine formation and contextual and social memory of mice. Increased protein synthesis through leucine supplementation ameliorates neuronal and behavioral defects of Nf1 mutant mice.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury

Vivinetto et al. identify the EMT-related transcription factor ZEB2 as a regulator of the astrocytic response to injury. Mouse models of either stroke or SCI show that knockout of Zeb2 in astrocytes attenuates astrogliosis, increases lesion sizes, and delays recovery motor function. Altogether, the findings suggest that astrogliosis is an EMT-like process.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Labeling and Characterization of Human GLP-1-Secreting L-cells in Primary Ileal Organoid Culture

Development of anti-diabetic drugs targeting the hormone-secreting intestinal enteroendocrine system is limited by a lack of human cellular models. Goldspink et al. generate human ileal organoids with fluorescently-labeled GLP-1-secreting L-cells, which respond to nutritional stimuli and are used for transcriptomic, peptidomic, and single-cell functional analyses.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Discovering How Heme Controls Genome Function Through Heme-omics

Liao et al. generate a heme-regulated chromatin atlas by amalgamating ATAC-seq and RNA-seq datasets from cells with normal and sub-physiological heme, and they identify parallel Bach1-dependent and Bach1-independent mechanisms that target heme-sensing chromatin hotspots. The hotspots harbor a DNA motif demarcating heme-regulated chromatin and genes not known to be heme regulated.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Landscape of Non-canonical Cysteines in Human VH Repertoire Revealed by Immunogenetic Analysis

Prabakaran and Chowdhury reveal the remarkable patterns of non-canonical cysteines in human antibody heavy chains (VHs) and their role in paratope diversification. These patterns mimic features observed separately in chicken, camel, llama, shark, and cow. These findings can help design and develop next-generation human antibodies and libraries.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics

Rostami et al. find that treatment type and timing from treatment exposure are key factors affecting cell-free DNA (cfDNA) release kinetics. Distinct mechanisms of cell death mediate the timing of release, and cellular senescence is a major determinant counteracting the process. Selective advancement of senescent cells toward apoptosis increases cfDNA release.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors

Yoshida et al. find that the upstream insular cortical silencing is converted to the downstream ventrolateral striatal activation in behaving animals. Parvalbumin- expressing interneurons in the ventrolateral striatum mediate this conversion through feedforward disinhibition.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair

Chen et al. showed that after bacterial lung injury, sphingosine-1-phosphate (S1P) is released from lung endothelial cells and regulates alveoli epithelial repair by promoting the progenitor function of alveolar type II cells via a S1P-S1PR2-YAP signaling axis. This work highlighted endothelial-epithelial interaction during lung repair mediated by bioactive lipid S1P.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection

The role of PD-1 in memory development is poorly understood. Here, Pauken et al. show that constitutive loss of PD-1 during acute infection causes overactivation of CD8+ T cells during the effector phase and impairs memory and recall responses. These data indicate PD-1 is required for optimal memory.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development

Renoux et al. investigate the role of the AP1 member Fosl2 in autoimmunity. They show that Fosl2 overexpression induces T cell-mediated systemic inflammation in transgenic mice, while Fosl2 deletion in T cells protects against induced autoimmunity. Furthermore, they suggest that Fosl2 is implicated in Treg development in the thymus.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages

Activated macrophages must fine-tune their inflammatory responses to promote host defense while limiting tissue damage. Alam et al. find that the transcription factor Spic restrains inflammatory responses and promotes iron efflux from activated macrophages, thereby calibrating macrophage responses during the resolution of inflammation.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Zygotic Nuclear F-Actin Safeguards Embryonic Development

Okuno et al. demonstrate that actin filaments assemble in the pronuclei of totipotent mouse zygotes. Zygotic nuclear F-actin regulates the proper formation and functions of pronuclei. Perturbations of the zygotic nuclear F-actin dynamics affect DNA damage responses in zygotes, leading to abnormal embryonic development.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Mapping of Influenza Virus RNA-RNA Interactions Reveals a Flexible Network

Influenza viruses assemble and package all eight viral RNA segments through intersegmental RNA-RNA interactions. Le Sage et al. establish a protocol to capture genome-wide influenza intersegmental RNA-RNA interactions. They show that the viral RNA interaction network is flexible, where hotspots on individual segments coordinate interaction with many other segments.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### T Cell-Intrinsic IRF5 Regulates T Cell Signaling, Migration, and Differentiation and Promotes Intestinal Inflammation

Yan et al. show that T cell-intrinsic IRF5 regulates T cell migration, proliferation, and cytokine production. IRF5 promotes TCR-initiated signaling and translocates to the nucleus, associating with promoters. T cell-intrinsic IRF5 enhances the severity of experimental colitis. CD4+ T cells from IRF5 disease-risk carriers show an increase in IRF5-dependent outcomes.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Control of Early B Cell Development by the RNA N6-Methyladenosine Methylation

Zheng et al. show that B-cell-specific deletion of RNA m6A methylation writer protein METTL14 results in severe defects in B cell development. RNA m6A plays critical roles in regulating gene expressions and controls two major transitions of early B cell development via different mechanisms.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Adipocyte-Derived Versican and Macrophage-Derived Biglycan Control Adipose Tissue Inflammation in Obesity

Proteoglycans have many functions, including providing a scaffold and regulating the inflammatory response. In this study, Han et al. show that adipose tissue proteoglycans affect inflammation and insulin resistance as a result of crosstalk between versican produced by adipocytes and biglycan produced by macrophages.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Widespread Inhibition, Antagonism, and Synergy in Mouse Olfactory Sensory Neurons In Vivo

Inagaki et al. demonstrate that odor produces not only excitatory but also inhibitory responses in mouse olfactory sensory neurons as a result of inverse agonism. They also find that responses to odor mixtures are extensively modulated by antagonism and synergy at the most peripheral level, depending on the odor concentrations.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells

Ruan et al. show that H1N1 influenza A virus cross-activates Gli1, a transcription factor in the sonic hedgehog pathway. Gli1 activation plays a role in downregulating the expression of intercellular junction proteins, increasing the permeability of the alveolar epithelial barrier, and promoting inflammation in the lung tissue.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### MZT Proteins Form Multi-Faceted Structural Modules in the γ-Tubulin Ring Complex

Wieczorek et al. show how the microproteins MZT1 and MZT2 expand binding interfaces across the γ-TuRC—the cell’s microtubule nucleating machinery—by forming similarly shaped, “modular” subcomplexes with the α-helical N-terminal domains of different γ-tubulin complex proteins (GCPs).

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### The Leucine-Rich Repeat Region of CARMIL1 Regulates IL-1-Mediated ERK Activation, MMP Expression, and Collagen Degradation

CARMILs regulate actin assembly, but their role in inflammation is unknown. Wang et al. show that fibroblasts require CARMIL1 for IL-1 signaling. Knockout of CARMIL1 reduces IL-1 signaling and collagen degradation. Cell-permeable, CARMIL1-binding peptides that block its interaction with IL-1 signaling molecules inhibit collagen degradation. CARMIL1 is a promising target for anti-inflammatory drug development.

in Cell Reports: Current Issue on June 30, 2020 12:00 AM.

• #### Forecasting unprecedented ecological fluctuations

by Samuel R. Bray, Bo Wang

Forecasting ‘Black Swan’ events in ecosystems is an important but challenging task. Many ecosystems display aperiodic fluctuations in species abundance spanning orders of magnitude in scale, which have vast environmental and economic impact. Empirical evidence and theoretical analyses suggest that these dynamics are in a regime where system nonlinearities limit accurate forecasting of unprecedented events due to poor extrapolation of historical data to unsampled states. Leveraging increasingly available long-term high-frequency ecological tracking data, we analyze multiple natural and experimental ecosystems (marine plankton, intertidal mollusks, and deciduous forest), and recover hidden linearity embedded in universal ‘scaling laws’ of species dynamics. We then develop a method using these scaling laws to reduce data dependence in ecological forecasting and accurately predict extreme events beyond the span of historical observations in diverse ecosystems.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Longitudinal wastewater sampling in buildings reveals temporal dynamics of metabolites

by Ethan D. Evans, Chengzhen Dai, Siavash Isazadeh, Shinkyu Park, Carlo Ratti, Eric J. Alm

Direct sampling of building wastewater has the potential to enable “precision public health” observations and interventions. Temporal sampling offers additional dynamic information that can be used to increase the informational content of individual metabolic “features”, but few studies have focused on high-resolution sampling. Here, we sampled three spatially close buildings, revealing individual metabolomics features, retention time (rt) and mass-to-charge ratio (mz) pairs, that often possess similar stationary statistical properties, as expected from aggregate sampling. However, the temporal profiles of features—providing orthogonal information to physicochemical properties—illustrate that many possess different feature temporal dynamics (fTDs) across buildings, with large and unpredictable single day deviations from the mean. Internal to a building, numerous and seemingly unrelated features, with mz and rt differences up to hundreds of Daltons and seconds, display highly correlated fTDs, suggesting non-obvious feature relationships. Data-driven building classification achieves high sensitivity and specificity, and extracts building-identifying features found to possess unique dynamics. Analysis of fTDs from many short-duration samples allows for tailored community monitoring with applicability in public health studies.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Multiplexing rhythmic information by spike timing dependent plasticity

by Nimrod Sherf, Shamir Maoz

Rhythmic activity has been associated with a wide range of cognitive processes including the encoding of sensory information, navigation, the transfer of information and others. Rhythmic activity in the brain has also been suggested to be used for multiplexing information. Multiplexing is the ability to transmit more than one signal via the same channel. Here we focus on frequency division multiplexing, in which different signals are transmitted in different frequency bands. Recent work showed that spike-timing-dependent plasticity (STDP) can facilitate the transfer of rhythmic activity downstream the information processing pathway. However, STDP has also been known to generate strong winner-take-all like competition between subgroups of correlated synaptic inputs. This competition between different rhythmicity channels, induced by STDP, may prevent the multiplexing of information. Thus, raising doubts whether STDP is consistent with the idea of multiplexing. This study explores whether STDP can facilitate the multiplexing of information across multiple frequency channels, and if so, under what conditions. We address this question in a modelling study, investigating the STDP dynamics of two populations synapsing downstream onto the same neuron in a feed-forward manner. Each population was assumed to exhibit rhythmic activity, albeit in a different frequency band. Our theory reveals that the winner-take-all like competitions between the two populations is limited, in the sense that different rhythmic populations will not necessarily fully suppress each other. Furthermore, we found that for a wide range of parameters, the network converged to a solution in which the downstream neuron responded to both rhythms. Yet, the synaptic weights themselves did not converge to a fixed point, rather remained dynamic. These findings imply that STDP can support the multiplexing of rhythmic information, and demonstrate how functionality (multiplexing of information) can be retained in the face of continuous remodeling of all the synaptic weights. The constraints on the types of STDP rules that can support multiplexing provide a natural test for our theory.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Stochastic ordering of complexoform protein assembly by genetic circuits

by Mikkel Herholdt Jensen, Eliza J. Morris, Hai Tran, Michael A. Nash, Cheemeng Tan

Top-down proteomics has enabled the elucidation of heterogeneous protein complexes with different cofactors, post-translational modifications, and protein membership. This heterogeneity is believed to play a previously unknown role in cellular processes. The different molecular forms of a protein complex have come to be called “complex isoform” or “complexoform”. Despite the elucidation of the complexoform, it remains unclear how and whether cellular circuits control the distribution of a complexoform. To help address this issue, we first simulate a generic three-protein complexoform to reveal the control of its distribution by the timing of gene transcription, mRNA translation, and protein transport. Overall, we ran 265 computational experiments: each averaged over 1,000 stochastic simulations. Based on the experiments, we show that genes arranged in a single operon, a cascade, or as two operons all give rise to the different protein composition of complexoform because of timing differences in protein-synthesis order. We also show that changes in the kinetics of expression, protein transport, or protein binding dramatically alter the distribution of the complexoform. Furthermore, both stochastic and transient kinetics control the assembly of the complexoform when the expression and assembly occur concurrently. We test our model against the biological cellulosome system. With biologically relevant rates, we find that the genetic circuitry controls the average final complexoform assembly and the variation in the assembly structure. Our results highlight the importance of both the genetic circuit architecture and kinetics in determining the distribution of a complexoform. Our work has a broad impact on our understanding of non-equilibrium processes in both living and synthetic biological systems.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### It’s about time: Analysing simplifying assumptions for modelling multi-step pathways in systems biology

by Niklas Korsbo, Henrik Jönsson

Thoughtful use of simplifying assumptions is crucial to make systems biology models tractable while still representative of the underlying biology. A useful simplification can elucidate the core dynamics of a system. A poorly chosen assumption can, however, either render a model too complicated for making conclusions or it can prevent an otherwise accurate model from describing experimentally observed dynamics. Here, we perform a computational investigation of sequential multi-step pathway models that contain fewer pathway steps than the system they are designed to emulate. We demonstrate when such models will fail to reproduce data and how detrimental truncation of a pathway leads to detectable signatures in model dynamics and its optimised parameters. An alternative assumption is suggested for simplifying such pathways. Rather than assuming a truncated number of pathway steps, we propose to use the assumption that the rates of information propagation along the pathway is homogeneous and, instead, letting the length of the pathway be a free parameter. We first focus on linear pathways that are sequential and have first-order kinetics, and we show how this assumption results in a three-parameter model that consistently outperforms its truncated rival and a delay differential equation alternative in recapitulating observed dynamics. We then show how the proposed assumption allows for similarly terse and effective models of non-linear pathways. Our results provide a foundation for well-informed decision making during model simplifications.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Emergence of cooperative bistability and robustness of gene regulatory networks

by Shintaro Nagata, Macoto Kikuchi

Gene regulatory networks (GRNs) are complex systems in which many genes regulate mutually to adapt the cell state to environmental conditions. In addition to function, the GRNs possess several kinds of robustness. This robustness means that systems do not lose their functionality when exposed to disturbances such as mutations or noise, and is widely observed at many levels in living systems. Both function and robustness have been acquired through evolution. In this respect, GRNs utilized in living systems are rare among all possible GRNs. In this study, we explored the fitness landscape of GRNs and investigated how robustness emerged in highly-fit GRNs. We considered a toy model of GRNs with one input gene and one output gene. The difference in the expression level of the output gene between two input states, “on” and “off”, was considered as fitness. Thus, the determination of the fitness of a GRN was based on how sensitively it responded to the input. We employed the multicanonical Monte Carlo method, which can sample GRNs randomly in a wide range of fitness levels, and classified the GRNs according to their fitness. As a result, the following properties were found: (1) Highly-fit GRNs exhibited bistability for intermediate input between “on” and “off”. This means that such GRNs responded to two input states by using different fixed points of dynamics. This bistability emerges necessarily as fitness increases. (2) These highly-fit GRNs were robust against noise because of their bistability. In other words, noise robustness is a byproduct of high fitness. (3) GRNs that were robust against mutations were not extremely rare among the highly-fit GRNs. This implies that mutational robustness is readily acquired through the evolutionary process. These properties are universal irrespective of the evolutionary pathway, because the results do not rely on evolutionary simulation.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Resilience of three-dimensional sinusoidal networks in liver tissue

by Jens Karschau, André Scholich, Jonathan Wise, Hernán Morales-Navarrete, Yannis Kalaidzidis, Marino Zerial, Benjamin M. Friedrich

Can three-dimensional, microvasculature networks still ensure blood supply if individual links fail? We address this question in the sinusoidal network, a plexus-like microvasculature network, which transports nutrient-rich blood to every hepatocyte in liver tissue, by building on recent advances in high-resolution imaging and digital reconstruction of adult mice liver tissue. We find that the topology of the three-dimensional sinusoidal network reflects its two design requirements of a space-filling network that connects all hepatocytes, while using shortest transport routes: sinusoidal networks are sub-graphs of the Delaunay graph of their set of branching points, and also contain the corresponding minimum spanning tree, both to good approximation. To overcome the spatial limitations of experimental samples and generate arbitrarily-sized networks, we developed a network generation algorithm that reproduces the statistical features of 0.3-mm-sized samples of sinusoidal networks, using multi-objective optimization for node degree and edge length distribution. Nematic order in these simulated networks implies anisotropic transport properties, characterized by an empirical linear relation between a nematic order parameter and the anisotropy of the permeability tensor. Under the assumption that all sinusoid tubes have a constant and equal flow resistance, we predict that the distribution of currents in the network is very inhomogeneous, with a small number of edges carrying a substantial part of the flow—a feature known for hierarchical networks, but unexpected for plexus-like networks. We quantify network resilience in terms of a permeability-at-risk, i.e., permeability as function of the fraction of removed edges. We find that sinusoidal networks are resilient to random removal of edges, but vulnerable to the removal of high-current edges. Our findings suggest the existence of a mechanism counteracting flow inhomogeneity to balance metabolic load on the liver.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Mechanistic model of hormonal contraception

by A. Armean Wright, Ghassan N. Fayad, James F. Selgrade, Mette S. Olufsen

Contraceptive drugs intended for family planning are used by the majority of married or in-union women in almost all regions of the world. The two most prevalent types of hormones associated with contraception are synthetic estrogens and progestins. Hormonal based contraceptives contain a dose of a synthetic progesterone (progestin) or a combination of a progestin and a synthetic estrogen. In this study we use mathematical modeling to understand better how these contraceptive paradigms prevent ovulation, special focus is on understanding how changes in dose impact hormonal cycling. To explain this phenomenon, we added two autocrine mechanisms essential to achieve contraception within our previous menstrual cycle models. This new model predicts mean daily blood concentrations of key hormones during a contraceptive state achieved by administering progestins, synthetic estrogens, or a combined treatment. Model outputs are compared with data from two clinical trials: one for a progestin only treatment and one for a combined hormonal treatment. Results show that contraception can be achieved with synthetic estrogen, with progestin, and by combining the two hormones. An advantage of the combined treatment is that a contraceptive state can be obtained at a lower dose of each hormone. The model studied here is qualitative in nature, but can be coupled with a pharmacokinetic/pharamacodynamic (PKPD) model providing the ability to fit exogenous inputs to specific bioavailability and affinity. A model of this type may allow insight into a specific drug’s effects, which has potential to be useful in the pre-clinical trial stage identifying the lowest dose required to achieve contraception.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Model-based approach for predicting the impact of genetic modifications on product yield in biopharmaceutical manufacturing—Application to influenza vaccine production

by Stefanie Duvigneau, Robert Dürr, Tanja Laske, Mandy Bachmann, Melanie Dostert, Achim Kienle

A large group of biopharmaceuticals is produced in cell lines. The yield of such products can be increased by genetic engineering of the corresponding cell lines. The prediction of promising genetic modifications by mathematical modeling is a valuable tool to facilitate experimental screening. Besides information on the intracellular kinetics and genetic modifications the mathematical model has to account for ubiquitous cell-to-cell variability. In this contribution, we establish a novel model-based methodology for influenza vaccine production in cell lines with overexpressed genes. The manipulation of the expression level of genes coding for host cell factors relevant for virus replication is achieved by lentiviral transduction. Since lentiviral transduction causes increased cell-to-cell variability due to different copy numbers and integration sites of the gene constructs we use a population balance modeling approach to account for this heterogeneity in terms of intracellular viral components and distributed kinetic parameters. The latter are estimated from experimental data of intracellular viral RNA levels and virus titers of infection experiments using cells overexpressing a single host cell gene. For experiments with cells overexpressing multiple host cell genes, only final virus titers were measured and thus, no direct estimation of the parameter distributions was possible. Instead, we evaluate four different computational strategies to infer these from single gene parameter sets. Finally, the best computational strategy is used to predict the most promising candidates for future modifications that show the highest potential for an increased virus yield in a combinatorial study. As expected, there is a trend to higher yields the more modifications are included.

in PLoS Computational Biology on June 29, 2020 09:00 PM.

• #### Different states of priority recruit different neural representations in visual working memory

by Qing Yu, Chunyue Teng, Bradley R. Postle

We used functional magnetic resonance imaging (fMRI) to investigate the neural codes for representing stimulus information held in different states of priority in working memory. Human participants (male and female) performed delayed recall for 2 oriented gratings that could appear in any of several locations. Priority status was manipulated by a retrocue, such that one became the prioritized memory item (PMI) and another the unprioritized memory item (UMI). Using inverted encoding models (IEMs), we found that, in early visual cortex, the orientation of the UMI was represented in a neural representation that was rotated relative to the PMI. In intraparietal sulcus (IPS), we observed the analogous effect for the representation of the location of the UMI. Taken together, these results provide evidence for a common remapping mechanism that may be responsible for representing stimulus identity and stimulus context with different levels of priority in working memory.

in PLoS Biology on June 29, 2020 09:00 PM.

## 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. Here, we investigate risk factors for the development of a clinical event using a 10‐year, multinational, retrospectively identified RIS dataset.

## Methods

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

## Results

Additional follow‐up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11–74 years), 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 cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium‐enhanced lesions during follow‐up was also associated with the risk of a seminal event. The reason for MRI and gadolinium‐enhancing lesions at baseline did not influence the risk of a subsequent clinical event.

## Interpretation

Approximately half of all 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. ANN NEUROL 2020

in Annals of Neurology on June 29, 2020 03:44 PM.

## Objective

Rett syndrome, CDKL5 ‐deficiency disorder, FOXG1 disorder, and MECP2 duplication disorder are developmental encephalopathies with shared and distinct features. Although they are 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 and Rett‐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 at seizure onset (2 months), whereas children with MECP2 duplication syndrome had the oldest median age at 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 at seizure onset in MECP2 duplication syndrome. Developmental regression occurred in all Rett syndrome participants (median = 18 months) but only 23 to 34% of the other disorders. Seizure incidence prior to the baseline visit was highest for CDKL5 deficiency disorder (96.2%) and lowest for Rett syndrome (47.5%). Other clinical features including seizure types and frequency differed among groups.

## Interpretation

Although 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. ANN NEUROL 2020

in Annals of Neurology on June 29, 2020 03:33 PM.

• #### Statistical mechanics of DNA-nanotube adsorption

Author(s): Shushanik Tonoyan, Davit Khechoyan, Yevgeni Mamasakhlisov, and Artem Badasyan

Attraction between the polycyclic aromatic surface elements of carbon nanotubes (CNTs) and the aromatic nucleotides of deoxyribonucleic acid (DNA) leads to reversible adsorption (physisorption) between the two, a phenomenon related to hybridization. We propose a Hamiltonian formulation for the zippe...

[Phys. Rev. E 101, 062422] Published Mon Jun 29, 2020

in Physical Review E: Biological physics on June 29, 2020 10:00 AM.

• #### Using Bayes factor hypothesis testing in neuroscience to establish evidence of absence

Nature Neuroscience, Published online: 29 June 2020; doi:10.1038/s41593-020-0660-4

Keysers et al. show why P values do not differentiate inconclusive null findings from those that provide important evidence for the absence of an effect. They provide a tutorial on how to use Bayesian hypothesis testing to overcome this issue.

in Nature Neuroscience on June 29, 2020 12:00 AM.

• #### When computational pipelines go ‘clank’

Nature Methods, Published online: 29 June 2020; doi:10.1038/s41592-020-0886-9

‘Omics pipeline builders and users face options and tough decisions.

in Nature Methods on June 29, 2020 12:00 AM.

• #### Mid-infrared metabolic imaging with vibrational probes

Nature Methods, Published online: 29 June 2020; doi:10.1038/s41592-020-0883-z

Small vibrational tags (azide, 13C-edited carbonyl and deuterium-labeled probes) were introduced as metabolic probes for mid-infrared imaging. The tags allow unprecedented in situ visualization of metabolism in cells and animals with high information throughput.

in Nature Methods on June 29, 2020 12:00 AM.

• #### Up to 100-fold speed-up and multiplexing in optimized DNA-PAINT

Nature Methods, Published online: 29 June 2020; doi:10.1038/s41592-020-0869-x

Hundred-fold-faster DNA-PAINT imaging is enabled by the introduction of concatenated, periodic DNA sequence motifs in the docking strand. Six orthogonal sequences are described for speed-optimized and highly multiplexed cellular imaging.

in Nature Methods on June 29, 2020 12:00 AM.

• #### Optogenetic control of gene expression in plants in the presence of ambient white light

Nature Methods, Published online: 29 June 2020; doi:10.1038/s41592-020-0868-y

PULSE is an optogenetic tool that consists of two modules with different wavelength sensitivities. Their interplay enables optogenetic access to gene expression in plants independently of ambient light.

in Nature Methods on June 29, 2020 12:00 AM.

• #### Cellular senescence and Alzheimer disease: the egg and the chicken scenario

Nature Reviews Neuroscience, Published online: 29 June 2020; doi:10.1038/s41583-020-0325-z

Ageing is the main risk factor for Alzheimer disease (AD), but the mechanisms connecting ageing to this disease remain incompletely understood. In this Review, Saez-Atienzar and Masliah examine whether cellular senescence may have a role in linking ageing and AD.

in Nature Reviews on June 29, 2020 12:00 AM.

• #### Stable gliding by undulating snakes

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0959-9

Everybody who has ever made a paper airplane and been disappointed as it spins out of control, crashing to the ground, knows how tricky achieving suitable trim and stability for gliding can be. But, somehow, wiggling flying snakes glide without tumbling.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Unconventional free charge in the correlated semimetal Nd2Ir2O7

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0955-0

Transport and optical conductivity measurements reveal the non-Fermi liquid behaviour in correlated semimetal Nd2Ir2O7. The result implies the emergent collective charge transport in this compound, not reconcilable with conventional band theory.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Realization of an anomalous Floquet topological system with ultracold atoms

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0949-y

Standard topological invariants commonly used in static systems are not enough to fully capture the topological properties of Floquet systems. In a periodically driven quantum gas, chiral edge modes emerge despite all Chern numbers being equal to zero.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Berry curvature memory through electrically driven stacking transitions

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0947-0

A memory device is proposed that uses a dynamical modification of the stacking order of few-layer WTe2 to encode information. The change in stacking modifies both the Berry curvature and the Hall transport, allowing two states to be distinguished.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Spin phase diagram of the interacting quantum Hall liquid

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0946-1

The spin polarization of a quantum Hall system is determined by a spin-resolved tunnelling method. This technique shows a substantial regime where the weakly interacting composite fermion picture is not valid.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Origin of strong-field-induced low-order harmonic generation in amorphous quartz

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0943-4

Strong-field-induced nonlinearities from the injection of electrons into the conduction band contribute to harmonic generation in amorphous quartz. Close to the damage threshold, they dominate over intraband and interband contributions.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Undulation enables gliding in flying snakes

Nature Physics, Published online: 29 June 2020; doi:10.1038/s41567-020-0935-4

Observations of flying snakes inform the development of a dynamical model of gliding taking undulation into account. This work suggests that aerial undulation has a different function in snakes than in other animals.

in Nature Physics on June 29, 2020 12:00 AM.

• #### Overcoming the energy gap law in near-infrared OLEDs by exciton–vibration decoupling

Nature Photonics, Published online: 29 June 2020; doi:10.1038/s41566-020-0653-6

Pt(ii) complexes allow the fabrication of efficient near-infrared organic light-emitting diodes that operate beyond the 900 nm region.

in Nature Photomics on June 29, 2020 12:00 AM.

• #### Reductive dearomative arylcarboxylation of indoles with CO2 via visible-light photoredox catalysis

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-17085-9

Catalytic reductive coupling of two electrophiles and one C = C bond is usually performed by two electron transfer metal catalysis. Herein, the authors show a visible light photoredox-catalyzed successive single electron transfer leading to dearomative arylcarboxylation of indoles with CO2 and generating indoline-3-carboxylic acids.

in Nature Communications on June 29, 2020 12:00 AM.

• #### MetaRibo-Seq measures translation in microbiomes

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-17081-z

Defining the functions of individual organisms or communities within microbiomes is a challenging task. Here, the authors develop MetaRibo-Seq, a method for simultaneous high-throughput ribosome profiling of organisms in uncultured microbiome samples.

in Nature Communications on June 29, 2020 12:00 AM.

• #### Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-17046-2

Tumor-draining lymph nodes are often the first site of metastasis in breast cancer patients. Here, the authors show that metastatic lymph nodes are characterized by the accumulation of suppressive regulatory T cells with a distinct phenotype compared to matched non-invaded lymph nodes and tumors.

in Nature Communications on June 29, 2020 12:00 AM.

• #### Long-term culture of human pancreatic slices as a model to study real-time islet regeneration

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-17040-8

The ability to culture live pancreatic tissue slices for long periods of time would enable longitudinal studies ex vivo. Here the authors culture human and mouse pancreatic slices in a perfluorocarbon-based culture system and show stable endocrine and exocrine function for up to ten days in culture.

in Nature Communications on June 29, 2020 12:00 AM.

• #### On-chip coherent microwave-to-optical transduction mediated by ytterbium in YVO4

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-16996-x

Long distance interfaces between superconducting quantum information processing nodes would require coherent, efficient and low-noise microwave-to-optical conversion. Here, the authors use Yb ion ensembles in yttrium orthovanadate to demonstrate a transducer with the potential to fulfill these requirements.

in Nature Communications on June 29, 2020 12:00 AM.

• #### Quantifying molecular bias in DNA data storage

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-16958-3

DNA is an attractive digital data storing medium due to high information density and longevity. Here the authors use millions of sequences to investigate inherent biases in DNA synthesis and PCR amplification.

in Nature Communications on June 29, 2020 12:00 AM.

• #### Iron imaging in myocardial infarction reperfusion injury

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-16923-0

Restoration of coronary blood flow after a heart attack may lead to reperfusion injury and pathologic iron deposition. Here, the authors perform magnetic susceptibility imaging showing its association with iron in a large animal model of myocardial infarction during wound healing, and showing feasibility in acute myocardial infarction patients undergoing percutaneous coronary intervention.

in Nature Communications on June 29, 2020 12:00 AM.

• #### Inverse iron oxide/metal catalysts from galvanic replacement

Nature Communications, Published online: 29 June 2020; doi:10.1038/s41467-020-16830-4

While typical catalysts involve oxide-supported metals, inverse catalysts of oxides on metal supports offer an attractive alternative. Here, authors prepare FeOx-coated Rh nanoparticles via galvanic replacement and dissolution-precipitation to form effective CO2 reduction catalysts.

in Nature Communications on June 29, 2020 12:00 AM.

• #### Neuromodulation of Gamma-Range Auditory Steady-State Responses: A Scoping Review of Brain Stimulation Studies

Neural oscillations represent a fundamental mechanism that enables coordinated action during normal brain functioning. Auditory steady-state responses (ASSRs) are used to test the ability to generate gamma-range activity. Different non-invasive brain stimulation (NIBS) techniques have the potential to modulate neural activation patterns that are aberrant in a variety of neuropsychiatric disorders. Here, we summarize the current state of knowledge on how different methods of NIBS (transcranial altering current stimulation—tACS, transcranial direct current stimulation—tDCS, transcranial random noise stimulation—tRNS, paired associative stimulation—PAS, repetitive transcranial magnetic stimulation—rTMS) affect the gamma-range ASSRs in both healthy and clinical populations. We show that the current research has been far from systematic and methodologically heterogeneous. Nevertheless, some brain stimulation techniques, especially tACS and rTMS show strong potential for further exploration. We outline the main findings and provide directions for further research into neuromodulation of ASSRs as a promising biomarker of different psychopathological conditions such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism.

in Frontiers in Systems Neuroscience on June 29, 2020 12:00 AM.

• #### The Role of Rif1 in telomere length regulation is separable from its role in origin firing

To examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ∆N-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that de-regulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-∆1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.

in eLife on June 29, 2020 12:00 AM.

• #### Tetramerisation of the CRISPR ring nuclease Crn3/Csx3 facilitates cyclic oligoadenylate cleavage

Type III CRISPR systems detect foreign RNA and activate the cyclase domain of the Cas10 subunit, generating cyclic oligoadenylate (cOA) molecules that act as a second messenger to signal infection, activating nucleases that degrade the nucleic acid of both invader and host. This can lead to dormancy or cell death; to avoid this, cells need a way to remove cOA from the cell once a viral infection has been defeated. Enzymes specialised for this task are known as ring nucleases, but are limited in their distribution. Here, we demonstrate that the widespread CRISPR associated protein Csx3, previously described as an RNA deadenylase, is a ring nuclease that rapidly degrades cyclic tetra-adenylate (cA4). The enzyme has an unusual cooperative reaction mechanism involving an active site that spans the interface between two dimers, sandwiching the cA4 substrate. We propose the name Crn3 (CRISPR associated ring nuclease 3) for the Csx3 family.

in eLife on June 29, 2020 12:00 AM.

• #### CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation

To investigate how the CARD14E138A psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14E138A mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14E138A rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14E138A induced more extensive skin inflammation and a severe systemic disease involving infiltration of myeloid cells in multiple organs, temperature reduction, weight loss and organ failure. This severe phenotype resembled acute exacerbations of generalized pustular psoriasis (GPP), a rare form of psoriasis that can be caused by CARD14 mutations in patients. CARD14E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14E138A signalling only in keratinocytes. These results suggest that anti-inflammatory therapies specifically targeting keratinocytes, rather than systemic biologicals, might be effective for GPP treatment early in disease progression.

in eLife on June 29, 2020 12:00 AM.

• #### A Tgfbr1/Snai1-dependent developmental module at the core of vertebrate axial elongation

Formation of the vertebrate postcranial body axis follows two sequential but distinct phases. The first phase generates pre-sacral structures (the so-called primary body) through the activity of the primitive streak on axial progenitors within the epiblast. The embryo then switches to generate the secondary body (post-sacral structures), which depends on axial progenitors in the tail bud. Here we show that the mammalian tail bud is generated through an independent functional developmental module, concurrent but functionally different from that generating the primary body. This module is triggered by convergent Tgfbr1 and Snai1 activities that promote an incomplete epithelial to mesenchymal transition on a subset of epiblast axial progenitors. This EMT is functionally different from that coordinated by the primitive streak, as it does not lead to mesodermal differentiation but brings axial progenitors into a transitory state, keeping their progenitor activity to drive further axial body extension.

in eLife on June 29, 2020 12:00 AM.

• #### A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21

Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we 'clone' the 34 MB long arm of HSA21 (HSA21q) as a mouse artificial chromosome (MAC). Through multiple steps of microcell-mediated chromosome transfer, we created a new Tc DS mouse model, Tc(HSA21q;MAC)1Yakaz ('TcMAC21'). TcMAC21 is not mosaic and contains 93% of HSA21q PCGs that are expressed and regulatable. TcMAC21 recapitulates many DS phenotypes including anomalies in heart, craniofacial skeleton and brain, molecular/cellular pathologies, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete genetic mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.

in eLife on June 29, 2020 12:00 AM.

• #### Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis

Neurons display different levels of vulnerability to Alzheimer’s pathology. Roussarie et al. experimentally profile and computationally model several relevant neuron types. Using a mouse-human framework, they identify genes linking Aß, aging, and tau in vulnerable neurons. Finally, they show experimentally that PTB, a regulator of tau splicing, contributes to vulnerability.

in Neuron: In press on June 29, 2020 12:00 AM.

## Graphical Abstract

Nectin‐2α, prominently expressed in the medial habenula (MHb), was localized at cholinergic neuron dendrites in synaptic regions of the MHb (clustered filled dots) in addition to the boundary between the adjacent somata of the clustered cholinergic neurons (edges of clustered open hexagons). This dendritic nectin‐2α formed puncta adherentia junctions cooperatively with afadin, cadherin‐8, p120‐catenin, β‐catenin, and αN‐catenin and regulated synapse formation.

## Abstract

The medial habenula (MHb) receives afferents from the triangular septum and the medial septal complex, projects efferents to the interpeduncular nucleus (IPN) in the midbrain to regulate dopamine and serotonin levels, and is implicated in stress, depression, memory, and nicotine withdrawal syndrome. We previously showed that the cell adhesion molecule nectin‐2α is localized at the boundary between adjacent somata of clustered cholinergic neurons and regulates the voltage‐gated A‐type K+ channel Kv4.2 localization at membrane specializations in the MHb. This adhesion apparatus, named nectin‐2α spots, is not associated with the nectin‐binding protein afadin or any classic cadherins and their binding proteins p120‐catenin and β‐catenin. We showed here that nectin‐2α was additionally localized at cholinergic neuron dendrites in synaptic regions of the MHb. The genetic ablation of nectin‐2 reduced the number of synapses in the MHb without affecting their morphology. Nectin‐2α was associated with afadin, cadherin‐8, p120‐catenin, β‐catenin, and αN‐catenin, forming puncta adherentia junctions (PAJs). Nectin‐2α was observed in the IPN, but not in the triangular septum or the medial septal complex. The genetic ablation of nectin‐2 did not affect synapse formation in the IPN. These results indicate that nectin‐2α forms two types of adhesion apparatus in the MHb, namely nectin‐2α spots at neighboring somata and PAJs at neighboring dendrites, and that dendritic PAJs regulate synapse formation in the MHb.

in Journal of Comparative Neurology on June 28, 2020 07:00 PM.

• #### Differential temporal and spatial post‐injury alterations in cerebral cell morphology and viability

We examined the chronology of infarct and the viability and morphological changes in neuroglia and neurons located in different brain regions on d1, d7, and d28 post β‐amyloid (Aβ) toxicity and endothelin‐1 induced ischemia (ET1) in rats.

## Abstract

Combination of ischemia and β‐amyloid (Aβ) toxicity has been shown to simultaneously increase neuro‐inflammation, endogenous Aβ deposition, and neurodegeneration. However, studies on the evolution of infarct and panorama of cellular degeneration as a synergistic or overlapping mechanism between ischemia and Aβ toxicity are lacking. Here, we compared fluorojade B (FJB) and hematoxylin and eosin (H&E) stains primarily to examine the chronology of infarct, and the viability and morphological changes in neuroglia and neurons located in different brain regions on d1, d7, and d28 post Aβ toxicity and endothelin‐1 induced ischemia (ET1) in rats. We demonstrated a regional difference in cellular degeneration between cortex, corpus callosum, striatum, globus pallidus, and thalamus after cerebral injury. Glial cells in the cortex and corpus callosum underwent delayed FJB staining from d7 to d28, but neurons in cortex disappeared within the first week of cerebral injury. Striatal lesion core and globus pallidus of Aβ + ET1 rats showed extensive degeneration of neuronal cells compared with ET1 rats alone starting from d1. Differential and exacerbated expressions of cyclooxygenase‐2 might be the cause of excessive neuronal demise in the striatum of Aβ + ET1 rats. Such an investigation may improve our understanding to identify and manipulate a critical therapeutic window post comorbid injury.

in Journal of Comparative Neurology on June 28, 2020 05:59 PM.

• #### Validation of the neurogenic orthostatic hypotension ratio with active standing

in Annals of Neurology on June 28, 2020 04:08 PM.

• #### 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 (a) low‐sensitivity neurons that selectively respond to large light decrements, (b) high‐sensitivity neurons that selectively encode small decrements, and (c) 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: (a) low‐sensitivity OFF‐RGCs that selectively respond to large light decrements, (b) high‐sensitivity OFF‐RGCs that selectively encode small decrements, and (c) 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.

in Journal of Comparative Neurology on June 28, 2020 02:20 PM.

• #### Inhibition of neural stem cell aging through the transient induction of reprogramming factors

Long‐term in vitro culture of neural stem cells (NSCs) resulted in aging‐related upregulation of inflammatory‐ and endoplasmic reticulum (ER) stress‐related genes. The induction of four reprogramming factors (Oct4, Sox2, Klf4, and c‐Myc) could decrease expression of the inflammatory and ER stress‐related genes during the long‐term culture.

## Abstract

Adult stem cells age during long‐term in vitro culture, and neural stem cells (NSCs), which can self‐renew and differentiate into neurons and glial cells, also display reduced differentiation potential after repeated passaging. However, the mechanistic details underlying this process remain unclear. In this study, we found that long‐term in vitro culture of NSCs resulted in aging‐related upregulation of inflammatory‐ and endoplasmic reticulum (ER) stress‐related genes, including the proinflammatory cytokines interleukin (IL)1β and IL6, the senescence‐associated enzyme matrix metallopeptidase 13 (MMP13), and the ER stress‐responsive transcription factor activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). However, the cyclic and transient induction of four reprogramming factors (POU domain, class 5, transcription factor 1, also known as octamer‐binding transcription factor 4; SRY [sex determining region Y]‐box 2; Kruppel‐like factor 4; and myelocytomatosis oncogene; collectively referred to as OSKM) can inhibit NSC aging, as indicated by the decreased expression of the inflammatory and ER stress‐related genes. We used ROSA‐4F NSCs, which express OSKM from only one allele, to minimize the potential for full reprogramming or tumor formation during NSC rejuvenation. We expect that this novel rejuvenation method will enhance the potential of NSCs as a clinical approach to the treatment of neurological diseases.

in Journal of Comparative Neurology on June 28, 2020 01:30 PM.

## Graphical Abstract

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 homolog 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.

in Journal of Comparative Neurology on June 28, 2020 01:21 PM.

• #### Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development, functional connectivity, and critical period plasticity

Depletion of microglia during cortical critical period profoundly alters glutamatergic synapse developmental trajectory Microglia is critical for visual cortex spine pruning, circuit refinement, intracortical connectivity, and critical period plasticity

## Abstract

Microglia populate the early developing brain and mediate pruning of the central synapses. Yet, little is known on their functional significance in shaping the developing cortical circuits. We hypothesize that the developing cortical circuits require microglia for proper circuit maturation and connectivity, and as such, ablation of microglia during the cortical critical period may result in a long‐lasting circuit abnormality. We administered PLX3397, a colony‐stimulating factor 1 receptor inhibitor, to mice starting at postnatal day 14 and through P28, which depletes >75% of microglia in the visual cortex (VC). This treatment largely covers the critical period (P19‐32) of VC maturation and plasticity. Patch clamp recording in VC layer 2/3 (L2/3) and L5 neurons revealed increased mEPSC frequency and reduced amplitude, and decreased AMPA/NMDA current ratio, indicative of altered synapse maturation. Increased spine density was observed in these neurons, potentially reflecting impaired synapse pruning. In addition, VC intracortical circuit functional connectivity, assessed by laser scanning photostimulation combined with glutamate uncaging, was dramatically altered. Using two photon longitudinal dendritic spine imaging, we confirmed that spine elimination/pruning was diminished during VC critical period when microglia were depleted. Reduced spine pruning thus may account for increased spine density and disrupted connectivity of VC circuits. Lastly, using single‐unit recording combined with monocular deprivation, we found that ocular dominance plasticity in the VC was obliterated during the critical period as a result of microglia depletion. These data establish a critical role of microglia in developmental cortical synapse pruning, maturation, functional connectivity, and critical period plasticity.

in Journal of Neuroscience Research on June 28, 2020 09:31 AM.

• #### Lesion network mapping demonstrates that mind‐wandering is associated with the default mode network

Using both novel and traditional lesion methods in humans, the neural networks responsible for mind‐wandering were studied. Both lesion analyses demonstrated that reduced mind‐wandering was associated with damage to brain regions within the default mode network.

## Abstract

Functional neuroimaging research has consistently associated brain structures within the default mode network (DMN) and frontoparietal network (FPN) with mind‐wandering. Targeted lesion research has documented impairments in mind‐wandering after damage to the medial prefrontal cortex (mPFC) and hippocampal regions associated with the DMN. However, no lesion studies to date have applied lesion network mapping to identify common networks associated with deficits in mind‐wandering. In lesion network mapping, resting‐state functional connectivity data from healthy participants are used to infer which brain regions are functionally connected to each lesion location from a sample with brain injury. In the current study, we conducted a lesion network mapping analysis to test the hypothesis that lesions affecting the DMN and FPN would be associated with diminished mind‐wandering. We assessed mind‐wandering frequency on the Imaginal Processes Inventory (IPI) in participants with brain injury (n  = 29) and healthy comparison participants without brain injury (n  = 19). Lesion network mapping analyses showed the strongest association of reduced mind‐wandering with the left inferior parietal lobule within the DMN. In addition, traditional lesion symptom mapping results revealed that reduced mind‐wandering was associated with lesions of the dorsal, ventral, and anterior sectors of mPFC, parietal lobule, and inferior frontal gyrus in the DMN (p  < 0.05 uncorrected). These findings provide novel lesion support for the role of the DMN in mind‐wandering and contribute to a burgeoning literature on the neural correlates of spontaneous cognition.

in Journal of Neuroscience Research on June 28, 2020 09:30 AM.

• #### Stability of delayed inertial neural networks on time scales: A unified matrix-measure approach

Publication date: October 2020

Source: Neural Networks, Volume 130

Author(s): Qiang Xiao, Tingwen Huang

in Neural Networks on June 27, 2020 06:00 PM.

• #### Sparse coding with a somato-dendritic rule

Publication date: Available online 26 June 2020

Source: Neural Networks

Author(s): Damien Drix, Verena V. Hafner, Michael Schmuker

in Neural Networks on June 27, 2020 06:00 PM.

• #### LRRTM4 is a member of the transsynaptic complex between rod photoreceptors and bipolar cells

Leucine rich repeat transmembrane (LRRTM) proteins are synaptic adhesion molecules with roles in synapse formation and signaling. LRRTM4 was found to reside at rod bipolar cell (BC) dendritic tips, where it colocalized with the transduction channel protein, TRPM1. LRRTM4 was not detected at dendritic tips of ON‐cone BCs. Following somatic knockout of LRRTM4 in BCs by subretinal injection and electroporation of CRISPR/Cas9, LRRTM4 was abolished or reduced in the dendritic tips of transfected cells. Knockout cells had a normal complement of TRPM1 at their dendritic tips, while GPR179 accumulation was partially reduced. In experiments with heterologously expressed protein, the extracellular domain of LRRTM4 was found to engage in heparan‐sulfate dependent binding with pikachurin. These results implicate LRRTM4 in the GPR179‐pikachurin‐dystroglycan transsynaptic complex at rod synapses.

## Abstract

Leucine rich repeat transmembrane (LRRTM) proteins are synaptic adhesion molecules with roles in synapse formation and signaling. LRRTM4 transcripts were previously shown to be enriched in rod bipolar cells (BCs), secondary neurons of the retina that form synapses with rod photoreceptors. Using two different antibodies, LRRTM4 was found to reside primarily at rod BC dendritic tips, where it colocalized with the transduction channel protein, TRPM1. LRRTM4 was not detected at dendritic tips of ON‐cone BCs. Following somatic knockout of LRRTM4 in BCs by subretinal injection and electroporation of CRISPR/Cas9, LRRTM4 was abolished or reduced in the dendritic tips of transfected cells. Knockout cells had a normal complement of TRPM1 at their dendritic tips, while GPR179 accumulation was partially reduced. In experiments with heterologously expressed protein, the extracellular domain of LRRTM4 was found to engage in heparan‐sulfate dependent binding with pikachurin. These results implicate LRRTM4 in the GPR179‐pikachurin‐dystroglycan transsynaptic complex at rod synapses.

in Journal of Comparative Neurology on June 27, 2020 05:35 PM.

• #### Light adaptation mechanisms in the eye of the fiddler crab Afruca tangeri

Dark‐adapting the fiddler crab eye at night triggers great changes in rhabdom diameters and crystalline cone shape, increasing optical sensitivity and acceptance angles. However, during daytime the eye remains effectively light‐adapted in the dark. Surprisingly, screening pigments do not appear to migrate to help moderate fluctuations in brightness.

## Abstract

A great diversity of adaptations is found among animals with compound eyes and even closely related taxa can show large variation in their light‐adaptation strategies. A prime example of a visual system evolved to function in specific light environments is the fiddler crab, used widely as a model to research aspects of crustacean vision and neural pathways. However, questions remain regarding how their eyes respond to the changes in brightness spanning many orders of magnitude, associated with their habitat and ecology. The fiddler crab Afruca tangeri forages at low tide on tropical and semi‐tropical mudflats, under bright sunlight and on moonless nights, suggesting that their eyes undergo effective light adaptation. Using synchrotron X‐ray tomography, light and transmission electron microscopy and in vivo ophthalmoscopy, we describe the ultrastructural changes in the eye between day and night. Dark adaptation at dusk triggered extensive widening of the rhabdoms and crystalline cone tips. This doubled the ommatidial acceptance angles and increased microvillar surface area for light capture in the rhabdom, theoretically boosting optical sensitivity 7.4 times. During daytime, only partial dark‐adaptation was achieved and rhabdoms remained narrow, indicating strong circadian control on the process. Bright light did not evoke changes in screening pigment distributions, suggesting a structural inability to adapt rapidly to the light level fluctuations frequently experienced when entering their burrow to escape predators. This should enable fiddler crabs to shelter for several minutes without undergoing significant dark‐adaptation, their vision remaining effectively adapted for predator detection when surfacing again in bright light.

in Journal of Comparative Neurology on June 27, 2020 03:06 PM.

• #### Dynamics of the fragile X mental retardation protein correlates with cellular and synaptic properties in primary auditory neurons following afferent deprivation

Fragile X mental retardation protein (FMRP) regulates cellular and synaptic properties in an activity‐dependent manner. Using unilateral cochlea removal as a method to deprive afferent input to the chicken cochlear neurons, we identified a persistent FMRP aggregation in a subset of neurons that undergo cell death. In addition, we found newly emerged or enhanced correlations of FMRP level with cellular and synaptic rearrangements in the surviving neurons after regaining their homeostasis. These results demonstrate that afferent input regulates FMRP expression and localization in ways associated with multiple types of neuronal responses and synaptic dynamics.

## Abstract

Afferent activity dynamically regulates neuronal properties and connectivity in the central nervous system. The Fragile X mental retardation protein (FMRP) is an RNA‐binding protein that regulates cellular and synaptic properties in an activity‐dependent manner. Whether and how FMRP level and localization are regulated by afferent input remains sparsely examined and how such regulation is associated with neuronal response to changes in sensory input is unknown. We characterized changes in FMRP level and localization in the chicken nucleus magnocellularis (NM), a primary cochlear nucleus, following afferent deprivation by unilateral cochlea removal. We observed rapid (within 2 hr) aggregation of FMRP immunoreactivity into large granular structures in a subset of deafferented NM neurons. Neurons that exhibited persistent FMRP aggregation at 12–24 hr eventually lost cytoplasmic Nissl substance, indicating cell death. A week later, FMRP expression in surviving neurons regained its homeostasis, with a slightly reduced immunostaining intensity and enhanced heterogeneity. Correlation analyses under the homeostatic status (7–14 days) revealed that neurons expressing relatively more FMRP had a higher capability of maintaining cell body size and ribosomal activity, as well as a better ability to detach inactive presynaptic terminals. Additionally, the intensity of an inhibitory postsynaptic protein, gephyrin, was reduced following deafferentation and was positively correlated with FMRP intensity, implicating an involvement of FMRP in synaptic dynamics in response to reduced afferent inputs. Collectively, this study demonstrates that afferent input regulates FMRP expression and localization in ways associated with multiple types of neuronal responses and synaptic rearrangements.

in Journal of Comparative Neurology on June 27, 2020 02:01 PM.

• #### Brain gyrification in wild and domestic canids: Has domestication changed the gyrification index in domestic dogs?

Comparative studies on canid cognition have revealed tantalizing evidence for some restructuring in the canine brain. Using quantitative magnetic resonance imaging, we compared the degree of cortical folding in wild and domestic canids. We demonstrate that this parameter is largely consistent across canid species although regional differences in gyrification exist.

## Abstract

Over the last 15 years, research on canid cognition has revealed that domestic dogs possess a surprising array of complex socio‐cognitive skills pointing to the possibility that the domestication process might have uniquely altered their brains; however, we know very little about how evolutionary processes (natural or artificial) might have modified underlying neural structure to support species‐specific behaviors. Evaluating the degree of cortical folding (i.e., gyrification) within canids may prove useful, as this parameter is linked to functional variation of the cerebral cortex. Using quantitative magnetic resonance imaging to investigate the impact of domestication on the canine cortical surface, we compared the gyrification index (GI) in 19 carnivore species, including six wild canid and 13 domestic dog individuals. We also explored correlations between global and local GI with brain mass, cortical thickness, white and grey matter volume and surface area. Our results indicated that GI values for domestic dogs are largely consistent with what would be expected for a canid of their given brain mass, although more variable than that observed in wild canids. We also found that GI in canids is positively correlated with cortical surface area, cortical thickness and total cortical grey matter volumes. While we found no evidence of global differences in GI between domestic and wild canids, certain regional differences in gyrification were observed.

in Journal of Comparative Neurology on June 27, 2020 09:18 AM.

• #### Retinal defocus and form‐deprivation induced regional differential gene expression of bone morphogenetic proteins in chick retinal pigment epithelium

We previously reported in young chicks bidirectional gene expression regulation of the BMP2 , 4 , and 7 in retinal pigment epithelium (RPE) after visual manipulation, tied to the direction of induced eye growth changes. Here we report local (regional) differences in expression patterns that were also treatment specific. Both BMP2 and BMP4 genes showed the expected increased expression with imposed myopic defocus (+10 D lens) after 2 and 48 hr, albeit limited to central and mid‐peripheral RPE zones. In contrast, the expected decrease in BMP2 gene expression with imposed hyperopic defocus (−10 D lens) was evident across all three zones after both 2 and 48 hr, with similar patterns observed after 48 hr with FD. Similar but smaller changes were recorded for BMP4 and BMP7 gene expression with the latter myopia‐inducing treatments.

## Abstract

We previously reported bidirectional gene expression regulation of the Bone Morphogenetic Proteins (BMP2 , 4 , and 7 ) in chick retinal pigment epithelium (RPE) in response to imposed optical defocus and form‐deprivation (FD). This study investigated whether there are local (regional) differences in these effects. 19‐day old White‐Leghorn chicks wore monocular +10 or − 10 D lenses, or diffusers (FD) for 2 or 48 hr, after which RPE samples were collected from both eyes, from a central circular zone (3 mm radius), and 3 mm wide annular mid‐peripheral and peripheral zones in all cases. BMP2 , 4 , and 7 gene expression levels in RPE from treated and fellow control eyes were compared as well as differences across zones. With the +10 D lens, increased expression of both BMP2 and BMP4 genes was observed in central and mid‐peripheral zones but not the peripheral zone after 2 and 48 hr. In contrast, with the −10 D lens BMP2 gene expression was significantly decreased in all three zones after 2 and 48 hr. Similar patterns of BMP2 gene expression were observed in all three zones after 48 hr of FD. Smaller changes were recorded for BMP4 and BMP7 gene expression for both myopia‐inducing treatments. That optical defocus‐ and FD‐induced changes in BMP gene expression in chick RPE show treatment‐dependent local (regional) differences suggest important differences in the nature and contributions of local retinal and underlying RPE regions to eye growth regulation.

in Journal of Comparative Neurology on June 27, 2020 09:09 AM.

• #### Shedding light on human cerebral lipofuscin: An explorative study on identification and quantification

The authors identified and quantified the age pigment lipofuscin within pial arterial walls and neocortical parenchyma of young drug‐resistant epilepsy patients. Lipofuscin functions as a marker of cumulative oxidative stress, and could provide insight in the pathophysiology of epilepsy.

## Abstract

Increased oxidative stress has been associated with several neurodegenerative diseases such as Alzheimer’s disease, but also with neurological diseases sharing pathophysiological pathways like epilepsy. Lipofuscin is a non‐degradable end‐product of oxidative stress; its cerebral presence reflects the cumulative amount of oxidative stress the brain has endured. In this study, we have observed prominent autofluorescent particles in the pial arterial wall and in neocortical parenchyma of young, drug‐resistant epilepsy patients (18‐28 years old) who underwent resective brain surgery (n=6), as well as in older control patients (n=3). With fluorescence spectroscopic imaging, brightfield microscopy, histochemistry and fluorescence lifetime imaging, these autofluorescent particles were identified as the age pigment lipofuscin. An evaluation of these lipofuscin particles using Imaris© software allowed robust quantification, while the 3D properties allowed visualization of the complex configuration. We elaborate on the usefulness of lipofuscin as a marker of cumulative oxidative stress in the brain. Furthermore, we speculate on the observed differences in particle size and density that we found between young patients and older controls, which could imply a role for lipofuscin in the pathophysiology of epilepsy and possibly other neurological diseases.

in Journal of Comparative Neurology on June 27, 2020 08:59 AM.

• #### The genome polishing tool POLCA makes fast and accurate corrections in genome assemblies

by Aleksey V. Zimin, Steven L. Salzberg

The introduction of third-generation DNA sequencing technologies in recent years has allowed scientists to generate dramatically longer sequence reads, which when used in whole-genome sequencing projects have yielded better repeat resolution and far more contiguous genome assemblies. While the promise of better contiguity has held true, the relatively high error rate of long reads, averaging 8–15%, has made it challenging to generate a highly accurate final sequence. Current long-read sequencing technologies display a tendency toward systematic errors, in particular in homopolymer regions, which present additional challenges. A cost-effective strategy to generate highly contiguous assemblies with a very low overall error rate is to combine long reads with low-cost short-read data, which currently have an error rate below 0.5%. This hybrid strategy can be pursued either by incorporating the short-read data into the early phase of assembly, during the read correction step, or by using short reads to “polish” the consensus built from long reads. In this report, we present the assembly polishing tool POLCA (POLishing by Calling Alternatives) and compare its performance with two other popular polishing programs, Pilon and Racon. We show that on simulated data POLCA is more accurate than Pilon, and comparable in accuracy to Racon. On real data, all three programs show similar performance, but POLCA is consistently much faster than either of the other polishing programs.

in PLoS Computational Biology on June 26, 2020 09:00 PM.

• #### A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics

by Fabian Konrath, Anna Mittermeier, Elena Cristiano, Jana Wolf, Alexander Loewer

The transcription factors NF-κB and p53 are key regulators in the genotoxic stress response and are critical for tumor development. Although there is ample evidence for interactions between both networks, a comprehensive understanding of the crosstalk is lacking. Here, we developed a systematic approach to identify potential interactions between the pathways. We perturbed NF-κB signaling by inhibiting IKK2, a critical regulator of NF-κB activity, and monitored the altered response of p53 to genotoxic stress using single cell time lapse microscopy. Fitting subpopulation-specific computational p53 models to this time-resolved single cell data allowed to reproduce in a quantitative manner signaling dynamics and cellular heterogeneity for the unperturbed and perturbed conditions. The approach enabled us to untangle the integrated effects of IKK/ NF-κB perturbation on p53 dynamics and thereby derive potential interactions between both networks. Intriguingly, we find that a simultaneous perturbation of multiple processes is necessary to explain the observed changes in the p53 response. Specifically, we show interference with the activation and degradation of p53 as well as the degradation of Mdm2. Our results highlight the importance of the crosstalk and its potential implications in p53-dependent cellular functions.

in PLoS Computational Biology on June 26, 2020 09:00 PM.

## Objective

Recent studies carried on amyotrophic lateral sclerosis patients suggest that the disease may initiate in the motor cortex and spread to its targets along the corticofugal tracts. In this study, we aimed at experimentally testing the corticofugal hypothesis of amyotrophic lateral sclerosis.

## Methods

Sod1 G86R and Fezf2 knockout mouse lines were crossed to generate a model that ubiquitously expresses a mutant of the murine Sod1 gene, a condition sufficient to induce progressive motor symptoms and premature death, but genetically lacks corticospinal neurons and other subcerebral projection neurons, one of the main populations of corticofugal neurons. Disease onset and survival were recorded, and weight and motor behaviour were longitudinally followed. Hyperreflexia and spasticity were monitored using electromyographic recordings. Neurodegeneration and gliosis were further assessed by histological techniques.

## Results

Absence of subcerebral projection neurons delayed disease onset, reduced weight loss and motor impairment, and increased survival without modifying disease duration. Absence of corticospinal neurons also limited pre‐symptomatic hyperreflexia, a typical component of the upper motor neuron syndrome.

## Interpretation

Major corticofugal tracts are critical to amyotrophic lateral sclerosis onset and progression. In the context of the disease, subcerebral projection neurons may carry detrimental signals to their downstream targets. In its whole, this study provides the first experimental arguments in favour of the corticofugal hypothesis of amyotrophic lateral sclerosis.

in Annals of Neurology on June 26, 2020 07:16 PM.

## Objective

Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff‐person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood.

## Methods

A cell‐based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model.

## Results

Glycine receptor function as assessed by glycine dose‐response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from two patients a decreased fraction of desensitized receptors was observed while closing of the ion channel remained fast. The glycine receptor N‐terminal residues 29A to 62G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals.

## Interpretation

Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, since the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in SPS or PERM patients.

in Annals of Neurology on June 26, 2020 07:09 PM.

• #### In vivo microstimulation with cathodic and anodic asymmetric waveforms modulates spatiotemporal calcium dynamics in cortical neuropil and pyramidal neurons of male mice

Electrical microstimulation can treat neurological disorders; however, the mechanisms defining therapeutic efficacy are poorly characterized. In the mouse cortex, increasing the stimulation waveform asymmetry differentially modulates the spatial distribution and level of sustained neuronal activation, depending on leading polarity, under mesoscale (top) and two‐photon (bottom) imaging. Blood vessels in red.

## Abstract

Electrical stimulation has been critical in the development of an understanding of brain function and disease. Despite its widespread use and obvious clinical potential, the mechanisms governing stimulation in the cortex remain largely unexplored in the context of pulse parameters. Modeling studies have suggested that modulation of stimulation pulse waveform may be able to control the probability of neuronal activation to selectively stimulate either cell bodies or passing fibers depending on the leading polarity. Thus, asymmetric waveforms with equal charge per phase (i.e., increasing the leading phase duration and proportionately decreasing the amplitude) may be able to activate a more spatially localized or distributed population of neurons if the leading phase is cathodic or anodic, respectively. Here, we use two‐photon and mesoscale calcium imaging of GCaMP6s expressed in excitatory pyramidal neurons of male mice to investigate the role of pulse polarity and waveform asymmetry on the spatiotemporal properties of direct neuronal activation with 10‐Hz electrical stimulation. We demonstrate that increasing cathodic asymmetry effectively reduces neuronal activation and results in a more spatially localized subpopulation of activated neurons without sacrificing the density of activated neurons around the electrode. Conversely, increasing anodic asymmetry increases the spatial spread of activation and highly resembles spatiotemporal calcium activity induced by conventional symmetric cathodic stimulation. These results suggest that stimulation polarity and asymmetry can be used to modulate the spatiotemporal dynamics of neuronal activity thus increasing the effective parameter space of electrical stimulation to restore sensation and study circuit dynamics.

in Journal of Neuroscience Research on June 26, 2020 07:00 PM.

## Abstract

We have previously shown that repetitive induction of long‐term potentiation (LTP) by glutamate (100 μM, 3 min, three times at 24‐hr intervals) provoked long‐lasting synaptic enhancement accompanied by synaptogenesis in rat hippocampal slice cultures, a phenomenon termed RISE (repetitive LTP‐induced synaptic enhancement). Here, we examined the role of Ca2+‐permeable (CP) AMPA receptors (AMPARs) in the establishment of RISE. We first found a component sensitive to the Joro‐spider toxin (JSTX), a blocker of CP‐AMPARs, in a field EPSP recorded from CA3‐CA1 synapses at 2–3 days after stimulation, but this component was not found for 9–10 days. We also observed that rectification of AMPAR‐mediated current appeared only 2–3 days after stimulation, using a whole‐cell patch clamp recording from CA1 pyramidal neurons. These findings indicate that CP‐AMPAR is transiently expressed in the developing phase of RISE. The blockade of CP‐AMPARs by JSTX for 24 hr at this developing phase inhibited RISE establishment, accompanied by the loss of small synapses at the ultrastructural level. These results suggest that transiently induced CP‐AMPARs play a critical role in synaptogenesis in the developing phase of long‐lasting hippocampal synaptic plasticity, RISE.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

The encoding of information in spike phase relative to local field potential (LFP) oscillations offers several theoretical advantages over equivalent firing rate codes. One notable example is provided by place and grid cells in the rodent hippocampal formation, which exhibit phase precession—firing at progressively earlier phases of the 6–12 Hz movement‐related theta rhythm as their spatial firing fields are traversed. It is often assumed that such phase coding relies on a high amplitude baseline oscillation with relatively constant frequency. However, sustained oscillations with fixed frequency are generally absent in LFP and spike train recordings from the human brain. Hence, we examine phase coding relative to LFP signals with broadband low‐frequency (2–20 Hz) power but without regular rhythmicity. We simulate a population of grid cells that exhibit phase precession against a baseline oscillation recorded from depth electrodes in human hippocampus. We show that this allows grid cell firing patterns to multiplex information about location, running speed and movement direction, alongside an arbitrary fourth variable encoded in LFP frequency. This is of particular importance given recent demonstrations that movement direction, which is essential for path integration, cannot be recovered from head direction cell firing rates. In addition, we investigate how firing phase might reduce errors in decoded location, including those arising from differences in firing rate across grid fields. Finally, we describe analytical methods that can identify phase coding in the absence of high amplitude LFP oscillations with approximately constant frequency, as in single unit recordings from the human brain and consistent with recent data from the flying bat. We note that these methods could also be used to detect phase coding outside of the spatial domain, and that multi‐unit activity can substitute for the LFP signal. In summary, we demonstrate that the computational advantages offered by phase coding are not contingent on, and can be detected without, regular rhythmicity in neural activity.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

When faced with changing contingencies, animals can use memory to flexibly guide actions, engaging both frontal and temporal lobe brain structures. Damage to the hippocampus (HPC) impairs episodic memory, and damage to the prefrontal cortex (PFC) impairs cognitive flexibility, but the circuit mechanisms by which these areas support flexible memory processing remain unclear. The present study investigated these mechanisms by temporarily inactivating the medial PFC (mPFC), the dorsal HPC (dHPC), and the ventral HPC (vHPC), individually and in combination, as rats learned spatial discriminations and reversals in a plus maze. Bilateral inactivation of either the dHPC or vHPC profoundly impaired spatial learning and memory, whereas bilateral mPFC inactivation primarily impaired reversal versus discrimination learning. Inactivation of unilateral mPFC together with the contralateral dHPC or vHPC impaired spatial discrimination and reversal learning, whereas ipsilateral inactivation did not. Flexible spatial learning thus depends on both the dHPC and vHPC and their functional interactions with the mPFC.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

The uncal apex is an anatomical landmark frequently used for segmenting the hippocampus into its anterior and posterior segments, a necessary step for computing many measurements of its long axis. It functions well, as it is both local to the hippocampus and easy to identify. However, in spite of widespread use and definition in the EADC‐ADNI Harmonized Hippocampal Protocol (HarP), how the uncal apex is influenced by gross hippocampal changes during normal aging has not been established, nor has the possible impact on measures of anterior hippocampus (aHPC) and posterior hippocampus (pHPC) volume. Here I drew upon three large data sets to describe and confirm these relationships, investigating them in one large data set and replicating my findings in the two others, evaluating a total of 4,434 hippocampi. I found the uncal apex fell in an increasingly more anterior position with increasing age. This age‐related retraction of the uncus began after age 36, with the sharpest effects arising after age 60. This phenomenon exaggerates age‐related aHPC volume decreases while simultaneously underestimating age‐related pHPC volume decreases, a pattern I confirmed by juxtaposing uncal apex and MNI space‐based landmarking. A hippocampally based reference frame was also rendered unstable by age‐related shifts in the posterior extent of the hippocampus. Both the uncal apex and hippocampal reference frame should therefore be used with caution in aging research, or in research involving other demographic or disease factors known to evoke gross changes in the hippocampus. Instead, MNI coordinate‐based heuristics may be appropriate for segmenting the hippocampus in study designs involving such factors. Apex‐based segmentation is still attractive, however, in study designs where advanced age and atrophy are not used as regressors, including investigations into long‐axis effects in healthy young adults. Progress toward localizing functional divisions within the hippocampus is needed to identify best practices for the field.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

It is well known that distributed learning (DL) leads to improved memory performance compared with massed learning (ML) (i.e., spacing effect). However, the extent to which the hippocampus is involved in the spacing effect at shorter and longer retention intervals remains unclear. To address this issue, two groups of participants were asked to encode face–scene pairs at 20‐min, 1‐day, and 1‐month intervals before they were scanned using fMRI during an associative recognition task. The pairs were repeated six times in either a massed (i.e., six times in 1 day) or a distributed (i.e., six times over 3 days, twice per day) manner. The results showed that compared with that in the ML group, the activation of the left hippocampus was stronger in the DL group when the participants retrieved old pairs correctly and rejected new pairs correctly at different retention intervals. In addition, the posterior hippocampus was more strongly activated when the new associations were rejected correctly after DL than ML, especially at the 1‐month interval. Hence, our results provide evidence that the hippocampus is involved in better memory performance after DL compared to ML at both shorter and longer retention intervals.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

Hippocampal mossy fibers have long been proposed to impose new patterns to learn onto CA3 neurons during new memory formation. However, inconsistent with this theory, we found in our previous study that mossy fiber stimulation induces only transient changes in CA3 spatial firing in a familiar environment. Here, we tested whether mossy fiber stimulation affects CA3 spatial firing differently between familiar and novel environments. We compared spatial firing of CA3 neurons before and after optogenetic stimulation of mossy fibers in freely behaving mice in a familiar and three sets of novel environments. We found that CA3 neurons are more responsive to mossy fiber stimulation in the novel than familiar environments. However, we failed to obtain evidence for long‐lasting effect of mossy fiber stimulation on spatial firing of CA3 neurons in both the familiar and novel environments. Our results provide further evidence against the view that mossy fibers carry teaching signals.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

There is evidence for a hippocampal long axis anterior–posterior (AP) differentiation in memory processing, which may have implications for the changes in episodic memory performance seen across development and aging. The hippocampus shows substantial structural changes with age, but the lifespan trajectories of hippocampal sub‐regions along the AP axis are not established. The aim of the present study was to test whether the micro‐ and macro‐structural age‐trajectories of the anterior (aHC) and posterior (pHC) hippocampus are different. In a single‐center longitudinal study, 1,790 cognitively healthy participants, 4.1–93.4 years of age, underwent a total of 3,367 MRI examinations and 3,033 memory tests sessions over 1–6 time points, spanning an interval up to 11.1 years. T1‐weighted scans were used to estimate the volume of aHC and pHC (macrostructure), and diffusion tensor imaging to measure mean diffusion (MD, microstructure) within each region. We found that the macro‐ and microstructural lifespan‐trajectories of aHC and pHC were clearly distinguishable, with partly common and partly unique variance shared with age. aHC showed a protracted period of microstructural development, while pHC microstructural development as indexed by MD was more or less completed in early childhood. In contrast, pHC showed larger unique aging‐related changes. An aHC–pHC difference was also observed for volume, with pHC changing relatively more with higher age. All regions showed age‐dependent relationships with episodic memory. aHC micro‐ and macrostructure was significantly related to verbal memory independently of age, but the relationships were still strongest among the older participants. We suggest that memory processes supported by each sub‐region improve or decline in concert with volumetric and microstructural changes in the same age‐period. Future research should disentangle the lifespan relationship between changes in these structural properties and different memory processes, encoding versus retrieval in particular, as well as other cognitive functions depending on the hippocampal long‐axis specialization.

in Hippocampus on June 26, 2020 06:32 PM.

## Abstract

In the mammalian brain, newly acquired memories depend on the hippocampus (HPC) for maintenance and recall, but over time, the neocortex takes over these functions, rendering memories HPC‐independent. The process responsible for this transformation is called systems memory consolidation . Reactivation of a well‐consolidated memory can trigger a temporary return to a HPC‐dependent state, a phenomenon known as systems memory reconsolidation . The neural mechanisms underlying systems memory consolidation and reconsolidation are not well understood. Here, we propose a neural model based on well‐documented mechanisms of synaptic plasticity and stability and describe a computational implementation that demonstrates the model's ability to account for a range of findings from the systems consolidation and reconsolidation literature. We derive several predictions from the computational model and suggest experiments that may test its validity.

in Hippocampus on June 26, 2020 06:32 PM.

• #### Issue Information ‐ TOC

in Hippocampus on June 26, 2020 06:32 PM.

• #### Issue Information ‐ Editorial Board

in Hippocampus on June 26, 2020 06:32 PM.

• #### Dynamical system based compact deep hybrid network for classification of Parkinson disease related EEG signals

Publication date: Available online 25 June 2020

Source: Neural Networks

Author(s): Syed Aamir Ali Shah, Lei Zhang, Abdul Bais

in Neural Networks on June 26, 2020 06:00 PM.

• #### Learning explicitly transferable representations for domain adaptation

Publication date: October 2020

Source: Neural Networks, Volume 130

Author(s): Mengmeng Jing, Jingjing Li, Ke Lu, Lei Zhu, Yang Yang

in Neural Networks on June 26, 2020 06:00 PM.

## Objective

Compared to the upper limb, lower limb distal nerve transfer (DNT) outcomes are poor, likely due to the longer length of regeneration required. DNT surgery to treat foot drop entails rerouting a tibial nerve branch to the denervated common fibular nerve stump to reinnervate the tibialis anterior muscle for ankle dorsiflexion. Conditioning electrical stimulation (CES) prior to nerve repair surgery accelerates nerve regeneration and promotes sensorimotor recovery. We hypothesize that CES prior to DNT will promote nerve regeneration to restore ankle dorsiflexion.

## Methods

One week following common fibular nerve crush, CES was delivered to the tibial nerve in half the animals, and at 2 weeks, all animals received a DNT. To investigate the effects of CES on nerve regeneration, a series of kinetic, kinematic, skilled locomotion, electrophysiologic, and immunohistochemical outcomes were assessed. The effects of CES on the nerve were investigated.

## Results

CES‐treated animals had significantly accelerated nerve regeneration (p  < 0.001), increased walking speed, and improved skilled locomotion. The injured limb had greater vertical peak forces, with improved duty factor, near‐complete recovery of braking, propulsive forces, and dorsiflexion (p  < 0.01). Reinnervation of the tibialis anterior muscle was confirmed with nerve conduction studies and immunohistochemical analysis of the neuromuscular junction. Immunohistochemistry demonstrated that CES does not induce Wallerian degeneration, nor does it cause macrophage infiltration of the distal tibial nerve.

## Interpretation

Tibial nerve CES prior to DNT significantly improved functional recovery of the common fibular nerve and its muscle targets without inducing injury to the donor nerve. ANN NEUROL 2020

in Annals of Neurology on June 26, 2020 04:14 PM.

• #### The effect of optic nerve section on form deprivation myopia in the guinea pig

Myopic eyes grow too long so images are focused short of the retina. What controls this excessive growth? We know that across species, deprivation of detailed vision (form deprivation, FD) increases the rate of eye elongation and induces myopia. When the FD ceases, these myopic eyes then slow their growth and recover from their myopia. We show here that in young mammalian eyes, this bidirectional response still occurs after the optic nerve is cut, implicating local retinal control of eye growth. However, the FD eye grows excessively after optic nerve section showing that the fine‐tuning of eye growth requires an intact optic nerve.

## 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 vitreous 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 artifact. 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.

in Journal of Comparative Neurology on June 26, 2020 03:12 PM.

• #### Distribution and localization of phosphatidylinositol 5‐phosphate, 4‐kinase alpha and beta in the brain

Phosphatidylinositol‐4,5‐bisphosphate (PI‐4,5‐P2) is critical for synaptic vesicle docking and fusion and is generated by either the type 1 phosphatidylinositol‐4‐phosphate 5‐kinases (PI4P5Ks) or the type 2 phosphatidylinositol‐5‐phosphate 4‐kinases (PI5P4Ks). In this study, we describe the neuro‐anatomical localization of PI5P4Kα and PI5P4Kβ in the normal brain. PI5P4Kα is expressed in both oligodendrocytes and some neurons, while PI5P4Kβ is expressed solely in neurons. By electron microscopy, both kinases are located in a peri‐synaptic distribution in axon terminals and dendritic spines, suggesting a role in neuro‐transmission, possibly through synaptic vesicle docking, recycling, and/or fusion.

## Abstract

Phosphatidylinositol‐4,5‐bisphosphate (PI‐4,5‐P2) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol‐1,4,5‐trisphosphate. PI‐4,5‐P2 can be generated by two families of kinases: type 1 phosphatidylinositol‐4‐phosphate 5‐kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol‐5‐phosphate 4‐kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kβ, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kβ is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kβ is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co‐localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kβ co‐localizes with the neuronal marker, NeuN. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunoperoxidase analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kβ. These results highlight the diverse cell‐autonomous expression of PI5P4Kα and PI5P4Kβ and support further exploration into their role in synaptic function in the brain.

in Journal of Comparative Neurology on June 26, 2020 03:12 PM.

• #### Functional organization and connectivity of the dorsal column nuclei complex reveals a sensorimotor integration and distribution hub

We review the neuroanatomical connections of the dorsal column nuclei complex (gracile, cuneate, external cuneate, X and Z nuclei) which highlight the connectivity to peripheral receptors as well as extensive direct connections to multiple sensorimotor brain regions. This connectivity highlights the role of the dorsal column nuclei complex in integrating and distributing somatosensory information serving discriminative touch, proprioception, and multimodal functional systems.

## Abstract

The dorsal column nuclei complex (DCN‐complex) includes the dorsal column nuclei (DCN, referring to the gracile and cuneate nuclei collectively), external cuneate, X, and Z nuclei, and the median accessory nucleus. The DCN are organized by both somatotopy and modality, and have a diverse range of afferent inputs and projection targets. The functional organization and connectivity of the DCN implicate them in a variety of sensorimotor functions, beyond their commonly accepted role in processing and transmitting somatosensory information to the thalamus, yet this is largely underappreciated in the literature. To consolidate insights into their sensorimotor functions, this review examines the morphology, organization, and connectivity of the DCN and their associated nuclei. First, we briefly discuss the receptors, afferent fibers, and pathways involved in conveying tactile and proprioceptive information to the DCN. Next, we review the modality and somatotopic arrangements of the remaining constituents of the DCN‐complex. Finally, we examine and discuss the functional implications of the myriad of DCN‐complex projection targets throughout the diencephalon, midbrain, and hindbrain, in addition to their modulatory inputs from the cortex. The organization and connectivity of the DCN‐complex suggest that these nuclei should be considered a complex integration and distribution hub for sensorimotor information.

in Journal of Comparative Neurology on June 26, 2020 03:10 PM.

• #### Spatially propagating activation of quorum sensing in Vibrio fischeri and the transition to low population density

Author(s): Keval Patel, Coralis Rodriguez, Eric V. Stabb, and Stephen J. Hagen

Spatially dispersed colonies of bacteria can communicate through the release and detection of signal molecules. In their experiment, the authors monitor biofluorescence induced in cells when the concentration of a molecular signal in a colony reaches a critical threshold. Simulations of a model with growth and diffusion reproduce the experimental data quite well.

[Phys. Rev. E 101, 062421] Published Fri Jun 26, 2020

in Physical Review E: Biological physics on June 26, 2020 10:00 AM.

• #### Temporal precision of molecular events with regulation and feedback

Author(s): Shivam Gupta, Sean Fancher, Hendrik C. Korswagen, and Andrew Mugler

Cellular behaviors such as migration, division, and differentiation rely on precise timing, and yet the molecular events that govern these behaviors are highly stochastic. We investigate regulatory strategies that decrease the timing noise of molecular events. Autoregulatory feedback increases noise...

[Phys. Rev. E 101, 062420] Published Fri Jun 26, 2020

in Physical Review E: Biological physics on June 26, 2020 10:00 AM.

• #### Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Baclofen, naltrexone and sorbitol synergistically contribute to PXT3003 effects on myelination in Pmp22 transgenic DRG co‐cultures (a) and motor phenotype in CMT1A rats (b). Recovery of neuromuscular junction innervation (c) plays a decisive role in the preservation of fast‐contracting motor fibers (d) which is uncoupled from dysmyelination in CMT1A rats.

## Abstract

Charcot–Marie–Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low‐dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co‐culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant (“translational”) study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003‐treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003‐treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003‐treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

in Journal of Neuroscience Research on June 26, 2020 08:30 AM.

• #### Widening the scope of diversity

Nature Neuroscience, Published online: 26 June 2020; doi:10.1038/s41593-020-0670-2

An overlooked bias in research practices and current global events call for a broader approach to addressing issues of diversity.

in Nature Neuroscience on June 26, 2020 12:00 AM.

• #### Publisher Correction: Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

Nature Neuroscience, Published online: 26 June 2020; doi:10.1038/s41593-020-0669-8

Publisher Correction: Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

in Nature Neuroscience on June 26, 2020 12:00 AM.

• #### Acknowledging female voices

Nature Neuroscience, Published online: 26 June 2020; doi:10.1038/s41593-020-0667-x

Citation count has become one of the most important methods to evaluate a scientist’s contributions. In an extensive analysis of citations from a number of leading neuroscience journals, Dworkin and colleagues find evidence of gender bias in citation practices that can have an adverse impact on women’s careers.

in Nature Neuroscience on June 26, 2020 12:00 AM.

• #### Publisher Correction: DeepSTORM3D: dense 3D localization microscopy and PSF design by deep learning

Nature Methods, Published online: 26 June 2020; doi:10.1038/s41592-020-0910-0

Publisher Correction: DeepSTORM3D: dense 3D localization microscopy and PSF design by deep learning

in Nature Methods on June 26, 2020 12:00 AM.

• #### Clogged filter

Nature Reviews Neuroscience, Published online: 26 June 2020; doi:10.1038/s41583-020-0341-z

Clogged filter

in Nature Reviews on June 26, 2020 12:00 AM.

• #### Cooling off time

Nature Reviews Neuroscience, Published online: 26 June 2020; doi:10.1038/s41583-020-0340-0

Cooling off time

in Nature Reviews on June 26, 2020 12:00 AM.

• #### Sleeping like a newborn (neuron)

Nature Reviews Neuroscience, Published online: 26 June 2020; doi:10.1038/s41583-020-0339-6

Sleeping like a newborn (neuron)

in Nature Reviews on June 26, 2020 12:00 AM.

• #### Navigating by neural orchestra

Nature Reviews Neuroscience, Published online: 26 June 2020; doi:10.1038/s41583-020-0338-7

Navigating by neural orchestra

in Nature Reviews on June 26, 2020 12:00 AM.

• #### Plants glow as they grow

Nature Photonics, Published online: 26 June 2020; doi:10.1038/s41566-020-0661-6

Plants glow as they grow

in Nature Photomics on June 26, 2020 12:00 AM.

• #### Super-resolution microscopy on a photonic chip

Nature Photonics, Published online: 26 June 2020; doi:10.1038/s41566-020-0656-3

Using a photonic chip to generate the patterns of light needed for structured illumination microscopy could reduce the cost and complexity of super-resolution imaging.

in Nature Photomics on June 26, 2020 12:00 AM.

• #### Earth-based clocks test general relativity

Nature Photonics, Published online: 26 June 2020; doi:10.1038/s41566-020-0654-5

Optical clocks held at slightly different heights provide a stringent test of general relativity comparable to space experiments and open new opportunities for clock-based geophysical sensing.

in Nature Photomics on June 26, 2020 12:00 AM.

• #### Refracting spacetime wave packets

Nature Photonics, Published online: 26 June 2020; doi:10.1038/s41566-020-0652-7

A particular class of focused, pulsed light beams can propagate self-similarly in free space at a fixed group velocity. Now, scientists present a law of refraction that determines how the group velocity of these beams changes as they refract at an interface between two materials.

in Nature Photomics on June 26, 2020 12:00 AM.

• #### Metalenses go atomically thick and tunable

Nature Photonics, Published online: 26 June 2020; doi:10.1038/s41566-020-0648-3

By utilizing exciton resonances in atomically thick semiconductors, researchers have now demonstrated the ultimate downscaling of optical lenses and reported on their efficacious electrical tunability.

in Nature Photomics on June 26, 2020 12:00 AM.

• #### The receptor PTPRU is a redox sensitive pseudophosphatase

Nature Communications, Published online: 26 June 2020; doi:10.1038/s41467-020-17076-w

Receptor-linked protein tyrosine phosphatases (RPTPs) usually contain an active membrane proximal domain and an inactive pseudophosphatase domain. Here, the authors characterize an RPTP with two pseudophosphatase domains, providing evidence that it may act as a decoy receptor for substrate sequestration.

in Nature Communications on June 26, 2020 12:00 AM.

• #### Cobalt-catalyzed highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids

Nature Communications, Published online: 26 June 2020; doi:10.1038/s41467-020-17057-z

A large number of marketed drugs contains a chiral carboxylic acid scaffold. Here, the authors report the asymmetric hydrogenation of α,β-unsaturated carboxylic acids to α-chiral carboxylic acids using a cobalt catalyst bearing an electron-donating chiral diphosphine ligand.

in Nature Communications on June 26, 2020 12:00 AM.

• #### An alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity

Nature Communications, Published online: 26 June 2020; doi:10.1038/s41467-020-17052-4

PDE3A modulators for cancer therapy cause serious side effects as they inhibit PDE3A phosphodiesterase activity, which is essential for the maturation of oocytes and the formation of platelets. Here, the authors identify a compound, nauclefine, that does not inhibit PDE3A activity but induces apoptosis by enabling a complex formation between PDE3A and SLFN12.

in Nature Communications on June 26, 2020 12:00 AM.

• #### Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury

Aim: Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI.

Methods: The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1β and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing (n = 10–14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10–15 days post-injury.

Results: Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1β expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment.

Conclusion: Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.

in Frontiers in Molecular Neuroscience on June 26, 2020 12:00 AM.

• #### Asymmetric Differences in the Gray Matter Volume and Functional Connections of the Amygdala Are Associated With Clinical Manifestations of Alzheimer’s Disease

Objective

Asymmetry is a subtle but pervasive aspect of the human brain, which may be altered in several neuropsychiatric conditions. Magnetic resonance imaging (MRI) studies have reported that cerebral structural asymmetries are altered in Alzheimer’s disease (AD), but most of these studies were conducted at the region-of-interest level. At the functional level, there are few reports of resting-state functional asymmetries based on functional MRI. In this study, we investigated lateral differences in structural volumes and strengths of functional connectivity between individuals with AD and healthy controls (HCs) at the voxel level.

Methods

Forty-eight patients with AD and 32 matched HCs were assessed. An analysis of voxel-based morphometry (VBM) of gray matter volume was performed at the whole-brain level to explore anatomical cerebral asymmetries in AD. We then performed a seed-to-whole-brain functional connectivity (FC) analysis to reveal FC asymmetries in AD. An asymmetry index (AI) was used to measure these changes, and the relationship between the structural and functional AIs and the clinical symptoms of AD was explored.

Results

A VBM analysis revealed a rightward and a leftward lateralization in the amygdala and the thalamus, respectively, in patients with AD. FC between the amygdala and the precuneus showed a rightward lateralization in AD, which was the opposite of the lateralization in the HCs. The asymmetric changes in structure and function were associated with disease severity and functional impairment in AD.

Conclusion

Our study highlights the value of considering asymmetries in the amygdala and the thalamus in clinical evaluations and their relevance to clinical measures.

in Frontiers in Neuroscience: Brain Imaging Methods on June 26, 2020 12:00 AM.

• #### The Effects of YAP and Its Related Mechanisms in Central Nervous System Diseases

Yes-associated protein (YAP) is a key effector downstream of the Hippo signaling pathway and plays an important role in the development of the physiology and pathology of the central nervous system (CNS), especially regulating cell proliferation, differentiation, migration, and apoptosis. However, the roles and underlying mechanisms of YAP in CNS diseases are still puzzling. Here, this review will systematically and comprehensively summarize the biological feature, pathological role, and underlying mechanisms of YAP in normal and pathologic CNS, which aims to provide insights into the potential molecular targets and new therapeutic strategies for CNS diseases.

in Frontiers in Neuroscience: Neurodegeneration on June 26, 2020 12:00 AM.

• #### Brainstem Organoids From Human Pluripotent Stem Cells

The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings.

in Frontiers in Neuroscience: Neurogenesis on June 26, 2020 12:00 AM.

• #### Neural Processing of Narratives: From Individual Processing to Viral Propagation

Narratives, in the form of, e.g., written stories, mouth-to-mouth accounts, audiobooks, fiction movies, and media-feeds, powerfully shape the perception of reality and widely influence human decision-making. In this review, we describe findings from recent neuroimaging studies unraveling how narratives influence the human brain, thus shaping perception, cognition, emotions, and decision-making. It appears that narrative sense-making relies on default-mode network (DMN) structures of the brain, especially precuneus. Activity in precuneus further seems to differ for fictitious vs. real narratives. Notably, high inter-subject correlation (ISC) of brain activity during narrative processing seems to predict the efficacy of a narrative. Factors that enhance the ISC of brain activity during narratives include higher levels of attention, emotional arousal, and negative emotional valence. Higher levels of attentional suspense seem to co-vary with activity in the temporoparietal junction, emotional arousal with activity in dorsal attention network, and negative emotional valence with activity in DMN. Lingering after-effects of emotional narratives have been further described in DMN, amygdala, and sensory cortical areas. Finally, inter-individual differences in personality, and cultural-background related analytical and holistic thinking styles, shape ISC of brain activity during narrative perception. Together, these findings offer promising leads for future studies elucidating the effects of narratives on the human brain, and how such effects might predict the efficacy of narratives in modulating decision-making.

in Frontiers in Human Neuroscience on June 26, 2020 12:00 AM.

• #### Anodal Transcranial Direct Current Stimulation Enhances Retention of Visuomotor Stepping Skills in Healthy Adults

Transcranial direct current stimulation (tDCS) paired with exercise training can enhance learning and retention of hand tasks; however, there have been few investigations of the effects of tDCS on leg skill improvements. The purpose of this study was to investigate whether tDCS paired with visuomotor step training can promote skill learning and retention. We hypothesized that pairing step training with anodal tDCS would improve skill learning and retention, evidenced by decreased step reaction times (RTs), both immediately (online skill gains) and 30 min after training (offline skill gains). Twenty healthy adults were randomly assigned to one of two groups, in which 20-min anodal or sham tDCS was applied to the lower limb motor cortex and paired with visuomotor step training. Step RTs were determined across three time points: (1) before brain stimulation (baseline); (2) immediately after brain stimulation (P0); and (3) 30 min after brain stimulation (P3). A continuous decline in RT was observed in the anodal tDCS group at both P0 and P3, with a significant decrease in RT at P3; whereas there were no improvements in RT at P0 and P3 in the sham group. These findings do not support our hypothesis that anodal tDCS enhances online learning, as RT was not decreased significantly immediately after stimulation. Nevertheless, the results indicate that anodal tDCS enhances offline learning, as RT was significantly decreased 30 min after stimulation, likely because of tDCS-induced neural modulation of cortical and subcortical excitability, synaptic efficacy, and spinal neuronal activity.

in Frontiers in Human Neuroscience on June 26, 2020 12:00 AM.

• #### Non-invasive Brain Stimulation of the Posterior Parietal Cortex Alters Postural Adaptation

Effective central sensory integration of visual, vestibular, and proprioceptive information is required to promote adaptability in response to changes in the environment during postural control. Patients with a lesion in the posterior parietal cortex (PPC) have an impaired ability to form an internal representation of body position, an important factor for postural control and adaptation. Suppression of PPC excitability has also been shown to decrease postural stability in some contexts. As of yet, it is unknown whether stimulation of the PPC may influence postural adaptation. This investigation aimed to identify whether transcranial direct current stimulation (tDCS) of the bilateral PPC could modulate postural adaptation in response to a bipedal incline postural adaptation task. Using young, healthy subjects, we delivered tDCS over bilateral PPC followed by bouts of inclined stance (incline-interventions). Analysis of postural after-effects identified differences between stimulation conditions for maximum lean after-effect (LAE; p = 0.005) as well as a significant interaction between condition and measurement period for the average position (p = 0.03). We identified impaired postural adaptability following both active stimulation conditions. Results reinforce the notion that the PPC is involved in motor adaptation and extend this line of research to the realm of standing posture. The results further highlight the role of the bilateral PPC in utilizing sensory feedback to update one’s internal representation of verticality and demonstrates the diffuse regions of the brain that are involved in postural control and adaptation. This information improves our understanding of the role of the cortex in postural control, highlighting the potential for the PPC as a target for sensorimotor rehabilitation.

in Frontiers in Human Neuroscience on June 26, 2020 12:00 AM.

• #### Eavesdropping on Autobiographical Memory: A Naturalistic Observation Study of Older Adults’ Memory Sharing in Daily Conversations

The retrieval of autobiographical memories is an integral part of everyday social interactions. Prior laboratory research has revealed that older age is associated with a reduction in the retrieval of autobiographical episodic memories, and the ability to elaborate these memories with episodic details. However, how age-related reductions in episodic specificity unfold in everyday social contexts remains largely unknown. Also, constraints of the laboratory-based approach have limited our understanding of how autobiographical semantic memory is linked to older age. To address these gaps in knowledge, we used a smartphone application known as the Electronically Activated Recorder, or “EAR,” to unobtrusively capture real-world conversations over 4 days. In a sample of 102 cognitively normal older adults, we extracted instances where memories and future thoughts were shared by the participants, and we scored the shared episodic memories and future thoughts for their make-up of episodic and semantic detail. We found that older age was associated with a reduction in real-world sharing of autobiographical episodic and semantic memories. We also found that older age was linked to less episodically and semantically detailed descriptions of autobiographical episodic memories. Frequency and level of detail of shared future thoughts yielded weaker relationships with age, which may be related to the low frequency of future thoughts in general. Similar to laboratory research, there was no correlation between autobiographical episodic detail sharing and a standard episodic memory test. However, in contrast to laboratory studies, episodic detail production while sharing autobiographical episodic memories was weakly related to episodic detail production while describing future events, unrelated to working memory, and not different between men and women. Overall, our findings provide novel evidence of how older age relates to episodic specificity when autobiographical memories are assessed unobtrusively and objectively “in the wild.”

in Frontiers in Human Neuroscience on June 26, 2020 12:00 AM.

• #### Multifrequency Dynamics of Cortical Neuromagnetic Activity Underlying Seizure Termination in Absence Epilepsy

Purpose

This study aimed to investigate the spectral and spatial signatures of neuromagnetic activity underlying the termination of absence seizures.

Methods

Magnetoencephalography (MEG) data were recorded from 18 drug-naive patients with childhood absence epilepsy (CAE). Accumulated source imaging (ASI) was used to analyze MEG data at the source level in seven frequency ranges: delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), gamma (30–80 Hz), ripple (80–250 Hz), and fast ripple (250–500 Hz).

Result

In the 1–4, 4–8, and 8–12 Hz ranges, the magnetic source during seizure termination appeared to be consistent over the ictal period and was mainly localized in the frontal cortex (FC) and parieto-occipito-temporal junction (POT). In the 12–30 and 30–80 Hz ranges, a significant reduction in source activity was observed in the frontal lobe during seizure termination as well as a decrease in peak source strength. The ictal peak source strength in the 1–4 Hz range was negatively correlated with the ictal duration of the seizure, whereas in the 30–80 Hz range, it was positively correlated with the course of epilepsy.

Conclusion

The termination of absence seizures is associated with a dynamic neuromagnetic process. Frequency-dependent changes in the FC were observed during seizure termination, which may be involved in the process of neural network interaction. Neuromagnetic activity in different frequency bands may play different roles in the pathophysiological mechanism during absence seizures.

in Frontiers in Human Neuroscience on June 26, 2020 12:00 AM.

• #### Case Report on Deep Brain Stimulation Rescue After Suboptimal MR-Guided Focused Ultrasound Thalamotomy for Essential Tremor: A Tractography-Based Investigation

Essential tremor (ET) is the most prevalent movement disorder in adults, and can often be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound (MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for treating ET, optimal targeting during MRgFUS is essential for efficacy and durability. Various studies have reported cases of tremor recurrence following MRgFUS and long-term outcome data is limited to 3–4 years. We present a tractography-based investigation on a case of DBS rescue for medically refractory ET that was treated with MRgFUS that was interrupted due to the development of dysarthria during the procedure. After initial improvement, her hand tremor started to recur within 6 months after treatment, and bilateral DBS was performed targeting the VIM 24 months after MRgFUS. DBS induced long-term tremor control with monopolar stimulation. Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT) and corticothalmic (CTT) tracts being modulated by the procedures to understand the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines, it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for further investigation of targeting the CTT when using neuromodulatory procedures to treat refractory ET for more permanent tremor relief.

in Frontiers in Human Neuroscience on June 26, 2020 12:00 AM.

• #### Real-Time Neuron Detection and Neural Signal Extraction Platform for Miniature Calcium Imaging

Real-time neuron detection and neural activity extraction are critical components of real-time neural decoding. In this paper, we propose a novel real-time neuron detection and activity extraction system using a dataflow framework to provide real-time performance and adaptability to new algorithms and hardware platforms. The proposed system was evaluated on simulated calcium imaging data, calcium imaging data with manual annotation, and calcium imaging data of the anterior lateral motor cortex. We found that the proposed system accurately detected neurons and extracted neural activities in real time without any requirement for expensive, cumbersome, or special-purpose computing hardware. We expect that the system will enable cost-effective, real-time calcium imaging-based neural decoding, leading to precise neuromodulation.

in Frontiers in Computational Neuroscience on June 26, 2020 12:00 AM.

• #### Density Visualization Pipeline: A Tool for Cellular and Network Density Visualization and Analysis

Neuron classification is an important component in analyzing network structure and quantifying the effect of neuron topology on signal processing. Current quantification and classification approaches rely on morphology projection onto lower-dimensional spaces. In this paper a 3D visualization and quantification tool is presented. The Density Visualization Pipeline (DVP) computes, visualizes and quantifies the density distribution, i.e., the “mass” of interneurons. We use the DVP to characterize and classify a set of GABAergic interneurons. Classification of GABAergic interneurons is of crucial importance to understand on the one hand their various functions and on the other hand their ubiquitous appearance in the neocortex. 3D density map visualization and projection to the one-dimensional x, y, z subspaces show a clear distinction between the studied cells, based on these metrics. The DVP can be coupled to computational studies of the behavior of neurons and networks, in which network topology information is derived from DVP information. The DVP reads common neuromorphological file formats, e.g., Neurolucida XML files, NeuroMorpho.orgSWC files and plain ASCII files. Full 3D visualization and projections of the density to 1D and 2D manifolds are supported by the DVP. All routines are embedded within the visual programming IDE VRL-Studio for Java which allows the definition and rapid modification of analysis workflows.

in Frontiers in Computational Neuroscience on June 26, 2020 12:00 AM.

• #### Homeostatic Plasticity in Epilepsy

In the healthy brain, neuronal excitability and synaptic strength are homeostatically regulated to keep neuronal network activity within physiological boundaries. Epilepsy is characterized by episodes of highly synchronized firing across in widespread neuronal populations, due to a failure in regulation of network activity. Here we consider epilepsy as a failure of homeostatic plasticity or as a maladaptive response to perturbations in the activity. How homeostatic compensation is involved in epileptogenic processes or in the chronic phase of epilepsy, is still debated. Although several theories have been proposed, there is relatively little experimental evidence to evaluate them. In this perspective, we will discuss recent results that shed light on the potential role of homeostatic plasticity in epilepsy. First, we will present some recent insights on how homeostatic compensations are probably active before and during epileptogenesis and how their actions are temporally regulated and closely dependent on the progression of pathology. Then, we will consider the dual role of transcriptional regulation during epileptogenesis, and finally, we will underline the importance of homeostatic plasticity in the context of therapeutic interventions for epilepsy. While classic pharmacological interventions may be counteracted by the epileptic brain to maintain its potentially dysfunctional set point, novel therapeutic approaches may provide the neuronal network with the tools necessary to restore its physiological balance.

in Frontiers in Cellular Neuroscience on June 26, 2020 12:00 AM.

• #### Distinct Target-Specific Mechanisms Homeostatically Stabilize Transmission at Pre- and Post-synaptic Compartments

Neurons must establish and stabilize connections made with diverse targets, each with distinct demands and functional characteristics. At Drosophila neuromuscular junctions (NMJs), synaptic strength remains stable in a manipulation that simultaneously induces hypo-innervation on one target and hyper-innervation on the other. However, the expression mechanisms that achieve this exquisite target-specific homeostatic control remain enigmatic. Here, we identify the distinct target-specific homeostatic expression mechanisms. On the hypo-innervated target, an increase in postsynaptic glutamate receptor (GluR) abundance is sufficient to compensate for reduced innervation, without any apparent presynaptic adaptations. In contrast, a target-specific reduction in presynaptic neurotransmitter release probability is reflected by a decrease in active zone components restricted to terminals of hyper-innervated targets. Finally, loss of postsynaptic GluRs on one target induces a compartmentalized, homeostatic enhancement of presynaptic neurotransmitter release called presynaptic homeostatic potentiation (PHP) that can be precisely balanced with the adaptations required for both hypo- and hyper-innervation to maintain stable synaptic strength. Thus, distinct anterograde and retrograde signaling systems operate at pre- and post-synaptic compartments to enable target-specific, homeostatic control of neurotransmission.

in Frontiers in Cellular Neuroscience on June 26, 2020 12:00 AM.

• #### Slit1 Protein Regulates SVZ-Derived Precursor Mobilization in the Adult Demyelinated CNS

Slit1 is a secreted axon guidance molecule, also involved in adult neurogenesis. In physiological conditions, Slit1 loss promotes ectopic dispersal of SVZ-derived neural precursors (SVZ-NPCs) into periventricular structures such as the corpus callosum. Demyelination of the corpus callosum triggers SVZ-NPC migration to ectopic locations and their recruitment by the lesion, suggesting a possible role for Slit1 in SVZ-NPCs ectopic dispersal regulation in pathological conditions. Here, we have investigated the function of Slit1 protein in the recruitment of SVZ-NPCs after CNS demyelination. We find that the dynamics of oligodendrogenesis and temporal profile of developmental myelination in Slit1–/– mice are similar to Slit1+/− controls. SVZ micro-dissection and RT-PCR from wild-type mice, show that Slits and Robos are physiologically regulated at the transcriptional level in response to corpus callosum demyelination suggesting their role in the process of SVZ-NPC ectopic migration in demyelinating conditions. Moreover, we find that the number of SVZ-NPCs recruited by the lesion increases in Sli1–/– mice compared to Slit1+/− mice, leading to higher numbers of Olig2+ cells within the lesion. Time-lapse video-microscopy of immuno-purified NPCs shows that Slit1-deficient cells migrate faster and make more frequent directional changes than control NPCs, supporting a cell-autonomous mechanism of action of Slit1 in NPC migration. In conclusion, while Slit1 does not affect the normal developmental process of oligodendrogenesis and myelination, it regulates adult SVZ-NPC ectopic migration in response to demyelination, and consequently oligodendrocyte renewal within the lesion.

in Frontiers in Cellular Neuroscience on June 26, 2020 12:00 AM.

• #### Pertussis Toxin Ameliorates Microglial Activation Associated With Ischemic Stroke

Objective: To investigate the effect and the underlying mechanism of Pertussis toxin (PTX) on microglia in the setting of cerebral ischemia.

Methods: We tested the effect of PTX 400 ng/days on middle cerebral artery occlusion stroke model by evaluating the neurologic function, infarct size, microglial distribution, and activation. In parallel, we also tested the effect of PTX on primary cultured microglia by evaluating microglial proliferation, activation, cytokine release, and CX3CR1 expression.

Results: PTX reduced the poststroke infarct size, improved the neurologic function as evaluated by Longa score, and reduced microglial aggregation and activation in the infarcted area. Further, PTX significantly decreased lipopolysaccharide-stimulated microglial proliferation, the release of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), and the expression of CX3CR1.

Interpretation: PTX treatment in stroke reduced microglial accumulation and activation in the infarct zone, resulting in a better functional outcome. The benefits of PTX treatment may be attributed to the reduced production of proinflammatory cytokine such as IL-1β and TNF-α and reduced expression of chemokine CX3CR1.

in Frontiers in Cellular Neuroscience on June 26, 2020 12:00 AM.

• #### Transient Hypothyroidism During Lactation Alters the Development of the Corpus Callosum in Rats. An in vivo Magnetic Resonance Image and Electron Microscopy Study

Magnetic resonance imaging (MRI) data of children with late diagnosed congenital hypothyroidism and cognitive alterations such as abnormal verbal memory processing suggest altered telencephalic commissural connections. The corpus callosum (CC) is the major inter-hemispheric commissure that contra-laterally connects neocortical areas. However, in late diagnosed neonates with congenital hypothyroidism, the possible effect of early transient and chronic postnatal hypothyroidism still remains unknown. We have studied the development of the anterior, middle and posterior CC, using in vivo MRI and electron microscopy in hypothyroid and control male rats. Four groups of methimazole (MMI) treated rats were studied. One group, as a model for early transient hypothyroidism, was MMI-treated from postnatal day (P) 0 to P21; some of these rats were also treated with L-thyroxine (T4) from P15 to 21. Another group modeling chronic hypothyroid, were treated with MMI from P0 to 150 and from embryonic day 10 to P170. The results obtained from these groups were compared with same age control rats. The normalized T2 signal obtained using MRI was higher in MMI-treated rats and correlated with a low number and percentage of myelinated axons. The number and density of myelinated axons decreased in transient and chronic hypothyroid rats at P150. The g-ratio (inner to outer diameter ratio) and the estimated conduction velocity of myelinated axons were similar between MMI-treated and controls, but the conduction delay decreased in the posterior CC of MMI-treated rats compared to controls. These data show that early postnatal transient and chronic hypothyroidism alters CC maturation in a way that may affect the callosal transfer of information. These alterations cannot be reversed after delayed T4-treatment. Our data support the findings of neurocognitive delay in late T4-treated children with congenital hypothyroidism.

in Frontiers in Neuroanatomy on June 26, 2020 12:00 AM.

• #### Food and Age: It Takes Two to Degenerate

in Frontiers in Ageing Neuroscience on June 26, 2020 12:00 AM.

• #### A pilot study of essential tremor: cerebellar GABA+/Glx ratio is correlated with tremor severity

Essential tremor is a common movement disorder with an unclear origin. Emerging evidence suggests the role of the cerebellum and the thalamus in tremor pathophysiology. We examined the two main neurotransmitte...

in Cerebellum and Ataxias on June 26, 2020 12:00 AM.

• #### Precision Calcium Imaging of Dense Neural Populations via a Cell-Body-Targeted Calcium Indicator

One-photon fluorescent imaging of calcium signals can capture the activity of hundreds of neurons across large fields of view but suffers from crosstalk from neuropil. Shemesh et al. engineer cell-body-targeted variants of fluorescent calcium indicators and show in mice and zebrafish that artifactual spikes and correlations are greatly reduced.

in Neuron: In press on June 26, 2020 12:00 AM.

• #### Neuroprotective effects of magnesium l-threonate in a hypoxic zebrafish model

Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutama...

in BMC Neuroscience on June 26, 2020 12:00 AM.

• #### Epigenome-based splicing prediction using a recurrent neural network

by Donghoon Lee, Jing Zhang, Jason Liu, Mark Gerstein

Alternative RNA splicing provides an important means to expand metazoan transcriptome diversity. Contrary to what was accepted previously, splicing is now thought to predominantly take place during transcription. Motivated by emerging data showing the physical proximity of the spliceosome to Pol II, we surveyed the effect of epigenetic context on co-transcriptional splicing. In particular, we observed that splicing factors were not necessarily enriched at exon junctions and that most epigenetic signatures had a distinctly asymmetric profile around known splice sites. Given this, we tried to build an interpretable model that mimics the physical layout of splicing regulation where the chromatin context progressively changes as the Pol II moves along the guide DNA. We used a recurrent-neural-network architecture to predict the inclusion of a spliced exon based on adjacent epigenetic signals, and we showed that distinct spatio-temporal features of these signals were key determinants of model outcome, in addition to the actual nucleotide sequence of the guide DNA strand. After the model had been trained and tested (with >80% precision-recall curve metric), we explored the derived weights of the latent factors, finding they highlight the importance of the asymmetric time-direction of chromatin context during transcription.

in PLoS Computational Biology on June 25, 2020 09:00 PM.

• #### Mechanobiological model for simulation of injured cartilage degradation via pro-inflammatory cytokines and mechanical stimulus

by Atte S. A. Eskelinen, Petri Tanska, Cristina Florea, Gustavo A. Orozco, Petro Julkunen, Alan J. Grodzinsky, Rami K. Korhonen

Post-traumatic osteoarthritis (PTOA) is associated with cartilage degradation, ultimately leading to disability and decrease of quality of life. Two key mechanisms have been suggested to occur in PTOA: tissue inflammation and abnormal biomechanical loading. Both mechanisms have been suggested to result in loss of cartilage proteoglycans, the source of tissue fixed charge density (FCD). In order to predict the simultaneous effect of these degrading mechanisms on FCD content, a computational model has been developed. We simulated spatial and temporal changes of FCD content in injured cartilage using a novel finite element model that incorporates (1) diffusion of the pro-inflammatory cytokine interleukin-1 into tissue, and (2) the effect of excessive levels of shear strain near chondral defects during physiologically relevant loading. Cytokine-induced biochemical cartilage explant degradation occurs near the sides, top, and lesion, consistent with the literature. In turn, biomechanically-driven FCD loss is predicted near the lesion, in accordance with experimental findings: regions near lesions showed significantly more FCD depletion compared to regions away from lesions (p<0.01). Combined biochemical and biomechanical degradation is found near the free surfaces and especially near the lesion, and the corresponding bulk FCD loss agrees with experiments. We suggest that the presence of lesions plays a role in cytokine diffusion-driven degradation, and also predisposes cartilage for further biomechanical degradation. Models considering both these cartilage degradation pathways concomitantly are promising in silico tools for predicting disease progression, recognizing lesions at high risk, simulating treatments, and ultimately optimizing treatments to postpone the development of PTOA.

in PLoS Computational Biology on June 25, 2020 09:00 PM.

• #### Ten simple rules for researchers while in isolation from a pandemic

by Hoe-Han Goh, Philip E. Bourne

in PLoS Computational Biology on June 25, 2020 09:00 PM.

• #### A validation framework for neuroimaging software: The case of population receptive fields

by Garikoitz Lerma-Usabiaga, Noah Benson, Jonathan Winawer, Brian A. Wandell

Neuroimaging software methods are complex, making it a near certainty that some implementations will contain errors. Modern computational techniques (i.e., public code and data repositories, continuous integration, containerization) enable the reproducibility of the analyses and reduce coding errors, but they do not guarantee the scientific validity of the results. It is difficult, nay impossible, for researchers to check the accuracy of software by reading the source code; ground truth test datasets are needed. Computational reproducibility means providing software so that for the same input anyone obtains the same result, right or wrong. Computational validity means obtaining the right result for the ground-truth test data. We describe a framework for validating and sharing software implementations, and we illustrate its usage with an example application: population receptive field (pRF) methods for functional MRI data. The framework is composed of three main components implemented with containerization methods to guarantee computational reproducibility. In our example pRF application, those components are: (1) synthesis of fMRI time series from ground-truth pRF parameters, (2) implementation of four public pRF analysis tools and standardization of inputs and outputs, and (3) report creation to compare the results with the ground truth parameters. The framework was useful in identifying realistic conditions that lead to imperfect parameter recovery in all four pRF implementations, that would remain undetected using classic validation methods. We provide means to mitigate these problems in future experiments. A computational validation framework supports scientific rigor and creativity, as opposed to the oft-repeated suggestion that investigators rely upon a few agreed upon packages. We hope that the framework will be helpful to validate other critical neuroimaging algorithms, as having a validation framework helps (1) developers to build new software, (2) research scientists to verify the software’s accuracy, and (3) reviewers to evaluate the methods used in publications and grants.

in PLoS Computational Biology on June 25, 2020 09:00 PM.

• #### Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions

Nucleotides comprise small molecules that perform critical signaling roles in biological systems. Adenosine-based nucleotides, including adenosine tri-, di-, and mono-phosphate, are controlled through their rapid degradation by diphosphohydrolases and ecto-nucleotidases (NDAs). The interplay between nucleotide signaling and degradation is especially important in synapses formed between cells, which create signaling ‘nanodomains’. Within these ‘nanodomains’, charged nucleotides interact with densely-packed membranes and biomolecules. While the contributions of electrostatic and steric interactions within such nanodomains are known to shape diffusion-limited reaction rates, less is understood about how these factors control the kinetics of nucleotidase activity. To quantify these factors, we utilized reaction-diffusion numerical simulations of 1) adenosine triphosphate (ATP) hydrolysis into adenosine monophosphate (AMP) and 2) AMP into adenosine (Ado) via two representative nucleotidases, CD39 and CD73. We evaluate these sequentially-coupled reactions in nanodomain geometries representative of extracellular synapses, within which we localize the nucleotidases. With this model, we find that 1) nucleotidase confinement reduces reaction rates relative to an open (bulk) system, 2) the rates of AMP and ADO formation are accelerated by restricting the diffusion of substrates away from the enzymes, and 3) nucleotidase co-localization and the presence of complementary (positive) charges to ATP enhance reaction rates, though the impact of these contributions on nucleotide pools depends on the degree to which the membrane competes for substrates. As a result, these contributions integratively control the relative concentrations and distributions of ATP and its metabolites within the junctional space. Altogether, our studies suggest that CD39 and CD73 nucleotidase activity within junctional spaces can exploit their confinement and favorable electrostatic interactions to finely control nucleotide signaling.

in PLoS Computational Biology on June 25, 2020 09:00 PM.

• #### Implications of localized charge for human influenza A H1N1 hemagglutinin evolution: Insights from deep mutational scans

by Chadi M. Saad-Roy, Nimalan Arinaminpathy, Ned S. Wingreen, Simon A. Levin, Joshua M. Akey, Bryan T. Grenfell

Seasonal influenza A viruses of humans evolve rapidly due to strong selection pressures from host immune responses, principally on the hemagglutinin (HA) viral surface protein. Based on mouse transmission experiments, a proposed mechanism for immune evasion consists of increased avidity to host cellular receptors, mediated by electrostatic charge interactions with negatively charged cell surfaces. In support of this, the HA charge of the globally circulating H3N2 has increased over time since its pandemic. However, the same trend was not seen in H1N1 HA sequences. This is counter-intuitive, since immune escape due to increased avidity (due itself to an increase in charge) was determined experimentally. Here, we explore whether patterns of local charge of H1N1 HA can explain this discrepancy and thus further associate electrostatic charge with immune escape and viral evolutionary dynamics. Measures of site-wise functional selection and expected charge computed from deep mutational scan data on an early H1N1 HA yield a striking division of residues into three groups, separated by charge. We then explored evolutionary dynamics of these groups from 1918 to 2008. In particular, one group increases in net charge over time and consists of sites that are evolving the fastest, that are closest to the receptor binding site (RBS), and that are exposed to solvent (i.e., on the surface). By contrast, another group decreases in net charge and consists of sites that are further away from the RBS and evolving slower, but also exposed to solvent. The last group consists of those sites in the HA core, with no change in net charge and that evolve very slowly. Thus, there is a group of residues that follows the same trend as seen for the entire H3N2 HA. It is possible that the H1N1 HA is under other biophysical constraints that result in compensatory decreases in charge elsewhere on the protein. Our results implicate localized charge in HA interactions with host cells, and highlight how deep mutational scan data can inform evolutionary hypotheses.

in PLoS Computational Biology on June 25, 2020 09:00 PM.

• #### The protean prion protein

by Jesús R. Requena

The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrPC) and the scrapie conformation (PrPSc). PrPC features a globular C-terminal domain containing 3 α-helices and a short β-sheet and a long flexible N-terminal tail whose exact conformation in vivo is not yet known and a metastable subdomain with β-strand propensity has been identified within it. The PrPSc conformation is very rare and has the characteristics of an amyloid. Furthermore, PrPSc is a prion, i.e., it is infectious. This involves 2 steps: (1) PrPSc can template PrPC and coerce it to adopt the PrPSc conformation and (2) PrPSc can be transmitted between individuals, by oral, parenteral, and other routes and thus propagate as an infectious agent. However, this is a simplification: On the one hand, PrPSc is not a single conformation, but rather, a set of alternative similar but distinct conformations. Furthermore, other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. Of these, one causes neurodegeneration, whereas the other does not. With its many conformers, PrP is a truly protean protein.

in PLoS Biology on June 25, 2020 09:00 PM.

• #### Mapping trends in insecticide resistance phenotypes in African malaria vectors

by Penelope A. Hancock, Chantal J. M. Hendriks, Julie-Anne Tangena, Harry Gibson, Janet Hemingway, Michael Coleman, Peter W. Gething, Ewan Cameron, Samir Bhatt, Catherine L. Moyes

Mitigating the threat of insecticide resistance in African malaria vector populations requires comprehensive information about where resistance occurs, to what degree, and how this has changed over time. Estimating these trends is complicated by the sparse, heterogeneous distribution of observations of resistance phenotypes in field populations. We use 6,423 observations of the prevalence of resistance to the most important vector control insecticides to inform a Bayesian geostatistical ensemble modelling approach, generating fine-scale predictive maps of resistance phenotypes in mosquitoes from the Anopheles gambiae complex across Africa. Our models are informed by a suite of 111 predictor variables describing potential drivers of selection for resistance. Our maps show alarming increases in the prevalence of resistance to pyrethroids and DDT across sub-Saharan Africa from 2005 to 2017, with mean mortality following insecticide exposure declining from almost 100% to less than 30% in some areas, as well as substantial spatial variation in resistance trends.

in PLoS Biology on June 25, 2020 09:00 PM.

• #### Partial deletion of p75NTR in large‐diameter DRG neurons exerts no influence upon the survival of peripheral sensory neurons in vivo

The cellular mechanism underpinning the p75NTR receptor regulated peripheral neuron survival is unclear. We identify that neuronal p75NTR expression is not essential for maintaining peripheral sensory neuron survival in health and after demyelinating neuropathy, providing new insights into the mechanism of p75NTR mediated peripheral nervous system functions.

## Abstract

The p75 neurotrophin receptor (p75NTR) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75NTR by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal‐specific conditional knockout strategy, we demonstrate the partial depletion of p75NTR in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2‐month‐old mice is not affected following the deletion of p75NTR in large‐diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75NTR in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75NTR is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo . Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75NTR expressed by a subtype of neurons in vivo . Thus, our findings provide new insights into the mechanism underpinning p75NTR‐mediated neuronal survival in the PNS.

in Journal of Neuroscience Research on June 25, 2020 07:00 PM.

## Abstract

The hippocampus has long been observed to encode a representation of an animal's position in space. Recent evidence suggests that the nature of this representation is somewhat predictive and can be modeled by learning a successor representation (SR) between distinct positions in an environment. However, this discretization of space is subjective making it difficult to formulate predictions about how some environmental manipulations should impact the hippocampal representation. Here, we present a model of place and grid cell firing as a consequence of learning a SR from a basis set of known neurobiological features—boundary vector cells (BVCs). The model describes place cell firing as the successor features of the SR, with grid cells forming a low‐dimensional representation of these successor features. We show that the place and grid cells generated using the BVC‐SR model provide a good account of biological data for a variety of environmental manipulations, including dimensional stretches, barrier insertions, and the influence of environmental geometry on the hippocampal representation of space.

in Hippocampus on June 25, 2020 01:43 PM.

• #### Zonisamide promotes survival of human‐induced pluripotent stem cell‐derived dopaminergic neurons in the striatum of female rats

We examined the effects of zonisamide on transplanted human dopaminergic neurons in the rat striatum and found that zonisamide facilitates the survival of dopamine neurons, an effect that may be related to an increase in the expression of SLIT‐and NTRK‐like protein 6 in rat striatum.

## Abstract

The transplantation of dopaminergic (DA) progenitors derived from pluripotent stem cells improves the behavior of Parkinson's disease model animals. However, the survival of DA progenitors is low, and the final yield of DA neurons is only approximately 0.3%–2% the number of transplanted cells. Zonisamide (ZNS) increases the number of survived DA neurons upon the transplantation of mouse‐induced pluripotent stem (iPS) cell‐derived DA progenitors in the rat striatum. In this study, we induced DA progenitors from human iPS cells and transplanted them into the striatum of female rats with daily administration of ZNS. The number of survived DA neurons was evaluated 1 and 4 months after transplantation by immunohistochemistry, which revealed that the number of survived DA neurons was significantly increased with the administration of ZNS. To assess the mechanism of action of ZNS, we performed a gene expression analysis to compare the gene expression profiles in striatum treated with or without ZNS. The analysis revealed that the expression of SLIT‐and NTRK‐like protein 6 (SLITRK6) was upregulated in rat striatum treated with ZNS. In conclusion, ZNS promotes the survival of DA neurons after the transplantation of human‐iPS cell‐derived DA progenitors in the rat striatum. SLITRK6 is suggested to be involved in this supportive effect of ZNS by modulating the environment of the host brain.

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### HSPGs glypican‐1 and glypican‐4 are human neuronal proteins characteristic of different neural phenotypes

Glypican‐1 (GPC1) and ‐4 (GPC4) have previously been reported as markers of lineage‐specific neural stem cells. Here, their pheonotypical characteristics were further examined under neuronal differentiation conditions in the presence of brain‐derived neurotrophic factor (BDNF) and platelet‐derived growth factor‐B (PDGF‐B). GPC1 and GPC4 demonstrated differential localized expression during long‐term (40–60 days) neuronal differentiation, suggesting different functions within neural cells. Under BDNF conditions, higher GPC4 to GPC1 gene expression ratio correlated with increased heterogeneity, increased proliferation, and increased GABAergic marker expression. In contrast, PDGF conditions resulted in higher GPC1 to GPC4 gene expression ratio and resulting in decreased heterogeneity, increased spontaneous activity, and increased dopaminergic marker expression. Our results confirm GPC1 and GPC4 as human neural proteins providing a potential set of novel markers to characterize different neural cell populations in terms of maturity, heterogeneity, and subtype differentiation.

## Abstract

Generating neurons from human stem cells has potential for brain damage therapy and neurogenesis modeling, but current efficacy is limited by culture heterogeneity and the lack of markers. We have previously reported the heparan sulfate proteoglycans (HSPGs) glypican‐1 (GPC1) and ‐4 (GPC4) as the markers of lineage‐specific human neural stem cells (hNSCs) and mediators of hNSC lineage potential. Here, we further examined phenotypical characteristics and GPC1 and GPC4 during neural differentiation of hNSCs in the presence of two neurogenic growth factors reported to bind to heparan sulfate: brain‐derived neurotrophic factor (BDNF) and platelet‐derived growth factor‐B (PDGF‐B). In hNSC neural cultures, GPC1 and GPC4 were expressed along neurites and cell bodies in long‐term (40–60 days) neural differentiation cultures demonstrating the areas of differential localization—suggesting potentially different functions. Neural differentiation cultures in the presence of BDNF or PDGF‐B generated phenotypically different neural cells with BDNF treatment associated with higher GPC4 versus GPC1 expression, increased heterogeneity, and differential neuron subtype marker expression to PDGF‐B cultures. PDGF‐B cultures exhibited higher levels of spontaneous activity and reduced heterogeneity over long‐term culture associated with decreased GPC4 . Untreated neural cultures were highly variable, supporting the use of neuroregulatory growth factors for guided differentiation. Targeted siRNA downregulation of GPC1/4 reduced neural differentiation markers and altered response to exogenous BDNF and PDGF‐B. This work confirms GPC1 and GPC4 as regulators of human neural differentiation and supports their use as novel markers of neural cell characterization.

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### 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 25, 2020 12:33 PM.

• #### 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 June 25, 2020 12:33 PM.

• #### 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 25, 2020 12:33 PM.

• #### Mu opioid receptor knockout mouse: Phenotypes with implications on restless legs syndrome

Restless legs syndrome (RLS) is a complex sensorimotor disorder in which the role of the endogenous opioid system is not clear. This study suggests that the anemia of inflammation and loss of circadian variations in dopaminergic or serotonergic systems could underlie the pathogenesis of RLS.

## Abstract

Restless legs syndrome (RLS) is characterized by an irresistible need to move the legs while sitting or lying at night with insomnia as a frequent consequence. Human RLS has been associated with abnormalities in the endogenous opioid system, the dopaminergic system, the iron regulatory system, anemia, and inflammatory and auto‐immune disorders. Our previous work indicates that mice lacking all three subtypes of opioid receptors have a phenotype similar to that of human RLS. To study the roles of each opioid receptor subtype in RLS, we first used mu opioid receptor knockout (MOR KO) mice based on our earlier studies using postmortem brain and cell culture. The KO mice showed decreased hemoglobin, hematocrit, and red blood cells (RBCs), with an appearance of microcytic RBCs indicating anemia. Together with decreased serum iron and transferrin, but increased ferritin levels, the anemia is similar to that seen with chronic inflammation in humans. A decreased serum iron level was also observed in the wildtype mice treated with an MOR antagonist. Iron was increased in the liver and spleen of the KO mice. Normal circadian variations in the dopaminergic and serotoninergic systems were absent in the KO mice. The KO mice showed hyperactivity and increased thermal sensitivity in wakefulness primarily during what would normally be the sleep phase similar to that seen in human RLS. Deficits in endogenous opioid system transmission could predispose to anemia of inflammation and loss of circadian variations in dopaminergic or serotonergic systems, thereby contributing to an RLS‐like phenotype.

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### Parallel astrocyte calcium signaling modulates olfactory bulb responses

Intersectional viral genetics allows for targeted expression in astrocytes. Olfactory bulb astrocyte calcium activity spatially matches neuronal activity patterns with odor stimulation. Manipulating astrocyte calcium activity alters neuronal activity and impacts olfactory behavior.

## Abstract

Astrocytes are the most abundant glial cell in the central nervous system. They modulate synaptic function through a variety of mechanisms, and yet remain relatively understudied with respect to overall neuronal circuit function. Exploiting the tractability of the mouse olfactory system, we manipulated astrocyte activity and examined how astrocytes modulate olfactory bulb responses. Toward this, we genetically targeted both astrocytes and neurons for in vivo widefield imaging of Ca2+ responses to odor stimuli. We found that astrocytes exhibited odor response maps that overlap with excitatory neuronal activity. By manipulating Ca2+ activity in astrocytes using chemical genetics we found that odor‐evoked neuronal activity was reciprocally affected, suggesting that astrocyte activation inhibits neuronal odor responses. Subsequently, behavioral experiments revealed that astrocyte manipulations affect both odor detection threshold and discrimination, suggesting that astrocytes play an active role in olfactory sensory processing circuits. Together, these studies show that astrocyte calcium signaling contributes to olfactory behavior through modulation of sensory circuits.

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### Redistribution of inhibitory force feedback between a long toe flexor and the major ankle extensor muscles following spinal cord injury

Golgi tendon organ pathways contribute to coordination of limb extensors during motor tasks including locomotion. Normally, these inhibitory force feedback pathways are flexibly weighted. We show that following spinal cord injury, force feedback is permanently reorganized. Balance is lost and biased inhibition emerges from toe flexors onto ankle extensors.

## Abstract

Inhibitory pathways from Golgi tendon organs project widely between muscles crossing different joints and axes of rotation. Evidence suggests that the strength and distribution of this intermuscular inhibition is dependent on motor task and corresponding signals from the brainstem. The purpose of the present study was to investigate whether this sensory network is altered after spinal cord hemisection as a potential explanation for motor deficits observed after spinal cord injury (SCI). Force feedback was assessed between the long toe flexor and ankle plantarflexor (flexor hallucis longus), and the three major ankle extensors, (combined gastrocnemius, soleus, and plantaris muscles) in the hind limbs of unanesthetized, decerebrate, female cats. Data were collected from animals with intact spinal cords (control) and lateral spinal hemisections (LSHs) including chronic LSH (4–20 weeks), subchronic LSH (2 weeks), and acute LSH. Muscles were stretched individually and in pairwise combinations to measure intermuscular feedback between the toe flexor and each of the ankle extensors. In control animals, three patterns were observed (balanced inhibition between toe flexor and ankle extensors, stronger inhibition from toe flexor to ankle extensor, and vice versa). Following spinal hemisection, only strong inhibition from toe flexors onto ankle extensors was observed independent of survival time. The results suggest immediate and permanent reorganization of force feedback in the injured spinal cord. The altered strength and distribution of force feedback after SCI may be an important future target for rehabilitation.

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### 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 June 25, 2020 12:33 PM.

## Abstract

Epidemiological data from the last decades point to an exponential growth in the number of obese people. Different behavioral factors, mainly associated with food consumption, appear to contribute significantly to its development. Concomitant with increased obesity rates, an increase in the consumption of fructose has been observed; therefore, fructose consumption has been implicated as an important obesogenic factor. However, changes in brain activity due to fructose consumption are possible, especially in relation to hypothalamic satiety mechanisms. In addition, the obese state may provide an environment of chronic inflammation and further contribute to the discontinuation of satiety mechanisms in the hypothalamus. We briefly review the intrinsic alterations to the increased adipose tissue, its connections with the hypothalamus in the control of energy signaling mechanisms and, consequently, the participation of fructose as a co‐adjuvant or trigger. Presenting the current context with clinical trials involving human and animal studies, we seek to contribute to a better understanding of the role of fructose in the progression of obesity.

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### Issue Information

in Journal of Neuroscience Research on June 25, 2020 12:33 PM.

• #### Evolution of cooperation under punishment

Author(s): Shiping Gao, Jinming Du, and Jinling Liang

Punishment has been considered as an effective mechanism for promoting and sustaining cooperation. In most existing models, punishment always comes as a third strategy alongside cooperation and defection, and it is commonly assumed to be executed based on individual decision rules rather than collec...

[Phys. Rev. E 101, 062419] Published Thu Jun 25, 2020

in Physical Review E: Biological physics on June 25, 2020 10:00 AM.

• #### Skepticism and rumor spreading: The role of spatial correlations

Author(s): Marco Antonio Amaral, W. G. Dantas, and Jeferson J. Arenzon

Critical thinking and skepticism are fundamental mechanisms that one may use to prevent the spreading of rumors, fake news, and misinformation. We consider a simple model in which agents without previous contact with the rumor, being skeptically oriented, may convince spreaders to stop their activit...

[Phys. Rev. E 101, 062418] Published Thu Jun 25, 2020

in Physical Review E: Biological physics on June 25, 2020 10:00 AM.

• #### Resting‐state connectivity and network parameter analysis in alcohol‐dependent males. A simultaneous EEG‐MEG study

Alcohol‐dependent individuals present a differential pattern of resting‐state EEG‐MEG connectivity, as well as local communication alterations in brain network. Results point toward difficulties in information flow efficiency and cost, and a possible compensatory effort.

## Abstract

There is supporting evidence of alcohol negative effects on the brain: neuroimaging and psychophysiological studies finding anatomical and functional connectivity (FC) changes associated with the dependence process. Thus, the aim of this work was to evaluate brain FC and network characteristics of alcohol‐dependent individuals in resting state. For this study, we included males diagnosed with alcohol dependence (N  = 25) and a group of healthy individuals (N  = 23). Simultaneous EEG‐MEG (electroencephalographic and magnetoencephalographic) activity was recorded in 5 min of eyes‐closed resting state. EEG‐MEG activity was preprocessed and FC was computed through the leakage‐corrected version of phase locking value (ciPLV). Additionally, local (degree, efficiency, clustering) and global (efficiency, characteristic path length) network parameters were computed. Connectivity analysis showed an increase in phase‐lagged synchronization, mainly between frontal and frontotemporal regions, in high beta band, and a decrease in interhemispheric gamma, for alcohol‐dependent individuals. Network analysis revealed intergroup differences at the local level for high beta, indicating higher degree, clustering, and efficiency, mostly at frontal nodes, together with a decrease in these measures at more posterior sites for patients’ group. The hyper‐synchronization in beta, next to the hypo‐synchronization in gamma, could indicate an alteration in communication between hemispheres, but also a possible functional compensation mechanism in neural circuits. This could be also supported by network characteristic data, where local alterations in communication are observed.

in Journal of Neuroscience Research on June 25, 2020 09:59 AM.

## Objective

CGRP pathway inhibitors are emerging treatments for migraine. CGRP‐mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.

## Methods

Middle cerebral artery was occluded for 12–60 minutes in mice. We compared infarct risk and volumes, collateral flow and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1–1 mg/kg) or rimegepant (single doses of 10–100 mg/kg) versus vehicle. We also determined their potency on CGRP‐induced relaxations in mouse and human vessels, in vitro .

## Results

Olcegepant (1 mg/kg, single dose) increased infarct risk after 12‐ to 20‐minute occlusions mimicking transient ischemic attacks (14/19 versus 6/18 with vehicle, relative risk 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score 9 versus 5 with vehicle, p = 0.008) after 60‐minute occlusion. Ten daily doses of 0.1‐1 mg/kg olcegepant yielded similar results. Rimegepant 10 mg/kg increased infarct volumes by 60% after 20‐minute ischemia (p = 0.03); 100 mg/kg caused 75% mortality after 60‐minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1 mg/kg increased infarct size after 30‐minute occlusion (1.6‐fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10‐fold more potent than rimegepant on CGRP‐induced relaxations in mouse aorta.

## Interpretation

Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition.

in Annals of Neurology on June 25, 2020 09:26 AM.

• #### Multidisciplinary guidance to manage comatose patients with severe COVID‐19

in Annals of Neurology on June 25, 2020 08:45 AM.

## Objective

To demonstrate that antibodies from patients with anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic‐like features in mice.

## Methods

Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti‐NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with patients' or controls' CSF through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic‐like behavior), memory, locomotor activity, and density of cell‐surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques.

## Results

In cultured neurons, patients' CSF, but not controls' CSF, caused a significant decrease of cell‐surface D1R and an increase of D2R clusters. In mice, patients' CSF caused a significant decrease of synaptic and total cell‐surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic‐like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of patients' CSF stopped.

## Interpretation

In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti‐NMDAR encephalitis cause reversible psychotic‐like features accompanied by changes (D1R decrease, D2R increase) in cell‐surface dopamine receptor clusters.

in Annals of Neurology on June 25, 2020 08:38 AM.

• #### Acute Cellular and Functional Changes With a Combinatorial Treatment of Ion Channel Inhibitors Following Spinal Cord Injury

Reducing the extent of secondary degeneration following spinal cord injury (SCI) is necessary to preserve function, but treatment options have thus far been limited. A combination of the ion channel inhibitors Lomerizine (Lom), YM872 and oxATP, to inhibit voltage-gated Ca2+ channels, Ca2+ permeable AMPA receptors, and purinergic P2X7 receptors respectively, effectively limits secondary consequences of injury in in vitro and in vivo models of CNS injury. Here, we investigated the efficacy of these inhibitors in a clinically relevant model of SCI. Fischer (F344) rats were subjected to a moderate (150 kD) contusive SCI at thoracic level T10 and assessed at 2 weeks or 10 weeks post-injury. Lom was delivered orally twice daily and YM872 and oxATP were delivered via osmotic mini-pump implanted at the time of SCI until 2 weeks following injury. Open field locomotion analysis revealed that treatment with the three inhibitors in combination improved the rate of functional recovery of the hind limb (compared to controls) as early as 1-day post-injury, with beneficial effects persisting to 14 days post-injury, while all three inhibitors were present. At 2 weeks following combinatorial treatment, the functional improvement was associated with significantly decreased cyst size, increased immunoreactivity of β-III tubulin+ve axons, myelin basic protein, and reduced lipid peroxidation by-products, and increased CC1+ve oligodendrocytes and NG2+ve/PDGFα+ve oligodendrocyte progenitor cell densities, compared to vehicle-treated SCI animals. The combination of Lom, oxATP, and YM872 shows preclinical promise for control of secondary degeneration following SCI, and further investigation of long-term sustained treatment is warranted.

in Frontiers in Molecular Neuroscience on June 25, 2020 12:00 AM.

• #### MiR224-5p Inhibitor Restrains Neuronal Apoptosis by Targeting NR4A1 in the Oxygen-Glucose Deprivation (OGD) Model

This study was designed to investigate the molecular mechanism of stroke and to explore the effect of miR-224-5p in hypoxic cortical neurons. Firstly, we established a middle cerebral artery occlusion (MCAO) model with Sprague–Dawley rats. Triphenyltetrazolium chloride (TTC) staining showed the brain infarction of an MCAO rat. Longa scores of rats were significantly increased in 12th, 24th, and 48th hours after MCAO. Then, we found that miR-224-5p was increased after MCAO in rats by qRT-PCR. In order to investigate the effect of miR-224-5p in hypoxic neurons, we established an oxygen-glucose deprivation (OGD) model with cortical neurons. MiR-224-5p was also upregulated in neurons after OGD by qRT-PCR. After transfection of the miR-224-5p inhibitor, the number of neurons in the anti-miR-224-5p group significantly increased (P < 0.01) in comparison to the anti-NC group. Furthermore, Tuj1+ (neuronal marker) staining and TUNEL assay (to detect apoptotic cells) were performed in neurons. The survival of neurons in the anti-miR-224-5p group was significantly improved (P < 0.01), while the apoptosis of neurons in the anti-miR-224-5p group was significantly decreased (P < 0.01), when compared with that of the anti-NC group. In addition, we predicted that potential target genes of miR-224-5p were nuclear receptor subfamily 4 group A member 1 (NR4A1), interleukin 1 receptor antagonist (IL1RN), and ring finger protein 38 (RNF38) with bioinformatics databases, such as TargetScan, miRDB, miRmap, and miRanda. The result of qRT-PCR confirmed that NR4A1 was significantly decreased after hypoxic injury (P < 0.01). Meanwhile, luciferase reporter’s assay indicated that NR4A1 was the direct target of miR-224-5p. Compared with the anti-miR-224-5p + siNC group, the number of cortical neurons and the length of the neuron axon in the anti-miR-224-5p + si-NR4A1 group were significantly decreased (P < 0.01), and the number of neuronal apoptosis in the anti-miR-224-5p + si-NR4A1 group was increased (P < 0.01). In conclusion, miR-224-5p played a crucial role in hypoxic neuron injury through NR4A1, which might be an important regulatory mechanism in OGD injury of neurons.

in Frontiers in Neuroscience: Neurodegeneration on June 25, 2020 12:00 AM.

• #### Alpha-Lipoic Acid Mediates Clearance of Iron Accumulation by Regulating Iron Metabolism in a Parkinson’s Disease Model Induced by 6-OHDA

The disruption of neuronal iron homeostasis and oxidative stress are related to the pathogenesis of Parkinson’s disease (PD). Alpha-lipoic acid (ALA) is a naturally occurring enzyme cofactor with antioxidant and iron chelator properties and has many known effects. ALA has neuroprotective effects on PD. However, its underlying mechanism remains unclear. In the present study, we established PD models induced by 6-hydroxydopamine (6-OHDA) to explore the neuroprotective ability of ALA and its underlying mechanism in vivo and in vitro. Our results showed that ALA could provide significant protection from 6-OHDA-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and iron. ALA significantly promoted the survival of the dopaminergic neuron in the 6-OHDA-induced PD rat model and remarkably ameliorated motor deficits by dramatically inhibiting the decrease in tyrosine hydroxylase expression and superoxide dismutase activity in the substantia nigra. Interestingly, ALA attenuated 6-OHDA-induced iron accumulation both in vivo and in vitro by antagonizing the 6-OHDA-induced upregulation of iron regulatory protein 2 and divalent metal transporter 1. These results indicated that the neuroprotective mechanism of ALA against neurological injury induced by 6-OHDA may be related to the regulation of iron homeostasis and reduced oxidative stress levels. Therefore, ALA may provide neuroprotective therapy for PD and other diseases related to iron metabolism disorder.

in Frontiers in Neuroscience: Neurodegeneration on June 25, 2020 12:00 AM.

• #### The After-Effect of Accelerated Intermittent Theta Burst Stimulation at Different Session Intervals

Objective

The study aims to investigate the after-effect of three sessions of intermittent theta-burst stimulation (iTBS) on motor cortical excitability. The iTBS was induced over the primary motor cortex (M1) at different time intervals.

Methods

The study has a crossover design. Sixteen participants were assigned to three groups and received different accelerated iTBS (aiTBS) protocols during each visit: (1) three continuous sessions with no interval (iTBS18000); (2) three iTBS sessions with 10-min intervals (iTBS600 × 310); and (3) three iTBS sessions with 30-min intervals (iTBS600 × 330). As washout period, each visit is separated by at least 7 days. We measured the motor cortical excitability changes and intracortical inhibition.

Results

A dose of 1,800 pulses of aiTBS per day is tolerable. The iTBS1800 led to a reduced cortical excitability; whereas iTBS600 × 310 and iTBS600 × 330 enhanced cortical excitability to a differential extent. After a total dose of 1,800 pulses, iTBS600 × 330 exhibited the longer effect and highest percentage of individuals with enhanced cortical excitability.

Conclusion

The results suggest that aiTBS protocols at different time intervals result in different motor cortical excitability after-effects.

in Frontiers in Neuroscience: Neural Technology on June 25, 2020 12:00 AM.

• #### Secondary Worsening Following DYT1 Dystonia Deep Brain Stimulation: A Multi-country Cohort

Objective: To reveal clinical characteristics of suboptimal responses to deep brain stimulation (DBS) in a multi-country DYT1 dystonia cohort.

Methods: In this multi-country multi-center retrospective study, we analyzed the clinical data of DYT1 patients who experienced suboptimal responses to DBS defined as <30% improvement in dystonia scales at the last follow-up compared with baseline. We used a literature-driven historical cohort of 112 DYT1 patients for comparison.

Results: Approximately 8% of our study cohort (11 out of 132) experienced suboptimal responses to DBS. Compared with the historical cohort, the multi-country cohort with suboptimal responses had a significantly younger age at onset (mean, 7.0 vs. 8.4 years; p = 0.025) and younger age at DBS (mean, 12.0 vs. 18.6 years; p = 0.019). Additionally, cranial involvement was more common in the multi-country cohort (before DBS, 64% vs. 45%, p = 0.074; before or after DBS, 91% vs. 47%, p = 0.001). Mean motor improvement at the last follow-up from baseline were 0% and 66% for the multi-country and historical cohorts, respectively. All 11 patients of the multi-country cohort had generalization of dystonia within 2.5 years after disease onset. All patients experienced dystonia improvement of >30% postoperatively; however, secondary worsening of dystonia commenced between 6 months and 3 years following DBS. The improvement at the last follow-up was less than 30% despite optimally-placed leads, a trial of multiple programming settings, and additional DBS surgeries in all patients. The on-/off-stimulation comparison at the long-term follow-up demonstrated beneficial effects of DBS despite missing the threshold of 30% improvement over baseline.

Conclusion: Approximately 8% of patients represent a more aggressive phenotype of DYT1 dystonia characterized by younger age at onset, faster disease progression, and cranial involvement, which seems to be associated with long-term suboptimal responses to DBS (e.g., secondary worsening). This information could be useful for both clinicians and patients in clinical decision making and patient counseling before and following DBS implantations. Patients with this phenotype may have different neuroplasticity, neurogenetics, or possibly distinct neurophysiology.

in Frontiers in Human Neuroscience on June 25, 2020 12:00 AM.

• #### Different Effects of 2 mA and 4 mA Transcranial Direct Current Stimulation on Muscle Activity and Torque in a Maximal Isokinetic Fatigue Task

Studies investigating the effects of transcranial direct current stimulation (tDCS) on fatigue and muscle activity have elicited measurable improvements using stimulation intensities ≤2 mA and submaximal effort tasks. The purpose of this study was to determine the effects of 2 mA and 4 mA anodal tDCS over the primary motor cortex (M1) on performance fatigability and electromyographic (EMG) activity of the leg muscles during a maximal isokinetic task in healthy young adults. A double-blind, randomized, sham-controlled crossover study design was applied. Twenty-seven active young adults completed four sessions, each spaced by 5–8 days. During session 1, dominance was verified with isokinetic strength testing, and subjects were familiarized with the fatigue task (FT). The FT protocol included 40 continuous maximum isokinetic contractions of the knee extensors and flexors (120°/s, concentric/concentric). During Sessions 2–4, tDCS was applied for 20 min with one of three randomly assigned intensities (sham, 2 mA or 4 mA) and the FT was repeated. The anode and cathode of the tDCS device were placed over C3 and the contralateral supraorbital area, respectively. A wireless EMG system collected muscle activity during the FT. The 2 mA tDCS condition had significantly less torque (65.9 ± 32.7 Nm) during the FT than both the sham (68.4 ± 33.9 Nm, p < 0.001) and 4 mA conditions (68.4 ± 33.9 Nm, p = 0.001). Furthermore, the 2 mA condition (33.8 ± 11.7%) had significantly less EMG activity during the FT than both the sham (39.7 ± 10.6%, p < 0.001) and 4 mA conditions (40.5 ± 13.4%, p = 0.001). Contrary to previous submaximal isometric fatigue investigations, the 2 mA tDCS condition significantly reduced torque production and EMG activity of the leg extensors during a maximal isokinetic FT compared with the sham and 4 mA conditions. Also, torque production and EMG activity in the 4 mA condition were not significantly different from sham. Thus, the effects of tDCS, and the underlying mechanisms, might not be the same for different tasks and warrants more investigation.

in Frontiers in Human Neuroscience on June 25, 2020 12:00 AM.

• #### Positive and Detached Reappraisal of Threatening Music in Younger and Older Adults

Past empirical studies have suggested that older adults preferentially use gaze-based mood regulation to lessen their negative experiences while watching an emotional scene. This preference for a low cognitively demanding regulatory strategy leaves open the question of whether the effortful processing of a more cognitively demanding reappraisal task is really spared from the general age-related decline. Because it does not allow perceptual attention to be redirected away from the emotional source, music provides an ideal way to address this question. The goal of our study was to examine the affective, behavioral, physiological, and cognitive outcomes of positive and detached reappraisal in response to negative musical emotion in younger and older adults. Participants first simply listened to a series of threatening musical excerpts and were then instructed to either positively reappraise or to detach themselves from the emotion elicited by music. Findings showed that, when instructed to simply listen to threatening music, older adults reported a more positive feeling associated with a smaller SCL in comparison with their younger counterparts. When implementing positive and detached reappraisal, participants showed more positive and more aroused emotional experiences, whatever the age group. We also found that the instruction to intentionally reappraise negative emotions results in a lesser cognitive cost for older adults in comparison with younger adults. Taken together, these data suggest that, compared to younger adults, older adults engage in spontaneous downregulation of negative affect and successfully implement downregulation instructions. This extends previous findings and brings compelling evidence that, even when auditory attention cannot be redirected away from the emotional source, older adults are still more effective at regulating emotions. Taking into account the age-associated decline in executive functioning, our results suggest that the working memory task could have distracted older adults from the reminiscences of the threat-evoking music, thus resulting in an emotional downregulation. Hence, even if they were instructed to implement reappraisal strategies, older adults might prefer distraction over engagement in reappraisal. This is congruent with the idea that, although getting older, people are more likely to be distracted from a negative source of emotion to maintain their well-being.

in Frontiers in Human Neuroscience on June 25, 2020 12:00 AM.

• #### Patterns of Focal- and Large-Scale Synchronization in Cognitive Control and Inhibition: A Review

Neural synchronization patterns are involved in several complex cognitive functions and constitute a growing trend in neuroscience research. While synchrony patterns in working memory have been extensively discussed, a complete understanding of their role in cognitive control and inhibition is still elusive. Here, we provide an up-to-date review on synchronization patterns underlying behavioral inhibition, extrapolating common grounds, and dissociating features with other inhibitory functions. Moreover, we suggest a schematic conceptual framework and highlight existing gaps in the literature, current methodological challenges, and compelling research questions for future studies.

in Frontiers in Human Neuroscience on June 25, 2020 12:00 AM.

• #### In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

Although physical exercise has been demonstrated to augment recovery of the post-stroke brain, the question of what level of exercise intensity optimizes neurological outcomes of post-stroke rehabilitation remains unsettled. In this study, we aim to clarify the mechanisms underlying the intensity-dependent effect of exercise on neurologic function, and thereby to help direct the clinical application of exercise-based neurorehabilitation. To do this, we used a well-established rat model of ischemic stroke consisting of cerebral ischemia induction through middle cerebral artery occlusion (MCAO). Ischemic rats were subsequently assigned either to a control group entailing post-stroke rest or to one of two exercise groups distinguished by the intensity of their accompanying treadmill regimens. After 24 h of reperfusion, exercise was initiated. Infarct volume, apoptotic cell death, and neurological defects were quantified in all groups at 3 days, and motor and cognitive functions were tracked up to day-28. Additionally, Western blotting was used to assess the influence of our interventions on several proteins related to synaptogenesis and neuroplasticity (growth-associated protein 43, a microtubule-associated protein, postsynaptic density-95, synapsin I, hypoxia-inducible factor-1α, brain-derived neurotrophic factor, nerve growth factor, tyrosine kinase B, and cAMP response element-binding protein). Our results were in equal parts encouraging and surprising. Both mild and intense exercise significantly decreased infarct volume, cell death, and neurological deficits. Motor and cognitive function, as determined using an array of tests such as beam balance, forelimb placing, and the Morris water maze, were also significantly improved by both exercise protocols. Interestingly, while an obvious enhancement of neuroplasticity proteins was shown in both exercise groups, mild exercise rats demonstrated a stronger effect on the expressions of Tau (p < 0.01), brain-derived neurotrophic factor (p < 0.01), and tyrosine kinase B (p < 0.05). These findings contribute to the growing body of literature regarding the positive effects of both mild and intense long-term treadmill exercise on brain injury, functional outcome, and neuroplasticity. Additionally, the results may provide a base for our future study regarding the regulation of HIF-1α on the BDNF/TrkB/CREB pathway in the biochemical processes underlying post-stroke synaptic plasticity.

in Frontiers in Cellular Neuroscience on June 25, 2020 12:00 AM.

• #### Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

Photoreceptor cell death and inflammation are known to occur progressively in retinal degenerative diseases such as age-related macular degeneration (AMD). However, the molecular mechanisms underlying these biological processes are largely unknown. Extracellular vesicles (EV) are essential mediators of cell-to-cell communication with emerging roles in the modulation of immune responses. EVs, including exosomes, encapsulate and transfer microRNA (miRNA) to recipient cells and in this way can modulate the environment of recipient cells. Dysregulation of EVs however is correlated to a loss of cellular homeostasis and increased inflammation. In this work we investigated the role of isolated retinal small-medium sized EV (s-mEV) which includes exosomes in both the healthy and degenerating retina. Isolated s-mEV from normal retinas were characterized using dynamic light scattering, transmission electron microscopy and western blotting, and quantified across 5 days of photo-oxidative damage-induced degeneration using nanotracking analysis. Small RNAseq was used to characterize the miRNA cargo of retinal s-mEV isolated from healthy and damaged retinas. Finally, the effect of exosome inhibition on cell-to-cell miRNA transfer and immune modulation was conducted using systemic daily administration of exosome inhibitor GW4869 and in situ hybridization of s-mEV-abundant miRNA, miR-124-3p. Electroretinography and immunohistochemistry was performed to assess functional and morphological changes to the retina as a result of GW4869-induced exosome depletion. Results demonstrated an inverse correlation between s-mEV concentration and photoreceptor survivability, with a decrease in s-mEV numbers following degeneration. Small RNAseq revealed that s-mEVs contained uniquely enriched miRNAs in comparison to in whole retinal tissue, however, there was no differential change in the s-mEV miRNAnome following photo-oxidative damage. Exosome inhibition via the use of GW4869 was also found to exacerbate retinal degeneration, with reduced retinal function and increased levels of inflammation and cell death demonstrated following photo-oxidative damage in exosome-inhibited mice. Further, GW4869-treated mice displayed impaired translocation of photoreceptor-derived miR-124-3p to the inner retina during damage. Taken together, we propose that retinal s-mEV and their miRNA cargo play an essential role in maintaining retinal homeostasis through immune-modulation, and have the potential to be used in targeted gene therapy for retinal degenerative diseases.

in Frontiers in Cellular Neuroscience on June 25, 2020 12:00 AM.

• #### SUMOylation in α-Synuclein Homeostasis and Pathology

The accumulation and aggregation of α-synuclein are central to Parkinson’s disease (PD), yet the molecular mechanisms responsible for these events are not fully understood. Post-translational modifications of α-synuclein regulate several of its properties, including degradation, interaction with proteins and membranes, aggregation and toxicity. SUMOylation is a post-translational modification involved in various nuclear and extranuclear processes, such as subcellular protein targeting, mitochondrial fission and synaptic plasticity. Protein SUMOylation increases in response to several stressful situations, from viral infections to trauma. In this framework, an increasing amount of evidence has implicated SUMOylation in several neurodegenerative diseases, including PD. This review will discuss recent findings in the role of SUMOylation as a regulator of α-synuclein accumulation, aggregation and toxicity, and its possible implication in neurodegeneration that underlies PD.

in Frontiers in Ageing Neuroscience on June 25, 2020 12:00 AM.

• #### An Activity-Mediated Transition in Transcription in Early Postnatal Neurons

The molecular mechanisms controlling brain development during early life are poorly understood. Stroud et al. characterize a postnatal switch in the transcriptional regulatory circuits that operate in maturing neurons and identify mechanisms by which neuronal activity and DNA methylation mediate this process.

in Neuron: In press on June 25, 2020 12:00 AM.

• #### Cell-Type-Specific Outcome Representation in the Primary Motor Cortex

Monitoring outcome is critical for acquiring skilled movements. Levy et al. describe activity in subpopulations of layer 2–3 motor cortex pyramidal neurons that distinctly report outcomes of previous successes and failures independent of kinematics and reward. These signals may serve as reinforcement learning processes involved in maintaining or learning skilled movements.

in Neuron: In press on June 25, 2020 12:00 AM.

• #### Natural scene statistics predict how humans pool information across space in surface tilt estimation

by Seha Kim, Johannes Burge

Visual systems estimate the three-dimensional (3D) structure of scenes from information in two-dimensional (2D) retinal images. Visual systems use multiple sources of information to improve the accuracy of these estimates, including statistical knowledge of the probable spatial arrangements of natural scenes. Here, we examine how 3D surface tilts are spatially related in real-world scenes, and show that humans pool information across space when estimating surface tilt in accordance with these spatial relationships. We develop a hierarchical model of surface tilt estimation that is grounded in the statistics of tilt in natural scenes and images. The model computes a global tilt estimate by pooling local tilt estimates within an adaptive spatial neighborhood. The spatial neighborhood in which local estimates are pooled changes according to the value of the local estimate at a target location. The hierarchical model provides more accurate estimates of groundtruth tilt in natural scenes and provides a better account of human performance than the local model. Taken together, the results imply that the human visual system pools information about surface tilt across space in accordance with natural scene statistics.

in PLoS Computational Biology on June 24, 2020 09:00 PM.

• #### Representation of foreseeable choice outcomes in orbitofrontal cortex triplet-wise interactions

by Emili Balaguer-Ballester, Ramon Nogueira, Juan M. Abofalia, Ruben Moreno-Bote, Maria V. Sanchez-Vives

Shared neuronal variability has been shown to modulate cognitive processing. However, the relationship between shared variability and behavioral performance is heterogeneous and complex in frontal areas such as the orbitofrontal cortex (OFC). Mounting evidence shows that single-units in OFC encode a detailed cognitive map of task-space events, but the existence of a robust neuronal ensemble coding for the predictability of choice outcome is less established. Here, we hypothesize that the coding of foreseeable outcomes is potentially unclear from the analysis of units activity and their pairwise correlations. However, this code might be established more conclusively when higher-order neuronal interactions are mapped to the choice outcome. As a case study, we investigated the trial-to-trial shared variability of neuronal ensemble activity during a two-choice interval-discrimination task in rodent OFC, specifically designed such that a lose-switch strategy is optimal by repeating the rewarded stimulus in the upcoming trial. Results show that correlations among triplets are higher during correct choices with respect to incorrect ones, and that this is sustained during the entire trial. This effect is not observed for pairwise nor for higher than third-order correlations. This scenario is compatible with constellations of up to three interacting units assembled during trials in which the task is performed correctly. More interestingly, a state-space spanned by such constellations shows that only correct outcome states that can be successfully predicted are robust over 100 trials of the task, and thus they can be accurately decoded. However, both incorrect and unpredictable outcome representations were unstable and thus non-decodeable, due to spurious negative correlations. Our results suggest that predictability of successful outcomes, and hence the optimal behavioral strategy, can be mapped out in OFC ensemble states reliable over trials of the task, and revealed by sufficiency complex neuronal interactions.

in PLoS Computational Biology on June 24, 2020 09:00 PM.

• #### Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

by Jakob Rosenbauer, Chengting Zhang, Benjamin Mattes, Ines Reinartz, Kyle Wedgwood, Simone Schindler, Claude Sinner, Steffen Scholpp, Alexander Schug

During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems.

in PLoS Computational Biology on June 24, 2020 09:00 PM.

• #### Pinning bipartite synchronization for inertial coupled delayed neural networks with signed digraph via non-reduced order method

Publication date: September 2020

Source: Neural Networks, Volume 129

Author(s): Shanshan Chen, Haijun Jiang, Binglong Lu, Zhiyong Yu, Liang Li

in Neural Networks on June 24, 2020 06:00 PM.