• #### Journal of Molecular Neuroscience

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

• #### Correction to: Intra-arterial Stem Cell Therapy Diminishes Inflammasome Activation After Ischemic Stroke: a Possible Role of Acid Sensing Ion Channel 1a

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

G9a is essential for dendritic plasticity and is associated with neurological disorders. The possible relationship between age-related hearing loss and G9a expression in the auditory cortex has not been fully explored. This study aimed to understand the expression patterns of G9a-mediated histone methylations in the auditory cortex during aging. Using immunofluorescence and western blotting, we demonstrated that a significant reduction in G9a expression observed in the auditory cortex of 24-month-old rats compared to 3-month-old rats, was associated with remarkable hearing threshold elevation and hair cell loss. Correspondingly, histone H3 lysine 9 (H3K9) mono- and dimethylation (marked by H3K9me1 and H3K9me2, respectively), which were regulated by G9a activity, also evidently decreased during aging. These findings, which merit further investigation, suggest a possible association between G9a-mediated histone methylations and central age-related hearing disorders.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

The pharmacological inhibition of glial activation is one of the new approaches for combating neuropathic pain in which the role of glia in the modulation of neuropathic pain has attracted significant interest and attention. Neuron-glial crosstalk is achieved with N-methyl-D-aspartate-2B receptor (NMDAR-2B) activation. This study aims to determine the effect of ifenprodil, a potent noncompetitive NMDAR-2B antagonist, on activated microglia, brain-derived neurotrophic factors (BDNF) and downstream regulatory element antagonist modulator (DREAM) protein expression in the spinal cord of streptozotocin-induced painful diabetic neuropathy (PDN) rats following formalin injection. In this experimentation, 48 Sprague-Dawley male rats were randomly selected and divided into four groups: (n = 12): control, PDN, and ifenprodil-treated PDN rats at 0.5 μg or 1.0 μg for 7 days. Type I diabetes mellitus was then induced by injecting streptozotocin (60 mg/kg, i.p.) into the rats which were then over a 2-week period allowed to progress into the early phase of PDN. Ifenprodil was administered in PDN rats while saline was administered intrathecally in the control group. A formalin test was conducted during the fourth week to induce inflammatory nerve injury, in which the rats were sacrificed at 72 h post-formalin injection. The lumbar enlargement region (L4–L5) of the spinal cord was dissected for immunohistochemistry and western blot analyses. The results demonstrated a significant increase in formalin-induced flinching and licking behavior with an increased spinal expression of activated microglia, BDNF and DREAM proteins. It was also shown that the ifenprodil-treated rats following both doses reduced the extent of their flinching and duration of licking in PDN in a dose-dependent manner. As such, ifenprodil successfully demonstrated inhibition against microglia activation and suppressed the expression of BDNF and DREAM proteins in the spinal cord of PDN rats. In conclusion, ifenprodil may alleviate PDN by suppressing spinal microglia activation, BDNF and DREAM proteins.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Long non-coding RNA (lncRNA) plays a crucial role in multiple disorders, while the role of it in Parkinson’s disease (PD) is still unclear. Here, the increased lncRNA NEAT1 was discovered in MPP+-induced SH-SY5Y cells. Then, we proved that NEAT1 decreasing suppressed MPP+-induced neuronal apoptosis, upregulation of α-syn and activation of NLRP3 inflammasome. Rescue experiments shown that the inhibition of NEAT1 decreasing to MPP+-induced activation of NLRP3 inflammasome and subsequent neuronal apoptosis can be reversed by overexpressed α-syn. Subsequently, we indicated the interaction between NEAT1 and miR-1301-3p, as well as between NEAT1 and miR-5047. Interesting, we found that NEAT1 decreasing repressed the expression of GJB1, a downstream target of miR-1301-3p and miR-5047, through promoting miR-1301-3p rather than miR-5047 expression. Finally, we transfected miR-1301-3p inhibitor to MPP+-induced SH-SY5Y cells following si-NEAT1, and found that downregulation of NEAT1 repressed α-syn-mediated the activation of NLRP3 inflammasome through regulating miR-1301-3p/GJB1 signaling pathway. Overall, our data demonstrated that NEAT1 decreasing effectively suppressed MPP+-induced neuronal apoptosis. Mechanismly, downregulation of NEAT1 repressed α-syn-induced activation of NLRP3 inflammasome via inhibiting the expression of GJB1 by targeting miR-1301-3p. Our study supported a new and reliable evidence for lncRNA NEAT1 as a potential target for PD treatment.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Autism spectrum disorder (ASD) is a genetic neurodevelopmental disorder involving multiple genes that occurs in early childhood, and a number of risk genes have been reported in previous studies. However, the molecular mechanism of the polygenic regulation leading to pathological changes in ASD remains unclear. First, we identified 8 dysregulated gene coexpression modules by analyzing blood transcriptome data from 96 children with ASD and 42 controls. These modules are rich in ASD risk genes and function related to metabolism, immunity, neurodevelopment, and signaling. The regulatory factors of each module including microRNA (miRNA) and transcription factors (TFs) were subsequently predicted based on transcriptional and posttranscriptional regulation. We identified a set of miRNAs that regulate metabolic and immune modules, as well as transcription factors that cause dysregulation of the modules, and we constructed a coregulatory network between the regulatory factors and modules. Our work reveals dysfunctional modules in children with ASD, elucidates the role of miRNA and transcription factor dysregulation in the pathophysiology of ASD, and helps us to further understand the underlying molecular mechanism of ASD.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Musculoskeletal pain is a widespread complex regional pain syndrome associated with altered emotional and cognitive functioning along with heightened physical disability that has become a global health concern. Effective management of this disorder and associated disabilities includes accurate diagnosis of its biomarkers and instituting mechanism–based therapeutic interventions. Herein, we explored the role of heraclin, a plant-derived molecule, in musculoskeletal pain and its underlying mechanistic approaches in an experimental mouse model. Reserpine (0.5 mg/kg) for 3 consecutive days evoked hyperalgesia, motor incoordination, lack of exploratory behavior, anxiety, and cognition lapse in mice. Reserpine-challenged mice displayed higher serum cytokine level, altered brain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10 mg/kg for 5 consecutive days) exerted analgesic effect and improved motor coordination and memory deficits in mice. Heraclin arrested serum cytokine rise, normalized brain neurotransmitter content, reduced tissue oxidative stress, and downregulated the nerve growth factor receptor expression. Therefore, it may be suggested that heraclin exerts beneficial effects against reserpine-induced musculoskeletal pain disorder possibly through the attenuation of NGFR-mediated pain and inflammatory signaling.

Graphical Abstract

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

To report the phenomenology of movement disorder (MD) in neurological Wilson disease (NWD), and correlate these with MRI, and biomarkers of oxidative stress, excitotoxicity, and inflammation. Eighty-two patients were included, and their phenomenology of MD was categorized. The severity of dystonia was assessed using the Burke-Fahn-Marsden score, and chorea, athetosis, myoclonus, and tremor on a 0–4 scale. The MRI changes were noted. Serum glutamate, cytokines, and oxidative stress markers were measured. Movement disorders were noted in 78/82 (95.1%) patients and included dystonia in 69 (84.1%), chorea in 31 (37.8%), tremor in 24 (29.3%), parkinsonism in 19 (23.2%), athetosis in 13 (15.9%), and myoclonus in 9 (11.0%) patients. Dystonia was more frequently observed in the patients with thalamic (76.8 vs 23.2%), globus pallidus (72.0 vs 28.0%), putamen (69.5 vs 30.5%), caudate (68.3 vs 31.7%) and brainstem (61.0 vs 39.0%) involvement, and tremor with cerebellar involvement (37.5 vs 5.2%). The median age of onset of neurological symptoms was 12 (5–50) years. WD patients had higher levels of malondialdehyde (MDA), glutamate, and cytokines (IL-6, IL-8, IL-10, and TNFα) and lower levels of glutathione and total antioxidant capacity (TAC) compared with the controls. Serum glutamate, IL-6, IL-8, and plasma MDA levels were increased with increasing neurological severity, while glutathione and TAC levels decreased. The severity of dystonia related to the number of MRI lesions. MD is the commonest neurological symptoms in WD. Oxidative stress, glutamate, and cytokine levels are increased in WD and correlate with neurological severity.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Isolated dystonia is a common movement disorder often caused by genetic mutations, although it is predominantly sporadic in nature. Common variants of dystonia-related genes were reported to be risk factors for idiopathic isolated dystonia. In this study, we aimed to analyse the roles of previously reported GTP cyclohydrolase (GCH1) and Torsin family 1 member A (TOR1A) polymorphisms in an Indian isolated dystonia case-control group. A total of 292 sporadic isolated dystonia patients and 316 control individuals were genotyped for single-nucleotide polymorphisms (SNPs) of GCH1 (rs3759664:G > A, rs12147422:A > G and rs10483639:C > G) and TOR1A (rs13300897:G > A, rs1801968:G > C, rs1182:G > T and rs3842225:G > Δ) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by direct Sanger sequencing. The statistical significance of allelic, genotypic and haplotypic associations of all of the SNPs were evaluated using the two-tailed Fisher exact test. The minor allele (A) of rs3759664 is significantly associated with isolated limb dystonia as a risk factor (p = 0.005). The minor allele (C) of rs1801968 is strongly associated with isolated dystonia (p < 0.0001) and most of its subtypes. The major allele of rs3842225 (G) may act as a significant risk factor for Writer’s cramp (p = 0.03). Four different haplogroups comprising of either rs1182 or rs3842225 or in combination with rs1801968 and rs13300897 were found to be significantly associated with isolated dystonia. No other allelic, genotypic or haplotypic association was found to be significant with isolated dystonia cohort or its endophenotype stratified groups. Our study suggests that TOR1A common variants have a significant role in isolated dystonia pathogenesis in the Indian population, whereas SNPs in the GCH1 gene may have a limited role.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

By measuring the cerebral infarction rate and neurological behavioral score of rats in a sham operation group, an MCAO model control group and an Erigeron breviscapus injection treatment group, we explored the therapeutic effects of Erigeron breviscapus injection on brain tissue and neuroethological injury in rats. Plasma samples were collected at 18 time points after intravenous injection of Erigeron breviscapus. The levels of scutellarin, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, chlorogenic acid and isochlorogenic acid B in rat plasma at the various time points were determined by an HPLC method, and drug concentration versus time plots were constructed to estimate the pharmacokinetic parameters. Finally, a PK-PD combined model was used to analyze the relationship between the blood concentration, time and therapeutic effects of the seven active components. The results of the pharmacodynamics studies showed that the cerebral infarction rate of rats in the Erigeron breviscapus injection group decreased significantly at 5 min, 10 min, 20 min, 6 h, 8 h, 18 h, 24 h, 32 h, 40 h and 48 h after cerebral ischemia. Abnormal neurological behavior scores were significantly reduced after 4 h of cerebral ischemia. The pharmacokinetics results showed that the seven chemical constituents in Erigeron breviscapus injection reached their highest detection value after 5 min of cerebral ischemia. The lowest detection values of scutellarin and isochlorogenic acid B appeared after 6 h of cerebral ischemia but could not be detected after 8 h. The lowest detection values of 5-caffeoylquinic acid and 4,5-dicaffeoylquinic acid were found in the third hour of cerebral ischemia but not after 4 h. The lowest detection values of 4-caffeoylquinic acid, 3,5-dicaffeoylquinic acid and chlorogenic acid were found during the second hour of cerebral ischemia but not at the third hour. However, at 18 h, 24 h, 32 h and 40 h of cerebral ischemia, the cerebral infarction rates of rats in the Erigeron breviscapus injection group were significantly reduced, with decreased values of 6.22%, 11.71%, 6.92% and 4.96%, respectively, and the effects were stronger than those after 5–20 min of cerebral ischemia. The decreased values reached their highest value after 24 h of cerebral ischemia. Our results show that the effects of Erigeron breviscapus injection on reducing the cerebral infarct rate in MCAO model rats are characterized by a fast onset and long maintenance time. The 5-min blood concentration in cerebral ischemia was the highest test value, and after this time, the cerebral infarction rate of MCAO rats began to decrease. However, the peak value of the effects lagged behind that of the plasma concentration. The maximum effective time for Erigeron breviscapus injection appeared 24 h after cerebral ischemia, which provides a reference for the screening of specific drugs for ischemic stroke, optimal dosing regimens and rational clinical drug use.

Graphical Abstract

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

This study aimed to clarify the regulation role of miR-708 and miR-335-3p in retinal ganglion cell (RGC) autophagy and apoptosis in glaucoma. Chronic glaucoma mice were established by laser photocoagulation. RGCs were isolated and transfected with a series of plasmids and the cultured in 60 mmHg pressure. miR-335-3p, miR-708, and ATG3 mRNA expressions were detected by qRT-PCR. Protein levels of ATG3, autophagy-related protein LC3, and p62 were detected by Western blot. The apoptosis of RGCs was detected by flow cytometry. The regulation role of miR-335-3p/miR-708 in ATG3 was confirmed by the dual-luciferase reporter gene. The expressions of several miRNAs were measured in retinal tissues from chronic glaucoma mice and RGCs under pressure conditions, and results showed that both miR-335-3p and miR-708 were down-regulated. Besides, the inhibition of miR-708 and miR-335-3p induced the apoptosis of RGCs through promoting autophagy. Also, miR-708 and miR-335-3p could bind to ATG3 and targeted regulated ATG3. Furthermore, the interference with miR-708/miR-335-3p induced RGC apoptosis by up-regulating ATG3 to promote autophagy. In general, the down-regulation of miR-708 and miR-335-3p contributed to the apoptosis of RGCs through promoting autophagy in glaucoma.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

SNP rs2043211 in CARD8 was found to have significant association with ischemic stroke. This study aimed to explore the possible association between rs2043211 and large-artery atherosclerosis stroke in Chinese and explain the possible mechanism. In total, 716 large-artery atherosclerosis stroke patients and 1088 controls were included in the study. Co-dominant, dominant, and recessive genetic models were constructed to evaluate the relationship between rs2043211 and large-artery atherosclerosis stroke risk by odds ratios with 95% confidence intervals. Stratified and interaction analyses were also done. We selected another 111 large-artery atherosclerosis stroke patients and measured the CARD8 levels in their plasma samples by enzyme-linked immunosorbent assay. Participants who carry T/T genotype have a higher risk of large-artery atherosclerosis stroke compared with those carry A/T or A/A genotypes (odds ratio = 1.35, 95% confidence intervals 1.03–1.77, P = 0.029). The higher risk for the T/T genotype is still notable in female, people with hypertension, and people without diabetes. In the interaction analysis, compared to the non-hypertensive participants with the wild homozygote type A/A, the hypertensive participants with the A/T+T/T homozygote had 3.27-fold increased risk (odds ratio = 3.27, 95% confidence intervals 2.33–4.60). The A/A group had lower CARD8 levels in plasma than the A/T and T/T group (P < 0.001). Further bioinformatics prediction indicated that the rs2043211 could significantly influence the mRNA secondary structure and protein expression of CARD8 (eQTL P = 9.8 × 10−198). The rs2043211 is probably a novel biomarker for large-artery atherosclerosis stroke in Chinese.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

To feel other’s pain would elicit empathy. Some theorists hypothesized that observing other’s pain may activate the primary emotion of maternal care instinct, which may function as a precursor of empathy. The maternal care instinct and empathy share the same genetic background and neuroendocrine underpinnings. An extensive body of research has shown that maternal behaviors relate to the oxytocinergic system, which has a strong influence on empathy. These studies suggest that the maternal care instinct may mediate the effect of oxytocin receptor gene (OXTR) on empathy. To provide evidence for this mediation, we used the subscale of CARE in Affective Neuroscience Personality Scales (ANPS) to measure the maternal care instinct and tested two OXTR single-nucleotide polymorphisms (SNPs), rs53576 and rs13316193, in 880 high school participants (588 females, 292 males; Mage = 16.51 years old, SD = 0.65). Results showed that the genotype of rs13316193 was indirectly associated with empathy via CARE, suggesting a mediating role of CARE in the pathway from OXTR to empathy. These findings may contribute to an understanding of how empathy emerges when one witnesses another person in pain.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Metachromatic leukodystrophy(MLD) is an autosomal recessive hereditary neurodegenerative lysosomal storage disorder caused by the mutations in arylsulfatase A gene (ARSA), which results in the deficiency of ARSA enzyme. The common clinical characteristics of MLD are abnormal gait, and then gradually appears ataxia, spastic quadriplegia, optic atrophy, cortical blindness, and dementia. We describe two patients in China who were diagnosed with MLD and find that the four ARSA gene mutations (c.1115G>A, c.302G>T, c.893 G> T, and c.302G>T) are associated with MLD, in which c.893 G>T and c.302G>T are novel mutations by gene sequence and clinical manifestations, to further understand the relationship between MLD and ARSA gene.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

The sweet taste receptor, which was identified approximately 20 years ago, mediates sweet taste recognition in humans and other vertebrates. With the development of genomics, metabonomics, structural biology, evolutionary biology, physiology, and neuroscience, as well as technical advances in these areas, our understanding of this important protein has resulted in substantial progress. This article reviews the structure, function, genetics, and evolution of the sweet taste receptor and offers meaningful insights into this G protein–coupled receptor, which may be helpful guidances for personalized feeding, diet, and medicine. Prospective directions for research on sweet taste receptors have also been proposed.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

FGF2 is a neurotrophic factor that can act as a key regulatory molecule of neuroprotection, neurogenesis, and angiogenesis in various injuries. To explore the genetic background of the FGF2 gene on DPN development, this study analyzed the correlation between SNPs in the 3'UTR of the FGF2 gene and their interaction with environmental factors in DPN patients of Han Chinese nationality. Sanger sequencing was used to analyze the FGF2 genotypes at the rs1048201, rs3804158, rs41348645, rs6854081, rs3747676, rs7683093, rs1476215, and rs1476217 loci in 150 DPN patients, 150 NDPN patients, and 150 healthy control patients. Plasma FGF2 levels were measured in all subjects by using ELISAs. Subjects carrying the T allele at the rs1048201 locus in the FGF2 gene had a significantly lower risk of developing DPN compared with subjects carrying the C allele (OR = 0.43, 95% CI = 0.33–0.56, p < 0.01). Subjects with the G genotype at the rs6854081 locus had an exceptionally higher risk of developing DPN than subjects with the T allele (OR = 1.66, 95% CI = 1.39–1.89, p < 0.01). Individuals harboring the G allele at the rs7683093 locus had a markedly higher risk of DPN than patients with the C allele (OR = 1.63, 95% CI = 1.36–1.87, p < 0.01). Finally, individuals having the A genotype at the rs1476215 locus had a significantly higher risk of DPN than individuals carrying the T allele (OR = 1.82, 95% CI = 1.53–2.02, p < 0.01). There was an interaction between age and alcohol consumption and the SNP rs7683093. SNPs at rs1048201, rs6854081, rs7683093, and rs1476215 in the FGF2 3’UTR were strongly associated with plasma levels of FGF2 (p < 0.05). SNPs at the rs1048201, rs6854081, rs7683093, and rs1476215 loci in the FGF2 gene were significantly associated with the risk of DPN. A possible mechanism is that these SNPs affect the expression level of FGF2 by interrupting the binding of microRNAs to target sites in the 3'UTR.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

The proliferation and migration of vascular smooth muscle cells (VSMCs) are involved in the pathogenesis of intracranial aneurysm (IA) formation and rupture. Interleukin enhancer binding factor 2 (ILF2) is known as the nuclear factor of activated T cells and regulates cell growth. This study was aimed to explore the effects of ILF2 on IA progression. Human brain VSMCs (hBVSMCs) were transfected with pCDNA3.1(+), pCDNA3.1(+)-ILF2, siRNA-negative control, and siRNA-ILF2. The transfection efficiency was then evaluated by determining ILF2 expression. The cell viability and apoptosis were determined using Cell Counting Kit-8 and Annexin V-FITC cell apoptosis assay kit, respectively. Real-time quantification PCR (RT-qPCR) was applied to measure the expression levels of apoptosis-related and inflammation-related genes. Finally, western blot was used to detect the expression level of Fas cell surface death receptor 95 (CD95) and Caspase 8. Overexpression of ILF2 could significantly increase cell viability and decrease cell apoptosis (P < 0.05), while knock-down of ILF2 showed opposite trends for hBVSMCs on cell viability and apoptosis (P < 0.05). RT-qPCR results showed that ILF2 knock-down downregulated the expression levels of BCL2 apoptosis regulator (BCL2), transcriptional regulator Myc-like (c-Myc), and caspase 1 (ICE) whereas upregulated the expression levels of CD95, p21, p53, and interleukin-13 (IL-13). Additionally, the protein expression levels of CD95 and Caspase 8 were significantly decreased after ILF2 overexpression while were significantly increased after ILF2 knock-down (P < 0.05). ILF2 knock-down may inhibit cell viability and promote cell apoptosis of hBVSMCs by regulating the expression levels of apoptosis-related genes and suppressing inflammatory response.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Multiple sclerosis (MS) is known as a chronic neuroinflammatory disorder typified by an immune-mediated demyelination process with ensuing axonal damage and loss. Sinomenine is a natural alkaloid with different therapeutic benefits, including anti-inflammatory and immunosuppressive activities. In this study, possible beneficial effects of sinomenine in an MOG-induced model of MS were determined. Sinomenine was given to MOG35–55-immunized C57BL/6 mice at doses of 25 or 100 mg/kg/day after onset of MS clinical signs till day 30 post-immunization. Analyzed data showed that sinomenine reduces severity of the clinical signs and to some extent decreases tissue level of pro-inflammatory cytokines IL-1β, IL-6, IL-18, TNFα, IL-17A, and increases level of anti-inflammatory IL-10. In addition, sinomenine successfully attenuated tissue levels of inflammasome NLRP3, ASC, and caspase 1 besides its reduction of intensity of neuroinflammation, demyelination, and axonal damage and loss in lumbar spinal cord specimens. Furthermore, immunoreactivity for MBP decreased and increased for GFAP and Iba1 after MOG-immunization, which was in part reversed upon sinomenine administration. Overall, sinomenine decreases EAE severity, which is attributed to its alleviation of microglial and astrocytic mobilization, demyelination, and axonal damage along with its suppression of neuroinflammation, and its beneficial effect is also associated with its inhibitory effects on inflammasome and pyroptotic pathways; this may be of potential benefit for the primary progressive phenotype of MS.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

### Abstract

Studies from our lab demonstrated that 1 × 105 intra-arterial mesenchymal stem cells (IA MSCs) at 6 h following ischemic stroke are efficacious owing to its maximum homing due to elevated stromal derived factor 1 (SDF1) in the tissue. Further, IA MSCs could abate the infarct progression, improve functional outcome, and decrease expression of calcineurin by modifying neuronal Ca2+ channels following ischemic stroke. Since stroke pathology also encompasses acidosis that worsens the condition; hence, the role of acid sensing ion channels (ASICs) in this context could not be overlooked. ASIC1a being the major contributor towards acidosis triggers Ca2+ ions overload which progressively contributes towards exacerbation of neuronal injury following ischemic insult. Inflammasome involvement in ischemic stroke is well reported as activated ASIC1a increases the expression of inflammasome in a pH-dependent manner to trigger inflammatory cascade. Hence, the current study aimed to identify if IA MSCs can decrease the production of inflammasome by attenuating ASIC1a expression to render neuroprotection. Ovariectomized Sprague Dawley (SD) rats exposed to middle cerebral artery occlusion (MCAo) for 90 min were treated with phosphate-buffered saline (PBS) or 1 × 105 MSCs IA at 6 h to check for the expression of ASIC1a and inflammasome in different groups. Inhibition studies were carried out to explore the underlying mechanism. Our results demonstrate that IA MSCs improves functional outcome and oxidative stress parameters, and decreases the expression of ASIC1a and inflammasomes in the cortical brain region after ischemic stroke. This study offers a preliminary evidence of the role of IA MSCs in regulating inflammasome by modulating ASIC1a.

in Journal of Molecular Neuroscience on February 01, 2021 12:00 AM.

• #### Diverse mechanisms regulating brain energy supply at the capillary level

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Thomas Pfeiffer, Yuening Li, David Attwell

in Current Opinion in Neurobiology on January 21, 2021 07:00 PM.

• #### Building an adaptive interface via unsupervised tracking of latent manifolds

Publication date: Available online 20 January 2021

Source: Neural Networks

Author(s): Fabio Rizzoglio, Maura Casadio, Dalia De Santis, Sandro Mussa-Ivaldi

in Neural Networks on January 21, 2021 02:00 PM.

• #### MaskLayer: Enabling scalable deep learning solutions by training embedded feature sets

Publication date: Available online 20 January 2021

Source: Neural Networks

Author(s): Remco Royen, Leon Denis, Quentin Bolsee, Pengpeng Hu, Adrian Munteanu

in Neural Networks on January 21, 2021 02:00 PM.

• #### A conditional Triplet loss for few-shot learning and its application to image co-segmentation

Publication date: Available online 20 January 2021

Source: Neural Networks

Author(s): Daming Shi, Maysam Orouskhani, Yasin Orouskhani

in Neural Networks on January 21, 2021 02:00 PM.

• #### Extracting and inserting knowledge into stacked denoising auto-encoders

Publication date: Available online 20 January 2021

Source: Neural Networks

Author(s): Jianbo Yu, Guoliang Liu

in Neural Networks on January 21, 2021 02:00 PM.

• #### Post-lockdown abatement of COVID-19 by fast periodic switching

by Michelangelo Bin, Peter Y. K. Cheung, Emanuele Crisostomi, Pietro Ferraro, Hugo Lhachemi, Roderick Murray-Smith, Connor Myant, Thomas Parisini, Robert Shorten, Sebastian Stein, Lewi Stone

COVID-19 abatement strategies have risks and uncertainties which could lead to repeating waves of infection. We show—as proof of concept grounded on rigorous mathematical evidence—that periodic, high-frequency alternation of into, and out-of, lockdown effectively mitigates second-wave effects, while allowing continued, albeit reduced, economic activity. Periodicity confers (i) predictability, which is essential for economic sustainability, and (ii) robustness, since lockdown periods are not activated by uncertain measurements over short time scales. In turn—while not eliminating the virus—this fast switching policy is sustainable over time, and it mitigates the infection until a vaccine or treatment becomes available, while alleviating the social costs associated with long lockdowns. Typically, the policy might be in the form of 1-day of work followed by 6-days of lockdown every week (or perhaps 2 days working, 5 days off) and it can be modified at a slow-rate based on measurements filtered over longer time scales. Our results highlight the potential efficacy of high frequency switching interventions in post lockdown mitigation. All code is available on Github at https://github.com/V4p1d/FPSP_Covid19. A software tool has also been developed so that interested parties can explore the proof-of-concept system.

in PLoS Computational Biology on January 21, 2021 02:00 PM.

• #### Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex

by Rachael L. Sumner, Meg J. Spriggs, Alexander D. Shaw

Neuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study presents a generative thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans. The model is combined with a commonly used visual sensory LTP paradigm and fit to the empirical EEG data using dynamic causal modelling. The thalamocortical model demonstrated remarkable accuracy recapitulating post-tetanus changes seen in invasive research, including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III, established major sites of LTP in visual cortex. These findings provide justification for the implementation of the presented thalamocortical model for ERP research, including to provide increased detail on the nature of changes that underlie LTP induced in visual cortex. Future applications include translating rodent findings to non-invasive research in humans concerning deficits to LTP that may underlie neurological and psychiatric disease.

in PLoS Computational Biology on January 21, 2021 02:00 PM.

• #### Friendly-rivalry solution to the iterated <i>n</i>-person public-goods game

by Yohsuke Murase, Seung Ki Baek

Repeated interaction promotes cooperation among rational individuals under the shadow of future, but it is hard to maintain cooperation when a large number of error-prone individuals are involved. One way to construct a cooperative Nash equilibrium is to find a ‘friendly-rivalry’ strategy, which aims at full cooperation but never allows the co-players to be better off. Recently it has been shown that for the iterated Prisoner’s Dilemma in the presence of error, a friendly rival can be designed with the following five rules: Cooperate if everyone did, accept punishment for your own mistake, punish defection, recover cooperation if you find a chance, and defect in all the other circumstances. In this work, we construct such a friendly-rivalry strategy for the iterated n-person public-goods game by generalizing those five rules. The resulting strategy makes a decision with referring to the previous m = 2n − 1 rounds. A friendly-rivalry strategy for n = 2 inherently has evolutionary robustness in the sense that no mutant strategy has higher fixation probability in this population than that of a neutral mutant. Our evolutionary simulation indeed shows excellent performance of the proposed strategy in a broad range of environmental conditions when n = 2 and 3.

in PLoS Computational Biology on January 21, 2021 02:00 PM.

• #### Unzipping of a double-stranded block copolymer DNA by a periodic force

Author(s): Ramu Kumar Yadav and Rajeev Kapri

Using Monte Carlo simulations, we study the hysteresis in unzipping of a double-stranded block copolymer DNA with $-{A}_{n}{B}_{n}-$ repeat units. Here $A$ and $B$ represent two different types of base pairs having two and three bonds, respectively, and $2n$ represents the number of such base pairs in a unit. The end...

[Phys. Rev. E 103, 012413] Published Thu Jan 21, 2021

in Physical Review E: Biological physics on January 21, 2021 10:00 AM.

• #### Fast deep learning correspondence for neuron tracking and identification in C.elegans using synthetic training. (arXiv:2101.08211v1 [q-bio.QM])

We present an automated method to track and identify neurons in C. elegans, called "fast Deep Learning Correspondence" or fDLC, based on the transformer network architecture. The model is trained once on empirically derived synthetic data and then predicts neural correspondence across held-out real animals via transfer learning. The same pre-trained model both tracks neurons across time and identifies corresponding neurons across individuals. Performance is evaluated against hand-annotated datasets, including NeuroPAL [1]. Using only position information, the method achieves 80.0% accuracy at tracking neurons within an individual and 65.8% accuracy at identifying neurons across individuals. Accuracy is even higher on a published dataset [2]. Accuracy reaches 76.5% when using color information from NeuroPAL. Unlike previous methods, fDLC does not require straightening or transforming the animal into a canonical coordinate system. The method is fast and predicts correspondence in 10 ms making it suitable for future real-time applications.

in arXiv: Quantitative Biology: Neurons and Cognition on January 21, 2021 01:30 AM.

• #### Zero-Cost Proxies for Lightweight NAS. (arXiv:2101.08134v1 [cs.LG])

Neural Architecture Search (NAS) is quickly becoming the standard methodology to design neural network models. However, NAS is typically compute-intensive because multiple models need to be evaluated before choosing the best one. To reduce the computational power and time needed, a proxy task is often used for evaluating each model instead of full training. In this paper, we evaluate conventional reduced-training proxies and quantify how well they preserve ranking between multiple models during search when compared with the rankings produced by final trained accuracy. We propose a series of zero-cost proxies, based on recent pruning literature, that use just a single minibatch of training data to compute a model's score. Our zero-cost proxies use 3 orders of magnitude less computation but can match and even outperform conventional proxies. For example, Spearman's rank correlation coefficient between final validation accuracy and our best zero-cost proxy on NAS-Bench-201 is 0.82, compared to 0.61 for EcoNAS (a recently proposed reduced-training proxy). Finally, we use these zero-cost proxies to enhance existing NAS search algorithms such as random search, reinforcement learning, evolutionary search and predictor-based search. For all search methodologies and across three different NAS datasets, we are able to significantly improve sample efficiency, and thereby decrease computation, by using our zero-cost proxies. For example on NAS-Bench-101, we achieved the same accuracy 4$\times$ quicker than the best previous result.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 21, 2021 01:30 AM.

• #### Illuminating the Space of Beatable Lode Runner Levels Produced By Various Generative Adversarial Networks. (arXiv:2101.07868v1 [cs.LG])

Generative Adversarial Networks (GANs) are capable of generating convincing imitations of elements from a training set, but the distribution of elements in the training set affects to difficulty of properly training the GAN and the quality of the outputs it produces. This paper looks at six different GANs trained on different subsets of data from the game Lode Runner. The quality diversity algorithm MAP-Elites was used to explore the set of quality levels that could be produced by each GAN, where quality was defined as being beatable and having the longest solution path possible. Interestingly, a GAN trained on only 20 levels generated the largest set of diverse beatable levels while a GAN trained on 150 levels generated the smallest set of diverse beatable levels, thus challenging the notion that more is always better when training GANs.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 21, 2021 01:30 AM.

• #### SEMULATOR: Emulating the Dynamics of Crossbar Array-based Analog Neural System with Regression Neural Networks. (arXiv:2101.07864v1 [cs.LG])

As deep neural networks require tremendous amount of computation and memory, analog computing with emerging memory devices is a promising alternative to digital computing for edge devices. However, because of the increasing simulation time for analog computing system, it has not been explored. To overcome this issue, analytically approximated simulators are developed, but these models are inaccurate and narrow down the options for peripheral circuits for multiply-accumulate operation (MAC). In this sense, we propose a methodology, SEMULATOR (SiMULATOR by Emulating the analog computing block) which uses a deep neural network to emulate the behavior of crossbar-based analog computing system. With the proposed neural architecture, we experimentally and theoretically shows that it emulates a MAC unit for neural computation. In addition, the simulation time is incomparably reduced when it compared to the circuit simulators such as SPICE.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 21, 2021 01:30 AM.

• #### Implicit Bias of Linear RNNs. (arXiv:2101.07833v1 [cs.LG])

Contemporary wisdom based on empirical studies suggests that standard recurrent neural networks (RNNs) do not perform well on tasks requiring long-term memory. However, precise reasoning for this behavior is still unknown. This paper provides a rigorous explanation of this property in the special case of linear RNNs. Although this work is limited to linear RNNs, even these systems have traditionally been difficult to analyze due to their non-linear parameterization. Using recently-developed kernel regime analysis, our main result shows that linear RNNs learned from random initializations are functionally equivalent to a certain weighted 1D-convolutional network. Importantly, the weightings in the equivalent model cause an implicit bias to elements with smaller time lags in the convolution and hence, shorter memory. The degree of this bias depends on the variance of the transition kernel matrix at initialization and is related to the classic exploding and vanishing gradients problem. The theory is validated in both synthetic and real data experiments.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 21, 2021 01:30 AM.

• #### Estimation of Relationship between Stimulation Current and Force Exerted during Isometric Contraction. (arXiv:1811.02795v2 [cs.HC] UPDATED)

In this study, we developed a method to estimate the relationship between stimulation current and volatility during isometric contraction. In functional electrical stimulation (FES), joints are driven by applying voltage to muscles. This technology has been used for a long time in the field of rehabilitation, and recently application oriented research has been reported. However, estimation of the relationship between stimulus value and exercise capacity has not been discussed to a great extent. Therefore, in this study, a human muscle model was estimated using the transfer function estimation method with fast Fourier transform. It was found that the relationship between stimulation current and force exerted could be expressed by a first-order lag system. In verification of the force estimate, the ability of the proposed model to estimate the exerted force under steady state response was found to be good.

in arXiv: Quantitative Biology: Neurons and Cognition on January 21, 2021 01:30 AM.

• #### An Efficient and Flexible Spike Train Model via Empirical Bayes. (arXiv:1605.02869v4 [q-bio.QM] UPDATED)

Accurate statistical models of neural spike responses can characterize the information carried by neural populations. But the limited samples of spike counts during recording usually result in model overfitting. Besides, current models assume spike counts to be Poisson-distributed, which ignores the fact that many neurons demonstrate over-dispersed spiking behaviour. Although the Negative Binomial Generalized Linear Model (NB-GLM) provides a powerful tool for modeling over-dispersed spike counts, the maximum likelihood-based standard NB-GLM leads to highly variable and inaccurate parameter estimates. Thus, we propose a hierarchical parametric empirical Bayes method to estimate the neural spike responses among neuronal population. Our method integrates both Generalized Linear Models (GLMs) and empirical Bayes theory, which aims to (1) improve the accuracy and reliability of parameter estimation, compared to the maximum likelihood-based method for NB-GLM and Poisson-GLM; (2) effectively capture the over-dispersion nature of spike counts from both simulated data and experimental data; and (3) provide insight into both neural interactions and spiking behaviours of the neuronal populations. We apply our approach to study both simulated data and experimental neural data. The estimation of simulation data indicates that the new framework can accurately predict mean spike counts simulated from different models and recover the connectivity weights among neural populations. The estimation based on retinal neurons demonstrate the proposed method outperforms both NB-GLM and Poisson-GLM in terms of the predictive log-likelihood of held-out data.

in arXiv: Quantitative Biology: Neurons and Cognition on January 21, 2021 01:30 AM.

• #### Evaluation and development of deep neural networks for image super-resolution in optical microscopy

Nature Methods, Published online: 21 January 2021; doi:10.1038/s41592-020-01048-5

This study explores the performance of deep-learning models for super-resolution imaging and introduces models that utilize frequency content information in the Fourier domain to improve SIM reconstruction under low-SNR conditions.

in Nature Methods on January 21, 2021 12:00 AM.

• #### The promise and peril of deep learning in microscopy

Nature Methods, Published online: 21 January 2021; doi:10.1038/s41592-020-01035-w

The promise and peril of deep learning in microscopy

in Nature Methods on January 21, 2021 12:00 AM.

• #### Maximum information states for coherent scattering measurements

Nature Physics, Published online: 21 January 2021; doi:10.1038/s41567-020-01137-4

Wavefront shaping can reduce uncertainties due to measurement noise through disordered media—key to many imaging applications. Optimal precision can be achieved using light fields that are eigenstates of an operator related to the medium’s scattering matrix.

in Nature Physics on January 21, 2021 12:00 AM.

• #### Disordered exchange is biased

Nature Physics, Published online: 21 January 2021; doi:10.1038/s41567-020-01127-6

The magnetic properties of intercalated metal dichalcogenides are dramatically affected by small crystal imperfections, potentially providing design principles and materials for spintronic devices.

in Nature Physics on January 21, 2021 12:00 AM.

• #### Exchange bias due to coupling between coexisting antiferromagnetic and spin-glass orders

Nature Physics, Published online: 21 January 2021; doi:10.1038/s41567-020-01123-w

Coexistence of a spin-glass phase with antiferromagnetism in an intercalated crystal produces a large exchange bias effect. This is due to the interplay of disorder and frustration.

in Nature Physics on January 21, 2021 12:00 AM.

• #### Gaussian-preserved, non-volatile shape morphing in three-dimensional microstructures for dual-functional electronic devices

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20843-4

Designing the functional diversification of electronic devices with morphable 3D structures in multistable states remains a challenge. Here, the authors present a Gaussian-preserved shape-morphing system to realize ultrafast shape morphing and non-volatile reconfiguration developing dual-functional electronic devices, such as switch, actuator, and antenna on microscale.

in Nature Communications on January 21, 2021 12:00 AM.

• #### Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20830-9

Large organized chromatin lysine (K) domains (LOCKs) are a genomic feature derived from the cluster of modified nucleosomes. Here the authors provide evidence that LOCKs discriminate primitive from differentiated cell populations and that they relate to transcription regulating events.

in Nature Communications on January 21, 2021 12:00 AM.

• #### Universal toxin-based selection for precise genome engineering in human cells

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20810-z

Genome engineering in cell lines or human stem cells often has poor efficiency, limiting the development of research and therapeutic applications. Here, the authors use a toxin-based selection system for precise bi-allelic engineering in cells and in vivo.

in Nature Communications on January 21, 2021 12:00 AM.

• #### SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20796-8

Valosin-Containing Protein (VCP) is linked to diverse degenerative diseases. Here, the authors show that Small VCP Interacting Protein (SVIP) recruits VCP to lysosomes, with gain and loss of SVIP muscle expression modifying neural degeneration, animal behaviour and lifespan.

in Nature Communications on January 21, 2021 12:00 AM.

• #### The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20768-y

The SARS-CoV-2 nucleocapsid (N) protein binds the viral RNA genome and contains two ordered domains flanked by three intrinsically-disordered regions. Here, the authors show that RNA binding induces liquid-liquid phase separation of N, which is driven by its central intrinsically-disordered region and is modulated by phosphorylation. The SARS-CoV-2 Membrane (M) protein also phase-separates with N, and three-component mixtures of N + M + RNA form mutually exclusive compartments containing N + M or N + RNA.

in Nature Communications on January 21, 2021 12:00 AM.

• #### GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20766-0

Mast cells are critical effectors of allergic inflammation and protection against parasitic infections. Here the authors demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of mast cell identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation.

in Nature Communications on January 21, 2021 12:00 AM.

• #### 3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20763-3

Currently technologies for monitoring and controlling neural activities in 3D models are lacking. Here the authors report a 3D high-density multielectrode array, with optical stimulation and drug delivery, to investigate neural circuit dynamics in engineered 3D neural tissues.

in Nature Communications on January 21, 2021 12:00 AM.

• #### Sarcoma classification by DNA methylation profiling

Nature Communications, Published online: 21 January 2021; doi:10.1038/s41467-020-20603-4

Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

in Nature Communications on January 21, 2021 12:00 AM.

• #### Lifelong lessons from my unexpected encounter with a synchrotron

Nature, Published online: 21 January 2021; doi:10.1038/d41586-021-00181-1

Biomedical scientist Vladimira Foteva didn’t imagine she would be working with physicists at an Australian particle accelerator when she began her PhD, but the experience taught her the value of collaboration across disciplines.

in Nature on January 21, 2021 12:00 AM.

• #### What new COVID variants mean for schools is not yet clear

Nature, Published online: 21 January 2021; doi:10.1038/d41586-021-00139-3

Children are no more susceptible to these lineages than adults are — and closing schools on the basis of incomplete information could have repercussions.

in Nature on January 21, 2021 12:00 AM.

• #### A deep-sea trench is a plastic dump — and a biodiversity hotspot

Nature, Published online: 21 January 2021; doi:10.1038/d41586-021-00138-4

Plastic bags and wrappers host a thriving community of ocean creatures.

in Nature on January 21, 2021 12:00 AM.

• #### Fast-spreading COVID variant can elude immune responses

Nature, Published online: 21 January 2021; doi:10.1038/d41586-021-00121-z

Evidence that a variant of the coronavirus identified in South Africa might compromise immunity sparks concerns about vaccine effectiveness.

in Nature on January 21, 2021 12:00 AM.

• #### COVID research updates: COVID vaccines might lose potency against new viral variants

Nature, Published online: 21 January 2021; doi:10.1038/d41586-020-00502-w

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

in Nature on January 21, 2021 12:00 AM.

• #### Biological Cybernetics

in Biological Cybernetics on January 21, 2021 12:00 AM.

• #### Journal of Neurology

in Journal of Neurology on January 21, 2021 12:00 AM.

### Abstract

All organisms must be able to adapt to changes in the environment. To this end, they have developed sophisticated regulatory mechanisms to ensure homeostasis. Control engineers, who must design similar regulatory systems, have developed a number of general principles that govern feedback regulation. These lead to constraints which impose trade-offs that arise when developing controllers to minimize the effect of external disturbances on systems. Here, we review some of these trade-offs, particularly Bode’s integral formula. We also highlight its connection to information theory, by showing that the constraints in sensitivity minimization can be cast as limitations on the information transmission through a system, and these have their root in causality. Finally, we look at how these constraints arise in two biological systems: glycolytic oscillations and the energy cost of perfect adaptation in a bacterial chemotactic pathway.

in Biological Cybernetics on January 21, 2021 12:00 AM.

### Objective

Guillain–Barré syndrome (GBS) induced by immune checkpoint inhibitors (ICIs) has been occasionally reported in randomized clinical trials (RCTs), but the post-marketing data are quite limited. This study aimed to comprehensively examine GBS events secondary to ICI treatments in the real-world patients based on the Food and Drug Administration Adverse Event Reporting System (FAERS).

### Methods

Reports from January 2004 to March 2020 were extracted from the FAERS. GBS cases related to ICIs were identified to characterize their clinical features. The disproportionality and Bayesian analysis were performed for the detection of GBS signals associated with ICIs.

### Results

In total, 149 GBS reports with ICIs as suspect drugs were screened out. These events were found to be more prevalent in adults ≥ 45 years (63.09%) and males (63.09%). The onsets of GBS were variable with a median time of 38 (range 0–628) days after ICI initiation. The outcomes tended to be severe with 61.74% hospitalization and 22.82% death. GBS events were most commonly reported in ipilimumab plus nivolumab treatment (24.83%), and this combination therapy also yielded stronger signal for GBS than other therapies based on the highest reporting odds ratio (ROR = 12.43, two-sided 95% CI = 8.62, 17.93), proportional reporting ratio (PRR = 12.39, χ2 = 300.90), information component (IC = 3.62, IC025 = 2.51) and empirical Bayes geometric mean (EBGM = 12.28, EBGM05 = 9.04).

### Conclusion

As complements to the safety data from RCTs, the current pharmacovigilance research helps establish a more detailed overview of ICI-related GBS, which facilitates the understanding of this rare adverse drug effect.

in Journal of Neurology on January 21, 2021 12:00 AM.

### Background

Rituximab is safe and effective for treating relapsing–remitting multiple sclerosis (RRMS) according to phase II and observational studies. There are limited data on disease activity after discontinuation and dose reduction. The objective of this study was to evaluate the effects on inflammatory disease activity after discontinuation or dose reduction of rituximab in patients with RRMS or clinically isolated syndrome (CIS).

### Methods

In this retrospective observational study, we included all RRMS and CIS patients ever treated with rituximab at the University Hospital of Umeå who had either; (1) discontinued treatment at any time or (2) reduced the dose to a mean of < 1000 mg yearly. The patients served as their own controls by contributing patient years on full dose, reduced dose, and off treatment.

### Results

A total of 225 patients treated with mean (SD) 6256 (2456) mg rituximab during mean (SD) 6.5 (2.0) years were included. There were no differences regarding the annualized relapse rates during full dose versus reduced dose or off treatment (0.02 versus < 0.01 and 0.02, p = 0.09), neither regarding proportion MRI scans with new or enlarged T2 lesions (0.03 versus 0.01 and 0.03, p = 0.37) or contrast-enhancing lesions (< 0.01 versus 0 and 0.02, p = 0.22).

### Conclusions

This study indicates that rituximab has long-term effects on inflammatory disease activity and that disease reactivation is rare in MS patients who discontinued treatment for any reason. It also suggests that treatment with low-dose rituximab (< 1000 mg yearly) is sufficient to maintain suppression of inflammatory disease activity in patients with stable disease.

in Journal of Neurology on January 21, 2021 12:00 AM.

### Objective

Adjuvant steroids have been used for the treatment of encephalitis, although there is limited data regarding its benefit. We described the use and impact of adjunctive steroids on adverse clinical outcomes (ACO) in adults with encephalitis.

### Methods

Retrospective observational study of 230 adults with encephalitis at two tertiary care hospital systems in Houston, Texas, between August 2008 and September 2017. An ACO was assessed at the time of death or discharge and defined as a Glasgow Outcome Scale 1–4. A propensity score analysis was performed.

### Results

Out of 230 adult encephalitis patients enrolled, 121 (52.6%) received steroids. Adjunctive steroids were given more frequently to those who had focal neurological deficits (P = 0.01), required mechanical ventilation (MV) (P = 0.01), had intensive care unit admission (P < 0.001), had white matter abnormalities (P = 0.01) or cerebral edema on magnetic resonance imaging of the brain (P = 0.003). An ACO was seen in 135 (58.7%) of patients. The use of adjunctive steroids did not impact ACOs (P = 0.52) on univariate analyses or after propensity score matching. Predictors for an ACO in logistic regression analyses included a Glasgow Coma Score (GCS) < 8, fever, MV, and cerebral edema.

### Interpretation

Adjunctive steroids are used more frequently in sicker patients and are not associated with improved clinical outcomes.

in Journal of Neurology on January 21, 2021 12:00 AM.

• #### The Effect of Spinal Cord Stimulation Frequency on the Neural Response and Perceived Sensation in Patients With Chronic Pain

Background

The effect of spinal cord stimulation (SCS) amplitude on the activation of dorsal column fibres has been widely studied through the recording of Evoked Compound Action Potentials (ECAPs), the sum of all action potentials elicited by an electrical stimulus applied to the fibres. ECAP amplitude grows linearly with stimulus current after a threshold, and a larger ECAP results in a stronger stimulus sensation for patients. This study investigates the effect of stimulus frequency on both the ECAP amplitude as well as the perceived stimulus sensation in patients undergoing SCS therapy for chronic back and/or leg pain.

Methods

Patients suffering with chronic neuropathic lower-back and/or lower-limb pain undergoing an epidural SCS trial were recruited. Patients were implanted according to standard practice, having two 8-contact leads (8 mm inter-electrode spacing) which overlapped 2–4 contacts around the T9/T10 interspace. Both lead together thus spanning about three vertebral levels. Neurophysiological recordings were taken during the patient’s trial phase at two routine follow-ups using a custom external stimulator capable of recording ECAPs in real-time from all non-stimulating contacts. Stimulation was performed at various vertebral levels, varying the frequency (ranging from 2 to 455 Hz) while all other stimulating variables were kept constant. During the experiments subjects were asked to rate the stimulation-induced sensation (paraesthesia) on a scale from 0 to 10.

Results

Frequency response curves showed an inverse relationship between stimulation sensation strength and ECAP amplitude, with higher frequencies generating smaller ECAPs but stronger stimulation-induced paraesthesia (at constant stimulation amplitude). Both relationships followed logarithmic trends against stimulus frequency meaning that the effects on ECAP amplitude and sensation are larger for smaller frequencies.

Conclusion

This work supports the hypothesis that SCS-induced paraesthesia is conveyed through both frequency coding and population coding, fitting known psychophysics of tactile sensory information processing. The inverse relationship between ECAP amplitude and sensation for increasing frequencies at fixed stimulus amplitude questions common assumptions of monotonic relationships between ECAP amplitude and sensation strength.

in Frontiers in Neuroscience: Neural Technology on January 21, 2021 12:00 AM.

• #### Deep Learning-Based Classification and Voxel-Based Visualization of Frontotemporal Dementia and Alzheimer’s Disease

in Frontiers in Neuroscience: Brain Imaging Methods on January 21, 2021 12:00 AM.

• #### The Correlations Between Plasma Fibrinogen With Amyloid-Beta and Tau Levels in Patients With Alzheimer’s Disease

Recent studies show that fibrinogen plays a role in the pathogenesis of Alzheimer’s disease (AD), which may be crucial to neurovascular damage and cognitive impairment. However, there are few clinical studies on the relationship between fibrinogen and AD. 59 11C-PiB-PET diagnosed AD patients and 76 age- and gender-matched cognitively normal controls were included to analyze the correlation between plasma β-amyloid (Aβ) and tau levels with fibrinogen levels. 35 AD patients and 76 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation between CSF Aβ and tau levels with fibrinogen levels. In AD patients, plasma fibrinogen levels were positively correlated with plasma Aβ40 and Aβ42 levels, and negatively correlated with CSF Aβ42 levels. Besides, fibrinogen levels were positively correlated with CSF total tau (t-tau), and phosphorylated tau-181 (p-tau) levels and positively correlated with the indicators of Aβ deposition in the brain, such as t-tau/Aβ42, p-tau/Aβ42 levels. In normal people, fibrinogen levels lack correlation with Aβ and tau levels in plasma and CSF. This study suggests that plasma fibrinogen levels are positively correlated with Aβ levels in the plasma and brain in AD patients. Fibrinogen may be involved in the pathogenesis of AD.

in Frontiers in Neuroscience: Neurodegeneration on January 21, 2021 12:00 AM.

• #### Edge-Aware Pyramidal Deformable Network for Unsupervised Registration of Brain MR Images

Deformable image registration is of essential important for clinical diagnosis, treatment planning, and surgical navigation. However, most existing registration solutions require separate rigid alignment before deformable registration, and may not well handle the large deformation circumstances. We propose a novel edge-aware pyramidal deformable network (referred as EPReg) for unsupervised volumetric registration. Specifically, we propose to fully exploit the useful complementary information from the multi-level feature pyramids to predict multi-scale displacement fields. Such coarse-to-fine estimation facilitates the progressive refinement of the predicted registration field, which enables our network to handle large deformations between volumetric data. In addition, we integrate edge information with the original images as dual-inputs, which enhances the texture structures of image content, to impel the proposed network pay extra attention to the edge-aware information for structure alignment. The efficacy of our EPReg was extensively evaluated on three public brain MRI datasets including Mindboggle101, LPBA40, and IXI30. Experiments demonstrate our EPReg consistently outperformed several cutting-edge methods with respect to the metrics of Dice index (DSC), Hausdorff distance (HD), and average symmetric surface distance (ASSD). The proposed EPReg is a general solution for the problem of deformable volumetric registration.

in Frontiers in Neuroscience: Brain Imaging Methods on January 21, 2021 12:00 AM.

• #### Interaction Between Mesenchymal Stem Cells and Retinal Degenerative Microenvironment

Retinal degenerative diseases (RDDs) are a group of diseases contributing to irreversible vision loss with yet limited therapies. Stem cell-based therapy is a promising novel therapeutic approach in RDD treatment. Mesenchymal stromal/stem cells (MSCs) have emerged as a leading cell source due to their neurotrophic and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Several pre-clinical studies have shown that MSCs have the potential to delay retinal degeneration, and recent clinical trials have demonstrated promising safety profiles for the application of MSCs in retinal disease. However, some of the clinical-stage MSC therapies have been unable to meet primary efficacy end points, and severe side effects were reported in some retinal “stem cell” clinics. In this review, we provide an update of the interaction between MSCs and the RDD microenvironment and discuss how to balance the therapeutic potential and safety concerns of MSCs' ocular application.

in Frontiers in Neuroscience: Neurodegeneration on January 21, 2021 12:00 AM.

• #### Nogo-C Inhibits Peripheral Nerve Regeneration by Regulating Schwann Cell Apoptosis and Dedifferentiation

While Nogo protein demonstrably inhibits nerve regeneration in the central nervous system (CNS), its effect on Schwann cells in peripheral nerve repair and regeneration following sciatic nerve injury remains unknown. In this research, We assessed the post-injury expression of Nogo-C in an experimental mouse model of sciatic nerve-crush injury. Nogo-C knockout (Nogo-C–/–) mouse was generated to observe the effect of Nogo-C on sciatic nerve regeneration, Schwann cell apoptosis, and myelin disintegration after nerve injury, and the effects of Nogo-C on apoptosis and dedifferentiation of Schwann cells were observed in vitro. We found that the expression of Nogo-C protein at the distal end of the injured sciatic nerve increased in wild type (WT) mice. Compared with the injured WT mice, the proportion of neuronal apoptosis was significantly diminished and the myelin clearance rate was significantly elevated in injured Nogo-C–/– mice; the number of nerve fibers regenerated and the degree of myelination were significantly elevated in Nogo-C–/– mice on Day 14 after injury. In addition, the recovery of motor function was significantly accelerated in the injured Nogo-C–/– mice. The overexpression of Nogo-C in primary Schwann cells using adenovirus-mediated gene transfer promoted Schwann cells apoptosis. Nogo-C significantly reduced the ratio of c-Jun/krox-20 expression, indicating its inhibition of Schwann cell dedifferentiation. Above all, we hold the view that the expression of Nogo-C increases following peripheral nerve injury to promote Schwann cell apoptosis and inhibit Schwann cell dedifferentiation, thereby inhibiting peripheral nerve regeneration.

in Frontiers in Neuroscience: Neurogenesis on January 21, 2021 12:00 AM.

• #### Alterations of Iron Level in the Bilateral Basal Ganglia Region in Patients With Middle Cerebral Artery Occlusion

Background and Purpose: The purpose of this study was to explore the changes of iron level using quantitative susceptibility mapping (QSM) in the bilateral basal ganglia region in middle cerebral artery occlusion (MCAO) patients with long-term ischemia.

Methods: Twenty-seven healthy controls and nine patients with MCAO were recruited, and their QSM images were obtained. The bilateral caudate nucleus (Cd), putamen (Pt), and globus pallidus (Gp) were selected as the regions of interest (ROIs). Susceptibility values of bilateral ROIs were calculated and compared between the affected side and unaffected side in patients with MCAO and between patients with MCAO and healthy controls. In addition, receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic capability of susceptibility values in differentiating healthy controls and patients with MCAO by the area under the curve (AUC).

Results: The susceptibility values of bilateral Cd were asymmetric in healthy controls; however, this asymmetry disappeared in patients with MCAO. In addition, compared with healthy controls, the average susceptibility values of the bilateral Pt in patients with MCAO were increased (P < 0.05), and the average susceptibility value of the bilateral Gp was decreased (P < 0.05). ROC curves showed that the susceptibility values of the Pt and Gp had a larger AUC (AUC = 0.700 and 0.889, respectively).

Conclusion: As measured by QSM, the iron levels of the bilateral basal ganglia region were significantly changed in patients with MCAO. Iron dyshomeostasis in the basal ganglia region might be involved in the pathophysiological process of middle cerebral artery stenosis and occlusion. These findings may provide a novel insight to profoundly address the pathophysiological mechanisms of MCAO.

in Frontiers in Neuroscience: Neurodegeneration on January 21, 2021 12:00 AM.

• #### Effects of Long-Term Meditation Practices on Sensorimotor Rhythm-Based Brain-Computer Interface Learning

Sensorimotor rhythm (SMR)-based brain–computer interfaces (BCIs) provide an alternative pathway for users to perform motor control using motor imagery. Despite the non-invasiveness, ease of use, and low cost, this kind of BCI has limitations due to long training times and BCI inefficiency—that is, the SMR BCI control paradigm may not work well on a subpopulation of users. Meditation is a mental training method to improve mindfulness and awareness and is reported to have positive effects on one’s mental state. Here, we investigated the behavioral and electrophysiological differences between experienced meditators and meditation naïve subjects in one-dimensional (1D) and two-dimensional (2D) cursor control tasks. We found numerical evidence that meditators outperformed control subjects in both tasks (1D and 2D), and there were fewer BCI inefficient subjects in the meditator group. Finally, we also explored the neurophysiological difference between the two groups and showed that the meditators had a higher resting SMR predictor, more stable resting mu rhythm, and a larger control signal contrast than controls during the task.

in Frontiers in Neuroscience: Neural Technology on January 21, 2021 12:00 AM.

• #### The Effects of Extracorporeal Shock Wave Therapy on Spastic Muscle of the Wrist Joint in Stroke Survivors: Evidence From Neuromechanical Analysis

Background: This study combined neuromechanical modeling analysis, muscle tone measurement from mechanical indentation and electrical impedance myography to assess the neural and peripheral contribution to spasticity post stroke at wrist joint. It also investigated the training effects and explored the underlying mechanism of radial extracorporeal shock wave (rESW) on spasticity.

Methods: People with first occurrence of stroke were randomly allocated to rESW intervention or control group. The intervention group received one session of rESW therapy, followed by routine therapy which was the same frequency and intensity as the control group. Outcome measures were: (1) NeuroFlexor method measured neural component (NC), elastic component (EC) and viscosity component (VC), and (2) myotonometer measured muscle tone (F) and stiffness (S), (3) electrical impedance myography measured resistance (R), reactance (X) and phase angle (θ); (4) modified Asworth scale; (5) Fugl Meyer Upper limb scale. All outcome measures were recorded at baseline, immediately post rESW and at 1-week follow-up. The differences between the paretic and non-paretic side were assessed by t-test. The effectiveness of rESW treatment were analyzed by repeated-measures one-way analysis of variance (ANOVA) at different time points.

Results: Twenty-seven participants completed the study. NC, EC, and VC of the Neuroflexor method, F and S from myotonometer were all significantly higher on the paretic side than those from the non-paretic side. R, X, and θ from electrical impedance were significantly lower on the paretic side than the non-paretic side. Immediately after rESW intervention, VC, F, and S were significantly reduced, and X was significantly increased. The clinical scores showed improvements immediate post rESW and at 1-week follow-up.

Conclusions: The observed changes in upper limb muscle properties adds further support to the theory that both the neural and peripheral components play a role in muscle spasticity. ESW intervention may be more effective in addressing the peripheral component of spasticity in terms of muscle mechanical properties changes. The clinical management of post stroke spasticity should take into consideration of both the neural and non-neural factors in order to identify optimal intervention regime.

in Frontiers in Neuroscience: Neural Technology on January 21, 2021 12:00 AM.

• #### Formulation of the Challenges in Brain-Computer Interfaces as Optimization Problems—A Review

Electroencephalogram (EEG) is one of the common modalities of monitoring the mental activities. Owing to the non-invasive availability of this system, its applicability has seen remarkable developments beyond medical use-cases. One such use case is brain-computer interfaces (BCI). Such systems require the usage of high resolution-based multi-channel EEG devices so that the data collection spans multiple locations of the brain like the occipital, frontal, temporal, and so on. This results in huge data (with high sampling rates) and with multiple EEG channels with inherent artifacts. Several challenges exist in analyzing data of this nature, for instance, selecting the optimal number of EEG channels or deciding what best features to rely on for achieving better performance. The selection of these variables is complicated and requires a lot of domain knowledge and non-invasive EEG monitoring, which is not feasible always. Hence, optimization serves to be an easy to access tool in deriving such parameters. Considerable efforts in formulating these issues as an optimization problem have been laid. As a result, various multi-objective and constrained optimization functions have been developed in BCI that has achieved reliable outcomes in device control like neuro-prosthetic arms, application control, gaming, and so on. This paper makes an attempt to study the usage of optimization techniques in formulating the issues in BCI. The outcomes, challenges, and major observations of these approaches are discussed in detail.

in Frontiers in Neuroscience: Brain Imaging Methods on January 21, 2021 12:00 AM.

• #### Resting State Functional Connectivity of Brain With Electroconvulsive Therapy in Depression: Meta-Analysis to Understand Its Mechanisms

Introduction: Electroconvulsive therapy (ECT) is a commonly used brain stimulation treatment for treatment-resistant or severe depression. This study was planned to find the effects of ECT on brain connectivity by conducting a systematic review and coordinate-based meta-analysis of the studies performing resting state fMRI (rsfMRI) in patients with depression receiving ECT.

Methods: We systematically searched the databases published up to July 31, 2020, for studies in patients having depression that compared resting-state functional connectivity (rsFC) before and after a course of pulse wave ECT. Meta-analysis was performed using the activation likelihood estimation method after extracting details about coordinates, voxel size, and method for correction of multiple comparisons corresponding to the significant clusters and the respective rsFC analysis measure with its method of extraction.

Results: Among 41 articles selected for full-text review, 31 articles were included in the systematic review. Among them, 13 articles were included in the meta-analysis, and a total of 73 foci of 21 experiments were examined using activation likelihood estimation in 10 sets. Using the cluster-level interference method, one voxel-wise analysis with the measure of amplitude of low frequency fluctuations and one seed-voxel analysis with the right hippocampus showed a significant reduction (p < 0.0001) in the left cingulate gyrus (dorsal anterior cingulate cortex) and a significant increase (p < 0.0001) in the right hippocampus with the right parahippocampal gyrus, respectively. Another analysis with the studies implementing network-wise (posterior default mode network: dorsomedial prefrontal cortex) resting state functional connectivity showed a significant increase (p < 0.001) in bilateral posterior cingulate cortex. There was considerable variability as well as a few key deficits in the preprocessing and analysis of the neuroimages and the reporting of results in the included studies. Due to lesser studies, we could not do further analysis to address the neuroimaging variability and subject-related differences.

Conclusion: The brain regions noted in this meta-analysis are reasonably specific and distinguished, and they had significant changes in resting state functional connectivity after a course of ECT for depression. More studies with better neuroimaging standards should be conducted in the future to confirm these results in different subgroups of depression and with varied aspects of ECT.

in Frontiers in Human Neuroscience on January 21, 2021 12:00 AM.

• #### A Functional MRI Paradigm for Efficient Mapping of Memory Encoding Across Sensory Conditions

We introduce a new and time-efficient memory-encoding paradigm for functional magnetic resonance imaging (fMRI). This paradigm is optimized for mapping multiple contrasts using a mixed design, using auditory (environmental/vocal) and visual (scene/face) stimuli. We demonstrate that the paradigm evokes robust neuronal activity in typical sensory and memory networks. We were able to detect auditory and visual sensory-specific encoding activities in auditory and visual cortices. Also, we detected stimulus-selective activation in environmental-, voice-, scene-, and face-selective brain regions (parahippocampal place and fusiform face area). A subsequent recognition task allowed the detection of sensory-specific encoding success activity (ESA) in both auditory and visual cortices, as well as sensory-unspecific positive ESA in the hippocampus. Further, sensory-unspecific negative ESA was observed in the precuneus. Among others, the parallel mixed design enabled sustained and transient activity comparison in contrast to rest blocks. Sustained and transient activations showed great overlap in most sensory brain regions, whereas several regions, typically associated with the default-mode network, showed transient rather than sustained deactivation. We also show that the use of a parallel mixed model had relatively little influence on positive or negative ESA. Together, these results demonstrate a feasible, versatile, and brief memory-encoding task, which includes multiple sensory stimuli to guarantee a comprehensive measurement. This task is especially suitable for large-scale clinical or population studies, which aim to test task-evoked sensory-specific and sensory-unspecific memory-encoding performance as well as broad sensory activity across the life span within a very limited time frame.

in Frontiers in Human Neuroscience on January 21, 2021 12:00 AM.

• #### An Evolutionary Perspective of Dyslexia, Stress, and Brain Network Homeostasis

Evolution fuels interindividual variability in neuroplasticity, reflected in brain anatomy and functional connectivity of the expanding neocortical regions subserving reading ability. Such variability is orchestrated by an evolutionarily conserved, competitive balance between epigenetic, stress-induced, and cognitive-growth gene expression programs. An evolutionary developmental model of dyslexia, suggests that prenatal and childhood subclinical stress becomes a risk factor for dyslexia when physiological adaptations to stress promoting adaptive fitness, may attenuate neuroplasticity in the brain regions recruited for reading. Stress has the potential to blunt the cognitive-growth functions of the predominantly right hemisphere Ventral and Dorsal attention networks, which are primed with high entropic levels of synaptic plasticity, and are critical for acquiring beginning reading skills. The attentional networks, in collaboration with the stress-responsive Default Mode network, modulate the entrainment and processing of the low frequency auditory oscillations (1–8 Hz) and visuospatial orienting linked etiologically to dyslexia. Thus, dyslexia may result from positive, but costly adaptations to stress system dysregulation: protective measures that reset the stress/growth balance of processing to favor the Default Mode network, compromising development of the attentional networks. Such a normal-variability conceptualization of dyslexia is at odds with the frequent assumption that dyslexia results from a neurological abnormality. To put the normal-variability model in the broader perspective of the state of the field, a traditional evolutionary account of dyslexia is presented to stimulate discussion of the scientific merits of the two approaches.

in Frontiers in Human Neuroscience on January 21, 2021 12:00 AM.

• #### A Functional Near-Infrared Spectroscopy Examination of the Neural Correlates of Cognitive Shifting in Dimensional Change Card Sort Task

This study aims to examine the neural correlates of cognitive shifting during the Dimensional Change Card Sort Task (DCCS) task with functional near-infrared spectroscopy. Altogether 49 children completed the DCCS tasks, and 25 children (Mage = 68.66, SD = 5.3) passing all items were classified into the Switch group. Twenty children (Mage = 62.05, SD = 8.13) committing more than one perseverative errors were grouped into the Perseverate group. The Switch group had Brodmann Area (BA) 9 and 10 activated in the pre-switch period and BA 6, 9, 10, 40, and 44 in the post-switch period. In contrast, the Perseverate group had BA 9 and 10 activated in the pre-switch period and BA 8, 9, 10 in the post-switch period. The general linear model results afford strong support to the “V-shape curve” hypothesis by identifying a significant decrease–increase cycle in BA 9 and 44, the neural correlations of cognitive shifting.

in Frontiers in Human Neuroscience on January 21, 2021 12:00 AM.

• #### Alzheimer’s Disease Projection From Normal to Mild Dementia Reflected in Functional Network Connectivity: A Longitudinal Study

Background

Alzheimer’s disease (AD) is the most common age-related problem and progresses in different stages, including mild cognitive impairment (early stage), mild dementia (middle-stage), and severe dementia (late-stage). Recent studies showed changes in functional network connectivity obtained from resting-state functional magnetic resonance imaging (rs-fMRI) during the transition from healthy aging to AD. By assuming that the brain interaction is static during the scanning time, most prior studies are focused on static functional or functional network connectivity (sFNC). Dynamic functional network connectivity (dFNC) explores temporal patterns of functional connectivity and provides additional information to its static counterpart.

Method

We used longitudinal rs-fMRI from 1385 scans (from 910 subjects) at different stages of AD (from normal to very mild AD or vmAD). We used group-independent component analysis (group-ICA) and extracted 53 maximally independent components (ICs) for the whole brain. Next, we used a sliding-window approach to estimate dFNC from the extracted 53 ICs, then group them into 3 different brain states using a clustering method. Then, we estimated a hidden Markov model (HMM) and the occupancy rate (OCR) for each subject. Finally, we investigated the link between the clinical rate of each subject with state-specific FNC, OCR, and HMM.

Results

All states showed significant disruption during progression normal brain to vmAD one. Specifically, we found that subcortical network, auditory network, visual network, sensorimotor network, and cerebellar network connectivity decrease in vmAD compared with those of a healthy brain. We also found reorganized patterns (i.e., both increases and decreases) in the cognitive control network and default mode network connectivity by progression from normal to mild dementia. Similarly, we found a reorganized pattern of between-network connectivity when the brain transits from normal to mild dementia. However, the connectivity between visual and sensorimotor network connectivity decreases in vmAD compared with that of a healthy brain. Finally, we found a normal brain spends more time in a state with higher connectivity between visual and sensorimotor networks.

Conclusion

Our results showed the temporal and spatial pattern of whole-brain FNC differentiates AD form healthy control and suggested substantial disruptions across multiple dynamic states. In more detail, our results suggested that the sensory network is affected more than other brain network, and default mode network is one of the last brain networks get affected by AD In addition, abnormal patterns of whole-brain dFNC were identified in the early stage of AD, and some abnormalities were correlated with the clinical score.

in Frontiers in Neural Circuits on January 21, 2021 12:00 AM.

• #### Development of Locomotor-Related Movements in Early Infancy

This mini-review focuses on the emergence of locomotor-related movements in early infancy. In particular, we consider multiples precursor behaviors of locomotion as a manifestation of the development of the neuronal networks and their link in the establishment of precocious locomotor skills. Despite the large variability of motor behavior observed in human babies, as in animals, afferent information is already processed to shape the behavior to specific situations and environments. Specifically, we argue that the closed-loop interaction between the neural output and the physical dynamics of the mechanical system should be considered to explore the complexity and flexibility of pattern generation in human and animal neonates.

in Frontiers in Cellular Neuroscience on January 21, 2021 12:00 AM.

• #### Attenuation of Native Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Volatile Anesthetic Sevoflurane in Mouse Thalamocortical Relay Neurons

As thalamocortical relay neurons are ascribed a crucial role in signal propagation and information processing, they have attracted considerable attention as potential targets for anesthetic modulation. In this study, we analyzed the effects of different concentrations of sevoflurane on the excitability of thalamocortical relay neurons and hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels, which play a decisive role in regulating membrane properties and rhythmic oscillatory activity. The effects of sevoflurane on single-cell excitability and native HCN channels were investigated in acutely prepared brain slices from adult wild-type mice with the whole-cell patch-clamp technique, using voltage-clamp and current-clamp protocols. Sevoflurane dose-dependently depressed membrane biophysics and HCN-mediated parameters of neuronal excitability. Respective half-maximal inhibitory and effective concentrations ranged between 0.30 (95% CI, 0.18–0.50) mM and 0.88 (95% CI, 0.40–2.20) mM. We witnessed a pronounced reduction of HCN dependent Ih current amplitude starting at a concentration of 0.45 mM [relative change at −133 mV; 0.45 mM sevoflurane: 0.85 (interquartile range, 0.79–0.92), n = 12, p = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34–0.62), n = 5, p < 0.001] with a half-maximal inhibitory concentration of 0.88 (95% CI, 0.40–2.20) mM. In contrast, effects on voltage-dependent channel gating were modest with significant changes only occurring at 1.47 mM [absolute change of half-maximal activation potential; 1.47 mM: −7.2 (interquartile range, −10.3 to −5.8) mV, n = 5, p = 0.020]. In this study, we demonstrate that sevoflurane inhibits the excitability of thalamocortical relay neurons in a concentration-dependent manner within a clinically relevant range. Especially concerning its effects on native HCN channel function, our findings indicate substance-specific differences in comparison to other anesthetic agents. Considering the importance of HCN channels, the observed effects might mechanistically contribute to the hypnotic properties of sevoflurane.

in Frontiers in Cellular Neuroscience on January 21, 2021 12:00 AM.

• #### Accurate Neuronal Soma Segmentation Using 3D Multi-Task Learning U-Shaped Fully Convolutional Neural Networks

Neuronal soma segmentation is a crucial step for the quantitative analysis of neuronal morphology. Automated neuronal soma segmentation methods have opened up the opportunity to improve the time-consuming manual labeling required during the neuronal soma morphology reconstruction for large-scale images. However, the presence of touching neuronal somata and variable soma shapes in images brings challenges for automated algorithms. This study proposes a neuronal soma segmentation method combining 3D U-shaped fully convolutional neural networks with multi-task learning. Compared to existing methods, this technique applies multi-task learning to predict the soma boundary to split touching somata, and adopts U-shaped architecture convolutional neural network which is effective for a limited dataset. The contour-aware multi-task learning framework is applied to the proposed method to predict the masks of neuronal somata and boundaries simultaneously. In addition, a spatial attention module is embedded into the multi-task model to improve neuronal soma segmentation results. The Nissl-stained dataset captured by the micro-optical sectioning tomography system is used to validate the proposed method. Following comparison to four existing segmentation models, the proposed method outperforms the others notably in both localization and segmentation. The novel method has potential for high-throughput neuronal soma segmentation in large-scale optical imaging data for neuron morphology quantitative analysis.

in Frontiers in Neuroanatomy on January 21, 2021 12:00 AM.

• #### Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease

The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.

in Frontiers in Ageing Neuroscience on January 21, 2021 12:00 AM.

• #### Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies

The goal of this review article is to provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure and function throughout life. We propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of, cognitive decline. Finally, we present examples of biological measures that may differentiate mechanisms of the cognitive reserve at the molecular, cellular, and network level.

in Frontiers in Ageing Neuroscience on January 21, 2021 12:00 AM.

• #### Correction: Drosophila PDGF/VEGF signaling from muscles to hepatocyte-like cells protects against obesity

in eLife on January 21, 2021 12:00 AM.

• #### Telomeric double-strand DNA-binding proteins DTN-1 and DTN-2 ensure germline immortality in Caenorhabditis elegans

Telomeres are nucleoprotein complexes at the ends of chromosomes and are indispensable for the protection and lengthening of terminal DNA. Despite the evolutionarily conserved roles of telomeres, the telomeric double-strand DNA (dsDNA)-binding proteins have evolved rapidly. Here, we identified double-strand telomeric DNA-binding proteins (DTN-1 and DTN-2) in Caenorhabditis elegans as non-canonical telomeric dsDNA-binding proteins. DTN-1 and DTN-2 are paralogous proteins that have three putative MYB-like DNA-binding domains and bind to telomeric dsDNA in a sequence-specific manner. DTN-1 and DTN-2 form complexes with the single-strand telomeric DNA-binding proteins POT-1 and POT-2 and constitutively localize to telomeres. The dtn-1 and dtn-2 genes function redundantly, and their simultaneous deletion results in progressive germline mortality, which accompanies telomere hyper-elongation and chromosomal bridges. Our study suggests that DTN-1 and DTN-2 are core shelterin components in C. elegans telomeres that act as negative regulators of telomere length and are essential for germline immortality.

in eLife on January 21, 2021 12:00 AM.

• #### Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength

The conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

in eLife on January 21, 2021 12:00 AM.

• #### The RNA-binding protein SFPQ preserves long-intron splicing and regulates circRNA biogenesis in mammals

Circular RNAs (circRNAs) represent an abundant and conserved entity of non-coding RNAs; however, the principles of biogenesis are currently not fully understood. Here, we identify two factors, splicing factor proline/glutamine rich (SFPQ) and non-POU domain-containing octamer-binding protein (NONO), to be enriched around circRNA loci. We observe a subclass of circRNAs, coined DALI circRNAs, with distal inverted Alu elements and long flanking introns to be highly deregulated upon SFPQ knockdown. Moreover, SFPQ depletion leads to increased intron retention with concomitant induction of cryptic splicing, premature transcription termination, and polyadenylation, particularly prevalent for long introns. Aberrant splicing in the upstream and downstream regions of circRNA producing exons are critical for shaping the circRNAome, and specifically, we identify missplicing in the immediate upstream region to be a conserved driver of circRNA biogenesis. Collectively, our data show that SFPQ plays an important role in maintaining intron integrity by ensuring accurate splicing of long introns, and disclose novel features governing Alu-independent circRNA production.

in eLife on January 21, 2021 12:00 AM.

• #### Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.

in eLife on January 21, 2021 12:00 AM.

• #### Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells

PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose proteins substrates and biological activities are poorly understood. We observed that PARP7 mRNA levels are lower in ovarian cancer patient samples compared to non-cancerous tissue, but PARP-7 protein nonetheless contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g., growth, migration). Global gene expression analyses in ovarian cancer cells subjected to PARP-7 depletion indicate biological roles for PARP-7 in cell-cell adhesion and gene regulation. To identify the MARylated substrates of PARP-7 in ovarian cancer cells, we developed an NAD+ analog-sensitive approach, which we coupled with mass spectrometry to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including cell-cell adhesion and cytoskeletal proteins. Specifically, we found that PARP-7 MARylates α-tubulin to promote microtubule instability, which may regulate ovarian cancer cell growth and motility. In sum, we identified an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes.

in eLife on January 21, 2021 12:00 AM.

• #### Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets

Poly(ADP-ribose) polymerase 7 (PARP-7) has emerged as a critically important member of a large enzyme family that catalyzes ADP-ribosylation in mammalian cells. PARP-7 is a critical regulator of the innate immune response. What remains unclear is the mechanism by which PARP-7 regulates this process, namely because the protein targets of PARP-7 mono-ADP-ribosylation (MARylation) are largely unknown. Here, we combine chemical genetics, proximity labeling, and proteome-wide amino acid ADP-ribosylation site profiling for identifying the direct targets and sites of PARP-7-mediated MARylation in a cellular context. We found that the inactive PARP family member, PARP-13—a critical regulator of the antiviral innate immune response—is a major target of PARP-7. PARP-13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. Proteome-wide ADP-ribosylation analysis reveals cysteine as a major MARylation acceptor of PARP-7. This study provides insight into PARP-7 targeting and MARylation site preference.

in eLife on January 21, 2021 12:00 AM.

• #### Hearing loss is associated with delayed neural responses to continuous speech

We investigated the impact of hearing loss on the neural processing of speech. Using a forward modelling approach, we compared the neural responses to continuous speech of 14 adults with sensorineural hearing loss with those of age-matched normal-hearing peers. Compared to their normal-hearing peers, hearing-impaired listeners had increased neural tracking and delayed neural responses to continuous speech in quiet. The latency also increased with the degree of hearing loss. As speech understanding decreased, neural tracking decreased in both population; however, a significantly different trend was observed for the latency of the neural responses. For normal-hearing listeners, the latency increased with increasing background noise level. However, for hearing-impaired listeners, this increase was not observed. Our results support that the neural response latency indicates the efficiency of neural speech processing. Hearing-impaired listeners process speech in silence less efficiently then normal-hearing listeners. Our results suggest that this reduction in neural speech processing efficiency is a gradual effect which occurs as hearing deteriorates. Moreover, the efficiency of neural speech processing in hearing-impaired listeners is already at its lowest level when listening to speech in quiet, while normal-hearing listeners show a further decrease in efficiently when the noise level increases. From our results, it is apparent that sound amplification does not solve hearing loss. Even when intelligibility is apparently perfect, hearing-impaired listeners process speech less efficiently.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### The VTA-BLA-NAc circuit for sex reward inhibited by VTA GABAergic neurons under stress in male mice

Anhedonia, inability to experience pleasure from rewarding or enjoyable activities, is the prominent symptom of depression that involves dysfunction of the reward processing system. Both genetic predisposition and life events are thought to increase the risk for depression, in particular life stress. The cellular mechanism underlying stress modulating the reward processing neural circuits and subsequently disrupting reward-related behaviors remains elusive. We identify the VTA-BLA-NAc pathway as being activated by sex reward. Blockade of this circuit induces depressive-like behaviors, while reactivation of VTA neurons associated with sexual rewarding experience acutely ameliorates the impairment of reward-seeking behaviors induced by chronic restraint stress. Our histological and electrophysiological results show that the VTA neuron subpopulation responding to restraint stress inhibits the responsiveness of the VTA dopaminergic neurons to sexual reward. Together, these results reveal the cellular mechanism by which stress influences the brain reward processing system and provide a potential target for depression treatment.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### Nodal GABA facilitates axon spike transmission in the spinal cord.

GABA is an inhibitory neurotransmitter that produces both postsynaptic and presynaptic inhibition. We describe here an opposing excitatory action of GABA that facilitates spike transmission at nodes of Ranvier in myelinated sensory axons in the spinal cord. This nodal facilitation results from axonal GABAA receptors that depolarize nodes toward threshold, enabling spike propagation past the many branch points that otherwise fail, as observed in spinal cords isolated from mice or rats. Activation of GABAergic neurons, either directly with optogenetics or indirectly with cutaneous stimulation, caused nodal facilitation that increased sensory transmission to motoneurons without postsynaptically exciting motoneurons. This increased transmission with optogenetic or cutaneous stimulation also occurred in awake mice and humans. Optogenetic inhibition of GABAergic neurons decreased sensory transmission, implying that axonal conduction relies on GABA. The concept of nodal facilitation likely generalizes to other large axons in the CNS, enabling recruitment of selective branches and functional pathways.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### Modulations of local synchrony over time lead to resting-state functional connectivity in a parsimonious large-scale brain model

Biophysical models of large-scale brain activity are a fundamental tool for understanding the mechanisms underlying the patterns observed with neuroimaging. These models combine a macroscopic description of the within- and between-ensemble dynamics of neurons within a single architecture. A challenge for these models is accounting for modulations of within-ensemble synchrony over time. Such modulations in local synchrony are fundamental for modeling behavioral tasks and resting-state activity. Another challenge comes from the difficulty in parametrizing large scale brain models which hinders researching principles related with between-ensembles differences. Here we derive a parsimonious large scale brain model that can describe fluctuations of local synchrony. Crucially, we do not reduce within-ensemble dynamics to macroscopic variables first, instead we consider within and between-ensemble interactions similarly while preserving their physiological differences. The dynamics of within-ensemble synchrony can be tuned with a parameter which manipulates local connectivity strength. We simulated resting-state static and time-resolved functional connectivity of alpha band envelopes in models with identical and dissimilar local connectivities. We show that functional connectivity emerges when there are high fluctuations of local and global synchrony simultaneously (i.e. metastable dynamics). We also show that for most ensembles, leaning towards local asynchrony or synchrony correlates with the functional connectivity with other ensembles, with the exception of some regions belonging to the default-mode network.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### Hyperoxia Inhibits the Growth of Mouse Forebrain Oligodendrocyte Progenitors

NG2 chondroitin sulfate proteoglycan positive oligodendrocyte progenitor cells (OPCs) reside throughout the brain. They divide asymmetrically and differentiate into myelinating oligodendrocytes throughout adulthood. OPCs have been successfully isolated from rodents using several techniques including magnetic beads, immunopanning and exploiting differential centripetal adhesion. Whereas rat OPCs are relatively simple to propagate in vitro, it has been difficult to expand mouse OPCs. Therefore, we evaluated the effects of oxygen levels, growth factors and extracellular matrix components to produce a simple and reproducible method to prepare large numbers of nearly homogenous cultures of primary mouse OPCs from postnatal day 0-2 mouse telencephala. Using the McCarthy and de Vellis mechanical separation method OPCs were separated from mixed culture of glial cells. When the OPCs were plated onto fibronectin coated tissue culture plates in a biochemically defined medium that contained fibroblast growth factor-2 (FGF-2) and platelet derived growth factor AA (PDGFAA), and they were maintained in a standard tissue culture incubator, they proliferated very slowly. By contrast, mouse OPCs doubled approximately every 7 days when maintained in a 2% oxygen, nitrogen buffered environment. After 3 passages, greater than 99% of these OPCs were NG2+/PDGFR+. In medium containing only FGF-2, mouse OPCs progressed to late stage OPCs whereupon A2B5 expression decreased and O4 expression increased. When these cells were differentiated between passages 1 and 3, the majority of the OPCs differentiated into MBP+ mature oligodendrocytes However, cells that were repeatedly passaged beyond 4 passages progressed to a late O4+ OPC (even with mitogens present) and when differentiated by mitogen removal a minority of the OPCs differentiated into MBP+ cells. These studies reveal significant differences between mouse and rat OPCs and an inhibitory role for oxygen in mouse OPC proliferation.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### Neuropsychological assessment and virtual reality training of social prediction in patients with cerebellar malformation

It has been proposed that impairments of the predictive function exerted by the cerebellum may account for social cognition deficits. Here, we integrated cerebellar functions in a predictive coding framework to elucidate how cerebellar alterations could affect the predictive processing of others' behavior. Experiment 1 demonstrated that cerebellar patients were impaired in relying on contextual information during action prediction, and this impairment was significantly associated with social cognition abilities. Experiment 2 indicated that patients with cerebellar malformation showed a domain-general deficit in using contextual information to predict both social and physical events. Experiment 3 provided first evidence that a social-prediction training in virtual reality could boost the ability to use context-based predictions to understand others' intentions. These findings shed new light on the predictive role of the cerebellum and its contribution to social cognition, paving the way for new approaches to the rehabilitation of the Cerebellar Cognitive Affective Syndrome.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### Pre-stimulus alpha activities predict the confidence in subjective judgment by modulating post-stimulus theta oscillation

Even when making arbitrary decisions, people tend to feel varying levels of confidence, which is associated with the pre-stimulus neural oscillation of the brain. We investigated varying confidence in a pure subjective judgment task, and how this confidence was predicted by pre-stimulus alpha oscillations. Participants made pure subjective judgments where their prior experience seems to be helpful but actually useless, and their fluctuating confidence was related to the choice boundary process rather than the evidence accumulation process, suggesting participants underwent varying confidence resulting from the internal signals. With EEG and MEG analyses, we not only revealed the linkage between confidence and pre-stimulus alpha activities, but also successfully located this linkage onto decision-making relevant brain areas, i.e. MCC/PCC and SMA. Moreover, we unveiled a specific pathway underlying such linkage, that is, the influence of pre-stimulus alpha activities on decision confidence was fulfilled through modulating post-stimulus theta activities of SMA.

in bioRxiv: Neuroscience on January 21, 2021 12:00 AM.

• #### News Feature: Tracing gold’s cosmic origin story [Earth, Atmospheric, and Planetary Sciences]

Astronomers thought they had finally figured out where the gold, platinum, and other heavy elements in the universe came from. In light of recent results, they’re not so sure. Desperate phone calls made in the dead of night rarely convey good news, much less first word of a major scientific...

in PNAS on January 20, 2021 08:33 PM.

• #### Liquid-crystal-based topological photonics [Physics]

Liquid crystals are complex fluids that allow exquisite control of light propagation thanks to their orientational order and optical anisotropy. Inspired by recent advances in liquid-crystal photo-patterning technology, we propose a soft-matter platform for assembling topological photonic materials that holds promise for protected unidirectional waveguides, sensors, and lasers. Crucial to...

in PNAS on January 20, 2021 08:33 PM.

• #### Glycoconjugate pathway connections revealed by sequence similarity network analysis of the monotopic phosphoglycosyl transferases [Biophysics and Computational Biology]

The monotopic phosphoglycosyl transferase (monoPGT) superfamily comprises over 38,000 nonredundant sequences represented in bacterial and archaeal domains of life. Members of the superfamily catalyze the first membrane-committed step in en bloc oligosaccharide biosynthetic pathways, transferring a phosphosugar from a soluble nucleoside diphosphosugar to a membrane-resident polyprenol phosphate. The singularity of...

in PNAS on January 20, 2021 08:33 PM.

• #### Interpretations of ground-state symmetry breaking and strong correlation in wavefunction and density functional theories [Physics]

Strong correlations within a symmetry-unbroken ground-state wavefunction can show up in approximate density functional theory as symmetry-broken spin densities or total densities, which are sometimes observable. They can arise from soft modes of fluctuations (sometimes collective excitations) such as spin-density or charge-density waves at nonzero wavevector. In this sense, an...

in PNAS on January 20, 2021 08:33 PM.

• #### Creating self-assembled arrays of mono-oxo (MoO3)1 species on TiO2(101) via deposition and decomposition of (MoO3)n oligomers [Chemistry]

Hierarchically ordered oxides are of critical importance in material science and catalysis. Unfortunately, the design and synthesis of such systems remains a key challenge to realizing their potential. In this study, we demonstrate how the deposition of small oligomeric (MoO3)1–6 clusters—formed by the facile sublimation of MoO3 powders—leads to the...

in PNAS on January 20, 2021 08:33 PM.

• #### Evolution in the weak-mutation limit: Stasis periods punctuated by fast transitions between saddle points on the fitness landscape [Evolution]

A mathematical analysis of the evolution of a large population under the weak-mutation limit shows that such a population would spend most of the time in stasis in the vicinity of saddle points on the fitness landscape. The periods of stasis are punctuated by fast transitions, in lnNe/s time (Ne,...

in PNAS on January 20, 2021 08:33 PM.

• #### Designing angle-independent structural colors using Monte Carlo simulations of multiple scattering [Engineering]

Disordered nanostructures with correlations on the scale of visible wavelengths can show angle-independent structural colors. These materials could replace dyes in some applications because the color is tunable and resists photobleaching. However, designing nanostructures with a prescribed color is difficult, especially when the application—cosmetics or displays, for example—requires specific component...

in PNAS on January 20, 2021 08:33 PM.

• #### Rational policymaking during a pandemic [Immunology and Inflammation]

Policymaking during a pandemic can be extremely challenging. As COVID-19 is a new disease and its global impacts are unprecedented, decisions are taken in a highly uncertain, complex, and rapidly changing environment. In such a context, in which human lives and the economy are at stake, we argue that using...

in PNAS on January 20, 2021 08:33 PM.

• #### Coronavirus replication-transcription complex: Vital and selective NMPylation of a conserved site in nsp9 by the NiRAN-RdRp subunit [Microbiology]

RNA-dependent RNA polymerases (RdRps) of the Nidovirales (Coronaviridae, Arteriviridae, and 12 other families) are linked to an amino-terminal (N-terminal) domain, called NiRAN, in a nonstructural protein (nsp) that is released from polyprotein 1ab by the viral main protease (Mpro). Previously, self-GMPylation/UMPylation activities were reported for an arterivirus NiRAN-RdRp nsp and...

in PNAS on January 20, 2021 08:00 PM.

• #### The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome [Microbiology]

The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis)....

in PNAS on January 20, 2021 08:00 PM.

• #### Passive filter design for fractional-order quaternion-valued neural networks with neutral delays and external disturbance

Publication date: Available online 20 January 2021

Source: Neural Networks

Author(s): Qiankun Song, Sihan Chen, Zhenjiang Zhao, Yurong Liu, Fuad E. Alsaadi

in Neural Networks on January 20, 2021 07:00 PM.

• #### Aggregative cycles evolve as a solution to conflicts in social investment

by Leonardo Miele, Silvia De Monte

Multicellular organization is particularly vulnerable to conflicts between different cell types when the body forms from initially isolated cells, as in aggregative multicellular microbes. Like other functions of the multicellular phase, coordinated collective movement can be undermined by conflicts between cells that spend energy in fuelling motion and ‘cheaters’ that get carried along. The evolutionary stability of collective behaviours against such conflicts is typically addressed in populations that undergo extrinsically imposed phases of aggregation and dispersal. Here, via a shift in perspective, we propose that aggregative multicellular cycles may have emerged as a way to temporally compartmentalize social conflicts. Through an eco-evolutionary mathematical model that accounts for individual and collective strategies of resource acquisition, we address regimes where different motility types coexist. Particularly interesting is the oscillatory regime that, similarly to life cycles of aggregative multicellular organisms, alternates on the timescale of several cell generations phases of prevalent solitary living and starvation-triggered aggregation. Crucially, such self-organized oscillations emerge as a result of evolution of cell traits associated to conflict escalation within multicellular aggregates.

in PLoS Computational Biology on January 20, 2021 02:00 PM.

• #### Estimating and interpreting secondary attack risk: Binomial considered biased

by Yushuf Sharker, Eben Kenah

The household secondary attack risk (SAR), often called the secondary attack rate or secondary infection risk, is the probability of infectious contact from an infectious household member A to a given household member B, where we define infectious contact to be a contact sufficient to infect B if he or she is susceptible. Estimation of the SAR is an important part of understanding and controlling the transmission of infectious diseases. In practice, it is most often estimated using binomial models such as logistic regression, which implicitly attribute all secondary infections in a household to the primary case. In the simplest case, the number of secondary infections in a household with m susceptibles and a single primary case is modeled as a binomial(m, p) random variable where p is the SAR. Although it has long been understood that transmission within households is not binomial, it is thought that multiple generations of transmission can be neglected safely when p is small. We use probability generating functions and simulations to show that this is a mistake. The proportion of susceptible household members infected can be substantially larger than the SAR even when p is small. As a result, binomial estimates of the SAR are biased upward and their confidence intervals have poor coverage probabilities even if adjusted for clustering. Accurate point and interval estimates of the SAR can be obtained using longitudinal chain binomial models or pairwise survival analysis, which account for multiple generations of transmission within households, the ongoing risk of infection from outside the household, and incomplete follow-up. We illustrate the practical implications of these results in an analysis of household surveillance data collected by the Los Angeles County Department of Public Health during the 2009 influenza A (H1N1) pandemic.

in PLoS Computational Biology on January 20, 2021 02:00 PM.

• #### Real-time resolution of short-read assembly graph using ONT long reads

by Son Hoang Nguyen, Minh Duc Cao, Lachlan Coin

A streaming assembly pipeline utilising real-time Oxford Nanopore Technology (ONT) sequencing data is important for saving sequencing resources and reducing time-to-result. A previous approach implemented in npScarf provided an efficient streaming algorithm for hybrid assembly but was relatively prone to mis-assemblies compared to other graph-based methods. Here we present npGraph, a streaming hybrid assembly tool using the assembly graph instead of the separated pre-assembly contigs. It is able to produce more complete genome assembly by resolving the path finding problem on the assembly graph using long reads as the traversing guide. Application to synthetic and real data from bacterial isolate genomes show improved accuracy while still maintaining a low computational cost. npGraph also provides a graphical user interface (GUI) which provides a real-time visualisation of the progress of assembly. The tool and source code is available at https://github.com/hsnguyen/assembly.

in PLoS Computational Biology on January 20, 2021 02:00 PM.

• #### Zika virus dynamics: Effects of inoculum dose, the innate immune response and viral interference

by Katharine Best, Dan H. Barouch, Jeremie Guedj, Ruy M. Ribeiro, Alan S. Perelson

Experimental Zika virus infection in non-human primates results in acute viral load dynamics that can be well-described by mathematical models. The inoculum dose that would be received in a natural infection setting is likely lower than the experimental infections and how this difference affects the viral dynamics and immune response is unclear. Here we study a dataset of experimental infection of non-human primates with a range of doses of Zika virus. We develop new models of infection incorporating both an innate immune response and viral interference with that response. We find that such a model explains the data better than models with no interaction between virus and the immune response. We also find that larger inoculum doses lead to faster dynamics of infection, but approximately the same total amount of viral production.

in PLoS Computational Biology on January 20, 2021 02:00 PM.

• #### Functional imaging of Bow Hunter's syndrome

in Annals of Neurology on January 20, 2021 12:07 PM.

• #### Self-Organizing Intelligent Matter: A blueprint for an AI generating algorithm. (arXiv:2101.07627v1 [cs.NE])

We propose an artificial life framework aimed at facilitating the emergence of intelligent organisms. In this framework there is no explicit notion of an agent: instead there is an environment made of atomic elements. These elements contain neural operations and interact through exchanges of information and through physics-like rules contained in the environment. We discuss how an evolutionary process can lead to the emergence of different organisms made of many such atomic elements which can coexist and thrive in the environment. We discuss how this forms the basis of a general AI generating algorithm. We provide a simplified implementation of such system and discuss what advances need to be made to scale it up further.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### Synaptic metaplasticity in binarized neural networks. (arXiv:2101.07592v1 [cs.NE])

Unlike the brain, artificial neural networks, including state-of-the-art deep neural networks for computer vision, are subject to "catastrophic forgetting": they rapidly forget the previous task when trained on a new one. Neuroscience suggests that biological synapses avoid this issue through the process of synaptic consolidation and metaplasticity: the plasticity itself changes upon repeated synaptic events. In this work, we show that this concept of metaplasticity can be transferred to a particular type of deep neural networks, binarized neural networks, to reduce catastrophic forgetting.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### A synthetic biology approach for the design of genetic algorithms with bacterial agents. (arXiv:2101.07540v1 [cs.NE])

Bacteria have been a source of inspiration for the design of evolutionary algorithms. At the beginning of the 20th century synthetic biology was born, a discipline whose goal is the design of biological systems that do not exist in nature, for example, programmable synthetic bacteria. In this paper, we introduce as a novelty the designing of evolutionary algorithms where all the steps are conducted by synthetic bacteria. To this end, we designed a genetic algorithm, which we have named BAGA, illustrating its utility solving simple instances of optimization problems such as function optimization, 0/1 knapsack problem, Hamiltonian path problem. The results obtained open the possibility of conceiving evolutionary algorithms inspired by principles, mechanisms and genetic circuits from synthetic biology. In summary, we can conclude that synthetic biology is a source of inspiration either for the design of evolutionary algorithms or for some of their steps, as shown by the results obtained in our simulation experiments.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### Intelligent Frame Selection as a Privacy-Friendlier Alternative to Face Recognition. (arXiv:2101.07529v1 [cs.CV])

The widespread deployment of surveillance cameras for facial recognition gives rise to many privacy concerns. This study proposes a privacy-friendly alternative to large scale facial recognition. While there are multiple techniques to preserve privacy, our work is based on the minimization principle which implies minimizing the amount of collected personal data. Instead of running facial recognition software on all video data, we propose to automatically extract a high quality snapshot of each detected person without revealing his or her identity. This snapshot is then encrypted and access is only granted after legal authorization. We introduce a novel unsupervised face image quality assessment method which is used to select the high quality snapshots. For this, we train a variational autoencoder on high quality face images from a publicly available dataset and use the reconstruction probability as a metric to estimate the quality of each face crop. We experimentally confirm that the reconstruction probability can be used as biometric quality predictor. Unlike most previous studies, we do not rely on a manually defined face quality metric as everything is learned from data. Our face quality assessment method outperforms supervised, unsupervised and general image quality assessment methods on the task of improving face verification performance by rejecting low quality images. The effectiveness of the whole system is validated qualitatively on still images and videos.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### A Surrogate-Assisted Variable Grouping Algorithm for General Large Scale Global Optimization Problems. (arXiv:2101.07430v1 [cs.NE])

Problem decomposition plays a vital role when applying cooperative coevolution (CC) to large scale global optimization problems. However, most learning-based decomposition algorithms either only apply to additively separable problems or face the issue of false separability detections. Directing against these limitations, this study proposes a novel decomposition algorithm called surrogate-assisted variable grouping (SVG). SVG first designs a general-separability-oriented detection criterion according to whether the optimum of a variable changes with other variables. This criterion is consistent with the separability definition and thus endows SVG with broad applicability and high accuracy. To reduce the fitness evaluation requirement, SVG seeks the optimum of a variable with the help of a surrogate model rather than the original expensive high-dimensional model. Moreover, it converts the variable grouping process into a dynamic-binary-tree search one, which facilitates reutilizing historical separability detection information and thus reducing detection times. To evaluate the performance of SVG, a suite of benchmark functions with up to 2000 dimensions, including additively and non-additively separable ones, were designed. Experimental results on these functions indicate that, compared with six state-of-the-art decomposition algorithms, SVG possesses broader applicability and competitive efficiency. Furthermore, it can significantly enhance the optimization performance of CC.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### ES-ENAS: Combining Evolution Strategies with Neural Architecture Search at No Extra Cost for Reinforcement Learning. (arXiv:2101.07415v1 [cs.LG])

We introduce ES-ENAS, a simple neural architecture search (NAS) algorithm for the purpose of reinforcement learning (RL) policy design, by combining Evolutionary Strategies (ES) and Efficient NAS (ENAS) in a highly scalable and intuitive way. Our main insight is noticing that ES is already a distributed blackbox algorithm, and thus we may simply insert a model controller from ENAS into the central aggregator in ES and obtain weight sharing properties for free. By doing so, we bridge the gap from NAS research in supervised learning settings to the reinforcement learning scenario through this relatively simple marriage between two different lines of research, and are one of the first to apply controller-based NAS techniques to RL. We demonstrate the utility of our method by training combinatorial neural network architectures for RL problems in continuous control, via edge pruning and weight sharing. We also incorporate a wide variety of popular techniques from modern NAS literature, including multiobjective optimization and varying controller methods, to showcase their promise in the RL field and discuss possible extensions. We achieve >90% network compression for multiple tasks, which may be special interest in mobile robotics with limited storage and computational resources.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### Training Learned Optimizers with Randomly Initialized Learned Optimizers. (arXiv:2101.07367v1 [cs.LG])

Learned optimizers are increasingly effective, with performance exceeding that of hand designed optimizers such as Adam~\citep{kingma2014adam} on specific tasks \citep{metz2019understanding}. Despite the potential gains available, in current work the meta-training (or `outer-training') of the learned optimizer is performed by a hand-designed optimizer, or by an optimizer trained by a hand-designed optimizer \citep{metz2020tasks}. We show that a population of randomly initialized learned optimizers can be used to train themselves from scratch in an online fashion, without resorting to a hand designed optimizer in any part of the process. A form of population based training is used to orchestrate this self-training. Although the randomly initialized optimizers initially make slow progress, as they improve they experience a positive feedback loop, and become rapidly more effective at training themselves. We believe feedback loops of this type, where an optimizer improves itself, will be important and powerful in the future of machine learning. These methods not only provide a path towards increased performance, but more importantly relieve research and engineering effort.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### Benchmarking Perturbation-based Saliency Maps for Explaining Deep Reinforcement Learning Agents. (arXiv:2101.07312v1 [cs.LG])

Recent years saw a plethora of work on explaining complex intelligent agents. One example is the development of several algorithms that generate saliency maps which show how much each pixel attributed to the agents' decision. However, most evaluations of such saliency maps focus on image classification tasks. As far as we know, there is no work which thoroughly compares different saliency maps for Deep Reinforcement Learning agents. This paper compares four perturbation-based approaches to create saliency maps for Deep Reinforcement Learning agents trained on four different Atari 2600 games. All four approaches work by perturbing parts of the input and measuring how much this affects the agent's output. The approaches are compared using three computational metrics: dependence on the learned parameters of the agent (sanity checks), faithfulness to the agent's reasoning (input degradation), and run-time.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### Guided parallelized stochastic gradient descent for delay compensation. (arXiv:2101.07259v1 [cs.LG])

Stochastic gradient descent (SGD) algorithm and its variations have been effectively used to optimize neural network models. However, with the rapid growth of big data and deep learning, SGD is no longer the most suitable choice due to its natural behavior of sequential optimization of the error function. This has led to the development of parallel SGD algorithms, such as asynchronous SGD (ASGD) and synchronous SGD (SSGD) to train deep neural networks. However, it introduces a high variance due to the delay in parameter (weight) update. We address this delay in our proposed algorithm and try to minimize its impact. We employed guided SGD (gSGD) that encourages consistent examples to steer the convergence by compensating the unpredictable deviation caused by the delay. Its convergence rate is also similar to A/SSGD, however, some additional (parallel) processing is required to compensate for the delay. The experimental results demonstrate that our proposed approach has been able to mitigate the impact of delay for the quality of classification accuracy. The guided approach with SSGD clearly outperforms sequential SGD and even achieves the accuracy close to sequential SGD for some benchmark datasets.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 20, 2021 01:30 AM.

• #### Library-based Fast Algorithm for Simulating the Hodgkin-Huxley Neuronal Networks. (arXiv:2101.07257v1 [q-bio.NC])

We present a modified library-based method for simulating the Hodgkin-Huxley (HH) neuronal networks. By pre-computing a high resolution data library during the interval of an action potential (spike), we can avoid evolving the HH equations during the spike and can use a large time step to raise efficiency. The library method can stably achieve at most 10 times of speedup compared with the regular Runge-Kutta method while capturing most statistical properties of HH neurons like the distribution of spikes which data is widely used in the statistical analysis like transfer entropy and Granger causality. The idea of library method can be easily and successfully applied to other HH-type models like the most prominent \textquotedblleft regular spiking\textquotedblright , \textquotedblleft fast spiking\textquotedblright , \textquotedblleft intrinsically bursting\textquotedblright{} and \textquotedblleft low-threshold spike\textquotedblright{} types of HH models.

in arXiv: Quantitative Biology: Neurons and Cognition on January 20, 2021 01:30 AM.

• #### NINJ1 mediates plasma membrane rupture during lytic cell death

Nature, Published online: 20 January 2021; doi:10.1038/s41586-021-03218-7

NINJ1 mediates plasma membrane rupture during lytic cell death

in Nature on January 20, 2021 12:00 AM.

• #### Decoding and perturbing decision states in real time

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03181-9

In macaque motor cortex, moment-to-moment fluctuations in neurally derived decision variables are tightly linked to decision state and predict behavioural choices with better accuracy than condition-averaged decision variables or the visual stimulus alone, and can be used to distinguish between different models of decision making.

in Nature on January 20, 2021 12:00 AM.

• #### Tracking break-induced replication shows that it stalls at roadblocks

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03172-w

A method of tracking break-induced replication reveals the details of this repair process and shows that it can be impaired by certain genomic elements and by transcription.

in Nature on January 20, 2021 12:00 AM.

• #### Survey of spiking in the mouse visual system reveals functional hierarchy

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03171-x

A large, open dataset containing parallel recordings from six visual cortical and two thalamic areas of the mouse brain is presented, from which the relative timing of activity in response to visual stimuli and behaviour is used to construct a hierarchy scheme that corresponds to anatomical connectivity data.

in Nature on January 20, 2021 12:00 AM.

• #### Striatal activity topographically reflects cortical activity

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03166-8

Simultaneous mapping of activity across the cortex and dorsal striatum in mice shows that activity in each part of the striatum precisely mirrors that in topographically associated cortical regions, consistently across behavioural contexts.

in Nature on January 20, 2021 12:00 AM.

• #### Restoring metabolism of myeloid cells reverses cognitive decline in ageing

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03160-0

In aged mice, inhibition of prostaglandin E2 (PGE2) signalling through its receptor EP2 improves cellular bioenergetics, reduces inflammatory responses and restores hippocampal plasticity to youthful levels, resulting in an improvement in spatial memory and cognition.

in Nature on January 20, 2021 12:00 AM.

• #### Dopamine-based mechanism for transient forgetting

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03154-y

A dopamine neuron that underpins transient forgetting in Drosophila is activated by the presentation of interfering stimuli immediately before memory retrieval, modulating this retrieval by stimulating a dopamine receptor in mushroom body neurons.

in Nature on January 20, 2021 12:00 AM.

• #### Monitoring hiring discrimination through online recruitment platforms

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03136-0

An analysis of the search behaviour of recruiters on a Swiss online recruitment platform shows that jobseekers from minority ethnic groups are less likely to be contacted by recruiters, and also provides evidence of gender-based discrimination.

in Nature on January 20, 2021 12:00 AM.

• #### A stable low-temperature H2-production catalyst by crowding Pt on α-MoC

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03130-6

A stable, low-temperature water–gas shift catalyst is achieved by crowding platinum atoms and clusters on α-molybdenum carbide; the crowding protects the support from oxidation that would cause catalyst deactivation.

in Nature on January 20, 2021 12:00 AM.

• #### Lessons from the host defences of bats, a unique viral reservoir

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03128-0

Unique biological traits of bats and adaptive evolution associated with flight confer immunotolerance of viral infection that may help to make bats special reservoir hosts for viruses.

in Nature on January 20, 2021 12:00 AM.

• #### Bulk–disclination correspondence in topological crystalline insulators

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03125-3

It is experimentally shown that topological states exist at crystallographic defects in the bulk and that disclination defects trap fractional charges characteristic of topological crystalline insulators.

in Nature on January 20, 2021 12:00 AM.

• #### A reprogrammable mechanical metamaterial with stable memory

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03123-5

A reprogrammable mechanical metamaterial constructed of bistable unit cells that can be switched independently and reversibly between two stable states with distinct mechanical properties using magnetic actuation is demonstrated.

in Nature on January 20, 2021 12:00 AM.

• #### Observation of the onset of a blue jet into the stratosphere

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03122-6

Observations from the International Space Station show a blue jet that is initiated by an intense blue flash in the top of a thunderstorm cloud.

in Nature on January 20, 2021 12:00 AM.

• #### Lake heatwaves under climate change

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03119-1

Modelling and remote sensing show that by the end of the twenty-first century, lake heatwaves will be several degrees Celsius warmer and some will be months longer, with potentially major adverse consequences for lake ecosystems.

in Nature on January 20, 2021 12:00 AM.

• #### Trapped fractional charges at bulk defects in topological insulators

Nature, Published online: 20 January 2021; doi:10.1038/s41586-020-03117-3

It is experimentally shown that crystallographic defects may trap fractional charges, as well as topological states, in the bulk of topological crystalline insulators.

in Nature on January 20, 2021 12:00 AM.

• #### Fly fighters

Nature Reviews Neuroscience, Published online: 20 January 2021; doi:10.1038/s41583-021-00430-2

In flies, neurons that are common to both sexes regulate aggressive approach, whereas other, sex-specific neurons control attack behaviours.

in Nature Reviews on January 20, 2021 12:00 AM.

• #### Author Correction: Anthropogenic modification of forests means only 40% of remaining forests have high ecosystem integrity

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-021-20999-7

Author Correction: Anthropogenic modification of forests means only 40% of remaining forests have high ecosystem integrity

in Nature Communications on January 20, 2021 12:00 AM.

• #### Author Correction: Nutrients cause grassland biomass to outpace herbivory

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-021-20985-z

Author Correction: Nutrients cause grassland biomass to outpace herbivory

in Nature Communications on January 20, 2021 12:00 AM.

• #### Author Correction: Accelerated single cell seeding in relapsed multiple myeloma

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-021-20978-y

Author Correction: Accelerated single cell seeding in relapsed multiple myeloma

in Nature Communications on January 20, 2021 12:00 AM.

• #### Single-cell analysis of Schistosoma mansoni identifies a conserved genetic program controlling germline stem cell fate

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20794-w

Our understanding of how the germline of the parasitic flatworm Schistosoma mansoni develops is limited. Here, the authors use single cell RNAseq and functional genomic analysis of juvenile worms to identify a regulatory program that mediates the fate of germline stem cells between proliferation and differentiation.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Pseudo-bilayer architecture enables high-performance organic solar cells with enhanced exciton diffusion length

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20791-z

The so-called pseudo-bilayer (PB) organic solar cell (OSC) device architecture can promote enhanced exciton dissociation and charge transport, leading to improved device performance. Here, the authors report high-efficiency OSCs that features a PB architecture and optimized ternary system.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Molecular determinants and mechanism for antibody cocktail preventing SARS-CoV-2 escape

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20789-7

Antibody cocktails represent a promising approach to prevent SARS-CoV-2 escape. Here, Ku et al., identify SARS-CoV-2 neutralizing antibodies from a phage library and identify an antibody combination that prevents viral escape and protects mice from viral challenge.

in Nature Communications on January 20, 2021 12:00 AM.

• #### UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20784-y

The mitochondrial network expands to accommodate cell growth, but how scaling occurs is unclear. Here, the authors show in C. elegans that ATFS-1 mitochondrial import is reduced when mitochondrial proteins are highly expressed, activating the unfolded protein response and causing expansion.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20770-4

Enantioselective functionalization of ubiquitous C(sp3)–H bonds via radical species has witnessed a renaissance in the past years. Here, the authors summarize the main achievements in the field by identifying two main reaction pathways determining the stereochemistry and give an outlook on future challenges and opportunities.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Structure of a microtubule-bound axonemal dynein

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20735-7

Axonemal dyneins are tethered to doublet microtubules inside cilia to drive ciliary beating but the mechanisms regulating their localization and function are poorly understood. Here authors report a cryo-EM reconstruction of a three-headed axonemal dynein natively bound to doublet microtubules isolated from cilia which provides a framework to understand the roles of individual subunits.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Short H2A histone variants are expressed in cancer

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20707-x

Short H2A variants are testis-specific histones that destabilize nucleosomes during spermatogenesis. In this study, the authors show that these variants are expressed in an array of different cancers and identify splicing changes associated with nucleosome instability in these malignancies.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Unravelling an oxygen-mediated reductive quenching pathway for photopolymerisation under long wavelengths

Nature Communications, Published online: 20 January 2021; doi:10.1038/s41467-020-20640-z

Photomediated-reversible-deactivation radical polymerisation has a limited scope of available photocatalysts due to multiple stringent requirements of properties. Here the authors show, an oxygen-mediated reductive quenching pathway for photoinduced electron transfer reversible addition-fragmentation chain transfer polymerisation.

in Nature Communications on January 20, 2021 12:00 AM.

• #### Daily briefing: How Biden will jump start climate action on his first day

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00169-x

US President Joe Biden’s first day will be a green sweep, the ten greatest predictions in physics and rogue antibodies could be driving severe COVID.

in Nature on January 20, 2021 12:00 AM.

• #### Zoom fatigue saps grant reviewers’ attention

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00161-5

Referees for the US National Institutes of Health report engaging less during virtual panel meetings — but most think review quality doesn’t suffer.

in Nature on January 20, 2021 12:00 AM.

• #### Hiring discrimination laid bare by mountain of data

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00157-1

Analysis of hundreds of thousands of job searches shows that recruiters will discriminate based on ethnicity and gender, and the neural circuitry behind a brief period of forgetting.

in Nature on January 20, 2021 12:00 AM.

• #### Fear of the empty

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00122-y

Broken dreams.

in Nature on January 20, 2021 12:00 AM.

• #### How science can put the Sustainable Development Goals back on track

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00104-0

The COVID-19 pandemic has disrupted the UN’s flagship plan to end poverty and protect the environment. Researchers need to launch a rapid response.

in Nature on January 20, 2021 12:00 AM.

• #### Mechanical memory written and read remotely

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00080-5

A device has been developed that consists of mechanical bits, analogous to the magnetic bits used in computer hard drives. Information encoded in the bits programs the mechanical properties of the device.

in Nature on January 20, 2021 12:00 AM.

• #### Electrons broken into pieces at crystal defects

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00079-y

Fractional electric charges have been observed at crystal defects in artificial structures resembling materials called topological crystalline insulators. Such fractional charges could have various engineering applications.

in Nature on January 20, 2021 12:00 AM.

• #### Ten computer codes that transformed science

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00075-2

From Fortran to arXiv.org, these advances in programming and platforms sent biology, climate science and physics into warp speed.

in Nature on January 20, 2021 12:00 AM.

• #### Biden’s science adviser, COVID reinfections and vaccine tests

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00074-3

The latest science news, in brief.

in Nature on January 20, 2021 12:00 AM.

• #### Reversal of immune-cell shutdown protects the ageing brain

Nature, Published online: 20 January 2021; doi:10.1038/d41586-021-00063-6

Immune cells called macrophages have been found to shut down major metabolic pathways during ageing. Restoring metabolism in these cells is sufficient to alleviate age-associated cognitive decline in mice.

in Nature on January 20, 2021 12:00 AM.

### Abstract

The free energy principle (FEP) in the neurosciences stipulates that all viable agents induce and minimize informational free energy in the brain to fit their environmental niche. In this study, we continue our effort to make the FEP a more physically principled formalism by implementing free energy minimization based on the principle of least action. We build a Bayesian mechanics (BM) by casting the formulation reported in the earlier publication (Kim in Neural Comput 30:2616–2659, 2018, https://doi.org/10.1162/neco_a_01115) to considering active inference beyond passive perception. The BM is a neural implementation of variational Bayes under the FEP in continuous time. The resulting BM is provided as an effective Hamilton’s equation of motion and subject to the control signal arising from the brain’s prediction errors at the proprioceptive level. To demonstrate the utility of our approach, we adopt a simple agent-based model and present a concrete numerical illustration of the brain performing recognition dynamics by integrating BM in neural phase space. Furthermore, we recapitulate the major theoretical architectures in the FEP by comparing our approach with the common state-space formulations.

in Biological Cybernetics on January 20, 2021 12:00 AM.

• #### Letter to the editors: comment on “Emerging themes in idiopathic intracranial hypertension”

in Journal of Neurology on January 20, 2021 12:00 AM.

• #### Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/− Mouse Model of Huntington's Disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

in Frontiers in Systems Neuroscience on January 20, 2021 12:00 AM.

• #### Scale-Free Dynamics in Animal Groups and Brain Networks

Collective phenomena fascinate by the emergence of order in systems composed of a myriad of small entities. They are ubiquitous in nature and can be found over a vast range of scales in physical and biological systems. Their key feature is the seemingly effortless emergence of adaptive collective behavior that cannot be trivially explained by the properties of the system's individual components. This perspective focuses on recent insights into the similarities of correlations for two apparently disparate phenomena: flocking in animal groups and neuronal ensemble activity in the brain. We first will summarize findings on the spontaneous organization in bird flocks and macro-scale human brain activity utilizing correlation functions and insights from critical dynamics. We then will discuss recent experimental findings that apply these approaches to the collective response of neurons to visual and motor processing, i.e., to local perturbations of neuronal networks at the meso- and microscale. We show how scale-free correlation functions capture the collective organization of neuronal avalanches in evoked neuronal populations in nonhuman primates and between neurons during visual processing in rodents. These experimental findings suggest that the coherent collective neural activity observed at scales much larger than the length of the direct neuronal interactions is demonstrative of a phase transition and we discuss the experimental support for either discontinuous or continuous phase transitions. We conclude that at or near a phase-transition neuronal information can propagate in the brain with similar efficiency as proposed to occur in the collective adaptive response observed in some animal groups.

in Frontiers in Systems Neuroscience on January 20, 2021 12:00 AM.

• #### Chronic Intermittent Hypobaric Hypoxia Restores Hippocampus Function and Rescues Cognitive Impairments in Chronic Epileptic Rats via Wnt/β-catenin Signaling

Epilepsy is a complex neurological disorder with frequent psychiatric, cognitive, and social comorbidities in addition to recurrent seizures. Cognitive impairment, one of the most common comorbidities, has severe adverse effects on quality of life. Chronic intermittent hypobaric hypoxia (CIHH) has demonstrated neuroprotective efficacy in several neurological disease models. In the present study, we examined the effects of CIHH on cognition and hippocampal function in chronic epileptic rats. CIHH treatment rescued deficits in spatial and object memory, hippocampal neurogenesis, and synaptic plasticity in pilocarpine-treated epileptic rats. The Wnt/β-catenin pathway has been implicated in neural stem cell proliferation and synapse development, and Wnt/β-catenin pathway inhibition effectively blocked the neurogenic effects of CIHH. Our findings indicate that CIHH rescues cognitive deficits in epileptic rats via Wnt/β-catenin pathway activation. This study establishes CIHH and Wnt/β-catenin pathway regulators as potential treatments for epilepsy- induced cognitive impairments.

in Frontiers in Molecular Neuroscience on January 20, 2021 12:00 AM.

• #### Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/β-Catenin Pathway After Ischemic Stroke

Ischemic stroke has been becoming one of the leading causes resulting in mortality and adult long-term disability worldwide. Post-stroke pneumonia is a common complication in patients with ischemic stroke and always associated with 1-year mortality. Though ambroxol therapy often serves as a supplementary treatment for post-stroke pneumonia in ischemic stroke patients, its effect on functional recovery and potential mechanism after ischemic stroke remain elusive. In the present study, the results indicated that administration of 70 mg/kg and 100 mg/kg enhanced functional recovery by virtue of decreasing infarct volume. The potential mechanism, to some extent, was due to promoting NSCs differentiation into neurons and interfering NSCs differentiation into astrocytes through increasing GCase expression to activate Wnt/β-catenin signaling pathway in penumbra after ischemic stroke, which advanced basic knowledge of ambroxol in regulating NSCs differentiation and provided a feasible therapy for ischemic stroke treatment, even in other brain disorders in clinic.

in Frontiers in Molecular Neuroscience on January 20, 2021 12:00 AM.

• #### Machine Learning Methods for Diagnosing Autism Spectrum Disorder and Attention- Deficit/Hyperactivity Disorder Using Functional and Structural MRI: A Survey

Here we summarize recent progress in machine learning model for diagnosis of Autism Spectrum Disorder (ASD) and Attention-deficit/Hyperactivity Disorder (ADHD). We outline and describe the machine-learning, especially deep-learning, techniques that are suitable for addressing research questions in this domain, pitfalls of the available methods, as well as future directions for the field. We envision a future where the diagnosis of ASD, ADHD, and other mental disorders is accomplished, and quantified using imaging techniques, such as MRI, and machine-learning models.

in Frontiers in Neuroinformatics on January 20, 2021 12:00 AM.

• #### Development and Health of Adults Formerly Placed in Infant Care Institutions – Study Protocol of the LifeStories Project

A growing volume of research from global data demonstrates that institutional care under conditions of deprivation is profoundly damaging to children, particularly during the critical early years of development. However, how these individuals develop over a life course remains unclear. This study uses data from a survey on the health and development of 420 children mostly under the age of three, placed in 12 infant care institutions between 1958 and 1961 in Zurich, Switzerland. The children exhibited significant delays in cognitive, social, and motor development in the first years of life. Moreover, a follow-up of a subsample of 143 children about 10 years later revealed persistent difficulties, including depression, school related-problems, and stereotypies. Between 2019 and 2021, these formerly institutionalized study participants were located through the Swiss population registry and invited to participate once again in the research project. Now in their early sixties, they are studied for their health, further development, and life-course trajectories. A mixed-methods approach using questionnaires, neuropsychological assessments, and narrative biographical interviews was implemented by a multidisciplinary team. Combining prospective and retrospective data with standardized quantitative and biographical qualitative data allows a rich reconstruction of life histories. The availability of a community sample from the same geographic location, the 1954–1961 cohort of the Zurich Longitudinal Studies, described in detail in a paper in this issue (Wehrle et al., 2020), enables comparison with an unaffected cohort. This article describes the study design and study participants in detail and discusses the potential and limitations of a comparison with a community sample. It outlines a set of challenges and solutions encountered in the process of a lifespan longitudinal study from early childhood into the cusp of old age with a potentially vulnerable sample and summarizes the lessons learned along the way.

in Frontiers in Human Neuroscience on January 20, 2021 12:00 AM.

• #### Modulation of Functional Connectivity and Low-Frequency Fluctuations After Brain-Computer Interface-Guided Robot Hand Training in Chronic Stroke: A 6-Month Follow-Up Study

Hand function improvement in stroke survivors in the chronic stage usually plateaus by 6 months. Brain-computer interface (BCI)-guided robot-assisted training has been shown to be effective for facilitating upper-limb motor function recovery in chronic stroke. However, the underlying neuroplasticity change is not well understood. This study aimed to investigate the whole-brain neuroplasticity changes after 20-session BCI-guided robot hand training, and whether the changes could be maintained at the 6-month follow-up. Therefore, the clinical improvement and the neurological changes before, immediately after, and 6 months after training were explored in 14 chronic stroke subjects. The upper-limb motor function was assessed by Action Research Arm Test (ARAT) and Fugl-Meyer Assessment for Upper-Limb (FMA), and the neurological changes were assessed using resting-state functional magnetic resonance imaging. Repeated-measure ANOVAs indicated that long-term motor improvement was found by both FMA (F[2,26] = 6.367, p = 0.006) and ARAT (F[2,26] = 7.230, p = 0.003). Seed-based functional connectivity analysis exhibited that significantly modulated FC was observed between ipsilesional motor regions (primary motor cortex and supplementary motor area) and contralesional areas (supplementary motor area, premotor cortex, and superior parietal lobule), and the effects were sustained after 6 months. The fALFF analysis showed that local neuronal activities significantly increased in central, frontal and parietal regions, and the effects were also sustained after 6 months. Consistent results in FC and fALFF analyses demonstrated the increase of neural activities in sensorimotor and fronto-parietal regions, which were highly involved in the BCI-guided training.

Clinical Trial Registration: This study has been registered at ClinicalTrials.gov with clinical trial registration number NCT02323061.

in Frontiers in Human Neuroscience on January 20, 2021 12:00 AM.

• #### Two-Level Domain Adaptation Neural Network for EEG-Based Emotion Recognition

Emotion recognition plays an important part in human-computer interaction (HCI). Currently, the main challenge in electroencephalogram (EEG)-based emotion recognition is the non-stationarity of EEG signals, which causes performance of the trained model decreasing over time. In this paper, we propose a two-level domain adaptation neural network (TDANN) to construct a transfer model for EEG-based emotion recognition. Specifically, deep features from the topological graph, which preserve topological information from EEG signals, are extracted using a deep neural network. These features are then passed through TDANN for two-level domain confusion. The first level uses the maximum mean discrepancy (MMD) to reduce the distribution discrepancy of deep features between source domain and target domain, and the second uses the domain adversarial neural network (DANN) to force the deep features closer to their corresponding class centers. We evaluated the domain-transfer performance of the model on both our self-built data set and the public data set SEED. In the cross-day transfer experiment, the ability to accurately discriminate joy from other emotions was high: sadness (84%), anger (87.04%), and fear (85.32%) on the self-built data set. The accuracy reached 74.93% on the SEED data set. In the cross-subject transfer experiment, the ability to accurately discriminate joy from other emotions was equally high: sadness (83.79%), anger (84.13%), and fear (81.72%) on the self-built data set. The average accuracy reached 87.9% on the SEED data set, which was higher than WGAN-DA. The experimental results demonstrate that the proposed TDANN can effectively handle the domain transfer problem in EEG-based emotion recognition.

in Frontiers in Human Neuroscience on January 20, 2021 12:00 AM.

• #### Animal Models for Anorexia Nervosa—A Systematic Review

Anorexia nervosa is an eating disorder characterized by intense fear of gaining weight and a distorted body image which usually leads to low caloric intake and hyperactivity. The underlying mechanism and pathogenesis of anorexia nervosa is still poorly understood. In order to learn more about the underlying pathophysiology of anorexia nervosa and to find further possible treatment options, several animal models mimicking anorexia nervosa have been developed. The aim of this review is to systematically search different databases and provide an overview of existing animal models and to discuss the current knowledge gained from animal models of anorexia nervosa. For the systematic data search, the Pubmed—Medline database, Embase database, and Web of Science database were searched. After removal of duplicates and the systematic process of selection, 108 original research papers were included in this systematic review. One hundred and six studies were performed with rodents and 2 on monkeys. Eighteen different animal models for anorexia nervosa were used in these studies. Parameters assessed in many studies were body weight, food intake, physical activity, cessation of the estrous cycle in female animals, behavioral changes, metabolic and hormonal alterations. The most commonly used animal model (75 of the studies) is the activity-based anorexia model in which typically young rodents are exposed to time-reduced access to food (a certain number of hours a day) with unrestricted access to a running wheel. Of the genetic animal models, one that is of particular interest is the anx/anx mice model. Animal models have so far contributed many findings to the understanding of mechanisms of hunger and satiety, physical activity and cognition in an underweight state and other mechanisms relevant for anorexia nervosa in humans.

in Frontiers in Human Neuroscience on January 20, 2021 12:00 AM.

• #### Neuromechanics of Dynamic Balance Tasks in the Presence of Perturbations

Understanding the neuromechanical responses to perturbations in humans may help to explain the reported improvements in stability performance and muscle strength after perturbation-based training. In this study, we investigated the effects of perturbations, induced by unstable surfaces, on the mechanical loading and the modular organization of motor control in the lower limb muscles during lunging forward and backward. Fifteen healthy adults performed 50 forward and 50 backward lunges on stable and unstable ground. Ground reaction forces, joint kinematics, and the electromyogram (EMG) of 13 lower limb muscles were recorded. We calculated the resultant joint moments and extracted muscle synergies from the stepping limb. We found sparse alterations in the resultant joint moments and EMG activity, indicating a little if any effect of perturbations on muscle mechanical loading. The time-dependent structure of the muscle synergy responsible for the stabilization of the body was modified in the perturbed lunges by a shift in the center of activity (later in the forward and earlier in the backward lunge) and a widening (in the backward lunge). Moreover, in the perturbed backward lunge, the synergy related to the body weight acceptance was not present. The found modulation of the modular organization of motor control in the unstable condition and related minor alteration in joint kinetics indicates increased control robustness that allowed the participants to maintain functionality in postural challenging settings. Triggering specific modulations in motor control to regulate robustness in the presence of perturbations may be associated with the reported benefits of perturbation-based training.

in Frontiers in Human Neuroscience on January 20, 2021 12:00 AM.

• #### BCNNM: A Framework for in silico Neural Tissue Development Modeling

Cerebral (“brain”) organoids are high-fidelity in vitro cellular models of the developing brain, which makes them one of the go-to methods to study isolated processes of tissue organization and its electrophysiological properties, allowing to collect invaluable data for in silico modeling neurodevelopmental processes. Complex computer models of biological systems supplement in vivo and in vitro experimentation and allow researchers to look at things that no laboratory study has access to, due to either technological or ethical limitations. In this paper, we present the Biological Cellular Neural Network Modeling (BCNNM) framework designed for building dynamic spatial models of neural tissue organization and basic stimulus dynamics. The BCNNM uses a convenient predicate description of sequences of biochemical reactions and can be used to run complex models of multi-layer neural network formation from a single initial stem cell. It involves processes such as proliferation of precursor cells and their differentiation into mature cell types, cell migration, axon and dendritic tree formation, axon pathfinding and synaptogenesis. The experiment described in this article demonstrates a creation of an in silico cerebral organoid-like structure, constituted of up to 1 million cells, which differentiate and self-organize into an interconnected system with four layers, where the spatial arrangement of layers and cells are consistent with the values of analogous parameters obtained from research on living tissues. Our in silico organoid contains axons and millions of synapses within and between the layers, and it comprises neurons with high density of connections (more than 10). In sum, the BCNNM is an easy-to-use and powerful framework for simulations of neural tissue development that provides a convenient way to design a variety of tractable in silico experiments.

in Frontiers in Computational Neuroscience on January 20, 2021 12:00 AM.

• #### A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene DARS1. The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. Dars1 knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing Dars1D367Y point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed Dars1D367Y/D367Y mice with Dars1-null carriers. The resulting Dars1D367Y/− offspring displayed a strong developmental delay compared to control Dars1D367Y/+ littermates, starting during embryogenesis. Only a small fraction of Dars1D367Y/− mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few Dars1D367Y/− mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, Dars1D367Y/− mice remained smaller and lighter than their Dars1D367Y/+ littermates. Despite this early developmental deficit, once they made it through early adolescence Dars1D367Y/− mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in Dars1D367Y/− mice compared to controls. Taken together, Dars1D367Y/− mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in Dars1 knockout mice, and can be leveraged to test potential HBSL therapeutics including DARS1 gene replacement therapy.

in Frontiers in Cellular Neuroscience on January 20, 2021 12:00 AM.

• #### Examinations of Bilateral Epileptiform Activities in Hippocampal Slices Obtained From Young Mice

Bilateral interconnections through the hippocampal commissure play important roles in synchronizing or spreading hippocampal seizure activities. Intact hippocampi or bilateral hippocampal slices have been isolated from neonatal or immature rats (6–7 or 12–21 days old, respectively) and the mechanisms underlying the bilateral synchrony of hippocampal epileptiform activities have been investigated. However, the feasibility of examining bilateral epileptiform activities of more developed hippocampal circuitry in vitro remains to be explored. For this, we prepared bilateral hippocampal slices from C57 black mice, a strain commonly used in neuroscience and for genetic/molecular modifications. Young mice (21–24-day-old) were used in most experiments. A 600-μm-thick slice was obtained from each mouse by horizontal vibratome sectioning. Bilateral dorsal hippocampal and connecting dorsal hippocampal commissure (DHC) tissues were preserved in the slice and extrahippocampal tissues were removed. Slices were recorded in a submerged chamber mainly at a room temperature (21–22°C). Bilateral CA3 areas were monitored by extracellular recordings, and unilateral electrical stimulation was used to elicit CA3 synaptic field potentials. The unilateral stimulation could elicit population spikes in the contralateral CA3 area. These contralateral spikes were attenuated by inhibiting synaptic transmission with cobalt-containing medium and were abolished when a cut was made at the DHC. Self-sustained and bilaterally correlated epileptiform potentials were observed following application of 4-aminopyradine and became independent after the DHC cut. Bilateral hippocampal activities were detectable in some slices of adult mice and/or at 35–36°C, but with smaller amplitudes and variable waveforms compared to those observed from slices of young mice and at the room temperature. Together, these observations suggested that examining bilateral epileptiform activities in hippocampal slices of young mice is feasible. The weaknesses and limitations of this preparation and our experimentation are discussed.

in Frontiers in Cellular Neuroscience on January 20, 2021 12:00 AM.

• #### Immune Regulation of Adult Neurogenic Niches in Health and Disease

Microglia regulate neuronal development during embryogenesis, postnatal development, and in specialized microenvironments of the adult brain. Recent evidence demonstrates that in adulthood, microglia secrete factors which modulate adult hippocampal neurogenesis by inhibiting cell proliferation and survival both in vitro and in vivo, maintaining a balance between cell division and cell death in neurogenic niches. These resident immune cells also shape the nervous system by actively pruning synapses during critical periods of learning and engulfing excess neurons. In neurodegenerative diseases, aberrant microglial activity can impede the proper formation and prevent the development of appropriate functional properties of adult born granule cells. Ablating microglia has been presented as a promising therapeutic approach to alleviate the brain of maladaptive immune response. Here, we review key mechanisms through which the immune system actively shapes neurogenic niches throughout the lifespan of the mammalian brain in both health and disease. We discuss how interactions between immune cells and developing neurons may be leveraged for pharmacological intervention and as a means to preserve adult neurogenesis.

in Frontiers in Cellular Neuroscience on January 20, 2021 12:00 AM.

• #### Long-Term Prognosis of Cognitive Function in Patients With Idiopathic Normal Pressure Hydrocephalus After Shunt Surgery

The long-term prognosis of cognitive function in patients with idiopathic normal pressure hydrocephalus (iNPH) remains unclear. This study aimed to determine the long-term prognosis of cognitive function in patients with iNPH, as well as the factors related to it. It included 48 patients with iNPH who were treated with cerebrospinal fluid shunting between January 2015 and December 2017 at Osaka Medical College Hospital, with follow-up evaluation of their cognitive function for >2 years. Cognitive function was measured using the Mini-Mental State Examination (MMSE) preoperatively and at 3 months, 1 and 2 years post-operatively. The mean MMSE score (22.4 ± 5.4 preoperatively) improved at 3 months [23.8 ± 5.0 (p = 0.0002)] and 1 year [23.7 ± 4.8 (p = 0.004)] post-operatively. At 2 years post-operatively, they were able to maintain their preoperative level (22.6 ± 5.3). The patients were classified in to the cognitive decline group [11 (23%) patients; a decrease in the MMSE score by ≥ 2 points 2 years after surgery] and the maintenance/improvement group [37 (77%) patients]. Univariate and receiver operating characteristic analyses were performed for the two groups to identify factors associated with cognitive prognosis. In both groups, the patients who were younger (p = 0.009) or had milder symptoms (p = 0.035) had a better long-term prognosis of cognitive function. The cutoffs for age and disease severity (idiopathic normal-pressure hydrocephalus grading scale; INPHGS) were 78 years (area under the curve = 0.77) and 5 points (area under the curve = 0.71), respectively. In conclusion, most patients (77%) were able to improve and maintain cognitive function for at least 2 years after surgery. The fact that disease severity and age are associated with cognitive prognosis suggests that early iNPH intervention is desirable to improve cognitive prognosis.

in Frontiers in Ageing Neuroscience on January 20, 2021 12:00 AM.

• #### AD7c-NTP Impairs Adult Striatal Neurogenesis by Affecting the Biological Function of MeCP2 in APP/PSl Transgenic Mouse Model of Alzheimer's Disease

The processes by which neural stem cells (NSCs) and neural precursor cells (NPCs) transform into the characteristic lineages observed in Alzheimer's disease (AD) are poorly characterized. Understanding these processes is of critical importance due to the increased prevalence of AD and the lack of effective AD strategies. Here, we used immunohistochemistry and Western blot to find out if MeCP2 was phosphorylated at a specific amino acid residue, Serine 421 (S421), and activated in response to AD-induced damage in amyloid precursor protein (APP)/PSl transgenic mice, altering its nuclear to cytoplasmic shuttling. Epigenetic examinations combined with chromatin immunoprecipitation and methylated DNA immunoprecipitation revealed that the translocation of MeCP2 from the nucleus to cytoplasm led to the loss of lineage-specific gene promoters (such as Gfap, Nestin, and Dcx), decreased transcriptional repression, and the activation of gene expression. Immunofluorescence data demonstrated that neurogenic progenitors with high levels of active phosphorylated MeCP2 at S421 (MeCP2 pS421) possessed a high probability of development into doublecortin (DCX)-expressing cells. AD7c-NTP will control neurogenic progenitor regeneration through its effects on MeCP2 pS421, leading to altered lineage-specific gene expression. This adds to the growing list of biological effects of AD7c-NTP in the brain and highlights MeCP2 as relevant to the plasticity of neural cells in the AD mice striatum.

in Frontiers in Ageing Neuroscience on January 20, 2021 12:00 AM.

• #### Past, Present, and Future of Non-invasive Brain Stimulation Approaches to Treat Cognitive Impairment in Neurodegenerative Diseases: Time for a Comprehensive Critical Review

Low birth rates and increasing life expectancy experienced by developed societies have placed an unprecedented pressure on governments and the health system to deal effectively with the human, social and financial burden associated to aging-related diseases. At present, ∼24 million people worldwide suffer from cognitive neurodegenerative diseases, a prevalence that doubles every five years. Pharmacological therapies and cognitive training/rehabilitation have generated temporary hope and, occasionally, proof of mild relief. Nonetheless, these approaches are yet to demonstrate a meaningful therapeutic impact and changes in prognosis. We here review evidence gathered for nearly a decade on non-invasive brain stimulation (NIBS), a less known therapeutic strategy aiming to limit cognitive decline associated with neurodegenerative conditions. Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation, two of the most popular NIBS technologies, use electrical fields generated non-invasively in the brain to long-lastingly enhance the excitability/activity of key brain regions contributing to relevant cognitive processes. The current comprehensive critical review presents proof-of-concept evidence and meaningful cognitive outcomes of NIBS in eight of the most prevalent neurodegenerative pathologies affecting cognition: Alzheimer’s Disease, Parkinson’s Disease, Dementia with Lewy Bodies, Primary Progressive Aphasias (PPA), behavioral variant of Frontotemporal Dementia, Corticobasal Syndrome, Progressive Supranuclear Palsy, and Posterior Cortical Atrophy. We analyzed a total of 70 internationally published studies: 33 focusing on Alzheimer’s disease, 19 on PPA and 18 on the remaining neurodegenerative pathologies. The therapeutic benefit and clinical significance of NIBS remains inconclusive, in particular given the lack of a sufficient number of double-blind placebo-controlled randomized clinical trials using multiday stimulation regimes, the heterogeneity of the protocols, and adequate behavioral and neuroimaging response biomarkers, able to show lasting effects and an impact on prognosis. The field remains promising but, to make further progress, research efforts need to take in account the latest evidence of the anatomical and neurophysiological features underlying cognitive deficits in these patient populations. Moreover, as the development of in vivo biomarkers are ongoing, allowing for an early diagnosis of these neuro-cognitive conditions, one could consider a scenario in which NIBS treatment will be personalized and made part of a cognitive rehabilitation program, or useful as a potential adjunct to drug therapies since the earliest stages of suh diseases. Research should also integrate novel knowledge on the mechanisms and constraints guiding the impact of electrical and magnetic fields on cerebral tissues and brain activity, and incorporate the principles of information-based neurostimulation.

in Frontiers in Ageing Neuroscience on January 20, 2021 12:00 AM.

• #### Collateral sensitivity associated with antibiotic resistance plasmids

Collateral sensitivity (CS) is a promising alternative approach to counteract the rising problem of antibiotic resistance (ABR). CS occurs when the acquisition of resistance to one antibiotic produces increased susceptibility to a second antibiotic. Recent studies have focused on CS strategies designed against ABR mediated by chromosomal mutations. However, one of the main drivers of ABR in clinically relevant bacteria is the horizontal transfer of ABR genes mediated by plasmids. Here, we report the first analysis of CS associated with the acquisition of complete ABR plasmids, including the clinically important carbapenem-resistance conjugative plasmid pOXA-48. In addition, we describe the conservation of CS in clinical E. coli isolates and its application to selectively kill plasmid-carrying bacteria. Our results provide new insights that establish the basis for developing CS-informed treatment strategies to combat plasmid-mediated ABR.

in eLife on January 20, 2021 12:00 AM.

• #### The Arabidopsis active demethylase ROS1 cis-regulates defense genes by erasing DNA methylation at promoter-regulatory regions

Active DNA demethylation has emerged as an important regulatory process of plant and mammalian immunity. However, very little is known about the mechanisms by which active demethylation controls transcriptional immune reprogramming and disease resistance. Here, we first show that the Arabidopsis active demethylase ROS1 promotes basal resistance towards Pseudomonas syringae by antagonizing RNA-directed DNA methylation (RdDM). Furthermore, we find that ROS1 facilitates the flagellin-triggered induction of the disease resistance gene RMG1 by limiting RdDM at the 3' boundary of a remnant RC/Helitron transposable element (TE) embedded in its promoter. We further identify flagellin-responsive ROS1 putative primary targets, and show that at a subset of promoters, ROS1 erases methylation at discrete regions exhibiting WRKY transcription factors (TFs) binding. In particular, we demonstrate that ROS1 removes methylation at the orphan immune receptor RLP43 promoter, to ensure DNA binding of WRKY TFs. Finally, we show that ROS1-directed demethylation of the RMG1 and RLP43 promoters is causal for both flagellin responsiveness of these genes and for basal resistance. Overall, these findings significantly advance our understanding of how active demethylases shape transcriptional immune reprogramming to enable antibacterial resistance.

in eLife on January 20, 2021 12:00 AM.

• #### Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues

Little is known about the metabolic regulation of rare cell populations because most metabolites are hard to detect in small numbers of cells. We previously described a method for metabolomic profiling of flow cytometrically-isolated hematopoietic stem cells (HSCs) that detects 60 metabolites in 10,000 cells (Agathocleous et al., 2017). Here we describe a new method involving hydrophilic liquid interaction chromatography and high-sensitivity orbitrap mass spectrometry that detected 160 metabolites in 10,000 HSCs, including many more glycolytic and lipid intermediates. We improved chromatographic separation, increased mass resolution, minimized ion suppression, and eliminated sample drying. Most metabolite levels did not significantly change during cell isolation. Mouse HSCs exhibited increased glycerophospholipids relative to bone marrow cells and methotrexate treatment altered purine biosynthesis. Circulating human melanoma cells were depleted for purine intermediates relative to subcutaneous tumors, suggesting decreased purine synthesis during metastasis. These methods facilitate the routine metabolomic analysis of rare cells from tissues.

in eLife on January 20, 2021 12:00 AM.

• #### Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes

We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo and human stem cells by expressing the transcription factor neurogenin‑2 (NGN2). Single cell RNA sequencing (scRNAseq) showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first two weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs and this difference in timing likely depends on functions downstream of NGN2.

in eLife on January 20, 2021 12:00 AM.

• #### Two contrasting mediodorsal thalamic circuits target the medial prefrontal cortex

At the heart of the prefrontal executive and limbic networks is the mediodorsal thalamus (MD). Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, virtually nothing is known about the physiology of neurons in MD. Here, we injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult (8 - 12 week old) male and female wildtype mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD[->]mPFC neurons). MD[->]mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. We found that that MD-M[->]mPFC neurons have longer membrane time constants, higher membrane resistance, less Hyperpolarization and Cyclic Nucleotide gated (HCN) channel activity, and more readily generate action potentials compared to MD-L[->]mPFC neurons. Additionally, MD-M[->]mPFC neurons have larger and more complex dendritic arbors compared to MD-L[->]mPFC neurons. These data demonstrating that the two populations of MD[->]mPFC neurons have distinct physiologies and morphologies suggests a differential role in thalamocortical information processing and potentially behavior.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Regeneration of spinal motor axons: Negative regulation by Celsr2 implicating Cdc42/Rac1 and JNK/c-Jun signaling

During development, cadherins Celsr2 and Celsr3 control axon navigation. Unlike Celsr3, Celsr2 remains expressed in the adult, suggesting unexplored roles in maintenance and repair. Here we show that Celsr2 knockdown promotes motor axon regeneration in mouse and human spinal cord explants and cultured motor neurons. Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun proteins. Using a branchial plexus injury model, we show that forelimb functional recovery is improved in Celsr2 mutant versus control mice. Compared to controls, in mutant mice, reinnervated biceps muscles are less atrophic, contain more newly formed neuromuscular junctions, and generate larger electromyographic potentials, while motor neuron survival and axon regeneration are improved. GTP-bound Rac1 and Cdc42, JNK and c-Jun are upregulated in injured mutant versus control spinal cord. In conclusion, Celsr2 negatively regulates motor axon regeneration via Cdc42/Rac1/JNK/c-Jun signaling and is a target for neural repair.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Background: Autism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 ), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children. Results: Using targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1 that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1 promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 x 10-6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1 promoter. There was a positive correlation between methylation at PGC-1 at CpG#1 and mtDNA copy number (Spearman r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1 at CpG#4 promoter and mtDNA copy number in controls (Spearman r = -0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1 methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1 at CpG#4 (Spearman r = -0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1 CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology. Conclusions: These data show an association between PGC-1 promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Transcriptome Analysis of Chloride Intracellular Channel Knockdown in Drosophila Identifies Oxidation-Reduction Function as Possible Mechanism of Altered Sensitivity to Ethanol Sedation

Chloride intracellular channels (CLICs) are a unique family of evolutionarily conserved metamorphic proteins, switching between stable conformations based on redox conditions. CLICs have been implicated in a wide variety biological processes including ion channel activity, apoptosis, membrane trafficking, and enzymatic oxidoreductase activity. Understanding the molecular mechanisms by which CLICs engage in these activities is an area of active research. Here, the sole Drosophila melanogaster ortholog, Clic, was targeted for RNAi knockdown to identify genes and biological processes associated with Clic expression. Clic knockdown had a substantial impact on global transcription, altering expression of over 9% of transcribed Drosophila genes. Overrepresentation analysis of differentially expressed genes identified enrichment of 23 Gene Ontology terms including Cytoplasmic Translation, Oxidation-Reduction Process, Heme Binding, Membrane, Cell Junction, and Nucleolus. The top term, Cytoplasmic Translation, was enriched almost exclusively with downregulated genes. Drosophila Clic and vertebrate ortholog Clic4have previously been tied to ethanol sensitivity and ethanol-regulated expression. Clic knockdown-responsive genes from the present study were found to overlap significantly with gene sets from 4 independently published studies related to ethanol exposure and sensitivity in Drosophila. Bioinformatic analysis of genes shared between these studies revealed an enrichment of genes related to amino acid metabolism, protein processing, oxidation-reduction processes, and lipid particles among others. To determine whether the modulation of ethanol sensitivity by Clic may be related to co-regulated oxidation-reduction processes, we evaluated the effect of hyperoxia on ethanol sedation in Clicknockdown flies. Consistent with previous findings, Clic knockdown reduced acute ethanol sedation sensitivity in flies housed under normoxia. However, this effect was reversed by exposure to hyperoxia, suggesting a common set of molecular-genetic mechanism may modulate each of these processes. This study suggests that Drosophila Clic has a major influence on regulation of oxidative stress signaling and that this function overlaps with the molecular mechanisms of acute ethanol sensitivity in the fly.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Differential requirement of NPHP1 for compartmentalized protein localization during photoreceptor outer segment development and maintenance

Nephrocystin (NPHP1) is a ciliary transition zone protein and its ablation causes nephronophthisis (NPHP) with partially penetrant retinal dystrophy. However, the precise requirements of NPHP1 in photoreceptors are not well understood. Here, we characterize retinal degeneration in a mouse model of NPHP1 and show that NPHP1 is required to prevent infiltration of inner segment plasma membrane proteins into the outer segment during the photoreceptor maturation. We demonstrate that Nphp1 gene-trap mutant mice, which were previously described as null, are in fact hypomorphs due to the production of a small quantity of functional mRNAs derived from nonsense-associated altered splicing and skipping of two exons including the one harboring the gene-trap. In homozygous mutant animals, inner segment plasma membrane proteins such as syntaxin-3 (STX3), synaptosomal-associated protein 25 (SNAP25), and interphotoreceptor matrix proteoglycan 2 (IMPG2) accumulate in the outer segment when outer segments are actively elongating. This phenotype, however, is spontaneously ameliorated after the outer segment elongation is completed. Retinal degeneration also occurs temporarily during the photoreceptor maturation but stops afterward. We further show that Nphp1 genetically interacts with Cep290, another NPHP gene, and that a reduction of Cep290 gene dose results in retinal degeneration that continues until adulthood in Nphp1 mutant mice. These findings demonstrate that NPHP1 is required for the confinement of inner segment plasma membrane proteins during the outer segment development, but its requirement diminishes as photoreceptors mature. Our study also suggests that additional mutations in other NPHP genes may influence the penetrance of retinopathy in human NPHP1 patients.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons

Homozygotic mutations in the GBA gene cause Gaucher's disease, moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations impair the activity of beta-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher's disease. In the brain, most of the pathological effects caused by GBA mutations have been attributed to the beta-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Here, we applied the bioluminescence imaging technology, immunohistochemical and gene expression analysis to investigate the consequences of microglial beta-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia co-cultures and in cell lines. Our data demonstrate the existence of a novel mechanism by which microglia sustain the antioxidant/detoxifying response mediated by the nuclear factor erythroid 2-related factor 2 in neurons. The central role played by microglia in this neuronal response in vivo was proven by pharmacological depletion of the lineage in the brain, while co-cultures experiments provided insight on the nature of this cell-to-cell communication showing that this mechanism requires a direct microglia-to-neuron contact supported by functional actin structures. Pharmacological inhibition of microglial beta-glucocerebrosidase was proven to induce morphological changes, turn on an anti-inflammatory/repairing pathway and hinder the microglia ability to activate the anti-oxidant/detoxifying response, thus increasing the neuronal susceptibility to neurotoxins. Altogether, our data suggest that microglial beta-glucocerebrosidase inhibition impairs microglia-to-neuron communication increasing the sensitivity of neurons to oxidative or toxic insults, thus providing a possible mechanism for the increased risk of neurodegeneration observed in carriers of GBA mutations.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Evaluation and resolution of many challenges of neural spike-sorting: a new sorter

We evaluate existing spike sorters and present a new one that resolves many sorting challenges. The new sorter, "called full binary pursuit" or FBP, comprises multiple steps. First, it thresholds and clusters to identify the waveforms of all unique neurons in the recording. Second, it uses greedy binary pursuit to optimally recognize the spike events in the original voltages. Third, it resolves spike events that are described more accurately as the superposition of spikes from two other neurons. Fourth, it resolves situations where the recorded neurons drift in amplitude or across electrode contacts during a long recording session. Comparison with other sorters on real and simulated ground-truth datasets reveals many of the failure modes of spike sorters. We suggest a set of post-sorting analyses that can improve the veracity of neural recordings by minimizing the intrusion of those failure modes into analysis and interpretation of neural data.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

Neurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called diffusion condensation. By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Shape analysis of gamma rhythm supports a superlinear inhibitory regime in an inhibition-stabilized network

Visual inspection of stimulus-induced gamma oscillations (30-70 Hz) often reveals a non-sinusoidal shape. Such distortions are a hallmark of non-linear systems and are also observed in mean-field models of gamma oscillations. A thorough characterization of the shape of the gamma cycle can therefore provide additional constraints on the operating regime of such models. However, the gamma waveform has not been quantitatively characterized, partially because the first harmonic of gamma, which arises because of the non-sinusoidal nature of the signal, is typically weak and gets masked due to a broadband increase in power related to spiking. To address this, we recorded spikes and local field potential (LFP) from the primary visual cortex (V1) of two awake female macaques while presenting full-field gratings or iso-luminant chromatic hues that produced huge gamma oscillations with prominent peaks at harmonic frequencies in the power spectra. We found that gamma and its first harmonic always maintained a specific phase relationship, resulting in a distinctive shape with a sharp trough and a shallow peak. Interestingly, a Wilson-Cowan (WC) model operating in an inhibition stabilized mode could replicate the findings, but only when the inhibitory population operated in the super-linear regime, as predicted recently. However, another recently developed model of gamma that operates in a linear regime driven by stochastic noise failed to produce salient harmonics or the observed shape. Our results impose additional constraints on models that generate gamma oscillations and their operating regimes.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Modeling Brain Connectivity Dynamics in Functional Magnetic Resonance Imaging via Particle Filtering

Interest in the studying of functional connections in the brain has grown considerably in the last decades, as many studies have pointed out that these interactions can play a role as markers of neurological diseases. Most studies in this field treat the brain network as a system of connections stationary in time, but dynamic features of brain connectivity can provide useful information, both on physiology and pathological conditions of the brain. In this paper, we propose the application of a computational methodology, named Particle Filter (PF), to study non-stationarities in brain connectivity in functional Magnetic Resonance Imaging (fMRI). The PF algorithm estimates timevarying hidden parameters of a first-order linear time-varying Vector Autoregressive model (VAR) through a Sequential Monte Carlo strategy. On simulated time series, the PF approach effectively detected and enabled to follow time-varying hidden parameters and it captured causal relationships among signals. The method was also applied to real fMRI data, acquired in presence of periodic tactile or visual stimulations, in different sessions. On these data, the PF estimates were consistent with current knowledge on brain functioning. Most importantly, the approach enabled to detect statistically significant modulations in the cause-effect relationship between brain areas, which correlated with the underlying visual stimulation pattern presented during the acquisition.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Architecture of the Neuro-Glia-Vascular System

Astrocytes connect the vasculature to neurons and mediate the supply of nutrients and biochemicals. They also remove metabolites from the neurons and extracellular environment. They are involved in a growing number of physiological and pathophysiological processes. Understanding the biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV) and how they support brain function is severely restricted by the lack of detailed cytoarchitecture. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3 of rat somatosensory cortical tissue with approximately 16000 morphologically detailed neurons, its microvasculature, and approximately 2500 morphologically detailed protoplasmic astrocytes. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the numbers and locations of astrocytes and astrocytic processes that support different types of neurons. This allows anatomical reconstruction of the spatial microdomains of astrocytes and their overlapping regions. The number and locations of end-feet connecting each astrocyte to the vasculature can be determined as well as the extent to which they cover the microvasculature. The structural analysis of the NGV circuit showed that astrocytic shape and numbers are constrained by vasculature's spatial occupancy and their functional role to form NGV connections. The digital reconstruction of the NGV is a resource that will enable a better understanding of the anatomical principles and geometric constraints which govern how astrocytes support brain function.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### A Large-Scale Brain Network Mechanism for Increased Seizure Propensity in Alzheimer's Disease

People with Alzheimer's disease (AD) are 6-10 times more likely to develop seizures than the healthy aging population. Leading hypotheses largely consider increased excitability of local cortical tissue as primarily responsible for increased seizure prevalence in AD. However, both local dynamics and large-scale brain network structure are believed to be crucial for determining seizure likelihood and phenotype. In this study, we combine computational modelling with electrophysiological data to demonstrate a potential large-scale brain network mechanism for increased seizure propensity in people with AD. EEG was recorded from 21 people with probable AD and 26 healthy controls. At the time of EEG acquisition, all participants were free from seizures. Whole brain functional connectivity derived from source-reconstructed EEG recordings was used to build subject-specific brain network models of seizure transitions using an approach previously validated on participants with epilepsy vs controls. As cortical tissue excitability was increased in the simulations, network models of AD simulations were more likely to transition into seizures than simulations from healthy controls. Our results suggest an increased group-level probability of developing seizures at a future time for AD participants. We subsequently used the model to assess seizure propensity of different regions across the cortex. We found the most important regions for seizure generation were those typically burdened by amyloid-beta at the early stages of AD, as previously reported by in-vivo and post-mortem staging of amyloid plaques. These included cingulate, medial temporal, and orbital regions. Analysis of these spatial distributions also give potential insight into mechanisms of increased susceptibility to generalized (as opposed to focal) seizures in AD vs controls. This research suggests avenues for future studies testing patients with seizures, e.g. co-morbid AD/epilepsy patients, and comparisons with PET and MRI scans to relate regional seizure propensity with amyloid/tau pathology and cortical atrophy.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Luminal nutrients activate distinct patterns in submucosal and myenteric neurons in the mouse small intestine

Nutrient signals sensed by enteroendocrine cells are conveyed to the enteric nervous system (ENS) to initiate intestinal reflexes. We addressed whether there are specific enteric pathways dedicated to detecting different luminal nutrients. Calcium imaging was performed on intact jejunal preparations from Wnt1-cre;R26R-GCaMP3 and Villin-cre;R26R-GCaMP3 mice which express a fluorescent calcium indicator in their ENS or intestinal epithelium, respectively. Glucose, acetate, and L-phenylalanine were perfused onto the mucosa whilst imaging underlying enteric neurons. Nutrient transport or diffusion across the mucosa was mimicked by applying nutrients onto sensory nerve endings in a villus, or onto myenteric ganglia. The nutrients perfused onto the mucosa each elicited Ca2+ transients in submucosal neurons and in distinct patterns of myenteric neurons. Notably, the neurochemical subtypes of myenteric neurons that responded differed between the nutrients, while submucosal responders were predominantly cholinergic. Nutrients applied into villi or onto ganglia did not elicit specific neuronal responses but did stimulate Ca2+ signaling in the mucosal epithelium. These data suggest that nutrients are first detected at the level of the epithelium and that the ENS is capable of discriminating between different compositions of luminal content. Furthermore, our data show that responses to mucosal stimulation are primarily in the myenteric plexus and submucosal neurons respond secondarily.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model

Microglial dysfunction is believed to play a pathogenic role in Alzheimer's disease (AD). Here, we characterize the amyloid-{beta} related pathology and microglial responses in an engineered APP knock-in mouse model of familial AD. This model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered glial responses and neurodegeneration. Leveraging multi-omics approaches, we found lipid accumulation and an exacerbated disease-associated transcriptomic response in methoxy-X04-positive, phagocytic microglia. Together, these findings highlight the potential of this novel, open-access mouse model to investigate AD pathogenesis and demonstrate that fibrillar A{beta} triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Assessment of Flourishing Levels of Individuals by Using Resting State fNIRS with Different Functional Connectivity Measures

Flourishing is an important criterion to assess wellbeing, however, controversies remain, particularly around assessing it with self report measures. Due to this reason, to be able to understand the underlying neural mechanisms of well being, researchers often utilize neuroimaging techniques. However, rather than individual answers, previous neuroimaging studies using statistical approaches provided an answer in average sense. To overcome these problems, we applied machine learning techniques to discriminate 43 highly flourishing from regular flourishing individuals by using a publicly available resting state functional near infrared spectroscopy (rsfNIRS) dataset to get an answer in individual level. We utilized both Pearson correlation (CC) and Dynamic Time Warping (DTW) algorithm to estimate functional connectivity from rs-fNIRS data on temporo-parieto-occipital region as input to nine different machine learning algorithms. Our results revealed that by utilizing oxyhemoglobin concentration change with Pearson correlation (CC HbO) and deoxy hemoglobin concentration change with dynamic time warping (DTW Hb), we could be able to classify flourishing individuals with 90 % accuracy with AUC 0.90 and 0.93 using nearest neighbor and Radial Basis Kernel Support Vector Machine. This finding suggests that temporoparietooccipital regional based resting state connectivity might be a potential biomarker to identify the levels of flourishing and using both connectivity measures might allow us to find different potential biomarkers.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Associations between lower limb isometric torque, isokinetic torque, and explosive force with phases of reactive stepping in young, healthy adults

Reactive stepping is one of the only strategies that can lead to successful stabilization following a large challenge to balance. Improving function of specific muscles associated with reactive stepping may improve features of reactive balance control. Accordingly, this study aimed to determine the relationship between lower limb muscle strength and explosive force with force plate-derived timing measures of reactive stepping. Nineteen young, healthy adults (27.6 {+/-} 3.0 years of age; 10 women: 9 men) responded to 6 perturbations (~13-15% of body weight) using an anterior lean-and-release system (causing a forward fall), where they were instructed to recover balance in as few steps as possible. Foot-off, swing, and restabilization times were estimated from force plates. Peak isokinetic torque, isometric torque, and explosive force of the knee extensors/flexors and plantar/dorsiflexors were measured using isokinetic dynamometry. Correlations were run based on a priori hypotheses and corrected for the number of comparisons (Bonferroni) for each variable. Knee extensor explosive force was negatively correlated with swing time (r = -0.582, p = 0.009). Knee flexor peak isometric torque also showed a negative association with restabilization time (r = -0.459, p = 0.048), however this was not statistically significant after correcting for multiple comparisons. There was no significant relationship between foot-off time and knee or plantar flexor explosive force (p > 0.025). These findings suggest that there may be utility to identifying specific aspects of reactive step timing when studying the relationship between muscle strength and reactive balance control. Exercise training aimed at improving falls risk should consider targeting specific aspects of muscle strength depending on specific deficits in reactive stepping.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Conserved Architecture of Brain Transcriptome Changes between Alzheimer's Disease and Progressive Supranuclear Palsy in Pathologically Affected and Unaffected Regions

We identify a striking correlation in the directionality and magnitude of gene expression changes in brain transcriptomes between Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). Further, the transcriptome architecture in AD and PSP is highly conserved between the temporal and cerebellar cortices, indicating highly similar transcriptional changes occur in pathologically affected and "unaffected" areas of the brain. These data have broad implications for interpreting transcriptomic data in neurodegenerative disorders.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### Pupillometry signatures of sustained attention and working memory

There exists an intricate relationship between attention and working memory. Recent work has further established that attention and working memory fluctuate synchronously, by tightly interleaving sustained attention and working memory tasks. This work has raised many open questions about physiological signatures underlying these behavioral fluctuations. Across two experiments, we explore pupil dynamics using real-time triggering in conjunction with an interleaved sustained attention and working memory task. In Experiment 1, we use behavioral real-time triggering and replicate recent findings from our lab (deBettencourt et al., 2019) that sustained attention fluctuates concurrently with the number of items maintained in working memory. Furthermore, highly attentive moments, detected via behavior, also exhibited larger pupil sizes. In Experiment 2, we develop a novel real-time pupil triggering technique to track pupil size fluctuations in real time and trigger working memory probes. We reveal that this pupil triggering procedure elicits differences in sustained attention, as indexed by response time. These experiments reflect methodological advances in real-time triggering and further characterize an important biomarker of sustained attention.

in bioRxiv: Neuroscience on January 20, 2021 12:00 AM.

• #### In This Issue [This Week in PNAS]

ENVIRONMENTAL SCIENCES Plumbojarosite, an insoluble lead–iron hydroxysulfate mineral. Image credit: Wikimedia Commons/John Sobolewski (JSS), licensed under CC BY 3.0. Reducing lead bioavailability in soil Childhood exposure to lead can lead to long-term adverse health effects. A significant source of lead exposure in children is contaminated soil and dust. Because of...

in PNAS on January 19, 2021 06:35 PM.

• #### Reply to Stuchlik et al.: The Younger Dryas onset at 12.87 ky B.P. is still ȷustified if the Laacher See eruption is considered [Physical Sciences]

We thank Stuchlík et al. for their comments (1) on our paper (2). First, for the sake of clarity, we note that Stuchlík et al. may have inadvertently stated “δ18O records in several ice cores from Greenland and Antarctica that were originally dated by the radiocarbon method.” This is obviously...

in PNAS on January 19, 2021 06:07 PM.

• #### Longitudinal shear stress response in human endothelial cells to atheroprone and atheroprotective conditions [Systems Biology]

The two main blood flow patterns, namely, pulsatile shear (PS) prevalent in straight segments of arteries and oscillatory shear (OS) observed at branch points, are associated with atheroprotective (healthy) and atheroprone (unhealthy) vascular phenotypes, respectively. The effects of blood flow-induced shear stress on endothelial cells (ECs) and vascular health have...

in PNAS on January 19, 2021 06:07 PM.

• #### Multiple domain interfaces mediate SARM1 autoinhibition [Neuroscience]

Axon degeneration is an active program of self-destruction mediated by the protein SARM1. In healthy neurons, SARM1 is autoinhibited and, upon injury autoinhibition is relieved, activating the SARM1 enzyme to deplete NAD+ and induce axon degeneration. SARM1 forms a homomultimeric octamer with each monomer composed of an N-terminal autoinhibitory ARM...

in PNAS on January 19, 2021 06:07 PM.

• #### Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency [Medical Sciences]

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity...

in PNAS on January 19, 2021 06:07 PM.

• #### Identification of the Younger Dryas onset was confused by the Laacher See volcanic eruption [Physical Sciences]

Cheng et al. (1) provide data on oxygen-isotope δ18O in nine speleothems of Younger Dryas (YD) age from caves situated in several continents between 42°27′ N and 21°05′ S and dated by the U-Th method. They compare this data with δ18O records in several ice cores from Greenland and Antarctica...

in PNAS on January 19, 2021 06:07 PM.

• #### A short ORF-encoded transcriptional regulator [Genetics]

Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define...

in PNAS on January 19, 2021 06:07 PM.

• #### PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease [Neuroscience]

DNA damage repair genes are modifiers of disease onset in Huntington’s disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find...

in PNAS on January 19, 2021 06:07 PM.

• #### Results from a 2020 field experiment encouraging voting by mail [Political Sciences]

The ability to cast a mail ballot can safeguard the franchise. However, because there are often additional procedural protections to ensure that a ballot cast in person counts, voting by mail can also jeopardize people’s ability to cast a recorded vote. An experiment carried out during the COVID-19 pandemic illustrates...

in PNAS on January 19, 2021 06:07 PM.

• #### Impact of transnational land acquisitions on local food security and dietary diversity [Sustainability Science]

Foreign investors have acquired approximately 90 million hectares of land for agriculture over the past two decades. The effects of these investments on local food security remain unknown. While additional cropland and intensified agriculture could potentially increase crop production, preferential targeting of prime agricultural land and transitions toward export-bound crops...

in PNAS on January 19, 2021 06:07 PM.

• #### Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction [Medical Sciences]

Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent...

in PNAS on January 19, 2021 06:07 PM.

• #### Live-cell epigenome manipulation by synthetic histone acetylation catalyst system [Biochemistry]

Chemical modifications of histones, such as lysine acetylation and ubiquitination, play pivotal roles in epigenetic regulation of gene expression. Methods to alter the epigenome thus hold promise as tools for elucidating epigenetic mechanisms and as therapeutics. However, an entirely chemical method to introduce histone modifications in living cells without genetic...

in PNAS on January 19, 2021 06:07 PM.

• #### Synaptotagmin-1-, Munc18-1-, and Munc13-1-dependent liposome fusion with a few neuronal SNAREs [Biochemistry]

Neurotransmitter release is governed by eight central proteins among other factors: the neuronal SNAREs syntaxin-1, synaptobrevin, and SNAP-25, which form a tight SNARE complex that brings the synaptic vesicle and plasma membranes together; NSF and SNAPs, which disassemble SNARE complexes; Munc18-1 and Munc13-1, which organize SNARE complex assembly; and the...

in PNAS on January 19, 2021 06:07 PM.

• #### Native American fire management at an ancient wildland-urban interface in the Southwest United States [Environmental Sciences]

The intersection of expanding human development and wildland landscapes—the “wildland–urban interface” or WUI—is one of the most vexing contexts for fire management because it involves complex interacting systems of people and nature. Here, we document the dynamism and stability of an ancient WUI that was apparently sustainable for more than...

in PNAS on January 19, 2021 06:07 PM.

• #### Bifurcation of excited state trajectories toward energy transfer or electron transfer directed by wave function symmetry [Chemistry]

This work explores the concept that differential wave function overlap between excited states can be engineered within a molecular chromophore. The aim is to control excited state wave function symmetries, so that symmetry matches or mismatches result in differential orbital overlap and define low-energy trajectories or kinetic barriers within the...

in PNAS on January 19, 2021 06:07 PM.

• #### Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner [Immunology and Inflammation]

Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune...

in PNAS on January 19, 2021 06:07 PM.

• #### Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus [Neuroscience]

Recurrent excitatory neural networks are unstable. In the hippocampus, excitatory mossy cells (MCs) receive strong excitatory inputs from dentate granule cells (GCs) and project back onto the proximal dendrites of GCs. By targeting the ipsi- and contralateral dentate gyrus (DG) along the dorsoventral axis of the hippocampus, MCs form an...

in PNAS on January 19, 2021 06:07 PM.

• #### Discovery of a hidden transient state in all bromodomain families [Biophysics and Computational Biology]

Bromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These posttranslational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly...

in PNAS on January 19, 2021 06:07 PM.

• #### Moireless correlations in ABCA graphene [Applied Physical Sciences]

Atomically thin van der Waals materials stacked with an interlayer twist have proven to be an excellent platform toward achieving gate-tunable correlated phenomena linked to the formation of flat electronic bands. In this work we demonstrate the formation of emergent correlated phases in multilayer rhombohedral graphene––a simple material that also...

in PNAS on January 19, 2021 06:07 PM.

• #### Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis [Neuroscience]

Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of...

in PNAS on January 19, 2021 06:07 PM.

## Abstract

Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus‐dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi‐stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.

in Hippocampus on January 19, 2021 04:39 PM.

• #### Disease-driven reduction in human mobility influences human-mosquito contacts and dengue transmission dynamics

by Kathryn L. Schaber, T. Alex Perkins, Alun L. Lloyd, Lance A. Waller, Uriel Kitron, Valerie A. Paz-Soldan, John P. Elder, Alan L. Rothman, David J. Civitello, William H. Elson, Amy C. Morrison, Thomas W. Scott, Gonzalo M. Vazquez-Prokopec

Heterogeneous exposure to mosquitoes determines an individual’s contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission (R, the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual’s positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual’s biting suitability and the number of mosquitoes in their home (>10 mosquitoes and 0.6 individual attractiveness significantly increased R). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers

by Sara Ibrahim Omar, Meng Zhao, Rohith Vedhthaanth Sekar, Sahar Arbabi Moghadam, Jack A. Tuszynski, Michael T. Woodside

The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses −1 programmed ribosomal frameshifting (−1 PRF) to control the relative expression of viral proteins. As modulating −1 PRF can inhibit viral replication, the RNA pseudoknot stimulating −1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through junctions formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting −1 PRF in SARS-CoV-2.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### A theory of memory for binary sequences: Evidence for a mental compression algorithm in humans

by Samuel Planton, Timo van Kerkoerle, Leïla Abbih, Maxime Maheu, Florent Meyniel, Mariano Sigman, Liping Wang, Santiago Figueira, Sergio Romano, Stanislas Dehaene

Working memory capacity can be improved by recoding the memorized information in a condensed form. Here, we tested the theory that human adults encode binary sequences of stimuli in memory using an abstract internal language and a recursive compression algorithm. The theory predicts that the psychological complexity of a given sequence should be proportional to the length of its shortest description in the proposed language, which can capture any nested pattern of repetitions and alternations using a limited number of instructions. Five experiments examine the capacity of the theory to predict human adults’ memory for a variety of auditory and visual sequences. We probed memory using a sequence violation paradigm in which participants attempted to detect occasional violations in an otherwise fixed sequence. Both subjective complexity ratings and objective violation detection performance were well predicted by our theoretical measure of complexity, which simply reflects a weighted sum of the number of elementary instructions and digits in the shortest formula that captures the sequence in our language. While a simpler transition probability model, when tested as a single predictor in the statistical analyses, accounted for significant variance in the data, the goodness-of-fit with the data significantly improved when the language-based complexity measure was included in the statistical model, while the variance explained by the transition probability model largely decreased. Model comparison also showed that shortest description length in a recursive language provides a better fit than six alternative previously proposed models of sequence encoding. The data support the hypothesis that, beyond the extraction of statistical knowledge, human sequence coding relies on an internal compression using language-like nested structures.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Bacterial fitness landscapes stratify based on proteome allocation associated with discrete aero-types

by Ke Chen, Amitesh Anand, Connor Olson, Troy E. Sandberg, Ye Gao, Nathan Mih, Bernhard O. Palsson

The fitness landscape is a concept commonly used to describe evolution towards optimal phenotypes. It can be reduced to mechanistic detail using genome-scale models (GEMs) from systems biology. We use recently developed GEMs of Metabolism and protein Expression (ME-models) to study the distribution of Escherichia coli phenotypes on the rate-yield plane. We found that the measured phenotypes distribute non-uniformly to form a highly stratified fitness landscape. Systems analysis of ME-model simulations suggest that this stratification results from discrete ATP generation strategies. Accordingly, we define “aero-types”, a phenotypic trait that characterizes how a balanced proteome can achieve a given growth rate by modulating 1) the relative utilization of oxidative phosphorylation, glycolysis, and fermentation pathways; and 2) the differential employment of electron-transport-chain enzymes. This global, quantitative, and mechanistic systems biology interpretation of fitness landscape formed upon proteome allocation offers a fundamental understanding of bacterial physiology and evolution dynamics.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Four different mechanisms for switching cell polarity

by Filipe Tostevin, Manon Wigbers, Lotte Søgaard-Andersen, Ulrich Gerland

The mechanisms and design principles of regulatory systems establishing stable polarized protein patterns within cells are well studied. However, cells can also dynamically control their cell polarity. Here, we ask how an upstream signaling system can switch the orientation of a polarized pattern. We use a mathematical model of a core polarity system based on three proteins as the basis to study different mechanisms of signal-induced polarity switching. The analysis of this model reveals four general classes of switching mechanisms with qualitatively distinct behaviors: the transient oscillator switch, the reset switch, the prime-release switch, and the push switch. Each of these regulatory mechanisms effectively implements the function of a spatial toggle switch, however with different characteristics in their nonlinear and stochastic dynamics. We identify these characteristics and also discuss experimental signatures of each type of switching mechanism.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Coincident glutamatergic depolarizations enhance GABA<sub>A</sub> receptor-dependent Cl<sup>-</sup> influx in mature and suppress Cl<sup>-</sup> efflux in immature neurons

by Aniello Lombardi, Peter Jedlicka, Heiko J. Luhmann, Werner Kilb

The impact of GABAergic transmission on neuronal excitability depends on the Cl--gradient across membranes. However, the Cl--fluxes through GABAA receptors alter the intracellular Cl- concentration ([Cl-]i) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl-]i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl- dynamics simulating either a simple ball-and-stick topology or a reconstructed CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl- influx at low and attenuates or reverses the Cl- efflux at high initial [Cl-]i. The size of glutamatergic influence on GABAergic Cl--fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl--fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl-]i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the attenuation of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl-]i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl--fluxes should be considered as a relevant factor of short-term plasticity.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Reconciling kinetic and thermodynamic models of bacterial transcription

by Muir Morrison, Manuel Razo-Mejia, Rob Phillips

The study of transcription remains one of the centerpieces of modern biology with implications in settings from development to metabolism to evolution to disease. Precision measurements using a host of different techniques including fluorescence and sequencing readouts have raised the bar for what it means to quantitatively understand transcriptional regulation. In particular our understanding of the simplest genetic circuit is sufficiently refined both experimentally and theoretically that it has become possible to carefully discriminate between different conceptual pictures of how this regulatory system works. This regulatory motif, originally posited by Jacob and Monod in the 1960s, consists of a single transcriptional repressor binding to a promoter site and inhibiting transcription. In this paper, we show how seven distinct models of this so-called simple-repression motif, based both on thermodynamic and kinetic thinking, can be used to derive the predicted levels of gene expression and shed light on the often surprising past success of the thermodynamic models. These different models are then invoked to confront a variety of different data on mean, variance and full gene expression distributions, illustrating the extent to which such models can and cannot be distinguished, and suggesting a two-state model with a distribution of burst sizes as the most potent of the seven for describing the simple-repression motif.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Rosetta design with co-evolutionary information retains protein function

by Samuel Schmitz, Moritz Ertelt, Rainer Merkl, Jens Meiler

Computational protein design has the ambitious goal of crafting novel proteins that address challenges in biology and medicine. To overcome these challenges, the computational protein modeling suite Rosetta has been tailored to address various protein design tasks. Recently, statistical methods have been developed that identify correlated mutations between residues in a multiple sequence alignment of homologous proteins. These subtle inter-dependencies in the occupancy of residue positions throughout evolution are crucial for protein function, but we found that three current Rosetta design approaches fail to recover these co-evolutionary couplings. Thus, we developed the Rosetta method ResCue (residue-coupling enhanced) that leverages co-evolutionary information to favor sequences which recapitulate correlated mutations, as observed in nature. To assess the protocols via recapitulation designs, we compiled a benchmark of ten proteins each represented by two, structurally diverse states. We could demonstrate that ResCue designed sequences with an average sequence recovery rate of 70%, whereas three other protocols reached not more than 50%, on average. Our approach had higher recovery rates also for functionally important residues, which were studied in detail. This improvement has only a minor negative effect on the fitness of the designed sequences as assessed by Rosetta energy. In conclusion, our findings support the idea that informing protocols with co-evolutionary signals helps to design stable and native-like proteins that are compatible with the different conformational states required for a complex function.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Selection for rapid uptake of scarce or fluctuating resource explains vulnerability of glycolysis to imbalance

by Albertas Janulevicius, G. Sander van Doorn

Glycolysis is a conserved central pathway in energy metabolism that converts glucose to pyruvate with net production of two ATP molecules. Because ATP is produced only in the lower part of glycolysis (LG), preceded by an initial investment of ATP in the upper glycolysis (UG), achieving robust start-up of the pathway upon activation presents a challenge: a sudden increase in glucose concentration can throw a cell into a self-sustaining imbalanced state in which UG outpaces LG, glycolytic intermediates accumulate and the cell is unable to maintain high ATP concentration needed to support cellular functions. Such metabolic imbalance can result in “substrate-accelerated death”, a phenomenon observed in prokaryotes and eukaryotes when cells are exposed to an excess of substrate that previously limited growth. Here, we address why evolution has apparently not eliminated such a costly vulnerability and propose that it is a manifestation of an evolutionary trade-off, whereby the glycolysis pathway is adapted to quickly secure scarce or fluctuating resource at the expense of vulnerability in an environment with ample resource. To corroborate this idea, we perform individual-based eco-evolutionary simulations of a simplified yeast glycolysis pathway consisting of UG, LG, phosphate transport between a vacuole and a cytosol, and a general ATP demand reaction. The pathway is evolved in constant or fluctuating resource environments by allowing mutations that affect the (maximum) reaction rate constants, reflecting changing expression levels of different glycolytic enzymes. We demonstrate that under limited constant resource, populations evolve to a genotype that exhibits balanced dynamics in the environment it evolved in, but strongly imbalanced dynamics under ample resource conditions. Furthermore, when resource availability is fluctuating, imbalanced dynamics confers a fitness advantage over balanced dynamics: when glucose is abundant, imbalanced pathways can quickly accumulate the glycolytic intermediate FBP as intracellular storage that is used during periods of starvation to maintain high ATP concentration needed for growth. Our model further predicts that in fluctuating environments, competition for glucose can result in stable coexistence of balanced and imbalanced cells, as well as repeated cycles of population crashes and recoveries that depend on such polymorphism. Overall, we demonstrate the importance of ecological and evolutionary arguments for understanding seemingly maladaptive aspects of cellular metabolism.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans

by Miri Gordin, Hagit Philip, Alona Zilberberg, Moriah Gidoni, Raanan Margalit, Christopher Clouser, Kristofor Adams, Francois Vigneault, Irun R. Cohen, Gur Yaari, Sol Efroni

The partial success of tumor immunotherapy induced by checkpoint blockade, which is not antigen-specific, suggests that the immune system of some patients contain antigen receptors able to specifically identify tumor cells. Here we focused on T-cell receptor (TCR) repertoires associated with spontaneous breast cancer. We studied the alpha and beta chain CDR3 domains of TCR repertoires of CD4 T cells using deep sequencing of cell populations in mice and applied the results to published TCR sequence data obtained from human patients. We screened peripheral blood T cells obtained monthly from individual mice spontaneously developing breast tumors by 5 months. We then looked at identical TCR sequences in published human studies; we used TCGA data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects. We now report that mice spontaneously developing breast cancer manifest shared, Public CDR3 regions in both their alpha and beta and that a significant number of women with early breast cancer manifest identical CDR3 sequences. These findings suggest that the development of breast cancer is associated, across species, with biomarker, exclusive TCR repertoires.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Reconstructing tumor evolutionary histories and clone trees in polynomial-time with SubMARine

by Linda K. Sundermann, Jeff Wintersinger, Gunnar Rätsch, Jens Stoye, Quaid Morris

Tumors contain multiple subpopulations of genetically distinct cancer cells. Reconstructing their evolutionary history can improve our understanding of how cancers develop and respond to treatment. Subclonal reconstruction methods cluster mutations into groups that co-occur within the same subpopulations, estimate the frequency of cells belonging to each subpopulation, and infer the ancestral relationships among the subpopulations by constructing a clone tree. However, often multiple clone trees are consistent with the data and current methods do not efficiently capture this uncertainty; nor can these methods scale to clone trees with a large number of subclonal populations. Here, we formalize the notion of a partially-defined clone tree (partial clone tree for short) that defines a subset of the pairwise ancestral relationships in a clone tree, thereby implicitly representing the set of all clone trees that have these defined pairwise relationships. Also, we introduce a special partial clone tree, the Maximally-Constrained Ancestral Reconstruction (MAR), which summarizes all clone trees fitting the input data equally well. Finally, we extend commonly used clone tree validity conditions to apply to partial clone trees and describe SubMARine, a polynomial-time algorithm producing the subMAR, which approximates the MAR and guarantees that its defined relationships are a subset of those present in the MAR. We also extend SubMARine to work with subclonal copy number aberrations and define equivalence constraints for this purpose. Further, we extend SubMARine to permit noise in the estimates of the subclonal frequencies while retaining its validity conditions and guarantees. In contrast to other clone tree reconstruction methods, SubMARine runs in time and space that scale polynomially in the number of subclones. We show through extensive noise-free simulation, a large lung cancer dataset and a prostate cancer dataset that the subMAR equals the MAR in all cases where only a single clone tree exists and that it is a perfect match to the MAR in most of the other cases. Notably, SubMARine runs in less than 70 seconds on a single thread with less than one Gb of memory on all datasets presented in this paper, including ones with 50 nodes in a clone tree. On the real-world data, SubMARine almost perfectly recovers the previously reported trees and identifies minor errors made in the expert-driven reconstructions of those trees. The freely-available open-source code implementing SubMARine can be downloaded at https://github.com/morrislab/submarine.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Genome-wide prediction of topoisomerase II<i>β</i> binding by architectural factors and chromatin accessibility

by Pedro Manuel Martínez-García, Miguel García-Torres, Federico Divina, José Terrón-Bautista, Irene Delgado-Sainz, Francisco Gómez-Vela, Felipe Cortés-Ledesma

DNA topoisomerase II-β (TOP2B) is fundamental to remove topological problems linked to DNA metabolism and 3D chromatin architecture, but its cut-and-reseal catalytic mechanism can accidentally cause DNA double-strand breaks (DSBs) that can seriously compromise genome integrity. Understanding the factors that determine the genome-wide distribution of TOP2B is therefore not only essential for a complete knowledge of genome dynamics and organization, but also for the implications of TOP2-induced DSBs in the origin of oncogenic translocations and other types of chromosomal rearrangements. Here, we conduct a machine-learning approach for the prediction of TOP2B binding using publicly available sequencing data. We achieve highly accurate predictions, with accessible chromatin and architectural factors being the most informative features. Strikingly, TOP2B is sufficiently explained by only three features: DNase I hypersensitivity, CTCF and cohesin binding, for which genome-wide data are widely available. Based on this, we develop a predictive model for TOP2B genome-wide binding that can be used across cell lines and species, and generate virtual probability tracks that accurately mirror experimental ChIP-seq data. Our results deepen our knowledge on how the accessibility and 3D organization of chromatin determine TOP2B function, and constitute a proof of principle regarding the in silico prediction of sequence-independent chromatin-binding factors.

in PLoS Computational Biology on January 19, 2021 02:00 PM.

• #### Ocean acidification boosts reproduction in fish via indirect effects

by Ivan Nagelkerken, Tiphaine Alemany, Julie M. Anquetin, Camilo M. Ferreira, Kim E. Ludwig, Minami Sasaki, Sean D. Connell

Ocean acidification affects species populations and biodiversity through direct negative effects on physiology and behaviour. The indirect effects of elevated CO2 are less well known and can sometimes be counterintuitive. Reproduction lies at the crux of species population replenishment, but we do not know how ocean acidification affects reproduction in the wild. Here, we use natural CO2 vents at a temperate rocky reef and show that even though ocean acidification acts as a direct stressor, it can indirectly increase energy budgets of fish to stimulate reproduction at no cost to physiological homeostasis. Female fish maintained energy levels by compensation: They reduced activity (foraging and aggression) to increase reproduction. In male fish, increased reproductive investment was linked to increased energy intake as mediated by intensified foraging on more abundant prey. Greater biomass of prey at the vents was linked to greater biomass of algae, as mediated by a fertilisation effect of elevated CO2 on primary production. Additionally, the abundance and aggression of paternal carers were elevated at the CO2 vents, which may further boost reproductive success. These positive indirect effects of elevated CO2 were only observed for the species of fish that was generalistic and competitively dominant, but not for 3 species of subordinate and more specialised fishes. Hence, species that capitalise on future resource enrichment can accelerate their reproduction and increase their populations, thereby altering species communities in a future ocean.

in PLoS Biology on January 19, 2021 02:00 PM.

• #### A novel terpene synthase controls differences in anti-aphrodisiac pheromone production between closely related <i>Heliconius</i> butterflies

by Kathy Darragh, Anna Orteu, Daniella Black, Kelsey J. R. P. Byers, Daiane Szczerbowski, Ian A. Warren, Pasi Rastas, Ana Pinharanda, John W. Davey, Sylvia Fernanda Garza, Diana Abondano Almeida, Richard M. Merrill, W. Owen McMillan, Stefan Schulz, Chris D. Jiggins

Plants and insects often use the same compounds for chemical communication, but not much is known about the genetics of convergent evolution of chemical signals. The terpene (E)-β-ocimene is a common component of floral scent and is also used by the butterfly Heliconius melpomene as an anti-aphrodisiac pheromone. While the biosynthesis of terpenes has been described in plants and microorganisms, few terpene synthases (TPSs) have been identified in insects. Here, we study the recent divergence of 2 species, H. melpomene and Heliconius cydno, which differ in the presence of (E)-β-ocimene; combining linkage mapping, gene expression, and functional analyses, we identify 2 novel TPSs. Furthermore, we demonstrate that one, HmelOS, is able to synthesise (E)-β-ocimene in vitro. We find no evidence for TPS activity in HcydOS (HmelOS ortholog of H. cydno), suggesting that the loss of (E)-β-ocimene in this species is the result of coding, not regulatory, differences. The TPS enzymes we discovered are unrelated to previously described plant and insect TPSs, demonstrating that chemical convergence has independent evolutionary origins.

in PLoS Biology on January 19, 2021 02:00 PM.

• #### Functional imaging of Bow Hunter's syndrome

in Annals of Neurology on January 19, 2021 01:01 PM.

• #### Mitochondrial dysfunction, mitophagy, and role of dynamin‐related protein 1 in Alzheimer's disease

Oxidative stress implicates mitochondrial damage and effects on mitochondrial function, production of ATP, mitochondrial dynamics and biogenesis. The mitochondrial dysfunction eventually demonstrates its lethal behaviour on Aβ clearance and mitochondrial fission, especially on the protein Drp1. In AD pathogenesis, Drp1 can play an important regulatory role in mitophagy and autophagy. The miR‐499 causes suppression of calcineurin‐mediated dephosphorylation of Drp1, whereas miR‐30a inhibits mitochondrial fission by suppressing p53 and subsequent Drp‐1 downstream signaling. Mitochondrial targeted antioxidant (MTA) molecules such as Mdivi1, SS31 and Dynasore can reduce excessive mitochondrial fission activity of Drp1 and restore normal mitochondrial functions, fusion‐fission activities, mitophagy and autophagy functions in clearing dead mitochondria for normal synaptic functions.

## Abstract

Alzheimer's disease (AD) is the most common type of dementia and progressive neurodegenerative disease. The presence of β‐amyloid (Aβ) plaques and phosphorylated Tau tangles are considered to be the two main hallmarks of AD. Recent findings have shown that different changes in the structure and dynamics of mitochondria play an important role in AD pathology progression. Mitochondrial changes in AD are expressed as enhanced mitochondrial fragmentation, altered mitochondrial dynamics, and changes in the expression of mitochondrial biogenesis genes in vitro and in vivo models. Therefore, targeting mitochondria and associated mitochondrial proteins seems to be a promising alternative instead of targeting Aβ and Tau in the prevention of Alzheimer's disease. The dynamin‐related protein (Drp1) is one such protein that plays an important role in the regulation of mitochondrial division and maintenance of mitochondrial structures. Few researchers have shown that inhibition of Drp1 GTPase activity in neuronal cells rescues excessive mitochondrial fragmentation. In addition, the growing evidence revealed that Drp1 can interact with both Aβ and Tau protein in human brain tissues and mouse models. In this review, we would like to update existing knowledge about various changes in and around mitochondria related to the pathogenesis of Alzheimer's disease, with particular emphasis on mitophagy and autophagy.

in Journal of Neuroscience Research on January 19, 2021 12:54 PM.

• #### Generalized stochastic microdosimetric model: The main formulation

Author(s): F. Cordoni, M. Missiaggia, A. Attili, S. M. Welford, E. Scifoni, and C. La Tessa

The present work introduces a rigorous stochastic model, called the generalized stochastic microdosimetric model (${\mathrm{GSM}}^{2}$), to describe biological damage induced by ionizing radiation. Starting from the microdosimetric spectra of energy deposition in tissue, we derive a master equation describing the t...

[Phys. Rev. E 103, 012412] Published Tue Jan 19, 2021

in Physical Review E: Biological physics on January 19, 2021 10:00 AM.

• #### Influence of far-red light coherence on the functional state of plants

Author(s): A. V. Budagovsky, N. V. Solovykh, O. N. Budagovskaya, and I. A. Budagovsky

The influence of the coherence of far-red (730 nm) light on the functional activity of plants was studied. Blackberry explants cultivated in vitro on an artificial nutrient medium served as a biological model. The explants were irradiated with light beams with different spatial and temporal coherenc...

[Phys. Rev. E 103, 012411] Published Tue Jan 19, 2021

in Physical Review E: Biological physics on January 19, 2021 10:00 AM.

• #### Bistability induced by a spontaneous twisting rate for a two-dimensional intrinsically curved filament

Author(s): Zicong Zhou

We find that a moderate intrinsic twisting rate (ITR) can induce a bistable state for a force-free two-dimensional intrinsically curved filament. There are two different configurations of equal energy in a bistable state so that the filament is clearly different from its three-dimensional counterpar...

[Phys. Rev. E 103, 012410] Published Tue Jan 19, 2021

in Physical Review E: Biological physics on January 19, 2021 10:00 AM.

• #### Master regulators as order parameters of gene expression states

Author(s): Andreas Krämer

Cell type-specific gene expression patterns are represented as memory states of a Hopfield neural network model. It is shown that order parameters of this model can be interpreted as concentrations of master transcription regulators that form concurrent positive feedback loops with a large number of...

[Phys. Rev. E 103, 012409] Published Tue Jan 19, 2021

in Physical Review E: Biological physics on January 19, 2021 10:00 AM.

• #### Faster Convergence in Deep-Predictive-Coding Networks to Learn Deeper Representations. (arXiv:2101.06848v1 [cs.AI])

Deep-predictive-coding networks (DPCNs) are hierarchical, generative models that rely on feed-forward and feed-back connections to modulate latent feature representations of stimuli in a dynamic and context-sensitive manner. A crucial element of DPCNs is a forward-backward inference procedure to uncover sparse states of a dynamic model, which are used for invariant feature extraction. However, this inference and the corresponding backwards network parameter updating are major computational bottlenecks. They severely limit the network depths that can be reasonably implemented and easily trained. We therefore propose a optimization strategy, with better empirical and theoretical convergence, based on accelerated proximal gradients.

We demonstrate that the ability to construct deeper DPCNs leads to receptive fields that capture well the entire notions of objects on which the networks are trained. This improves the feature representations. It yields completely unsupervised classifiers that surpass convolutional and convolutional-recurrent autoencoders and are on par with convolutional networks trained in a supervised manner. This is despite the DPCNs having orders of magnitude fewer parameters.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 19, 2021 01:30 AM.

• #### Design Fast Algorithms For Hodgkin-Huxley Neuronal Networks. (arXiv:2101.06627v1 [q-bio.NC])

The stiffness of the Hodgkin-Huxley (HH) equations during an action potential (spike) limits the use of large time steps. We observe that the neurons can be evolved independently between spikes, $i.e.,$ different neurons can be evolved with different methods and different time steps. This observation motivates us to design fast algorithms to raise efficiency. We present an adaptive method, an exponential time differencing (ETD) method and a library-based method to deal with the stiff period. All the methods can use time steps one order of magnitude larger than the regular Runge-Kutta methods to raise efficiency while achieving precise statistical properties of the original HH neurons like the largest Lyapunov exponent and mean firing rate. We point out that the ETD and library methods can stably achieve maximum 8 and 10 times of speedup, respectively.

in arXiv: Quantitative Biology: Neurons and Cognition on January 19, 2021 01:30 AM.

• #### Performance Analysis and Improvement of Parallel Differential Evolution. (arXiv:2101.06599v1 [cs.NE])

Differential evolution (DE) is an effective global evolutionary optimization algorithm using to solve global optimization problems mainly in a continuous domain. In this field, researchers pay more attention to improving the capability of DE to find better global solutions, however, the computational performance of DE is also a very interesting aspect especially when the problem scale is quite large. Firstly, this paper analyzes the design of parallel computation of DE which can easily be executed in Math Kernel Library (MKL) and Compute Unified Device Architecture (CUDA). Then the essence of the exponential crossover operator is described and we point out that it cannot be used for better parallel computation. Later, we propose a new exponential crossover operator (NEC) that can be executed parallelly with MKL/CUDA. Next, the extended experiments show that the new crossover operator can speed up DE greatly. In the end, we test the new parallel DE structure, illustrating that the former is much faster.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 19, 2021 01:30 AM.

• #### Deep-Mobility: A Deep Learning Approach for an Efficient and Reliable 5G Handover. (arXiv:2101.06558v2 [cs.LG] UPDATED)

5G cellular networks are being deployed all over the world and this architecture supports ultra-dense network (UDN) deployment. Small cells have a very important role in providing 5G connectivity to the end users. Exponential increases in devices, data and network demands make it mandatory for the service providers to manage handovers better, to cater to the services that a user desire. In contrast to any traditional handover improvement scheme, we develop a 'Deep-Mobility' model by implementing a deep learning neural network (DLNN) to manage network mobility, utilizing in-network deep learning and prediction. We use network key performance indicators (KPIs) to train our model to analyze network traffic and handover requirements. In this method, RF signal conditions are continuously observed and tracked using deep learning neural networks such as the Recurrent neural network (RNN) or Long Short-Term Memory network (LSTM) and system level inputs are also considered in conjunction, to take a collective decision for a handover. We can study multiple parameters and interactions between system events along with the user mobility, which would then trigger a handoff in any given scenario. Here, we show the fundamental modeling approach and demonstrate usefulness of our model while investigating impacts and sensitivities of certain KPIs from the user equipment (UE) and network side.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 19, 2021 01:30 AM.

• #### Multi-objective Search of Robust Neural Architectures against Multiple Types of Adversarial Attacks. (arXiv:2101.06507v1 [cs.LG])

Many existing deep learning models are vulnerable to adversarial examples that are imperceptible to humans. To address this issue, various methods have been proposed to design network architectures that are robust to one particular type of adversarial attacks. It is practically impossible, however, to predict beforehand which type of attacks a machine learn model may suffer from. To address this challenge, we propose to search for deep neural architectures that are robust to five types of well-known adversarial attacks using a multi-objective evolutionary algorithm. To reduce the computational cost, a normalized error rate of a randomly chosen attack is calculated as the robustness for each newly generated neural architecture at each generation. All non-dominated network architectures obtained by the proposed method are then fully trained against randomly chosen adversarial attacks and tested on two widely used datasets. Our experimental results demonstrate the superiority of optimized neural architectures found by the proposed approach over state-of-the-art networks that are widely used in the literature in terms of the classification accuracy under different adversarial attacks.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 19, 2021 01:30 AM.

• #### Interactions of SARS-CoV-2 spike protein and transient receptor potential (TRP) cation channels could explain smell, taste, and/or chemesthesis disorders. (arXiv:2101.06294v1 [q-bio.NC])

A significant subset of patients infected by SARS-CoV-2 presents olfactory, taste, and/or chemesthesis (OTC) disorders (OTCD). These patients recover rapidly, eliminating damage of sensory nerves. Discovering that S protein contains two ankyrin repeat binding motifs (S-ARBMs) and some TRP cation channels, implicated in OTC, have ankyrin repeat domains (TRPs-ARDs), I hypothesized that interaction of S-ARBMs and TRPs-ARDs could dysregulate the function of the latter and thus explains OTCD. Of note, some TRPs-ARDs are expressed in the olfactory epithelium, taste buds, trigeminal neurons in the oronasal cavity and vagal neurons in the trachea/lungs. Furthermore, this hypothesis is supported by studies that have shown: (i) respiratory viruses interact with TRPA1 and TRPV1 on sensory nerves and epithelial cells in the airways, (ii) the respiratory pathophysiology in COVID-19 patients is similar to lungs injuries produced by the sensitization of TRPV1 and TRPV4, and (iii) resolvin D1 and D2 shown to reduce SARS-CoV-2-induced inflammation, directly inhibit TRPA1, TRPV1, TRPV3 and TRPV4. Herein, results of blind dockings of S-ARBMs, 408-RQIAPG-413 (in RBD but distal from the ACE-2 binding region) and 905-RFNGIG-910 (in HR1), into TRPA1, TRPV1 and TRPV4 suggest that S-ARBMs interact with ankyrin repeat 6 of TRPA1 near an active site, and ankyrin repeat 3-4 of TRPV1 near cysteine 258 supposed to be implicated in the formation of inter-subunits disulfide bond. These findings suggest that S-ARBMs affect TRPA1, TRPV1 and TRPV4 function by interfering with channel assembly and trafficking. After an experimental confirmation of these interactions, among possible preventive treatments against COVID-19, the use of pharmacological manipulation (probably inhibition) of TRPs-ARDs to control or mitigate sustained pro-inflammatory response.

in arXiv: Quantitative Biology: Neurons and Cognition on January 19, 2021 01:30 AM.

• #### Controllable reset behavior in domain wall-magnetic tunnel junction artificial neurons for task-adaptable computation. (arXiv:2101.03095v1 [cond-mat.mes-hall] CROSS LISTED)

Neuromorphic computing with spintronic devices has been of interest due to the limitations of CMOS-driven von Neumann computing. Domain wall-magnetic tunnel junction (DW-MTJ) devices have been shown to be able to intrinsically capture biological neuron behavior. Edgy-relaxed behavior, where a frequently firing neuron experiences a lower action potential threshold, may provide additional artificial neuronal functionality when executing repeated tasks. In this study, we demonstrate that this behavior can be implemented in DW-MTJ artificial neurons via three alternative mechanisms: shape anisotropy, magnetic field, and current-driven soft reset. Using micromagnetics and analytical device modeling to classify the Optdigits handwritten digit dataset, we show that edgy-relaxed behavior improves both classification accuracy and classification rate for ordered datasets while sacrificing little to no accuracy for a randomized dataset. This work establishes methods by which artificial spintronic neurons can be flexibly adapted to datasets.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 19, 2021 01:30 AM.

• #### Learning without feedback: Fixed random learning signals allow for feedforward training of deep neural networks. (arXiv:1909.01311v2 [stat.ML] UPDATED)

While the backpropagation of error algorithm enables deep neural network training, it implies (i) bidirectional synaptic weight transport and (ii) update locking until the forward and backward passes are completed. Not only do these constraints preclude biological plausibility, but they also hinder the development of low-cost adaptive smart sensors at the edge, as they severely constrain memory accesses and entail buffering overhead. In this work, we show that the one-hot-encoded labels provided in supervised classification problems, denoted as targets, can be viewed as a proxy for the error sign. Therefore, their fixed random projections enable a layerwise feedforward training of the hidden layers, thus solving the weight transport and update locking problems while relaxing the computational and memory requirements. Based on these observations, we propose the direct random target projection (DRTP) algorithm and demonstrate that it provides a tradeoff between accuracy and computational cost that is suitable for adaptive edge computing devices.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 19, 2021 01:30 AM.

• #### Publisher Correction: Method of the Year: spatially resolved transcriptomics

Nature Methods, Published online: 19 January 2021; doi:10.1038/s41592-021-01065-y

Publisher Correction: Method of the Year: spatially resolved transcriptomics

in Nature Methods on January 19, 2021 12:00 AM.

• #### Degradation of complex arabinoxylans by human colonic Bacteroidetes

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20737-5

Human gut bacteria can degrade arabinoxylans, polysaccharides found in dietary fiber. Here, Pereira et al. identify a bacterial gene cluster encoding esterases for degradation of complex arabinoxylans. The action of these enzymes results in accumulation of ferulic acid, a phenolic compound with antioxidative and immunomodulatory properties.

in Nature Communications on January 19, 2021 12:00 AM.

• #### A network-based framework for shape analysis enables accurate characterization of leaf epidermal cells

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20730-y

While cell shape is crucial for function and development of organisms, versatile frameworks for cell shape quantification, comparison, and classification remain underdeveloped. Here, the authors use a network-based framework for Arabidopsis leaf epidermal cell shape characterization and classification.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Passerini-type reaction of boronic acids enables α-hydroxyketones synthesis

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20727-7

Multicomponent reactions enable the rapid construction of diverse molecular scaffolds with modularity and step economy. In this work, the authors report the use of boronic acids as carbon nucleophiles in a Passerini-type three-component coupling reaction towards an expanded inventory of α-hydroxyketones.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20723-x

Durable response rate to anti-PD-1/PD-L1 therapy remains relatively low in patients with cancer. Here the authors show that metformin-loaded mannose-modified macrophage-derived microparticles reprogram the tumor immune microenvironment and improve responses to anti-PD-1 therapy.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Ionic liquid enables highly efficient low temperature desalination by directional solvent extraction

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20706-y

Directional Solvent Extraction is an emerging non-membrane desalination technology for sea water desalination but is limited by throughput and energy efficiency. Here, the authors demonstrate that the production rate and energy efficiency can be increased by using ionic liquids as directional solvent.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Rab1-AMPylation by Legionella DrrA is allosterically activated by Rab1

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20702-2

The Legionella effector DrrA AMPylates the host protein Rab1 during infection, but the mechanism is still under debate. Here, the authors provide structural insights into the low-affinity DrrA:Rab1 interaction, showing that Rab1 allosterically activates DrrA through a non-conventional binding mechanism.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Genomic epidemiology of SARS-CoV-2 reveals multiple lineages and early spread of SARS-CoV-2 infections in Lombardy, Italy

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20688-x

The Lombardy region of Italy was heavily affected early in the SARS-CoV-2 pandemic. Here, the authors use whole genome sequencing and show that there were multiple introductions into the region, with transmission occurring before the first case was detected.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Floquet spin states in OLEDs

Nature Communications, Published online: 19 January 2021; doi:10.1038/s41467-020-20148-6

Organic semiconductors employed in light-emitting diodes (OLEDs) allow for magnetic resonance studies that explore light-matter interactions in the ultrastrong-drive regime, where the Rabi frequency exceeds the Larmor frequency. The authors report the formation of Floquet spin states in OLEDs.

in Nature Communications on January 19, 2021 12:00 AM.

• #### Experimental Brain Research

in Experimental Brain Research on January 19, 2021 12:00 AM.

• #### Class I HDAC Inhibitor Improves Synaptic Proteins and Repairs Cytoskeleton Through Regulating Synapse-Related Genes In vitro and In vivo

β-amyloid (Aβ) is an important protein molecule in the pathology of Alzheimer’s disease (AD). Accumulation of Aβ leads to the loss of dendritic spines and synapses. These impairments can be ameliorated by histone deacetylase inhibitors (HDACI). However, the mechanisms of HDACIs underlying the effect on synapse are not fully understood. In this study, we examined the relationship between HDAC activity and synapse-related genes and proteins by the administration of a class I HDAC inhibitor, BG45, in the exogenous Aβ-treated cells and mice. Our studies showed that the treatment of HF-488-Aβ1–42 to SH-SY5Y cells first increased the expression of the postsynaptic dendritic protein (PSD), then decreased it after 36 h. BG45 can alleviate the reduction of the expression of PSD-95 as well as spinophilin and cytoskeletal protein induced by HF-488-Aβ1–42 aggregation in SH-SY5Y cells. Similar to the results in vitro, PSD-95 in the hippocampus was temporarily increased in the early days of intravenous injection HF-488-Aβ1–40 to the mice, followed by the decreased expression of PSD-95 on the 9th day. In further studies, for the mice treated with Aβ for 9 days, we found that BG45 decreased the expression of HDAC1 and 2, increased the expression of PSD-95, spinophilin, and synaptophysin (SYP). Our data also showed that BG45 upregulated levels of three synapse-related genes and proteins GRIK2, SCN3B, and SYNPR. These findings suggest that the exogenous Aβ may stimulate transiently the expression of PSD-95 at an early stage, but subsequently contribute to synaptic defects. HDAC1 and 2 are involved in synaptic defects, and BG45 may improve the expression of synaptic and cytoskeletal proteins and repair cytoskeletal damage by specifically inhibiting HDAC1 and 2, thereby modulating synapse-related genes. BG45 might be a potential therapeutic agent for the treatment of an early stage of Aβ-related neurodegenerative disease.

in Frontiers in Ageing Neuroscience on January 19, 2021 12:00 AM.

• #### The two roles of complex III in plants

Atomic structures of mitochondrial enzyme complexes in plants are shedding light on their multiple functions.

in eLife on January 19, 2021 12:00 AM.

• #### Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229E

Seasonal coronaviruses (OC43, 229E, NL63 and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here, we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively-selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.

in eLife on January 19, 2021 12:00 AM.

• #### Phenotypic and molecular evolution across 10,000 generations in laboratory budding yeast populations

Laboratory experimental evolution provides a window into the details of the evolutionary process. To investigate the consequences of long-term adaptation, we evolved 205 Saccharomyces cerevisiae populations (124 haploid and 81 diploid) for ~10,000,000 generations in three environments. We measured the dynamics of fitness changes over time, finding repeatable patterns of declining adaptability. Sequencing revealed that this phenotypic adaptation is coupled with a steady accumulation of mutations, widespread genetic parallelism, and historical contingency. In contrast to long-term evolution in E. coli, we do not observe long-term coexistence or populations with highly elevated mutation rates. We find that evolution in diploid populations involves both fixation of heterozygous mutations and frequent loss-of-heterozygosity events. Together, these results help distinguish aspects of evolutionary dynamics that are likely to be general features of adaptation across many systems from those that are specific to individual organisms and environmental conditions.

in eLife on January 19, 2021 12:00 AM.

• #### Climate-driven deoxygenation elevates fishing vulnerability for the ocean's widest ranging shark

Climate-driven expansions of ocean hypoxic zones are predicted to concentrate pelagic fish in oxygenated surface layers, but how expanding hypoxia and fisheries will interact to affect threatened pelagic sharks remains unknown. Here, analysis of satellite-tracked blue sharks and environmental modelling in the eastern tropical Atlantic oxygen minimum zone (OMZ) shows shark maximum dive depths decreased due to combined effects of decreasing dissolved oxygen (DO) at depth, high sea surface temperatures, and increased surface-layer net primary production. Multiple factors associated with climate-driven deoxygenation contributed to blue shark vertical habitat compression, potentially increasing their vulnerability to surface fisheries. Greater intensity of longline fishing effort occurred above the OMZ compared to adjacent waters. Higher shark catches were associated with strong DO gradients, suggesting potential aggregation along suitable DO gradients contributed to habitat compression and higher fishing-induced mortality. Fisheries controls to counteract deoxygenation effects on shark catches will be needed as oceans continue warming.

in eLife on January 19, 2021 12:00 AM.

• #### Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron

The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic 'KNDy' neurons co-express kisspeptin, neurokinin B (NKB) and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close, non-synaptic appositions with the GnRH neuron dendron. Electrophysiology and confocal GCaMP6 imaging demonstrated that, despite all three neuropeptides being released from KNDy terminals, only kisspeptin was able to activate the GnRH neuron dendron. Mice with a selective deletion of kisspeptin from KNDy neurons failed to exhibit pulsatile hormone secretion but maintained synchronized episodic KNDy neuron behavior thought to depend on recurrent NKB and dynorphin transmission. This indicates that KNDy neurons drive episodic hormone secretion through highly redundant neuropeptide co-transmission orchestrated by differential postsynaptic neuropeptide receptor expression at the GnRH neuron dendron and KNDy neuron.

in eLife on January 19, 2021 12:00 AM.

• #### Atomic structures of respiratory complex III2, complex IV, and supercomplex III2-IV from vascular plants

Mitochondrial complex III (CIII2) and complex IV (CIV), which can associate into a higher-order supercomplex (SC III2+IV), play key roles in respiration. However, structures of these plant complexes remain unknown. We present atomic models of CIII2, CIV, and SC III2+IV from Vigna radiata determined by single-particle cryoEM. The structures reveal plant-specific differences in the MPP domain of CIII2 and define the subunit composition of CIV. Conformational heterogeneity analysis of CIII2 revealed long-range, coordinated movements across the complex, as well as the motion of CIII2’s iron-sulfur head domain. The CIV structure suggests that, in plants, proton translocation does not occur via the H channel. The supercomplex interface differs significantly from that in yeast and bacteria in its interacting subunits, angle of approach and limited interactions in the mitochondrial matrix. These structures challenge long-standing assumptions about the plant complexes and generate new mechanistic hypotheses.

in eLife on January 19, 2021 12:00 AM.

• #### Behavioral role of PACAP reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations

The neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAP role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.

in eLife on January 19, 2021 12:00 AM.

• #### Freshwater monitoring by nanopore sequencing

While traditional microbiological freshwater tests focus on the detection of specific bacterial indicator species, including pathogens, direct tracing of all aquatic DNA through metagenomics poses a profound alternative. Yet, in situ metagenomic water surveys face substantial challenges in cost and logistics. Here, we present a simple, fast, cost-effective and remotely accessible freshwater diagnostics workflow centred around the portable nanopore sequencing technology. Using defined compositions and spatiotemporal microbiota from surface water of an example river in Cambridge (UK), we provide optimised experimental and bioinformatics guidelines, including a benchmark with twelve taxonomic classification tools for nanopore sequences. We find that nanopore metagenomics can depict the hydrological core microbiome and fine temporal gradients in line with complementary physicochemical measurements. In a public health context, these data feature relevant sewage signals and pathogen maps at species level resolution. We anticipate that this framework will gather momentum for new environmental monitoring initiatives using portable devices.

in eLife on January 19, 2021 12:00 AM.

• #### Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.

in eLife on January 19, 2021 12:00 AM.

• #### fruitless tunes functional flexibility of courtship circuitry during development

Drosophila male courtship is controlled by the male-specific products of the fruitless (fruM) gene and its expressing neuronal circuitry. fruM is considered a master gene that controls all aspects of male courtship. By temporally and spatially manipulating fruM expression, we found that fruM is required during a critical developmental period for innate courtship towards females, while its function during adulthood is involved in inhibiting male-male courtship. By altering or eliminating fruM expression, we generated males that are innately heterosexual, homosexual, bisexual, or without innate courtship but could acquire such behavior in an experience-dependent manner. These findings show that fruM is not absolutely necessary for courtship but is critical during development to build a sex circuitry with reduced flexibility and enhanced efficiency, and provide a new view about how fruM tunes functional flexibility of a sex circuitry instead of switching on its function as conventionally viewed.

in eLife on January 19, 2021 12:00 AM.

• #### VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7

Chemotherapy-induced neuropathic pain is a clinically relevant adverse effect of several anticancer drugs leading to dose reduction or therapy discontinuation. The lack of knowledge about the mechanisms of neuropathy development and pain chronicization makes chemotherapy-induced neuropathic pain treatment an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a neurotoxicity biomarker in a model of chemotherapy-induced neuropathy, and its decrease has been related to pain relief. Aim of this study was to clarify the VEGF-A-dependent pain signaling in the CNS for individuating new targeted therapeutic approaches. In mice, the intrathecal infusion of VEGF-A induced a dose-dependent noxious hypersensitivity mediated by the VEGF receptor 1 (VEGFR-1) as demonstrated by pharmacological and genetic tools. In electrophysiological study, VEGF-A stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord, VEGF-A increased in astrocytes of animals affected by neuropathy suggesting this cell population as a source of the potent pain mediator. Accordingly, the selective knockdown of astrocytic VEGF-A, by shRNAmir, blocked the development of oxaliplatin-induced neuropathic pain. Besides, the anti-VEGFR-1 mAb D16F7 (previously described as anticancer) effectively relieved neuropathic pain induced by chemotherapeutic agents. In conclusion, astrocyte-released VEGF-A is a new player in the complex neuron-glia network that oversees physiological and pathological pain and D16F7 mAb rises as a potent pain killer strategy.

in bioRxiv: Neuroscience on January 19, 2021 12:00 AM.

• #### The neuroprotective effects of Sonic hedgehog pathway agonist SAG in a rat model of neonatal stroke

Objective: Neonatal stroke affects 1 in 2800 live births and is a major cause of neurological injury. The Sonic Hedgehog (Shh) signaling pathway is critical for central nervous system (CNS) development and has neuroprotective and reparative effects in different CNS injury models. Previous studies have demonstrated beneficial effects of small molecule Shh-Smoothened-agonist (SAG) against neonatal cerebellar injury and it improves Down syndrome-related brain structural deficits in mice. Here, we investigated SAG neuroprotection in rat models of neonatal ischemia-reperfusion (stroke) and adult focal white matter injury. Methods: We used transient middle cerebral artery occlusion at P10 and ethidium bromide injection in adult rats to induce damage. Following surgery and SAG or vehicle treatment we analyzed tissue loss, cell proliferation and fate, and behavioral outcome. Results: We report that a single dose of SAG administered following neonatal stroke preserved brain volume, reduced inflammation, enhanced oligodendrocyte progenitor cell (OPC) and EC proliferation, and resulted in long-term cognitive improvement. Single-dose SAG also promoted proliferation of OPCs following focal demyelination in the adult rat. Conclusion: These findings indicate benefit of one-time SAG treatment post-insult in reducing brain injury and improving behavioral outcome after experimental neonatal stroke.

in bioRxiv: Neuroscience on January 19, 2021 12:00 AM.

• #### Surface GluA1 and glutamate transmission are increased in VPS35 D620N neurons and altered by LRRK2 kinase inhibition

Vacuolar protein sorting 35 (VPS35) regulates receptor recycling from endosomes. A mutation in VPS35 (D620N) leads to autosomal-dominant, late-onset Parkinsons disease. A knock-in mouse model was used to study the neurobiology of VPS35 D620N. In brain tissue, we confirm previous findings that the mutation results in reduced binding of VPS35 with WASH-complex member FAM21, and robustly elevated phosphorylation of the LRRK2 kinase substrate Rab10. In cultured cortical neurons, the mutation results in increased endosomal recycling protein density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate release, and GluA1 surface expression. LRRK2 kinase inhibition exerted genotype-specific effects on GluA1 surface expression, but did not impact glutamate release phenotypes. These results improve our understanding of the early effects of the D620N mutation on cellular functions that are specific to neurons. These observations provide candidate pathophysiological pathways that may drive eventual transition to late-stage parkinsonism in VPS35 families, and support a synaptopathy model of neurodegeneration.

in bioRxiv: Neuroscience on January 19, 2021 12:00 AM.

• #### Autism Spectrum Disorder is a Risk Factor for PTSD-like Memory Formation

The predisposition of Autism Spectrum Disorder (ASD) to Post-Traumatic Stress Disorder (PTSD) remained to be established. Here, we show that exposure to a single mild stressful event induces maladaptive memory, which recapitulates all features of PTSD, and is associated with the broad dysfunction of the prefrontal-hippocampo-amygdalar network. Using optogenetics, we demonstrate that prefrontal cortex hyperactivation triggers this PTSD-like memory. Finally, we show that recontextualization of the traumatic event normalizes maladaptive memory in ASD conditions. Overall, this study provides the first direct demonstration that ASD represents a risk factor for PTSD and uncovers new mechanisms that underlie pathological memory formation.

in bioRxiv: Neuroscience on January 19, 2021 12:00 AM.

• #### Peripapillary hyper‐reflective ovoid masslike structures in astronauts

in Annals of Neurology on January 18, 2021 02:59 PM.

• #### Biceps activity synchronous with inspiration after phrenic nerve transfer

in Annals of Neurology on January 18, 2021 02:49 PM.

• #### Reply to “Peripapillary hyper‐reflective ovoid masslike structures in astronauts”

in Annals of Neurology on January 18, 2021 02:28 PM.

## Objective

Progressive Multifocal Leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and evaluate preliminary efficacy of polyomavirus JC (JCPyV)‐specific T cell therapy in a cohort of hematological patients with PML.

## Methods

Between 2014 and 2019, nine patients with a diagnosis of “definite PML” according to the 2013 consensus showing progressive clinical deterioration received JCPyV‐specific T cells (JCPyV‐LTC). Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen‐derived peptides.

## Results

None of the patients experienced treatment‐related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV‐specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, that was interpreted as a sign of immune control and that regressed spontaneously without the need for steroid treatment. Six out of nine patients achieved PML control, with five alive and in good clinical conditions at their last follow‐up.

## Interpretation

Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy.

in Annals of Neurology on January 18, 2021 11:06 AM.

• #### Immunocytochemical and Ultrastructural Organization of the Taste Thalamus of the Tree Shrew (Tupaia belangeri)

The synaptic circuitry of primary sensory thalamic nuclei has been well characterized and show striking similarities both in terminal morphology and chemical characteristics. The exception to this is the taste thalamus, the VPMP. A past study of synaptic circuitry in the rat taste thalamus (VPMpc) revealed marked differences from other nuclei like the LGN and MGN. Our data demonstrates that the tree shrew VPMP shares synaptic characteristics common to primary sensory thalamic nuclei including presynaptic interneuron dendrites, large VGluT2 positive terminals, and triadic arrangements in glomeruli.

## Abstract

Ventroposterior medialis parvocellularis (VPMP) nucleus of the primate thalamus receives direct input from the nucleus of the solitary tract, whereas the homologous thalamic structure in the rodent does not. To reveal whether the synaptic circuitries in these nuclei lend evidence for conservation of design principles in the taste thalamus across species or across sensory thalamus in general, we characterized the ultrastructural and molecular properties of the VPMP in a close relative of primates, the tree shrew (Tupaia belangeri), and compared these to known properties of the taste thalamus in rodent, and the visual thalamus in mammals. Electron microscopy analysis to categorize the synaptic inputs in the VPMP revealed that the largest‐size terminals contained many vesicles and formed large synaptic zones with thick postsynaptic density on multiple, medium‐caliber dendrite segments. Some formed triads within glomerular arrangements. Smaller‐sized terminals contained dark mitochondria; most formed a single asymmetric or symmetric synapse on small‐diameter dendrites. Immuno‐EM experiments revealed that the large‐size terminals contained VGLUT2, whereas the small‐size terminal populations contained VGLUT1 or ChAT. These findings provide evidence that the morphological and molecular characteristics of synaptic circuitry in the tree shrew VPMP are similar to that in non‐chemical sensory thalamic nuclei. Furthermore, the results indicate that all primary sensory nuclei of the thalamus in higher mammals share a structural template for processing thalamocortical sensory information. In contrast, substantial morphological and molecular differences in rodent versus tree shrew taste nuclei suggest a fundamental divergence in cellular processing mechanisms of taste input in these two species.

in Journal of Comparative Neurology on January 18, 2021 09:07 AM.

• #### A Novel Prediction Approach for Exploring PM2.5 Spatiotemporal Propagation Based on Convolutional Recursive Neural Networks. (arXiv:2101.06213v1 [cs.LG])

The spread of PM2.5 pollutants that endanger health is difficult to predict because it involves many atmospheric variables. These micron particles can spread rapidly from their source to residential areas, increasing the risk of respiratory disease if exposed for long periods. The prediction system of PM2.5 propagation provides more detailed and accurate information as an early warning system to reduce health impacts on the community. According to the idea of transformative computing, the approach we propose in this paper allows computation on the dataset obtained from massive-scale PM2.5 sensor nodes via wireless sensor network. In the scheme, the deep learning model is implemented on the server nodes to extract spatiotemporal features on these datasets. This research was conducted by using dataset of air quality monitoring systems in Taiwan. This study presents a new model based on the convolutional recursive neural network to generate the prediction map. In general, the model is able to provide accurate predictive results by considering the bonds among measurement nodes in both spatially and temporally. Therefore, the particulate pollutant propagation of PM2.5 could be precisely monitored by using the model we propose in this paper.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 18, 2021 01:30 AM.

• #### A New Artificial Neuron Proposal with Trainable Simultaneous Local and Global Activation Function. (arXiv:2101.06100v1 [cs.NE])

The activation function plays a fundamental role in the artificial neural network learning process. However, there is no obvious choice or procedure to determine the best activation function, which depends on the problem. This study proposes a new artificial neuron, named global-local neuron, with a trainable activation function composed of two components, a global and a local. The global component term used here is relative to a mathematical function to describe a general feature present in all problem domain. The local component is a function that can represent a localized behavior, like a transient or a perturbation. This new neuron can define the importance of each activation function component in the learning phase. Depending on the problem, it results in a purely global, or purely local, or a mixed global and local activation function after the training phase. Here, the trigonometric sine function was employed for the global component and the hyperbolic tangent for the local component. The proposed neuron was tested for problems where the target was a purely global function, or purely local function, or a composition of two global and local functions. Two classes of test problems were investigated, regression problems and differential equations solving. The experimental tests demonstrated the Global-Local Neuron network's superior performance, compared with simple neural networks with sine or hyperbolic tangent activation function, and with a hybrid network that combines these two simple neural networks.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 18, 2021 01:30 AM.

• #### Mean-field approximations of networks of spiking neurons with short-term synaptic plasticity. (arXiv:2101.06057v1 [q-bio.NC])

Low-dimensional descriptions of spiking neural network dynamics are an effective tool for bridging different scales of organization of brain structure and function. Recent advances in deriving mean-field descriptions for networks of coupled oscillators have sparked the development of a new generation of neural mass models. Of notable interest are mean-field descriptions of all-to-all coupled quadratic integrate-and-fire (QIF) neurons, which have already seen numerous extensions and applications. These extensions include different forms of short-term adaptation (STA) considered to play an important role in generating and sustaining dynamic regimes of interest in the brain. It is an open question, however, whether the incorporation of pre-synaptic forms of synaptic plasticity driven by single neuron activity would still permit the derivation of mean-field equations using the same method. Here, we discuss this problem using an established model of short-term synaptic plasticity at the single neuron level, for which we present two different approaches for the derivation of the mean-field equations. We compare these models with a recently proposed mean-field approximation that assumes stochastic spike timings. In general, the latter fails to accurately reproduce the macroscopic activity in networks of deterministic QIF neurons with distributed parameters. We show that the mean-field models we propose provide a more accurate description of the network dynamics, although they are mathematically more involved. Thus, we provide novel insight into the macroscopic effects of short-term synaptic plasticity in spiking neural networks, as well as two different mean-field descriptions for future investigations of such networks.

in arXiv: Quantitative Biology: Neurons and Cognition on January 18, 2021 01:30 AM.

• #### The Geometry of Deep Generative Image Models and its Applications. (arXiv:2101.06006v1 [cs.LG])

Generative adversarial networks (GANs) have emerged as a powerful unsupervised method to model the statistical patterns of real-world data sets, such as natural images. These networks are trained to map random inputs in their latent space to new samples representative of the learned data. However, the structure of the latent space is hard to intuit due to its high dimensionality and the non-linearity of the generator, which limits the usefulness of the models. Understanding the latent space requires a way to identify input codes for existing real-world images (inversion), and a way to identify directions with known image transformations (interpretability). Here, we use a geometric framework to address both issues simultaneously. We develop an architecture-agnostic method to compute the Riemannian metric of the image manifold created by GANs. The eigen-decomposition of the metric isolates axes that account for different levels of image variability. An empirical analysis of several pretrained GANs shows that image variation around each position is concentrated along surprisingly few major axes (the space is highly anisotropic) and the directions that create this large variation are similar at different positions in the space (the space is homogeneous). We show that many of the top eigenvectors correspond to interpretable transforms in the image space, with a substantial part of eigenspace corresponding to minor transforms which could be compressed out. This geometric understanding unifies key previous results related to GAN interpretability. We show that the use of this metric allows for more efficient optimization in the latent space (e.g. GAN inversion) and facilitates unsupervised discovery of interpretable axes. Our results illustrate that defining the geometry of the GAN image manifold can serve as a general framework for understanding GANs.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 18, 2021 01:30 AM.

• #### Convolutional Neural Network with Pruning Method for Handwritten Digit Recognition. (arXiv:2101.05996v1 [cs.CV])

CNN model is a popular method for imagery analysis, so it could be utilized to recognize handwritten digits based on MNIST datasets. For higher recognition accuracy, various CNN models with different fully connected layer sizes are exploited to figure out the relationship between the CNN fully connected layer size and the recognition accuracy. Inspired by previous pruning work, we performed pruning methods of distinctiveness on CNN models and compared the pruning performance with NN models. For better pruning performances on CNN, the effect of angle threshold on the pruning performance was explored. The evaluation results show that: for the fully connected layer size, there is a threshold, so that when the layer size increases, the recognition accuracy grows if the layer size smaller than the threshold, and falls if the layer size larger than the threshold; the performance of pruning performed on CNN is worse than on NN; as pruning angle threshold increases, the fully connected layer size and the recognition accuracy decreases. This paper also shows that for CNN models trained by the MNIST dataset, they are capable of handwritten digit recognition and achieve the highest recognition accuracy with fully connected layer size 400. In addition, for same dataset MNIST, CNN models work better than big, deep, simple NN models in a published paper.

in arXiv: Computer Science: Neural and Evolutionary Computing on January 18, 2021 01:30 AM.

• #### Temporally distinct myeloid cell responses mediate damage and repair after cerebrovascular injury

Nature Neuroscience, Published online: 18 January 2021; doi:10.1038/s41593-020-00773-6

This study shows how different myeloid cell types contribute to damage and repair following cerebrovascular injury, a pathology common to many central nervous system disorders, and offers new therapeutic opportunities to improve clinical outcomes.

in Nature Neuroscience on January 18, 2021 12:00 AM.

• #### Accounting for taste

Nature Reviews Neuroscience, Published online: 18 January 2021; doi:10.1038/s41583-021-00429-9

The innate responses of mice to sweet-tasting or bitter-tasting stimuli can be modulated by top-down feedback from the cortex.

in Nature Reviews on January 18, 2021 12:00 AM.

• #### Publisher Correction: A charge-density-wave topological semimetal

Nature Physics, Published online: 18 January 2021; doi:10.1038/s41567-021-01169-4

Publisher Correction: A charge-density-wave topological semimetal

in Nature Physics on January 18, 2021 12:00 AM.

• #### When silicon is like a cuprate

Nature Physics, Published online: 18 January 2021; doi:10.1038/s41567-020-01162-3

Recent advances in spectroscopy give access to the decay time of excitations in disordered insulating silicon close to the metal–insulator transition, revealing similarities to high-temperature cuprate superconductors.

in Nature Physics on January 18, 2021 12:00 AM.

• #### Observation of a marginal Fermi glass

Nature Physics, Published online: 18 January 2021; doi:10.1038/s41567-020-01149-0

The combination of disorder and strong interactions makes it hard to understand the nature of doped silicon’s insulating phase. State-of-the-art spectroscopy measurements show marginal electronic behaviour reminiscent of what is seen in the cuprates.

in Nature Physics on January 18, 2021 12:00 AM.

• #### Decay and recurrence of non-Gaussian correlations in a quantum many-body system

Nature Physics, Published online: 18 January 2021; doi:10.1038/s41567-020-01139-2

Starting from a strongly correlated state, with highly non-Gaussian correlations, a Gaussian state can emerge dynamically over time. Experiments with ultracold atoms show how the mixing between phase and density fluctuations plays the crucial role.

in Nature Physics on January 18, 2021 12:00 AM.

• #### Motility-induced fracture reveals a ductile-to-brittle crossover in a simple animal’s epithelia

Nature Physics, Published online: 18 January 2021; doi:10.1038/s41567-020-01134-7

Characterizing the epithelial tissue of a shape-shifting marine animal as an integrated composite material reveals a ductile-to-brittle phase transition that captures how the tissue responds to failure.

in Nature Physics on January 18, 2021 12:00 AM.

• #### Clocking Auger electrons

Nature Physics, Published online: 18 January 2021; doi:10.1038/s41567-020-01111-0

Self-referenced attosecond streaking enables in situ measurements of Auger emission in atomic neon excited by femtosecond pulses from an X-ray free-electron laser with subfemtosecond time resolution and despite the jitter inherent to X-ray free-electron lasers.

in Nature Physics on January 18, 2021 12:00 AM.

• #### Author Correction: Three-phase electric power driven electroluminescent devices

Nature Communications, Published online: 18 January 2021; doi:10.1038/s41467-021-20976-0

Author Correction: Three-phase electric power driven electroluminescent devices

in Nature Communications on January 18, 2021 12:00 AM.

• #### Publisher Correction: Magnetic field detection limits for ultraclean graphene Hall sensors

Nature Communications, Published online: 18 January 2021; doi:10.1038/s41467-021-20969-z

Publisher Correction: Magnetic field detection limits for ultraclean graphene Hall sensors

in Nature Communications on January 18, 2021 12:00 AM.

• #### Author Correction: Time reversed optical waves by arbitrary vector spatiotemporal field generation

Nature Communications, Published online: 18 January 2021; doi:10.1038/s41467-021-20944-8

Author Correction: Time reversed optical waves by arbitrary vector spatiotemporal field generation

in Nature Communications on January 18, 2021 12:00 AM.

• #### Transmembrane Collagens in Neuromuscular Development and Disorders

Neuromuscular development is a multistep process and involves interactions among various extracellular and transmembrane molecules that facilitate the precise targeting of motor axons to synaptogenic regions of the target muscle. Collagenous proteins with transmembrane domains have recently emerged as molecules that play essential roles in multiple aspects of neuromuscular formation. Membrane-associated collagens with interrupted triple helices (MACITs) are classified as an unconventional subtype of the collagen superfamily and have been implicated in cell adhesion in a variety of tissues, including the neuromuscular system. Collagen XXV, the latest member of the MACITs, plays an essential role in motor axon growth within the developing muscle. In humans, loss-of-function mutations of collagen XXV result in developmental ocular motor disorders. In contrast, collagen XIII contributes to the formation and maintenance of neuromuscular junctions (NMJs), and disruption of its function leads to the congenital myasthenic syndrome. Transmembrane collagens are conserved not only in mammals but also in organisms such as C. elegans, where a single MACIT, COL-99, has been documented to function in motor innervation. Furthermore, in C. elegans, a collagen-like transmembrane protein, UNC-122, is implicated in the structural and functional integrity of the NMJ. This review article summarizes recent advances in understanding the roles of transmembrane collagens and underlying molecular mechanisms in multiple aspects of neuromuscular development and disorders.

in Frontiers in Molecular Neuroscience on January 18, 2021 12:00 AM.

• #### Temporal Vestibular Deficits in synaptojanin 1 (synj1) Mutants

The lipid phosphatase synaptojanin 1 (synj1) is required for the disassembly of clathrin coats on endocytic compartments. In neurons such activity is necessary for the recycling of endocytosed membrane into synaptic vesicles. Mutations in zebrafish synj1 have been shown to disrupt the activity of ribbon synapses in sensory hair cells. After prolonged mechanical stimulation of hair cells, both phase locking of afferent nerve activity and the recovery of spontaneous release of synaptic vesicles are diminished in synj1 mutants. Presumably as a behavioral consequence of these synaptic deficits, synj1 mutants are unable to maintain an upright posture. To probe vestibular function with respect to postural control in synj1 mutants, we developed a method for assessing the vestibulospinal reflex (VSR) in larvae. We elicited the VSR by rotating the head and recorded tail movements. As expected, the VSR is completely absent in pcdh15a and lhfpl5a mutants that lack inner ear function. Conversely, lhfpl5b mutants, which have a selective loss of function of the lateral line organ, have normal VSRs, suggesting that the hair cells of this organ do not contribute to this reflex. In contrast to mechanotransduction mutants, the synj1 mutant produces normal tail movements during the initial cycles of rotation of the head. Both the amplitude and temporal aspects of the response are unchanged. However, after several rotations, the VSR in synj1 mutants was strongly diminished or absent. Mutant synj1 larvae are able to recover, but the time required for the reappearance of the VSR after prolonged stimulation is dramatically increased in synj1 mutants. Collectively, the data demonstrate a behavioral correlate of the synaptic defects caused by the loss of synj1 function. Our results suggest that defects in synaptic vesicle recycling give rise to fatigue of ribbons synapses and possibly other synapses of the VS circuit, leading to the loss of postural control.

in Frontiers in Molecular Neuroscience on January 18, 2021 12:00 AM.

• #### Gonadal Cycle-Dependent Expression of Genes Encoding Peptide-, Growth Factor-, and Orphan G-Protein-Coupled Receptors in Gonadotropin- Releasing Hormone Neurons of Mice

Rising serum estradiol triggers the surge release of gonadotropin-releasing hormone (GnRH) at late proestrus leading to ovulation. We hypothesized that proestrus evokes alterations in peptidergic signaling onto GnRH neurons inducing a differential expression of neuropeptide-, growth factor-, and orphan G-protein-coupled receptor (GPCR) genes. Thus, we analyzed the transcriptome of GnRH neurons collected from intact, proestrous and metestrous GnRH-green fluorescent protein (GnRH-GFP) transgenic mice using Affymetrix microarray technique. Proestrus resulted in a differential expression of genes coding for peptide/neuropeptide receptors including Adipor1, Prokr1, Ednrb, Rtn4r, Nmbr, Acvr2b, Sctr, Npr3, Nmur1, Mc3r, Cckbr, and Amhr2. In this gene cluster, Adipor1 mRNA expression was upregulated and the others were downregulated. Expression of growth factor receptors and their related proteins was also altered showing upregulation of Fgfr1, Igf1r, Grb2, Grb10, and Ngfrap1 and downregulation of Egfr and Tgfbr2 genes. Gpr107, an orphan GPCR, was upregulated during proestrus, while others were significantly downregulated (Gpr1, Gpr87, Gpr18, Gpr62, Gpr125, Gpr183, Gpr4, and Gpr88). Further affected receptors included vomeronasal receptors (Vmn1r172, Vmn2r-ps54, and Vmn1r148) and platelet-activating factor receptor (Ptafr), all with marked downregulation. Patch-clamp recordings from mouse GnRH-GFP neurons carried out at metestrus confirmed that the differentially expressed IGF-1, secretin, and GPR107 receptors were operational, as their activation by specific ligands evoked an increase in the frequency of miniature postsynaptic currents (mPSCs). These findings show the contribution of certain novel peptides, growth factors, and ligands of orphan GPCRs to regulation of GnRH neurons and their preparation for the surge release.

in Frontiers in Molecular Neuroscience on January 18, 2021 12:00 AM.

• #### Seizure Freedom After Epilepsy Surgery and Higher Baseline Cognition May Be Associated With a Negatively Correlated Epilepsy Network in Temporal Lobe Epilepsy

Background: Brain regions positively correlated with the epileptogenic zone in patients with temporal lobe epilepsy vary in spread across the brain and in the degree of correlation to the temporal lobes, thalamus, and limbic structures, and these parameters have been associated with pre-operative cognitive impairment and seizure freedom after epilepsy surgery, but negatively correlated regions have not been as well studied. We hypothesize that connectivity within a negatively correlated epilepsy network may predict which patients with temporal lobe epilepsy will respond best to surgery.

Methods: Scalp EEG and resting state functional MRI (rsfMRI) were collected from 19 patients with temporal lobe epilepsy and used to estimate the irritative zone. Using patients’ rsfMRI, the negatively correlated epilepsy network was mapped by determining all the brain voxels that were negatively correlated with the voxels in the epileptogenic zone and the spread and average connectivity within the network was determined.

Results: Pre-operatively, connectivity within the negatively correlated network was inversely related to the spread (diffuseness) of that network and positively associated with higher baseline verbal and logical memory. Pre-operative connectivity within the negatively correlated network was also significantly higher in patients who would go on to be seizure free.

Conclusion: Patients with higher connectivity within brain regions negatively correlated with the epilepsy network had higher baseline memory function, narrower network spread, and were more likely to be seizure free after surgery.

in Frontiers in Neuroscience: Brain Imaging Methods on January 18, 2021 12:00 AM.

• #### Secondary Degeneration of White Matter After Focal Sensorimotor Cortical Ischemic Stroke in Rats

Ischemic lesions could lead to secondary degeneration in remote regions of the brain. However, the spatial distribution of secondary degeneration along with its role in functional deficits is not well understood. In this study, we explored the spatial and connectivity properties of white matter (WM) secondary degeneration in a focal unilateral sensorimotor cortical ischemia rat model, using advanced microstructure imaging on a 14 T MRI system. Significant axonal degeneration was observed in the ipsilateral external capsule and even remote regions including the contralesional external capsule and corpus callosum. Further fiber tractography analysis revealed that only fibers having direct axonal connections with the primary lesion exhibited a significant degeneration. These results suggest that focal ischemic lesions may induce remote WM degeneration, but limited to fibers tied to the primary lesion. These “direct” fibers mainly represent perilesional, interhemispheric, and subcortical axonal connections. At last, we found that primary lesion volume might be the determining factor of motor function deficits.

in Frontiers in Neuroscience: Brain Imaging Methods on January 18, 2021 12:00 AM.

• #### Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

The incidence of metabolic disorders, as well as of neurodegenerative diseases—mainly the sporadic forms of Alzheimer’s and Parkinson’s disease—are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer’s and Parkinson’s disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer’s and Parkinson’s disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia.

in Frontiers in Neuroscience: Neurodegeneration on January 18, 2021 12:00 AM.

• #### White Matter Atrophy in Type 2 Diabetes Mellitus Patients With Mild Cognitive Impairment

Type 2 diabetes mellitus (T2DM) patients are highly susceptible to developing dementia, especially for those with mild cognitive impairment (MCI), but its underlying cause is still unclear. In this study, we performed a battery of neuropsychological tests and high-resolution sagittal T1-weighted structural imaging to explore how T2DM affects white matter volume (WMV) and cognition in 30 T2DM-MCI patients, 30 T2DM with normal cognition (T2DM-NC) patients, and 30 age-, sex-, and education-matched healthy control (HC) individuals. The WMV of the whole brain was obtained with automated segmentation methods. Correlations between the WMV of each brain region and neuropsychological tests were analyzed in the T2DM patients. The T2DM-NC patients and HC individuals did not reveal any significant differences in WMV. Compared with the T2DM-NC group, the T2DM-MCI group showed statistically significant reduction in the WMV of seven brain regions, mainly located in the frontotemporal lobe and limbic system, five of which significantly correlated with Montreal Cognitive Assessment (MoCA) scores. Subsequently, we evaluated the discriminative ability of these five regions for MCI in T2DM patients. The WMV of four regions, including left posterior cingulate, precuneus, insula, and right rostral middle frontal gyrus had high diagnostic value for MCI detection in T2DM patients (AUC > 0.7). Among these four regions, left precuneus WMV presented the best diagnostic value (AUC: 0.736; sensitivity: 70.00%; specificity: 73.33%; Youden index: 0.4333), but with no significant difference relative to the minimum AUC. In conclusion, T2DM could give rise to the white matter atrophy of several brain regions. Each WMV of left posterior cingulate, precuneus, insula, and right rostral middle frontal gyrus could be an independent imaging biomarker to detect cognitive impairment at the early stage in T2DM patients and play an important role in its pathophysiological mechanism.

in Frontiers in Neuroscience: Brain Imaging Methods on January 18, 2021 12:00 AM.

• #### A Head-Mounted Multi-Camera System for Electrophysiology and Behavior in Freely-Moving Mice

Advances in the ability to monitor freely-moving mice may prove valuable for the study of behavior and its neural correlates. Here we present a head-mounted multi-camera system comprised of inexpensive miniature analog camera modules, and illustrate its use for investigating natural behaviors such as prey capture, courtship, sleep, jumping, and exploration. With a four-camera headset, monitoring the eyes, ears, whiskers, rhinarium, and binocular visual field can all be achieved simultaneously with high-density electrophysiology. With appropriate focus and positioning, all eye movements can be captured, including cyclotorsion. For studies of vision and eye movements, cyclotorsion provides the final degree of freedom required to reconstruct the visual scene in retinotopic coordinates or to investigate the vestibulo-ocular reflex in mice. Altogether, this system allows for comprehensive measurement of freely-moving mouse behavior, enabling a more holistic, and multimodal approach to investigate ethological behaviors and other processes of active perception.

in Frontiers in Neuroscience: Neural Technology on January 18, 2021 12:00 AM.

• #### Correlation Between Cerebral Venous Oxygen Level and Cognitive Status in Patients With Alzheimer’s Disease Using Quantitative Susceptibility Mapping

Purpose

To quantitatively assess the blood oxygen levels of the cerebral vein using quantitative susceptibility mapping (QSM), and to analyze the correlation between magnetic susceptibility value (MSV) and clinical laboratory indicators/cognitive scores in patients with Alzheimer’s disease (AD).

Materials and Methods

Fifty-nine patients (21 males and 38 females) with clinically confirmed AD (AD group) and 22 control subjects (12 males, 10 females; CON group) were recruited. Clinical data and laboratory examination indexes were collected. All patients underwent Mini-mental State Examination, Montreal Cognitive Assessment, Clock Drawing Task, and Activity of Daily Living Scale test, as well as a routine MRI and enhanced gradient echo T2 star weighted angiography (ESWAN).

Results

Higher cerebral venous MSV was observed in AD group compared to CON group, significant differences were observed for bilateral thalamus veins and left dentate nucleus veins. The MSV of bilateral thalamus veins, bilateral internal cerebral veins, and bilateral dentate nucleus veins had significant negative correlation with Mini-mental State Examination score; the MSV of bilateral thalamus veins, bilateral dentate nucleus veins, right septal vein had a significant negative correlation with Montreal Cognitive Assessment scores; a significant negative correlation between the MSV of bilateral thalamus veins, left dentate nucleus vein, right septal vein and the Clock Drawing Task score; the MSV of bilateral thalamus veins, left dentate nucleus vein had a significant negative correlation with Activity of Daily Living Scale score. The MSV of left dentate nucleus vein was positively correlated with the course of the disease, the MSV of bilateral septal vein were positively correlated with the total cholesterol, and the MSV of left septal vein had a positive correlation with LDL.

Conclusion

Decreasing cerebral venous oxygen level in AD patients may affect cognitive status, and associated with the deterioration of the disease in AD patients.

in Frontiers in Neuroscience: Neurodegeneration on January 18, 2021 12:00 AM.

• #### Disrupted Subcortical-Cortical Connections in a Phonological but Not Semantic Task in Chinese Children With Dyslexia

in Frontiers in Human Neuroscience on January 18, 2021 12:00 AM.

• #### Neuroanatomical Alterations in Patients With Tinnitus Before and After Sound Therapy: A Combined VBM and SCN Study

Many neuroanatomical alterations have been detected in patients with tinnitus in previous studies. However, little is known about the morphological and structural covariance network (SCN) changes before and after long-term sound therapy. This study aimed to explore alterations in brain anatomical and SCN changes in patients with idiopathic tinnitus using voxel-based morphometry (VBM) analysis 24 weeks before and after sound therapy. Thirty-three tinnitus patients underwent magnetic resonance imaging scans at baseline and after 24 weeks of sound therapy. Twenty-six age- and sex-matched healthy control (HC) individuals also underwent two scans over a 24-week interval; 3.0T MRI and high-resolution 3D structural images were acquired with a 3D-BRAVO pulse sequence. Structural image data preprocessing was performed using the VBM8 toolbox. The Tinnitus Handicap Inventory (THI) score was assessed for the severity of tinnitus before and after treatment. Two-way mixed model analysis of variance (ANOVA) and post hoc analyses were performed to determine differences between the two groups (patients and HCs) and between the two scans (at baseline and on the 24th week). Student-Newman-Keuls (SNK) tests were used in the post hoc analysis. Interaction effects between the two groups and the two scans demonstrated significantly different gray matter (GM) volume in the right parahippocampus gyrus, right caudate, left superior temporal gyrus, left cuneus gyrus, and right calcarine gyrus; we found significantly decreased GM volume in the above five brain regions among the tinnitus patients before sound therapy (baseline) compared to that in the HC group. The 24-week sound therapy group demonstrated significantly greater brain volume compared with the baseline group among these brain regions. We did not find significant differences in brain regions between the 24-week sound therapy and HC groups. The SCN results showed that the left superior temporal gyrus and left rolandic operculum were significantly different in nodal efficiency, nodal degree centrality, and nodal betweenness centrality after FDR correction. This study characterized the effect of sound therapy on brain GM volume, especially in the left superior temporal lobe. Notably, sound therapy had a normalizing effect on tinnitus patients.

in Frontiers in Human Neuroscience on January 18, 2021 12:00 AM.

• #### A Look Into the Power of fNIRS Signals by Using the Welch Power Spectral Estimate for Deception Detection

Neuroimaging technologies have improved our understanding of deception and also exhibit their potential in revealing the origins of its neural mechanism. In this study, a quantitative power analysis method that uses the Welch power spectrum estimation of functional near-infrared spectroscopy (fNIRS) signals was proposed to examine the brain activation difference between the spontaneous deceptive behavior and controlled behavior. The power value produced by the model was applied to quantify the activity energy of brain regions, which can serve as a neuromarker for deception detection. Interestingly, the power analysis results generated from the Welch spectrum estimation method demonstrated that the spontaneous deceptive behavior elicited significantly higher power than that from the controlled behavior in the prefrontal cortex. Meanwhile, the power findings also showed significant difference between the spontaneous deceptive behavior and controlled behavior, indicating that the reward system was only involved in the deception. The proposed power analysis method for processing fNIRS data provides us an additional insight to understand the cognitive mechanism of deception.

in Frontiers in Human Neuroscience on January 18, 2021 12:00 AM.

• #### Immersive Virtual Reality Reminiscence Reduces Anxiety in the Oldest-Old Without Causing Serious Side Effects: A Single-Center, Pilot, and Randomized Crossover Study

Background: Dementia is one the major problems of aging societies, and, novel and effective non-drug therapies are required as interventions in the oldest-old to prevent cognitive decline.

Objective: This study aims to examine the efficacy and safety of reminiscence using immersive virtual reality (iVR reminiscence) focusing on anxiety that often appears with cognitive decline. The secondary objective is to reveal the preference for VR image types for reminiscence: live-action (LA) or computer graphics (CG).

Methods: This was a pilot, open-label, and randomized crossover study which was conducted on January 2020 at a single nursing home. The subjects were randomly divided into two groups (A or B) in equal numbers, and they alternately viewed two types of VR images (LA and CG) themed on the mid- to late Showa era (A.D. 1955–1980) in Japan. In group A, the CG images were viewed first, and then the LA images were viewed (CG→ LA). In group B, the images were viewed in the opposite order (LA→ CG). Before VR viewing, subjects responded to Mini-Mental State Examination (MMSE) Japanese version and State-Trait Anxiety Inventory (STAI) Japanese version. After viewing the first and second VR, subjects responded to STAI and the numerical rating scale (NRS) for satisfaction and side effects (nausea, dizziness, headache, and tiredness).

Results: Ten subjects participated in this study. The values of analyses are presented in the mean (SD). The age was 87.1 years (4.2), and the MMSE was 28.5 (1.8). The total STAI score before VR viewing was 36.1 (7.2), but it significantly decreased to 26.8 (4.9) after the first VR viewing (P = 0.0010), and further decreased to 23.4 (2.8) after the second VR viewing (P < 0.001). The NRS score for satisfaction tended to be higher after viewing LA in group A (CG→ LA) (CG vs. LA; 7.0 (2.3) vs. 8.6 (1.5), P = 0.0993), while in group B (LA→ CG), the score after CG was slightly lower than that after LA. There were no serious side effects.

Conclusions: This study suggests that iVR reminiscence can reduce anxiety in the oldest-old without causing serious side effects. Furthermore, the impacts might be better with LA images.

in Frontiers in Human Neuroscience on January 18, 2021 12:00 AM.

• #### Effect of Repeated Anodal HD-tDCS on Executive Functions: Evidence From a Pilot and Single-Blinded fNIRS Study

Executive functions are of vital importance in the process of active cognition, which is thought to be associated with the dorsolateral prefrontal cortex (DLPFC). As a valid brain stimulation technology, high-definition transcranial direct current stimulation (HD-tDCS) has been used to optimize cognitive function in healthy adults. Substantial evidence indicates that short-term or single anodal tDCS sessions over the left DLPFC will enhance the performance of executive functions. However, the changes in performance and cortical activation of executive functions after modulation by repeated anodal HD-tDCS is as yet unexplored. This study aims to examine changes in three core components of executive functions (inhibitory control, working memory, and cognitive flexibility) produced by nine HD-tDCS sessions (1.5 mA, over left DLPFC, 20 min per session), and to use functional near-infrared spectroscopy (fNIRS) to bilaterally record DLPFC neural activity. A total of 43 participants were divided randomly into two study groups (anodal group vs. sham group) to complete nine interventions. Our results demonstrate that the enhancement of cognitive flexibility in the anodal group was significantly better than that in the sham group. Additionally, a Stroop effect-related decrease in oxygenated hemoglobin (HbO) concentration in the DLPFC was observed in the anodal group but not the sham group. In conclusion, our study found that repeated anodal HD-tDCS sessions can significantly promote cognitive flexibility, one of the core components of executive function, and that alterations in DLPFC activation can enhance our understanding of the neuroplastic modifications modulated by HD-tDCS.

in Frontiers in Human Neuroscience on January 18, 2021 12:00 AM.

• #### Training-Induced Neural Plasticity in Youth: A Systematic Review of Structural and Functional MRI Studies

Experience-dependent neural plasticity is high in the developing brain, presenting a unique window of opportunity for training. To optimize existing training programs and develop new interventions, it is important to understand what processes take place in the developing brain during training. Here, we systematically review MRI-based evidence of training-induced neural plasticity in children and adolescents. A total of 71 articles were included in the review. Significant changes in brain activation, structure, microstructure, and structural and functional connectivity were reported with different types of trainings in the majority (87%) of the studies. Significant correlation of performance improvement with neural changes was reported in 51% of the studies. Yet, only 48% of the studies had a control condition. Overall, the review supports the hypothesized neural changes with training while at the same time charting empirical and methodological desiderata for future research.

in Frontiers in Human Neuroscience on January 18, 2021 12:00 AM.

• #### A Physical Perspective to the Inductive Function of Myelin—A Missing Piece of Neuroscience

Starting from the inductance in neurons, two physical origins are discussed, which are the coil inductance of myelin and the piezoelectric effect of the cell membrane. The direct evidence of the coil inductance of myelin is the opposite spiraling phenomenon between adjacent myelin sheaths confirmed by previous studies. As for the piezoelectric effect of the cell membrane, which has been well-known in physics, the direct evidence is the mechanical wave accompany with action potential. Therefore, a more complete physical nature of neural signals is provided. In conventional neuroscience, the neural signal is a pure electrical signal. In our new theory, the neural signal is an energy pulse containing electrical, magnetic, and mechanical components. Such a physical understanding of the neural signal and neural systems significantly improve the knowledge of the neurons. On the one hand, we achieve a corrected neural circuit of an inductor-capacitor-capacitor (LCC) form, whose frequency response and electrical characteristics have been validated by previous studies and the modeling fitting of artifacts in our experiments. On the other hand, a number of phenomena observed in neural experiments are explained. In particular, they are the mechanism of magnetic nerve stimulations and ultrasound nerve stimulations, the MRI image contrast issue and Anode Break Excitation. At last, the biological function of myelin is summarized. It is to provide inductance in the process of neural signal, which can enhance the signal speed in peripheral nervous systems and provide frequency modulation function in central nervous systems.

in Frontiers in Neural Circuits on January 18, 2021 12:00 AM.

• #### HMGA1 Induction of miR-103/107 Forms a Negative Feedback Loop to Regulate Autophagy in MPTP Model of Parkinson’s Disease

Autophagy dysfunction has been directly linked with the onset and progression of Parkinson’s disease (PD), but the underlying mechanisms are not well understood. High-mobility group A1 (HMGA1), well-known chromatin remodeling proteins, play pivotal roles in diverse biological processes and diseases. Their function in neural cell death in PD, however, have not yet been fully elucidated. Here, we report that HMGA1 is highly induced during dopaminergic cell death in vitro and mice models of PD in vivo. Functional studies using genetic knockdown of endogenous HMGA1 show that HMGA1 signaling inhibition accelerates neural cell death, at least partially through aggravating MPP+-induced autophagic flux reduction resulting from partial block in autophagic flux at the terminal stages, indicating a novel potential neuroprotective role for HMGA1 in dopaminergic neurons death. MicroRNA-103/107 (miR-103/107) family, which is highly expressed in neuron, coordinately ensures proper end-stage autophagy. We further illustrate that MPP+/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced HMGA1 elevation counterparts the effect of miR-103/107 downregulation by directly binding to their promoters, respectively, sustaining their expression in MPP+-damaged MN9D cells and modulates autophagy through CDK5R1/CDK5 signaling pathway. We also find that HMGA1 is a direct target of miR-103/107 family. Thus, our results suggest that HMGA1 forms a negative feedback loop with miR-103/107-CDK5R1/CDK5 signaling to regulate the MPP+/MPTP-induced autophagy impairment and neural cell death. Collectively, we identify a paradigm for compensatory neuroprotective HMGA1 signaling in dopaminergic neurons that could have important therapeutic implications for PD.

in Frontiers in Cellular Neuroscience on January 18, 2021 12:00 AM.

• #### Microvascular Alterations in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder associated with continual decline in cognition and ability to perform routine functions such as remembering familiar places or understanding speech. For decades, amyloid beta (Aβ) was viewed as the driver of AD, triggering neurodegenerative processes such as inflammation and formation of neurofibrillary tangles (NFTs). This approach has not yielded therapeutics that cure the disease or significant improvements in long-term cognition through removal of plaques and Aβ oligomers. Some researchers propose alternate mechanisms that drive AD or act in conjunction with amyloid to promote neurodegeneration. This review summarizes the status of AD research and examines research directions including and beyond Aβ, such as tau, inflammation, and protein clearance mechanisms. The effect of aging on microvasculature is highlighted, including its contribution to reduced blood flow that impairs cognition. Microvascular alterations observed in AD are outlined, emphasizing imaging studies of capillary malfunction. The review concludes with a discussion of two therapies to protect tissue without directly targeting Aβ for removal: (1) administration of growth factors to promote vascular recovery in AD; (2) inhibiting activity of a calcium-permeable ion channels to reduce microglial activation and restore cerebral vascular function.

in Frontiers in Cellular Neuroscience on January 18, 2021 12:00 AM.

• #### Dorsal-Ventral Differences in Retinal Structure in the Pigmented Royal College of Surgeons Model of Retinal Degeneration

Retinitis pigmentosa is a family of inherited retinal degenerations associated with gradual loss of photoreceptors, that ultimately leads to irreversible vision loss. The Royal College of Surgeon's (RCS) rat carries a recessive mutation affecting mer proto-oncogene tyrosine kinase (merTK), that models autosomal recessive disease. The aim of this study was to understand the glial, microglial, and photoreceptor changes that occur in different retinal locations with advancing disease. Pigmented RCS rats (RCS-p+/LAV) and age-matched isogenic control rdy (RCS-rdy +p+/LAV) rats aged postnatal day 18 to 6 months were evaluated for in vivo retinal structure and function using optical coherence tomography and electroretinography. Retinal tissues were assessed using high resolution immunohistochemistry to evaluate changes in photoreceptors, glia and microglia in the dorsal, and ventral retina. Photoreceptor dysfunction and death occurred from 1 month of age. There was a striking difference in loss of photoreceptors between the dorsal and ventral retina, with a greater number of photoreceptors surviving in the dorsal retina, despite being adjacent a layer of photoreceptor debris within the subretinal space. Loss of photoreceptors in the ventral retina was associated with fragmentation of the outer limiting membrane, extension of glial processes into the subretinal space that was accompanied by possible adhesion and migration of mononuclear phagocytes in the subretinal space. Overall, these findings highlight that breakdown of the outer limiting membrane could play an important role in exacerbating photoreceptor loss in the ventral retina. Our results also highlight the value of using the RCS rat to model sectorial retinitis pigmentosa, a disease known to predominantly effect the inferior retina.

in Frontiers in Cellular Neuroscience on January 18, 2021 12:00 AM.

• #### The Impact of COVID-19 Quarantine on Patients With Dementia and Family Caregivers: A Nation-Wide Survey

Introduction

Previous studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine.

Methods

The study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features.

Results

4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress.

Conclusion

Our study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.

in Frontiers in Ageing Neuroscience on January 18, 2021 12:00 AM.

• #### Sleep Disturbance is Associated With Higher Plasma Aβ Levels in Cognitively Normal Adults—A Population-Based Cross-Sectional Study

Objective: Growing evidence suggests that sleep disturbance is a risk factor for Alzheimer's disease (AD). Amyloid-β (Aβ) deposition in the brain is a main pathophysiology of AD. Considering that peripheral Aβ level is associated with brain Aβ deposition, the present study investigated the relationship between sleep disturbance and plasma Aβ levels.

Methods: This is a population-based cross-sectional study. A total of 1,459 participants from a village in the suburbs of Xi'an, China, were enrolled from January 3, 2017 to March 26, 2017. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and a PSQI score of <5 points was considered as good sleep quality and a PSQI score of >10 points as poor sleep quality. Cognitive function was assessed with the Mini-Mental State Examination (MMSE). Fasting venous blood was taken in the morning, and the plasma Aβ levels were measured using ELISA. The relationships between plasma Aβ levels and sleep quality were analyzed using multiple linear regression.

Results: Among the participants, 231 had poor sleep quality (15.83%). The log-transformed Aβ40 level had significant differences among the different sleep groups (F = 3.216, p = 0.040). The log-transformed Aβ40 level was higher in the poor sleep quality group than that in the general sleep quality group [87.17 (73.42, 107.34) vs. 89.69 (74.81, 125.79) pg/ml, p = 0.016]. In bivariate analysis, sleep quality was negatively associated with the log-transformed plasma Aβ40 level (β = −0.025, p = 0.011).

Conclusion: In the community population, poorer sleep quality is associated with a higher plasma Aβ40 level. This indicated that sleep disturbance might also involve in dysfunction of peripheral Aβ clearance.

in Frontiers in Ageing Neuroscience on January 18, 2021 12:00 AM.

• #### Risk Factors of Vitamin D Deficiency in Chinese Ischemic Stroke Patients: A Cross-Sectional Study

Purpose

Lower serum vitamin D has been reported to be associated with stroke. This study aimed to analyze the risk factors of vitamin deficiency in Chinese stroke patients, and further analyze its impact in different gender and their clinical variables.

Methods

982 stroke patients were enrolled. Laboratory parameters such as serum vitamin D, apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), ApoA-I/ApoB, cholesterol (CH), fibrinogen (FIB), blood glucose (Glu), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were collected and recorded. The severity of stroke was assessed by National Institute of Health Stroke Scale (NIHSS) score. Based on their serum vitamin D level, patients were divided into three groups: Vitamin D deficiency (<50 nmol/L), vitamin D insufficiency (≥50–75 nmol/L) and vitamin D sufficiency (≥75 nmol/L) and differences were compared among the three groups. Statistical analyses were done to assess the risk factors for serum vitamin D deficiency in our ischemic stroke patients.

Results

Gender, NIHSS, and FIB showed significant differences among the vitamin D groups (P < 0.001 ∼ P = 0.002). The female gender (OR = 2.422, P < 0.001), severity of stroke using NIHSS (OR = 1.055, P = 0.008) and FIB (OR = 1.256, P = 0.005) were risk factors of vitamin D deficiency in ischemic stroke patients. In subgroup analysis, NIHSS was significantly associated with vitamin D deficiency in the male group (OR = 1.087, P = 0.002) and higher FIB group (OR = 1.078, P = 0.001).

Conclusions

The female gender, severity of stroke using NIHSS and FIB were risk factors for vitamin D deficiency in our incident stroke patients. NIHSS was more sensitive to vitamin D deficiency in male ischemic stroke patients. Besides, under higher FIB circumstance, the increasing NIHSS score was more related to the vitamin D deficiency. Levels of vitamin D in patients with ischemic stroke should be well monitored during the disease cascade.

in Frontiers in Ageing Neuroscience on January 18, 2021 12:00 AM.

• #### Using a Discourse Task to Explore Semantic Ability in Persons With Cognitive Impairment

This paper uses a discourse task to explore aspects of semantic production in persons with various degree of cognitive impairment and healthy controls. The purpose of the study was to test if an in-depth semantic analysis of a cognitive-linguistic challenging discourse task could differentiate persons with a cognitive decline from those with a stable cognitive impairment. Both quantitative measures of semantic ability, using tests of oral lexical retrieval, and qualitative analysis of a narrative were used to detect semantic difficulties. Besides group comparisons a classification experiment was performed to investigate if the discourse features could be used to improve classification of the participants who had a stable cognitive impairment from those who had cognitively declined. In sum, both types of assessment methods captured difficulties between the groups, but tests of oral lexical retrieval most successfully differentiated between the cognitively stable and the cognitively declined group. Discourse features improved classification accuracy and the best combination of features discriminated between participants with a stable cognitive impairment and those who had cognitively declined with an area under the curve (AUC) of 0.93.

in Frontiers in Ageing Neuroscience on January 18, 2021 12:00 AM.

• #### Age-Associated Differences of Modules and Hubs in Brain Functional Networks

Healthy aging is usually accompanied by changes in the functional modular organization of the human brain, which may result in the decline of cognition and underlying brain dysfunction. However, the relationship between age-related brain functional modular structure differences and cognition remain debatable. In this study, we investigated the age-associated differences of modules and hubs from young, middle and old age groups, using resting-state fMRI data from a large cross-sectional adulthood sample. We first divided the subjects into three age groups and constructed an individual-level network for each subject. Subsequently, a module-guided group-level network construction method was applied to form a weighted network for each group from which functional modules were detected. The intra- and inter-modular connectivities were observed negatively correlated with age. According to the detected modules, we found the number of connector hubs in the young group was more than middle-age and old group, while the quantity of provincial hubs in middle-age group was discovered more than other two groups. Further ROI-wise analysis shows that different hubs have distinct age-associated trajectories of intra- and inter-modular connections, which suggests the different types of topological role transitions in functional networks across age groups. Our results indicated an inverse association between functional segregation/integration with age, which demonstrated age-associated differences in communication effeciency. This study provides a new perspective and useful information to better understand the normal aging of brain networks.

in Frontiers in Ageing Neuroscience on January 18, 2021 12:00 AM.

• #### Equity, Diversity and Inclusion: Racial inequity in grant funding from the US National Institutes of Health

Biomedical science and federal funding for scientific research are not immune to the systemic racism that pervades American society. A groundbreaking analysis of NIH grant success revealed in 2011 that grant applications submitted to the National Institutes of Health in the US by African-American or Black Principal Investigators (PIs) are less likely to be funded than applications submitted by white PIs, and efforts to narrow this funding gap have not been successful. A follow-up study in 2019 showed that this has not changed. Here, we review those original reports, as well as the response of the NIH to these issues, which we argue has been inadequate. We also make recommendations on how the NIH can address racial disparities in grant funding and call on scientists to advocate for equity in federal grant funding.

in eLife on January 18, 2021 12:00 AM.

• #### Endothelial cell type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain

Vascular endothelial cells (vECs) in the brain exhibit structural and functional heterogeneity. Fenestrated, permeable brain vasculature mediates neuroendocrine function, body-fluid regulation, and neural immune responses, however its vascular formation remains poorly understood. Here we show that specific combinations of vascular endothelial growth factors (Vegfs) are required to selectively drive fenestrated vessel formation in the zebrafish myelencephalic choroid plexus (mCP). We found that the combined, but not individual, loss of Vegfab, Vegfc, and Vegfd causes severely impaired mCP vascularization with little effect on neighboring non-fenestrated brain vessel formation, demonstrating fenestrated-vEC-specific angiogenic requirements. This Vegfs-mediated vessel-selective patterning also involves Ccbe1. Expression analyses, cell-type-specific ablation, and paracrine activity-deficient vegfc mutant characterization reveal that vEC-autonomous Vegfc and meningeal fibroblast-derived Vegfab and Vegfd are critical for mCP vascularization. These results define molecular cues and cell types essential for directing fenestrated CP vascularization and indicate that vECs' distinct molecular requirements for angiogenesis underlie brain vessel heterogeneity.

in eLife on January 18, 2021 12:00 AM.

• #### Bi-channel Image Registration and Deep-learning Segmentation (BIRDS) for efficient, versatile 3D mapping of mouse brain

We have developed an open-source software called BIRDS (bi-channel image registration and deep-learning segmentation) for the mapping and analysis of 3D microscopy data and applied this to the mouse brain. The BIRDS pipeline includes image pre-processing, bi-channel registration, automatic annotation, creation of a 3D digital frame, high-resolution visualization, and expandable quantitative analysis. This new bi-channel registration algorithm is adaptive to various types of whole-brain data from different microscopy platforms and shows dramatically improved registration accuracy. Additionally, as this platform combines registration with neural networks, its improved function relative to other platforms lies in the fact that the registration procedure can readily provide training data for network construction, while the trained neural network can efficiently segment incomplete/defective brain data that is otherwise difficult to register. Our software is thus optimized to enable either minute-timescale registration-based segmentation of cross-modality, whole-brain datasets or real-time inference-based image segmentation of various brain regions of interest. Jobs can be easily submitted and implemented via a Fiji plugin that can be adapted to most computing environments.

in eLife on January 18, 2021 12:00 AM.

• #### Ablation of STAT3 in Purkinje cells reorganizes cerebellar synaptic plasticity in long-term fear memory network

Emotional memory processing engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network are unclear. Here, we illustrate that synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Transcriptome analyses revealed that PC-specific STAT3 knockout (STAT3PKO) results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber (PF) to PC synapses was larger in STAT3PKO mice than in wild-type (WT) littermates. Fear conditioning induced long-term depression of PF–PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in WT littermates. STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory.

in eLife on January 18, 2021 12:00 AM.

• #### Regulatory roles of Escherichia coli 5' UTR and ORF-internal RNAs detected by 3' end mapping

Many bacterial genes are regulated by RNA elements in their 5´ untranslated regions (UTRs). However, the full complement of these elements is not known even in the model bacterium Escherichia coli. Using complementary RNA-sequencing approaches, we detected large numbers of 3´ ends in 5´ UTRs and open reading frames (ORFs), suggesting extensive regulation by premature transcription termination. We documented regulation for multiple transcripts, including spermidine induction involving Rho and translation of an upstream ORF for an mRNA encoding a spermidine efflux pump. In addition to discovering novel sites of regulation, we detected short, stable RNA fragments derived from 5´ UTRs and sequences internal to ORFs. Characterization of three of these transcripts, including an RNA internal to an essential cell division gene, revealed that they have independent functions as sRNA sponges. Thus, these data uncover an abundance of cis- and trans-acting RNA regulators in bacterial 5´ UTRs and internal to ORFs.

in eLife on January 18, 2021 12:00 AM.

• #### Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci

To uncover novel significant association signals (p<5×10−8), genome-wide association studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5 × 10−8≤p<5×10−4) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and embryonic stem cell (ESC)-derived hypothalamic-like neurons. This approach, with its extremely low false-positive rate, identified 15 loci at p<5×10−5 in the 2010 GWAS, of which 13 achieved genome-wide significance by 2018, including at NAV1, MTIF3, and ADCY3. Eighty percent of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing data sets without increasing sample size.

in eLife on January 18, 2021 12:00 AM.

• #### Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells

Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown. Here we show that deleting FLCN activates TFE3, upregulating its downstream E-box genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, deletion of FLCN or its binding partners FNIP1/FNIP2 also induces interferon response genes, but independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.

in eLife on January 18, 2021 12:00 AM.

• #### Global and local tension measurements in biomimetic skeletal muscle tissues reveals early mechanical homeostasis

Tension and mechanical properties of muscle tissue are tightly related to proper skeletal muscle function, which makes experimental access to the biomechanics of muscle tissue formation a key requirement to advance our understanding of muscle function and development. Recently developed elastic in vitro culture chambers allow for raising 3D muscle tissue under controlled conditions and to measure global tissue force generation. However, these chambers are inherently incompatible with high resolution microscopy limiting their usability to global force measurements, and preventing the exploitation of modern fluorescence based investigation methods for live and dynamic measurements. Here we present a new chamber design pairing global force measurements, quantified from post deflection, with local tension measurements obtained from elastic hydrogel beads embedded in muscle tissue. High resolution 3D video microscopy of engineered muscle formation, enabled by the new chamber, shows an early mechanical tissue homeostasis that remains stable in spite of continued myotube maturation.

in eLife on January 18, 2021 12:00 AM.

• #### Cytomegalovirus restricts ICOSL expression on antigen presenting cells disabling T cell co-stimulation and contributing to immune evasion

Viral infections are controlled, and very often cleared, by activated T lymphocytes. The inducible co-stimulator (ICOS) mediates its functions by binding to its ligand ICOSL, enhancing T-cell activation and optimal germinal center (GC) formation. Here, we show that ICOSL is heavily downmodulated during infection of antigen presenting cells by different herpesviruses. We found that, in murine cytomegalovirus (MCMV), the immunoevasin m138/fcr-1 physically interacts with ICOSL, impeding its maturation and promoting its lysosomal degradation. This viral protein counteracts T-cell responses, in an ICOS-dependent manner, and limits virus control during the acute MCMV infection. Additionally, we report that blockade of ICOSL in MCMV-infected mice critically regulates the production of MCMV-specific antibodies due to a reduction of T follicular helper and GC B cells. Altogether, these findings reveal a novel mechanism evolved by MCMV to counteract adaptive immune surveillance, and demonstrates a role of the ICOS:ICOSL axis in the host defense against herpesviruses.

in eLife on January 18, 2021 12:00 AM.

• #### Issue Information

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Annals of Neurology: Volume 89, Number 2, February 2020

An intraoperative Laser Speckle Imaging (LSI) perfusion map of the left hemisphere of a living human brain (frontal lobe to the left, occipital lobe to the right) at a mean arterial pressure of 72 mmHg during hemicraniectomy. By adjusting blood pressure pharmacologically, LSI can visualize changes in cerebral perfusion and its autoregulation. See Hecht et al. pp 358–368 in this issue.

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Parafoveal Change and Dopamine Loss in the Retina with Parkinson's Disease

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Letter to the Editor Concerning Barton and Ranalli

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Reply to “Letter to the Editor Concerning Barton and Ranalli”

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

The purpose of this study was to compare the diagnostic accuracy of antemortem 11C‐Pittsburgh compound B (PIB) and 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.

## Methods

One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non‐AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate–high AD neuropathological change (ADNC).

## Results

One hundred one participants were included (mean age = 67.2 years, 41 females, Mini‐Mental State Examination = 21.9, PET‐to‐autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non‐AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate–high ADNC (96%, 95% confidence interval [CI] = 89–100% vs 80%, 95% CI = 68–92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76–95% vs 84%, 95% CI = 74–93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92–100%) and specificity was 98% (95% CI = 93–100%). Nine of 24 patients with incongruent reads were found to have co‐occurrence of AD and non‐AD pathologies.

## Interpretation

In our sample enriched for younger onset cognitive impairment, PIB‐PET had higher sensitivity than FDG‐PET for intermediate–high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389–401

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Emerging data indicate an increased risk of cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and highlight the potential impact of coronavirus disease (COVID‐19) on the management and outcomes of acute stroke. We conducted a systematic review and meta‐analysis to evaluate the aforementioned considerations.

## Methods

We performed a meta‐analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS‐CoV‐2 infection status. We used a random‐effects model. Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).

## Results

We identified 18 cohort studies including 67,845 patients. Among patients with SARS‐CoV‐2, 1.3% (95% CI = 0.9–1.6%, I 2 = 87%) were hospitalized for cerebrovascular events, 1.1% (95% CI = 0.8–1.3%, I 2 = 85%) for ischemic stroke, and 0.2% (95% CI = 0.1–0.3%, I 2 = 64%) for hemorrhagic stroke. Compared to noninfected contemporary or historical controls, patients with SARS‐CoV‐2 infection had increased odds of ischemic stroke (OR = 3.58, 95% CI = 1.43–8.92, I 2 = 43%) and cryptogenic stroke (OR = 3.98, 95% CI = 1.62–9.77, I 2 = 0%). Diabetes mellitus was found to be more prevalent among SARS‐CoV‐2 stroke patients compared to noninfected historical controls (OR = 1.39, 95% CI = 1.00–1.94, I 2 = 0%). SARS‐CoV‐2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR = 1.42, 95% CI = 0.65–3.10, I 2 = 0%) or endovascular thrombectomy (OR = 0.78, 95% CI = 0.35–1.74, I 2 = 0%) among hospitalized ischemic stroke patients during the COVID‐19 pandemic. Odds of in‐hospital mortality were higher among SARS‐CoV‐2 stroke patients compared to noninfected contemporary or historical stroke patients (OR = 5.60, 95% CI = 3.19–9.80, I 2 = 45%).

## Interpretation

SARS‐CoV‐2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular. It may also be related to an increased mortality risk. ANN NEUROL 2021;89:380–388

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Charcot–Marie–Tooth disease (CMT) reduces health‐related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT‐specific QOL outcome measure (pCMT‐QOL).

## Methods

Development and validation of the pCMT‐QOL patient‐reported outcome measure were iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus‐group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia.

## Results

We conducted systematic literature reviews and analysis of generic QOL measures to identify 6 domains relevant to QOL in children with CMT. Sixty items corresponding to those domains were developed de novo, or identified from literature review and CMT‐specific modification of items from the pediatric Neuro‐QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT‐QOL measure. From 2010 to 2016, the pCMT‐QOL working version was administered to 398 children aged 8 to 18 years seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test–retest reliability, internal consistency, convergent validity, item response theory analysis, and longitudinal analysis, to develop the final pCMT‐QOL patient‐reported outcome measure.

## Interpretation

The pCMT‐QOL patient‐reported outcome measure is a reliable, valid, and sensitive measure of health‐related QOL for children with CMT. ANN NEUROL 2021;89:369–379

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Loss of cerebral autoregulation (CA) plays a key role in secondary neurologic injury. However, the regional distribution of CA impairment after acute cerebral injury remains unclear because, in clinical practice, CA is only assessed within a limited compartment. Here, we performed large‐scale regional mapping of cortical perfusion and CA in patients undergoing decompressive surgery for malignant hemispheric stroke.

## Methods

In 24 patients, autoregulation over the affected hemisphere was calculated based on direct, 15 to 20‐minute cortical perfusion measurement with intraoperative laser speckle imaging and mean arterial blood pressure (MAP) recording. Cortical perfusion was normalized against noninfarcted tissue and 6 perfusion categories from 0% to >100% were defined. The interaction between cortical perfusion and MAP was estimated using a linear random slope model and Pearson correlation.

## Results

Cortical perfusion and CA impairment were heterogeneously distributed across the entire hemisphere. The degree of CA impairment was significantly greater in areas with critical hypoperfusion (40–60%: 0.42% per mmHg and 60–80%: 0.46% per mmHg) than in noninfarcted (> 100%: 0.22% per mmHg) or infarcted (0–20%: 0.29% per mmHg) areas (*p < 0.001). Pearson correlation confirmed greater CA impairment at critically reduced perfusion (20–40%: r = 0.67; 40–60%: r = 0.68; and 60–80%: r = 0.68) compared to perfusion > 100% (r = 0.36; *p < 0.05). Tissue integrity had no impact on the degree of CA impairment.

## Interpretation

In hemispheric stroke, CA is impaired across the entire hemisphere to a variable extent. Autoregulation impairment was greatest in hypoperfused and potentially viable tissue, suggesting that precise localization of such regions is essential for effective tailoring of perfusion pressure‐based treatment strategies. ANN NEUROL 2021;89:358–368

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor‐first phenotype. Here, we aimed at identifying a brain‐clinical signature that predicts dementia in iRBD.

## Methods

A brain‐clinical signature was identified in 48 patients with polysomnography‐confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD.

## Results

One latent variable explained 31% of the brain‐clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053–4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283–17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD.

## Interpretation

We identified a brain‐clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341–357

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard‐therapy control group.

## Methods

A randomized, double‐blind, dose‐escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)‐confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures.

## Results

Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post‐SDA (both p < 0.01) compared with 2‐hour baseline in treatment versus control groups with adjustment for seizure burden.

## Interpretation

Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327–340

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

This study was undertaken to gain insights into structural networks associated with stimulation‐induced dysarthria (SID) and to predict stimulation‐induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS).

## Methods

Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation‐induced worsening of intelligibility in a structural connectome. The resulting fiber‐based atlas structure was then validated in a leave‐one‐out design.

## Results

Fibers determined as discriminative for stimulation‐induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al‐Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p < 0.001) of the variance of stimulation‐induced change in intelligibility in a leave‐one‐out analysis.

## Interpretation

This study demonstrates that SID in essential tremor patients is associated with both motor cortex and cerebellar connectivity. Furthermore, the identified fiber‐based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in essential tremor patients with thalamic DBS. ANN NEUROL 2021;89:315–326

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Silent New Brain MRI Lesions in Children with MOG‐Antibody Associated Disease

Anti‐myelin oligodendrocyte glycoprotein immunoglobulin G (MOG‐IgG) antibodies are associated clinically with either a monophasic or relapsing disease course. We investigated the frequency and clinical importance of acquired asymptomatic brain magnetic resonance imaging (MRI) lesions in a prospective incident cohort of 74 MOG‐IgG positive children with serial MRI scans over a median of 5 years from presentation. Silent new lesions were detected in 14% of MOG‐IgG positive participants, most commonly within the first months post‐onset, with a positive predictive value for clinically relapsing disease of only 20%. Detection of asymptomatic lesions alone need not prompt initiation of chronic immunotherapy. ANN NEUROL 2021;89:408–413

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.

## Methods

In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open‐label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.

## Results

In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty‐seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223–535) vs 124 days (95% CI = 33–149); OLT: 426 days (95% CI = 258–628) vs 106 days (95% CI = 11–149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug‐resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.

## Interpretation

Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304–314

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Hyperkinesias and Echolalia in Primary Familial Brain Calcification

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha‐synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age‐ and sex‐matched controls in a population‐based incident‐cohort study.

## Methods

We used a population‐based, 1991 to 2010 incident‐cohort study of alpha‐synucleinopathies. A movement‐disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream‐enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined.

## Results

Among the 444 incident cases of alpha‐synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha‐synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha‐synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0–217.2, p < 0.0001), higher in dementia with Lewy bodies than in Parkinson disease (OR = 2.57, 95% CI: 1.50–4.40, p = 0.0004), and higher in men than in women with Parkinson disease, dementia with Lewy bodies, or Parkinson disease dementia (OR = 3.70, 95% CI: 2.07–6.62, p < 0.0001), but did not increase mortality risk.

## Interpretation

Our cohort had RBD incidence of 3.4%. Overall RBD increased to 23.8% after 15 years, with an overall incidence of 2.5 cases per 100 person‐years. With 53 times greater lifetime incidence in alpha‐synucleinopathy patients than in controls, RBD was more likely to develop in dementia with Lewy bodies than in Parkinson disease or Parkinson disease dementia, and in men than in women, but did not increase mortality risk within our cohort. ANN NEUROL 2021;89:293–303

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations.

## Methods

We performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database–DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death.

## Results

Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty‐two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty‐four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001).

## Interpretation

Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2021;89:280–292

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### A Transcriptome‐Based Drug Discovery Paradigm for Neurodevelopmental Disorders

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin‐associated proteins, transcription factors, and RNA‐binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called “transcriptome reversal” for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene‐expression signatures associated with disease states. ANN NEUROL 2021;89:199–211

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long‐term outcome after intracerebral hemorrhage.

## Methods

We performed a prospective, community‐based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May 31, 2013. A neuroradiologist rated the diagnostic brain CT for acute intracerebral hemorrhage features and SVD biomarkers. We used severity of white matter lucencies and cerebral atrophy, and the number of lacunes to calculate the CT SVD score. We assessed the association between CT SVD biomarkers and either death, or death or dependence (modified Rankin Scale scores = 4–6) 1 year after first‐ever intracerebral hemorrhage using logistic regression, adjusting for known predictors of outcome.

## Results

Within 1 year of intracerebral hemorrhage, 224 (56%) of 402 patients died. In separate models, 1‐year death was associated with severe atrophy (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.44–4.49, p = 0.001) but not lacunes or severe white matter lucencies, and CT SVD sum score ≥ 1 (aOR = 2.50, 95% CI = 1.40–4.45, p = 0.002). Two hundred seventy‐seven (73%) of 378 patients with modified Rankin Scale data were dead or dependent at 1 year. In separate models, 1‐year death or dependence was associated with severe atrophy (aOR = 3.67, 95% CI = 1.71–7.89, p = 0.001) and severe white matter lucencies (aOR = 2.18, 95% CI = 1.06–4.51, p = 0.035) but not lacunes, and CT SVD sum score ≥ 1 (aOR = 2.81, 95% CI = 1.45–5.46, p = 0.002).

## Interpretation

SVD biomarkers on the diagnostic brain CT are associated with 1‐year death and dependence after intracerebral hemorrhage, independent of known predictors of outcome. ANN NEUROL 2021;89:266–279

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objectives

African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non‐Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences.

## Methods

Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs‐fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area‐based SES were included in mediation analyses.

## Results

Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f 2 = 0.05, p < 0.001). SES mediated the relationship between race and cortical volumes. There were no significant race effects for amyloid, tau, or rs‐fc signature.

## Interpretation

Modifiable factors, such as differences in social contexts and resources, particularly area‐level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254–265

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss‐of‐function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402–407

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).

## Methods

We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age‐ and sex‐matched (±5 years) stroke‐free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist‐to‐hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen.

## Results

The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63–3.76) and MA (OR = 3.50, 95% CI = 2.19–5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61–5.47; OR = 4.32 for MA, 95% CI = 2.16–8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32–4.61; OR = 3.61 for MA, 95% CI = 1.75–7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right‐to‐left shunt in patients with PFO.

## Interpretation

MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2021;89:242–253

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here.

## Methods

In the tetrodotoxin model, we used 16‐channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasm patients.

## Results

Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow wave sleep. In addition, the ensuing interictal up states of slow wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations, as it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp‐up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasm patients.

## Interpretation

Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies. ANN NEUROL 2021;89:226–241

in Annals of Neurology on January 16, 2021 05:31 PM.

## Objective

Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA.

## Methods

We conducted an international, double‐blind, randomized, placebo‐controlled, parallel‐group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015‐002762‐23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks.

## Results

One hundred fifty‐five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (−1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of –2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.

## Interpretation

In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212–225

in Annals of Neurology on January 16, 2021 05:31 PM.

• #### Select neurotrophins promote oligodendrocyte progenitor cell process outgrowth in the presence of chondroitin sulfate proteoglycans

Oligodendrocyte progenitor cells cannot extend cellular process in the presence of Chondroitin Sulfate Proteoglycans. Treatment of OPCs with different neurotrophic factors (BDNF, GDNF, and NT‐3) allows OPCs to overcome the inhibitory effects of CSPGs, allowing for OPC process outgrowth which is a critical step in the differentiation of OPCs.

## Abstract

Axonal damage and the subsequent interruption of intact neuronal pathways in the spinal cord are largely responsible for the loss of motor function after injury. Further exacerbating this loss is the demyelination of neighboring uninjured axons. The post‐injury environment is hostile to repair, with inflammation, a high expression of chondroitin sulfate proteoglycans (CSPGs) around the glial scar, and myelin breakdown. Numerous studies have demonstrated that treatment with the enzyme chondroitinase ABC (cABC) creates a permissive environment around a spinal lesion that permits axonal regeneration. Neurotrophic factors like brain‐derived neurotrophic factor (BDNF), glial cell line‐derived neurotrophic factor (GDNF), neurotrophic factor‐3 (NT‐3), and ciliary neurotrophic factor (CNTF) have been used to promote neuronal survival and stimulate axonal growth. CSPGs expressed near a lesion also inhibit migration and differentiation of endogenous oligodendrocyte progenitor cells (OPCs) in the spinal cord, and cABC treatment can neutralize this inhibition. This study examined the neurotrophins commonly used to stimulate axonal regeneration after injury and their potential effects on OPCs cultured in the presence of CSPGs. The results reveal differential effects on OPCs, with BDNF and GDNF promoting process outgrowth and NT‐3 stimulating differentiation of OPCs, while CNTF appears to have no observable effect. This finding suggests that certain neurotrophic agents commonly utilized to stimulate axonal regeneration after a spinal injury may also have a beneficial effect on the endogenous oligodendroglial cells as well.

in Journal of Neuroscience Research on January 16, 2021 04:06 PM.

## Abstract

In the hippocampus, spatial and nonspatial information are jointly represented as a neural map in which locations associated with salient features are over‐represented by increased densities of relevant place cells. Although we recently demonstrated that experience‐dependent establishment of these disproportionate maps is governed by selective stabilization of salient place cells following their conversion from non‐place cells, the underlying mechanism for pre‐established map reorganization remained to be understood. To this end, we investigated the changes in CA1 functional cellular maps imaged using two‐photon calcium imaging in mice performing a reward‐rearrangement task in virtual reality. Mice were pre‐trained on a virtual linear track with a visual landmark and a reward in two distinct locations. Then, they were re‐trained on the same track with the exception that the location of reward was shifted to match the landmark location. We found that, in contrast to de novo map formation, robust map reorganization occurred through parallel coordination of new place field formation, lateral shifting of existing place fields, and selective stabilization of place fields encoding salient locations. Our findings demonstrate that intricate interplay between multiple forms of cellular dynamics enables rapid updating of information stored in hippocampal maps.

in Hippocampus on January 16, 2021 12:05 PM.

## Abstract

The extinction of contextual fear is commonly an essential requirement for successful exposure therapy for fear disorders. However, experimental work on extinction of contextual fear is limited, and there little or no directly relevant theoretical work. Here, we extend BACON, a neurocomputational model of context fear conditioning that provides plausible explanations for a number of aspects of context fear conditioning, to deal with extinction (calling the model BaconX). In this model, contextual representations are formed in the hippocampus and association of fear to them occurs in the amygdala. Representation creation, conditionability, and development of between‐session extinction are controlled by degree of confidence (assessed by the Bayesian weight of evidence) that an active contextual representation is in fact that of the current context (i.e., is “valid”). The model predicts that: (1) extinction which persists between sessions will occur only if at a sessions end there is high confidence that the active representation is valid. It follows that the shorter the context placement‐to‐US (shock) interval (“PSI”) and the less is therefore learned about context, the longer extinction sessions must be for enduring extinction to occur, while too short PSIs will preclude successful extinction. (2) Short‐PSI deficits can be rescued by contextual exposure even after conditioning has occurred. (3) Learning to discriminate well between a conditioned and similar safe context requires representations of each to form, which may not occur if PSI was too short. (4) Extinction‐causing inhibition must be applied downstream of the conditioning locus for reasonable generalization properties to be generated. (5) Context change tends to cause return of extinguished contextual fear. (6). Extinction carried out in the conditioning context generalizes better than extinction executed in contexts to which fear has generalized (as done in exposure therapy). (7) BaconX suggests novel approaches to exposure therapy.

in Hippocampus on January 16, 2021 11:56 AM.

• #### Longitudinal fields and transverse rotations

Nature Photonics, Published online: 15 January 2021; doi:10.1038/s41566-020-00756-w

Electromagnetic fields in light waves are mainly transverse to propagation direction but actually also have longitudinal components, which may give rise to unexpected optical phenomena involving the angular momentum of light, such as transverse spin and optical torques.

in Nature Photomics on January 15, 2021 12:00 AM.

• #### Lessons From Deep Neural Networks for Studying the Coding Principles of Biological Neural Networks

One of the central goals in systems neuroscience is to understand how information is encoded in the brain, and the standard approach is to identify the relation between a stimulus and a neural response. However, the feature of a stimulus is typically defined by the researcher's hypothesis, which may cause biases in the research conclusion. To demonstrate potential biases, we simulate four likely scenarios using deep neural networks trained on the image classification dataset CIFAR-10 and demonstrate the possibility of selecting suboptimal/irrelevant features or overestimating the network feature representation/noise correlation. Additionally, we present studies investigating neural coding principles in biological neural networks to which our points can be applied. This study aims to not only highlight the importance of careful assumptions and interpretations regarding the neural response to stimulus features but also suggest that the comparative study between deep and biological neural networks from the perspective of machine learning can be an effective strategy for understanding the coding principles of the brain.

in Frontiers in Systems Neuroscience on January 15, 2021 12:00 AM.

• #### Novel Phosphorylation-State Specific Antibodies Reveal Differential Deposition of Ser26 Phosphorylated Aβ Species in a Mouse Model of Alzheimer’s Disease

Aggregation and deposition of amyloid-β (Aβ) peptides in extracellular plaques and in the cerebral vasculature are prominent neuropathological features of Alzheimer’s disease (AD) and closely associated with the pathogenesis of AD. Amyloid plaques in the brains of most AD patients and transgenic mouse models exhibit heterogeneity in the composition of Aβ deposits, due to the occurrence of elongated, truncated, and post-translationally modified Aβ peptides. Importantly, changes in the deposition of these different Aβ variants are associated with the clinical disease progression and considered to mark sequential phases of plaque and cerebral amyloid angiopathy (CAA) maturation at distinct stages of AD. We recently showed that Aβ phosphorylated at serine residue 26 (pSer26Aβ) has peculiar characteristics in aggregation, deposition, and neurotoxicity. In the current study, we developed and thoroughly validated novel monoclonal and polyclonal antibodies that recognize Aβ depending on the phosphorylation-state of Ser26. Our results demonstrate that selected phosphorylation state-specific antibodies were able to recognize Ser26 phosphorylated and non-phosphorylated Aβ with high specificity in enzyme-linked immunosorbent assay (ELISA) and Western Blotting (WB) assays. Furthermore, immunofluorescence analyses with these antibodies demonstrated the occurrence of pSer26Aβ in transgenic mouse brains that show differential deposition as compared to non-phosphorylated Aβ (npAβ) or other modified Aβ species. Notably, pSer26Aβ species were faintly detected in extracellular Aβ plaques but most prominently found intraneuronally and in cerebral blood vessels. In conclusion, we developed new antibodies to specifically differentiate Aβ peptides depending on the phosphorylation state of Ser26, which are applicable in ELISA, WB, and immunofluorescence staining of mouse brain tissues. These site- and phosphorylation state-specific Aβ antibodies represent novel tools to examine phosphorylated Aβ species to further understand and dissect the complexity in the age-related and spatio-temporal deposition of different Aβ variants in transgenic mouse models and human AD brains.

in Frontiers in Molecular Neuroscience on January 15, 2021 12:00 AM.

• #### The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.

in Frontiers in Molecular Neuroscience on January 15, 2021 12:00 AM.

• #### Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death.

in Frontiers in Neuroscience: Neurodegeneration on January 15, 2021 12:00 AM.

• #### Increased Brain Iron Detection by Voxel-Based Quantitative Susceptibility Mapping in Type 2 Diabetes Mellitus Patients With an Executive Function Decline

Purpose

Brain iron accumulation has been suggested as a pathomechanism in patients with type 2 diabetes mellitus (T2DM) with cognitive impairment. This research aims to examine the total-brain pattern of iron accumulation in relation to executive function decline in patients with T2DM by voxel-based quantitative susceptibility mapping (QSM) analysis.

Materials and Methods

A total of 32 patients with T2DM and 34 age- and sex-matched healthy controls (HCs) were enrolled in this study. All participants underwent brain magnetic resonance examination, and 48 individuals underwent cognitive function assessments. Imaging data were collected with three-dimensional fast low-angle shot sequences to achieve magnitude as well as phase images. Using voxel-based QSM analysis, we compared the voxel-wise susceptibility values of the whole brain among groups and explored whether the susceptibility values had correlations with cognitive data.

Results

Among the 66 participants, cognitive function was estimated in 23 patients with T2DM (11 males and 12 females; average age, 64.65 ± 8.44 years) and 25 HCs (13 males and 12 females; average age, 61.20 ± 7.62 years). T2DM patients exhibited significantly (t = 4.288, P < 0.001) lower Montreal Cognitive Assessment (MoCA) scores [T2DM, 27 (27, 28); HCs, 29 (28, 29); normal standard ≥ 26)] and higher Trail-making Test (TMT)-A/TMT-B scores [71 (51, 100)/185 (149, 260)] than HCs [53 (36.5, 63.5)/150 (103, 172.5)] (Z = 2.612, P = 0.009; Z = 2.797, P = 0.005). Subjects with T2DM showed significantly higher susceptibility values than HCs in the caudate/putamen/pallidum, frontal inferior triangular gyrus, and precentral gyrus on the right hemisphere. In contrast (HC > T2DM), no region showed a significant difference in susceptibility values between the groups. The correlation analysis between susceptibility values and cognitive function scores was tested by voxel-based susceptibility value with sex and age as covariates. After multiple comparison correction, in T2DM patients, the left thalamus showed a significant relationship with TMT-A (R2 = 0.53, P = 0.001). The right thalamus and left thalamus showed a significant relationship with TMT-B (R2 = 0.35, P = 0.019; and R2 = 0.38, P = 0.017, respectively). In HCs, the cluster of right precentral/middle frontal gyrus/inferior frontal gyrus/inferior triangular gyrus showed a significant relationship with TMT-B (R2 = 0.59, P = 0.010). No relationship was found between the susceptibility values with MoCA in the brain region in both two groups.

Conclusion

Patients with T2DM presented declined cognitive assessments and elevated iron deposition in the striatum and frontal lobe, suggesting that executive function decline in T2DM might be associated with the cerebral iron burden and that changes in susceptibility values may represent a latent quantitative imaging marker for early assessment of cognitive decline in patients with T2DM.

in Frontiers in Neuroscience: Brain Imaging Methods on January 15, 2021 12:00 AM.

• #### Electromyogram (EMG) Removal by Adding Sources of EMG (ERASE)—A Novel ICA-Based Algorithm for Removing Myoelectric Artifacts From EEG

Electroencephalographic (EEG) recordings are often contaminated by electromyographic (EMG) artifacts, especially when recording during movement. Existing methods to remove EMG artifacts include independent component analysis (ICA), and other high-order statistical methods. However, these methods can not effectively remove most of EMG artifacts. Here, we proposed a modified ICA model for EMG artifacts removal in the EEG, which is called EMG Removal by Adding Sources of EMG (ERASE). In this new approach, additional channels of real EMG from neck and head muscles (reference artifacts) were added as inputs to ICA in order to “force” the most power from EMG artifacts into a few independent components (ICs). The ICs containing EMG artifacts (the “artifact ICs”) were identified and rejected using an automated procedure. ERASE was validated first using both simulated and experimentally-recorded EEG and EMG. Simulation results showed ERASE removed EMG artifacts from EEG significantly more effectively than conventional ICA. Also, it had a low false positive rate and high sensitivity. Subsequently, EEG was collected from 8 healthy participants while they moved their hands to test the realistic efficacy of this approach. Results showed that ERASE successfully removed EMG artifacts (on average, about 75% of EMG artifacts were removed when using real EMGs as reference artifacts) while preserving the expected EEG features related to movement. We also tested the ERASE procedure using simulated EMGs as reference artifacts (about 63% of EMG artifacts removed). Compared to conventional ICA, ERASE removed on average 26% more EMG artifacts from EEG. These findings suggest that ERASE can achieve significant separation of EEG signal and EMG artifacts without a loss of the underlying EEG features. These results indicate that using additional real or simulated EMG sources can increase the effectiveness of ICA in removing EMG artifacts from EEG. Combined with automated artifact IC rejection, ERASE also minimizes potential user bias. Future work will focus on improving ERASE so that it can also be used in real-time applications.

in Frontiers in Neuroscience: Neural Technology on January 15, 2021 12:00 AM.

• #### Intensity and Dose of Neuromuscular Electrical Stimulation Influence Sensorimotor Cortical Excitability

Neuromuscular electrical stimulation (NMES) of the nervous system has been extensively used in neurorehabilitation due to its capacity to engage the muscle fibers, improving muscle tone, and the neural pathways, sending afferent volleys toward the brain. Although different neuroimaging tools suggested the capability of NMES to regulate the excitability of sensorimotor cortex and corticospinal circuits, how the intensity and dose of NMES can neuromodulate the brain oscillatory activity measured with electroencephalography (EEG) is still unknown to date. We quantified the effect of NMES parameters on brain oscillatory activity of 12 healthy participants who underwent stimulation of wrist extensors during rest. Three different NMES intensities were included, two below and one above the individual motor threshold, fixing the stimulation frequency to 35 Hz and the pulse width to 300 μs. Firstly, we efficiently removed stimulation artifacts from the EEG recordings. Secondly, we analyzed the effect of amplitude and dose on the sensorimotor oscillatory activity. On the one hand, we observed a significant NMES intensity-dependent modulation of brain activity, demonstrating the direct effect of afferent receptor recruitment. On the other hand, we described a significant NMES intensity-dependent dose-effect on sensorimotor activity modulation over time, with below-motor-threshold intensities causing cortical inhibition and above-motor-threshold intensities causing cortical facilitation. Our results highlight the relevance of intensity and dose of NMES, and show that these parameters can influence the recruitment of the sensorimotor pathways from the muscle to the brain, which should be carefully considered for the design of novel neuromodulation interventions based on NMES.

in Frontiers in Neuroscience: Brain Imaging Methods on January 15, 2021 12:00 AM.

• #### Increased Sestrin3 Contributes to Post-ischemic Seizures in the Diabetic Condition

Seizures are among the most common neurological sequelae of stroke, and diabetes notably increases the incidence of post-ischemic seizures. Recent studies have indicated that Sestrin3 (SESN3) is a regulator of a proconvulsant gene network in human epileptic hippocampus. But the association of SESN3 and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of SESN3 in seizures following transient cerebral ischemia in diabetes. Diabetes was induced in adult male mice and rats via intraperitoneal injection of streptozotocin (STZ). Forebrain ischemia (15 min) was induced by bilateral common carotid artery occlusion, the 2-vessel occlusion (2VO) in mice and 4-vessel occlusion (4VO) in rats. Our results showed that 59% of the diabetic wild-type mice developed seizures after ischemia while no seizures were observed in non-diabetic mice. Although no apparent cell death was detected in the hippocampus of seizure mice within 24 h after the ischemic insult, the expression of SESN3 was significantly increased in seizure diabetic mice after ischemia. The post-ischemic seizure incidence significantly decreased in SESN3 knockout mice. Furthermore, all diabetic rats suffered from post-ischemic seizures and non-diabetic rats have no seizures. Electrophysiological recording showed an increased excitatory synaptic transmission and intrinsic membrane excitability in dentate granule cells of the rat hippocampus, together with decreased IA currents and Kv4.2 expression levels. The above results suggest that SESN3 up-regulation may contribute to neuronal hyperexcitability and seizure generation in diabetic animals after ischemia. Further studies are needed to explore the molecular mechanism of SESN3 in seizure generation after ischemia in diabetic conditions.

in Frontiers in Neuroscience: Neurodegeneration on January 15, 2021 12:00 AM.

• #### Numerical Magnitude Affects Accuracy but Not Precision of Temporal Judgments

A Theory of Magnitude (ATOM) suggests that space, time, and quantities are processed through a generalized magnitude system. ATOM posits that task-irrelevant magnitudes interfere with the processing of task-relevant magnitudes as all the magnitudes are processed by a common system. Many behavioral and neuroimaging studies have found support in favor of a common magnitude processing system. However, it is largely unknown whether such cross-domain monotonic mapping arises from a change in the accuracy of the magnitude judgments or results from changes in precision of the processing of magnitude. Therefore, in the present study, we examined whether large numerical magnitude affects temporal accuracy or temporal precision, or both. In other words, whether numerical magnitudes change our temporal experience or simply bias duration judgments. The temporal discrimination (between comparison and standard duration) paradigm was used to present numerical magnitudes (“1,” “5,” and “9”) across varied durations. We estimated temporal accuracy (PSE) and precision (Weber ratio) for each numerical magnitude. The results revealed that temporal accuracy (PSE) for large (9) numerical magnitude was significantly lower than that of small (1) and identical (5) magnitudes. This implies that the temporal duration was overestimated for large (9) numerical magnitude compared to small (1) and identical (5) numerical magnitude, in line with ATOM’s prediction. However, no influence of numerical magnitude was observed on temporal precision (Weber ratio). The findings of the present study suggest that task-irrelevant numerical magnitude selectively affects the accuracy of processing of duration but not duration discrimination itself. Further, we argue that numerical magnitude may not directly affect temporal processing but could influence via attentional mechanisms.

in Frontiers in Human Neuroscience on January 15, 2021 12:00 AM.

• #### The Brain Emotional Systems in Addictions: From Attachment to Dominance/Submission Systems

in Frontiers in Human Neuroscience on January 15, 2021 12:00 AM.

• #### Alterations of Cerebral Hemodynamics and Network Properties Induced by Newsvendor Problem in the Human Prefrontal Cortex

While many publications have reported brain hemodynamic responses to decision-making under various conditions of risk, no inventory management scenarios, such as the newsvendor problem (NP), have been investigated in conjunction with neuroimaging. In this study, we hypothesized (I) that NP stimulates the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) joined with frontal polar area (FPA) significantly in the human brain, and (II) that local brain network properties are increased when a person transits from rest to the NP decision-making phase. A 77-channel functional near infrared spectroscopy (fNIRS) system with wide field-of-view (FOV) was employed to measure frontal cerebral hemodynamics in response to NP in 27 healthy human subjects. NP-induced changes in oxy-hemoglobin concentration, Δ[HbO], were investigated using a general linear model (GLM) and graph theory analysis (GTA). Significant activation induced by NP was shown in both DLPFC and OFC+FPA across all subjects. Specifically, higher risk NP with low-profit margins (LM) activated left-DLPFC but deactivated right-DLPFC in 14 subjects, while lower risk NP with high-profit margins (HM) stimulated both DLPFC and OFC+FPA in 13 subjects. The local efficiency, clustering coefficient, and path length of the network metrics were significantly enhanced under NP decision making. In summary, multi-channel fNIRS enabled us to identify DLPFC and OFC+FPA as key cortical regions of brain activations when subjects were making inventory-management risk decisions. We demonstrated that challenging NP resulted in the deactivation within right-DLPFC due to higher levels of stress. Also, local brain network properties were increased when a person transitioned from the rest phase to the NP decision-making phase.

in Frontiers in Human Neuroscience on January 15, 2021 12:00 AM.

• #### Increased Amygdala-Paracentral Lobule/Precuneus Functional Connectivity Associated With Patients With Mood Disorder and Suicidal Behavior

Mood disorder patients have greater suicide risk than members of the general population, but how suicidal behavior relates to brain functions has not been fully elucidated. This study investigated how functional connectivity (FC) values between the right/left amygdala and the whole brain relate to suicidal behavior in patients with mood disorder. The participants in this study were 100 mood disorder patients with suicidal behavior (SB group), 120 mood disorder patients with non-suicidal behavior (NSB group), and 138 age- and gender-matched healthy controls (HC group). Whole-brain FC values among the three groups were compared using an analysis of covariance (ANCOVA). Compared to the NSB and HC groups, increased FC values in the right amygdala-bilateral paracentral lobule/precuneus circuit were observed in the SB group (Bonferroni-corrected, p < 0.017). The FC values in the NSB group did not differ significantly from those in the HC group (Bonferroni-corrected, p > 0.017). Moreover, there were no significant differences in FC values between mood disorder patients with suicide attempt (SA group) and mood disorder patients with suicidal ideation (SI group), while the FC values between the right amygdala and bilateral paracentral lobule/precuneus in the SA group were higher than the mean in the SI group. These findings suggest that right amygdala-paracentral lobule/precuneus dysfunction has an important role in patients with mood disorder and suicidal behavior.

in Frontiers in Human Neuroscience on January 15, 2021 12:00 AM.

• #### Abnormal Static and Dynamic Local-Neural Activity in COPD and Its Relationship With Pulmonary Function and Cognitive Impairments

Patients with chronic obstructive pulmonary disease (COPD) are characterized by attenuated pulmonary function and are frequently reported with cognitive impairments, especially memory impairments. The mechanism underlying the memory impairments still remains unclear. We applied resting-state functional magnetic resonance imaging (RS-fMRI) to compare the brain local activities with static and dynamic amplitude of low-frequency fluctuations (sALFF, dALFF) among patients with COPD (n = 32) and healthy controls (HC, n = 30). Compared with HC, COPD patients exhibited decreased sALFF in the right basal ganglia and increased dALFF in the bilateral parahippocampal/hippocampal gyrus. The reduced the left basal ganglia was associated with lower oxygen partial pressure. Besides, the increased dALFF in the left hippocampal/parahippocampal cortex was associated with poor semantic-memory performance and the increased dALFF in the left hippocampal/parahippocampal cortex was associated the forced vital capacity. The present study revealed the abnormal static and dynamic local-neural activities in the basal ganglia and parahippocampal/hippocampal cortex in COPD patient and its relationship with poor lung function and semantic-memory impairments.

in Frontiers in Human Neuroscience on January 15, 2021 12:00 AM.

• #### Origins, Development, and Compartmentation of the Granule Cells of the Cerebellum

Granule cells (GCs) are the most numerous cell type in the cerebellum and indeed, in the brain: at least 99% of all cerebellar neurons are granule cells. In this review article, we first consider the formation of the upper rhombic lip, from which all granule cell precursors arise, and the way by which the upper rhombic lip generates the external granular layer, a secondary germinal epithelium that serves to amplify the upper rhombic lip precursors. Next, we review the mechanisms by which postmitotic granule cells are generated in the external granular layer and migrate radially to settle in the granular layer. In addition, we review the evidence that far from being a homogeneous population, granule cells come in multiple phenotypes with distinct topographical distributions and consider ways in which the heterogeneity of granule cells might arise during development.

in Frontiers in Neural Circuits on January 15, 2021 12:00 AM.

• #### Subsampled Directed-Percolation Models Explain Scaling Relations Experimentally Observed in the Brain

Recent experimental results on spike avalanches measured in the urethane-anesthetized rat cortex have revealed scaling relations that indicate a phase transition at a specific level of cortical firing rate variability. The scaling relations point to critical exponents whose values differ from those of a branching process, which has been the canonical model employed to understand brain criticality. This suggested that a different model, with a different phase transition, might be required to explain the data. Here we show that this is not necessarily the case. By employing two different models belonging to the same universality class as the branching process (mean-field directed percolation) and treating the simulation data exactly like experimental data, we reproduce most of the experimental results. We find that subsampling the model and adjusting the time bin used to define avalanches (as done with experimental data) are sufficient ingredients to change the apparent exponents of the critical point. Moreover, experimental data is only reproduced within a very narrow range in parameter space around the phase transition.

in Frontiers in Neural Circuits on January 15, 2021 12:00 AM.

• #### Neuronal and Synaptic Plasticity in the Visual Thalamus in Mouse Models of Glaucoma

Homeostatic plasticity plays important role in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), the early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes related to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma—the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, when IOP rises. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in 9-month-old D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner. These data suggest that glaucoma-associated changes to neuronal excitability and synaptic inputs in the dLGN might represent a combination of both stabilizing/homeostatic plasticity and pathological dysfunction.

in Frontiers in Cellular Neuroscience on January 15, 2021 12:00 AM.

• #### Antidromic Spike Propagation and Dissimilar Expression of P2X, 5-HT, and TRPV1 Channels in Peripheral vs. Central Sensory Axons in Meninges

Background: The terminal branches of the trigeminal nerve in meninges are supposed to be the origin site of migraine pain. The main function of these peripheral sensory axons is the initiation and propagation of spikes in the orthodromic direction to the second order neurons in the brainstem. The stimulation of the trigeminal ganglion induces the release of the neuropeptide CGRP in meninges suggesting the antidromic propagation of excitation in these fibers. However, the direct evidence on antidromic spike traveling in meningeal afferents is missing.

Methods: By recording of spikes from peripheral or central parts of the trigeminal nerve in rat meninges, we explored their functional activity and tested the expression of ATP-, serotonin-, and capsaicin-gated receptors in the distal vs. proximal parts of these nerves.

Results: We show the significant antidromic propagation of spontaneous spikes in meningeal nerves which was, however, less intense than the orthodromic nociceptive traffic due to higher number of active fibers in the latter. Application of ATP, serotonin and capsaicin induced a high frequency nociceptive firing in peripheral processes while, in central parts, only ATP and capsaicin were effective. Disconnection of nerve from trigeminal ganglion dramatically reduced the tonic antidromic activity and attenuated the excitatory action of ATP.

Conclusion: Our data indicate the bidirectional nociceptive traffic and dissimilar expression of P2X, 5-HT and TRPV1 receptors in proximal vs. distal parts of meningeal afferents, which is important for understanding the peripheral mechanisms of migraine pain.

in Frontiers in Cellular Neuroscience on January 15, 2021 12:00 AM.

• #### From Maternal Diet to Neurodevelopmental Disorders: A Story of Neuroinflammation

Providing the appropriate quantity and quality of food needed for both the mother’s well-being and the healthy development of the offspring is crucial during pregnancy. However, the macro- and micronutrient intake also impacts the body’s regulatory supersystems of the mother, such as the immune, endocrine, and nervous systems, which ultimately influence the overall development of the offspring. Of particular importance is the association between unhealthy maternal diet and neurodevelopmental disorders in the offspring. Epidemiological studies have linked neurodevelopmental disorders like autism spectrum disorders, attention-deficit-hyperactivity disorder, and schizophrenia, to maternal immune activation (MIA) during gestation. While the deleterious consequences of diet-induced MIA on offspring neurodevelopment are increasingly revealed, neuroinflammation is emerging as a key underlying mechanism. In this review, we compile the evidence available on how the mother and offspring are both impacted by maternal dietary imbalance. We specifically explore the various inflammatory and anti-inflammatory effects of dietary components and discuss how changes in inflammatory status can prime the offspring brain development toward neurodevelopmental disorders. Lastly, we discuss research evidence on the mechanisms that sustain the relationship between maternal dietary imbalance and offspring brain development, involving altered neuroinflammatory status in the offspring, as well as genetic to cellular programming notably of microglia, and the evidence that the gut microbiome may act as a key mediator.

in Frontiers in Cellular Neuroscience on January 15, 2021 12:00 AM.

• #### Dentate Granule Cells Recruited in the Home Environment Display Distinctive Properties

The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established. Using fosGFP transgenic mice, we observed ex vivo that DGCs recruited in animals maintained in the home cage condition are mature neurons that display a longer dendritic tree and lower excitability compared with non-activated cells. The higher GABAA receptor-mediated shunting inhibition contributes to the lower excitability of DGCs activated in the home environment by shifting the input resistance towards lower values. Remarkably, that shunting inhibition is neither observed in non-activated DGCs nor in DGCs activated during training in virtual reality. In short, our results suggest that strong shunting inhibition and reduced excitability could constitute a distinctive neural signature of mature DGCs recruited in the context of the home environment.

in Frontiers in Cellular Neuroscience on January 15, 2021 12:00 AM.

• #### High Contrast Allows the Retina to Compute More Than Just Contrast

The goal of sensory processing is to represent the environment of an animal. All sensory systems share a similar constraint: they need to encode a wide range of stimulus magnitudes within their narrow neuronal response range. The most efficient way, exploited by even the simplest nervous systems, is to encode relative changes in stimulus magnitude rather than the absolute magnitudes. For instance, the retina encodes contrast, which are the variations of light intensity occurring in time and in space. From this perspective, it is easy to understand why the bright plumage of a moving bird gains a lot of attention, while an octopus remains motionless and mimics its surroundings for concealment. Stronger contrasts simply cause stronger visual signals. However, the gains in retinal performance associated with higher contrast are far more than what can be attributed to just a trivial linear increase in signal strength. Here we discuss how this improvement in performance is reflected throughout different parts of the neural circuitry, within its neural code and how high contrast activates many non-linear mechanisms to unlock several sophisticated retinal computations that are virtually impossible in low contrast conditions.

in Frontiers in Cellular Neuroscience on January 15, 2021 12:00 AM.

• #### Structural and Functional Features of Developing Brain Capillaries, and Their Alteration in Schizophrenia

Schizophrenia affects more than 1% of the world’s population and shows very high heterogeneity in the positive, negative, and cognitive symptoms experienced by patients. The pathogenic mechanisms underlying this neurodevelopmental disorder are largely unknown, although it is proposed to emerge from multiple genetic and environmental risk factors. In this work, we explore the potential alterations in the developing blood vessel network which could contribute to the development of schizophrenia. Specifically, we discuss how the vascular network evolves during early postnatal life and how genetic and environmental risk factors can lead to detrimental changes. Blood vessels, capillaries in particular, constitute a dynamic and complex infrastructure distributing oxygen and nutrients to the brain. During postnatal development, capillaries undergo many structural and anatomical changes in order to form a fully functional, mature vascular network. Advanced technologies like magnetic resonance imaging and near infrared spectroscopy are now enabling to study how the brain vasculature and its supporting features are established in humans from birth until adulthood. Furthermore, the contribution of the different neurovascular unit elements, including pericytes, endothelial cells, astrocytes and microglia, to proper brain function and behavior, can be dissected. This investigation conducted among different brain regions altered in schizophrenia, such as the prefrontal cortex, may provide further evidence that schizophrenia can be considered a neurovascular disorder.

in Frontiers in Cellular Neuroscience on January 15, 2021 12:00 AM.

• #### Retinal Thickness Changes Over Time in a Murine AD Model APPNL-F/NL-F

Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL−F/NL−F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals.

Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve.

Results: In the APPNL−F/NL−F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old.

Conclusions: In the APPNL−F/NL−F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL−F/NL−F AD model may help us better understand the different retinal changes during the progression of AD.

in Frontiers in Ageing Neuroscience on January 15, 2021 12:00 AM.

• #### Cognitive and Behavioral Inhibition Deficits in Parkinson’s Disease: The Hayling Test as a Reliable Marker

Objective

The present study seeks to provide an overview of executive (inhibition and flexibility) deficits in Parkinson’s disease (PD) by combining a cognitive and behavioral approach.

Methods

Fifteen PD patients and 15 healthy controls underwent a neuropsychological and behavioral assessment including the Hayling and Trails Tests, the Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease (QUIP-RS), the Behavior Rating Inventory of Executive Function (BRIEF-A), and the Short Form-36 Health Survey (SF-36). The level of awareness of executive functioning was also analyzed. We finally explored how these neuropsychological and clinical outcomes could relate to each other.

Results

PD patients performed significantly worse in both neuropsychological tasks designed to evaluate inhibition abilities. They also reported more inhibition difficulties in everyday life and poorer quality of life. Associations between neuropsychological measures and self-reports were found. Moreover, as indicated by the discrepancy score, PD patients were as accurate as their relatives in self-reporting their executive daily difficulties.

Conclusion

Inhibition and cognitive flexibility impairments assessed by the neuropsychological tests (Hayling and Trails tests) seem to capture daily life executive problems in PD. Furthermore, our study provides a deeper understanding of PD patients’ and their relatives’ experience of these executive dysfunctions.

in Frontiers in Ageing Neuroscience on January 15, 2021 12:00 AM.

• #### Absence of Uptake and Prion-Like Spreading of Alpha-Synuclein and Tau After Intravitreal Injection of Preformed Fibrils

Although very different in etiology and symptoms, numerous neurodegenerative diseases can be classified as proteinopathies. More so, evidence indicates that the key misfolded proteins at the basis of different neuropathies might share common mechanisms of propagation. As such, the prion-like spreading of protein aggregates through the neural network is subject of intensive research focus and requires adequate models. Here, we made use of the well-defined architecture and large accessibility of the visual system, of which the retinotopic connections represent a simple route of anterograde signaling and an elegant model to investigate transsynaptic, prion-like spreading. In two independent studies, uptake and seeding of alpha-synuclein and tau were examined after intravitreal injection of preformed fibrils. However, extracellular matrix components in the vitreous space and at the vitreoretinal surface appeared to act as a barrier for the entry of both fibrils into the retina. These results show that further experimental refinement is needed to fully realize the potential of the visual system as a model for studying the molecular and cellular mechanisms of anterograde, transsynaptic spreading of prion-like proteins.

in Frontiers in Ageing Neuroscience on January 15, 2021 12:00 AM.

• #### Abnormal Topological Organization of Sulcal Depth-Based Structural Covariance Networks in Parkinson's Disease

Recent research on Parkinson's disease (PD) has demonstrated the topological abnormalities of structural covariance networks (SCNs) using various morphometric features from structural magnetic resonance images (sMRI). However, the sulcal depth (SD)-based SCNs have not been investigated. In this study, we used SD to investigate the topological alterations of SCNs in 60 PD patients and 56 age- and gender-matched healthy controls (HC). SCNs were constructed by thresholding SD correlation matrices of 68 regions and analyzed using graph theoretical approaches. Compared with HC, PD patients showed increased normalized clustering coefficient and normalized path length, as well as a reorganization of degree-based and betweenness-based hubs (i.e., less frontal hubs). Moreover, the degree distribution analysis showed more high-degree nodes in PD patients. In addition, we also found the increased assortativity and reduced robustness under a random attack in PD patients compared to HC. Taken together, these findings indicated an abnormal topological organization of SD-based SCNs in PD patients, which may contribute in understanding the pathophysiology of PD at the network level.

in Frontiers in Ageing Neuroscience on January 15, 2021 12:00 AM.

• #### Decreased Retinal Vascular Density in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI): An Optical Coherence Tomography Angiography (OCTA) Study

Background

To explore the retinal vascular density changes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients using optical coherence tomography angiography (OCTA).

Methods

We recruit 62 AD patients, 47 MCI patients, and 49 cognitively healthy controls (HC) in this study. All participants in the study received a comprehensive ophthalmological and neurological evaluation, including global cognitive screening, as well as the Mini-Mental State Examination (MMSE), and completed the following eye examinations: visual acuity (VA), intraocular pressure (IOP), examination with slit-lamp, fundus photography (Version 1.5.0.0, NIDEK CO, LTD) and Optical coherence tomography imaging (software ReVue version 2017.1.0.155, Optovue Inc., Fremont, CA, United States). The visual rating scales for atrophy and white matter lesion in MRI was evaluated for all the patients with AD and MCI.

Results

In the AD patient group, the superficial vascular density in the superior, inferior and whole retina was 44.64 ± 3.34, 44.65 ± 3.55, and 44.66 ± 3.36, respectively. These values were 44.24 ± 3.15, 43.72 ± 3.16, and 44 ± 3.07, respectively, in the MCI patient group. After multivariate analysis of the generalized linear model, adjustments for the confounding factors of sex, age, hypertension, diabetes and the quality index of OCTA image, the superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group (P < 0.05): 46.94 ± 2.04, 46.67 ± 2.26, and 46.82 ± 2.08, respectively. No difference in the area of the FAZ among the three groups was observed (AD group: 0.34 ± 0.11 mm2; MCI group: 0.36 ± 0.12 mm2; control group: 0.33 ± 0.12 mm2, p > 0.05). The ganglion cell complex (GCC) thickness, inner parafovea thickness, and peripapillary retinal nerve fiber layer (p-RNFL) thickness were associated with the superficial vascular density. We found no significant correlation between the global cognition (MMSE scores) or between the Fazekas score and retinal OCT angiogram flow density.

Conclusion

The superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group. Our findings suggest the retinal microvascular dysfunction occurred in MCI and AD.

in Frontiers in Ageing Neuroscience on January 15, 2021 12:00 AM.

• #### Post-status epilepticus treatment with the Fyn inhibitor, saracatinib, improves cognitive function in mice

Status epilepticus (SE) is a life-threatening neurological disorder. The hippocampus, as an important area of the brain that regulates cognitive function, is usually damaged after SE, and cognitive deficits of...

in BMC Neuroscience on January 15, 2021 12:00 AM.

• #### INN/ENNS/JNNS - Membership Applic. Form

Publication date: March 2021

Source: Neural Networks, Volume 135

Author(s):

in Neural Networks on January 14, 2021 08:15 PM.

• #### Editorial Board

Publication date: March 2021

Source: Neural Networks, Volume 135

Author(s):

in Neural Networks on January 14, 2021 08:15 PM.

• #### Current Events

Publication date: March 2021

Source: Neural Networks, Volume 135

Author(s):

in Neural Networks on January 14, 2021 08:15 PM.

• #### A neurodynamic optimization approach to supervised feature selection via fractional programming

Publication date: Available online 14 January 2021

Source: Neural Networks

Author(s): Yadi Wang, Xiaoping Li, Jun Wang

in Neural Networks on January 14, 2021 08:15 PM.

• #### Sex and age influence gonadal steroid hormone receptor distributions relative to estrogen receptor β‐containing neurons in the mouse hypothalamic paraventricular nucleus

Light and electron microscopic studies reveal that gonadal steroids may directly and indirectly influence PVN neurons via nuclear (a) and extranuclear (b) gonadal hormone receptors in a sex‐specific manner. AR, androgen receptor; ER, estrogen receptor; GPER, G‐protein–coupled estrogen receptor.

## Abstract

Within the hypothalamic paraventricular nucleus (PVN), estrogen receptor (ER) β and other gonadal hormone receptors play a role in central cardiovascular processes. However, the influence of sex and age on the cellular and subcellular relationships of ERβ with ERα, G‐protein ER (GPER1), as well as progestin and androgen receptors (PR and AR) in the PVN is uncertain. In young (2‐ to 3‐month‐old) females and males, ERβ‐enhanced green fluorescent protein (EGFP) containing neurons were approximately four times greater than ERα‐labeled and PR‐labeled nuclei in the PVN. In subdivisions of the PVN, young females, compared to males, had: (1) more ERβ‐EGFP neurons in neuroendocrine rostral regions; (2) fewer ERα‐labeled nuclei in neuroendocrine and autonomic projecting medial subregions; and (3) more ERα‐labeled nuclei in an autonomic projecting caudal region. In contrast, young males, compared to females, had approximately 20 times more AR‐labeled nuclei, which often colocalized with ERβ‐EGFP in neuroendocrine (approximately 70%) and autonomic (approximately 50%) projecting subregions. Ultrastructurally, in soma and dendrites, PVN ERβ‐EGFP colocalized primarily with extranuclear AR (approximately 85% soma) and GPER1 (approximately 70% soma). Aged (12‐ to 24‐month‐old) males had more ERβ‐EGFP neurons in a rostral neuroendocrine subregion compared to aged females and females with accelerated ovarian failure (AOF) and in a caudal autonomic subregion compared to post‐AOF females. Late‐aged (18‐ to 24‐month‐old) females compared to early‐aged (12‐ to 14‐month‐old) females and AOF females had fewer AR‐labeled nuclei in neuroendrocrine and autonomic projecting subregions. These findings indicate that gonadal steroids may directly and indirectly influence PVN neurons via nuclear and extranuclear gonadal hormone receptors in a sex‐specific manner.

in Journal of Comparative Neurology on January 14, 2021 03:56 PM.

• #### Ten simple rules for tackling your first mathematical models: A guide for graduate students by graduate students

by Korryn Bodner, Chris Brimacombe, Emily S. Chenery, Ariel Greiner, Anne M. McLeod, Stephanie R. Penk, Juan S. Vargas Soto

in PLoS Computational Biology on January 14, 2021 02:00 PM.

• #### Probabilistic transmission models incorporating sequencing data for healthcare-associated <i>Clostridioides difficile</i> outperform heuristic rules and identify strain-specific differences in transmission

by David William Eyre, Mirjam Laager, A Sarah Walker, Ben S. Cooper, Daniel J. Wilson, on behalf of the CDC Modeling Infectious Diseases in Healthcare Program (MInD-Healthcare)

Fitting stochastic transmission models to electronic patient data can offer detailed insights into the transmission of healthcare-associated infections and improve infection control. Pathogen whole-genome sequencing may improve the precision of model inferences, but computational constraints have limited modelling applications predominantly to small datasets and specific outbreaks, whereas large-scale sequencing studies have mostly relied on simple rules for identifying/excluding plausible transmission. We present a novel approach for integrating detailed epidemiological data on patient contact networks in hospitals with large-scale pathogen sequencing data. We apply our approach to study Clostridioides difficile transmission using a dataset of 1223 infections in Oxfordshire, UK, 2007–2011. 262 (21% [95% credibility interval 20–22%]) infections were estimated to have been acquired from another known case. There was heterogeneity by sequence type (ST) in the proportion of cases acquired from another case with the highest rates in ST1 (ribotype-027), ST42 (ribotype-106) and ST3 (ribotype-001). These same STs also had higher rates of transmission mediated via environmental contamination/spores persisting after patient discharge/recovery; for ST1 these persisted longer than for most other STs except ST3 and ST42. We also identified variation in transmission between hospitals, medical specialties and over time; by 2011 nearly all transmission from known cases had ceased in our hospitals. Our findings support previous work suggesting only a minority of C. difficile infections are acquired from known cases but highlight a greater role for environmental contamination than previously thought. Our approach is applicable to other healthcare-associated infections. Our findings have important implications for effective control of C. difficile.

in PLoS Computational Biology on January 14, 2021 02:00 PM.

• #### Versatile CRISPR/Cas9-mediated mosaic analysis by gRNA-induced crossing-over for unmodified genomes

by Sarah E. Allen, Gabriel T. Koreman, Ankita Sarkar, Bei Wang, Mariana F. Wolfner, Chun Han

Mosaic animals have provided the platform for many fundamental discoveries in developmental biology, cell biology, and other fields. Techniques to produce mosaic animals by mitotic recombination have been extensively developed in Drosophila melanogaster but are less common for other laboratory organisms. Here, we report mosaic analysis by gRNA-induced crossing-over (MAGIC), a new technique for generating mosaic animals based on DNA double-strand breaks produced by CRISPR/Cas9. MAGIC efficiently produces mosaic clones in both somatic tissues and the germline of Drosophila. Further, by developing a MAGIC toolkit for 1 chromosome arm, we demonstrate the method’s application in characterizing gene function in neural development and in generating fluorescently marked clones in wild-derived Drosophila strains. Eliminating the need to introduce recombinase-recognition sites in the genome, this simple and versatile system simplifies mosaic analysis in Drosophila and can in principle be applied in any organism that is compatible with CRISPR/Cas9.

in PLoS Biology on January 14, 2021 02:00 PM.

• #### Neuronal localization of m1 muscarinic receptor immunoreactivity in the monkey basolateral amygdala

Using antibodies to calcium/calmodulin‐dependent protein kinase II (CaMK) as a marker for pyramidal neurons (PNs) in the monkey basolateral amygdala (BNC) it was shown that virtually all PNs in the BNC express type 1 muscarinic receptors (m1Rs). Additional studies indicated that one‐third of inhibitory interneurons (INs) expressing glutamic acid decarboxylase (GAD), and 60% of parvalbumin immunoreactive INs (PV) were also m1R+. These results indicate that expression of m1Rs in BNC INs is greater in the monkey versus the rat.

## Abstract

The basolateral nuclear complex (BNC) of the amygdala plays an important role in the generation of emotional/motivational behavior and the consolidation of emotional memories. Activation of M1 cholinergic receptors (M1Rs) in the BNC is critical for memory consolidation. Previous receptor binding studies in the monkey amygdala demonstrated that the BNC has a high density of M1Rs, but did not have sufficient resolution to identify which neurons in the BNC expressed them. This was accomplished in the present immunohistochemical investigation using an antibody for the m1 receptor (m1R). Analysis of m1Rs in the monkey BNC using immunoperoxidase techniques revealed that their expression was very dense in the BNC, and suggested that virtually all of the pyramidal projection neurons (PNs) in all of the BNC nuclei were m1R‐immunoreactive (m1R+). This was confirmed with dual‐labeling immunofluorescence using staining for calcium/calmodulin‐dependent protein kinase II (CaMK) as a marker for BNC PNs. However, additional dual‐labeling studies indicated that one‐third of inhibitory interneurons (INs) expressing glutamic acid decarboxylase (GAD) were also m1R+. Moreover, the finding that 60% of parvalbumin (PV) immunoreactive neurons were m1R+ indicated that this IN subpopulation was the main GAD+ subpopulation exhibiting m1R expression. The cholinergic innervation of the amygdala is greatly reduced in Alzheimer's disease and there is currently considerable interest in developing selective M1R positive allosteric modulators (PAMs) to treat the symptoms. The results of the present study indicate that M1Rs in both PNs and INs in the primate BNC would be targeted by M1R PAMs.

in Journal of Comparative Neurology on January 14, 2021 12:23 PM.

• #### Evaluating diffusion resistance of a constriction in a membrane channel by the method of boundary homogenization

Author(s): Alexei T. Skvortsov, Leonardo Dagdug, Alexander M. Berezhkovskii, Ian R. MacGillivray, and Sergey M. Bezrukov

In this paper we analyze diffusive transport of noninteracting electrically uncharged solute molecules through a cylindrical membrane channel with a constriction located in the middle of the channel. The constriction is modeled by an infinitely thin partition with a circular hole in its center. The ...

[Phys. Rev. E 103, 012408] Published Thu Jan 14, 2021

in Physical Review E: Biological physics on January 14, 2021 10:00 AM.

• #### Firing statistics in the bistable regime of neurons with homoclinic spike generation

Author(s): Jan-Hendrik Schleimer, Janina Hesse, Susana Andrea Contreras, and Susanne Schreiber

Neuronal voltage dynamics of regularly firing neurons typically has one stable attractor: either a fixed point (like in the subthreshold regime) or a limit cycle that defines the tonic firing of action potentials (in the suprathreshold regime). In two of the three spike onset bifurcation sequences t...

[Phys. Rev. E 103, 012407] Published Thu Jan 14, 2021

in Physical Review E: Biological physics on January 14, 2021 10:00 AM.

• #### The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders in offspring, but the pathomechanism is largely unknown. The aim of our study was to analyse the molecular mechanisms contributing to synaptic alterations in hippocampi of adolescent rats exposed prenatally to MIA. MIA was evoked in pregnant female rats by i.p. administration of lipopolysaccharide at gestation day 9.5. Hippocampi of offspring (52–53-days-old rats) were analysed using transmission electron microscopy (TEM), qPCR and Western blotting. Moreover, mitochondrial membrane potential, activity of respiratory complexes, and changes in glutathione system were measured. It was found that MIA induced changes in hippocampi morphology, especially in the ultrastructure of synapses, including synaptic mitochondria, which were accompanied by impairment of mitochondrial electron transport chain and decreased mitochondrial membrane potential. These phenomena were in agreement with increased generation of reactive oxygen species, which was evidenced by a decreased reduced/oxidised glutathione ratio and an increased level of dichlorofluorescein (DCF) oxidation. Activation of cyclin-dependent kinase 5, and phosphorylation of glycogen synthase kinase 3β on Ser9 occurred, leading to its inhibition and, accordingly, to hypophosphorylation of microtubule associated protein tau (MAPT). Abnormal phosphorylation and dysfunction of MAPT, the manager of the neuronal cytoskeleton, harmonised with changes in synaptic proteins. In conclusion, this is the first study demonstrating widespread synaptic changes in hippocampi of adolescent offspring prenatally exposed to MIA.

in Frontiers in Molecular Neuroscience on January 14, 2021 12:00 AM.

• #### Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration

Over the past decades, the human life span has dramatically increased, and therefore, a steady increase in diseases associated with age (such as Alzheimer’s disease and Parkinson’s disease) is expected. In these neurodegenerative diseases, there is a cognitive decline and memory loss, which accompany increased systemic inflammation, the inflamm-aging, and the insulin resistance. Despite numerous studies of age-related pathologies, data on the contribution of brain insulin resistance and innate immunity components to aging are insufficient. Recently, much research has been focused on the consequences of nutrients and adiposity- and nutrient-related signals in brain aging and cognitive decline. Moreover, given the role of metainflammation in neurodegeneration, lifestyle interventions such as calorie restriction may be an effective way to break the vicious cycle of metainflammation and have a role in social behavior. The various effects of calorie restriction on metainflammation, insulin resistance, and neurodegeneration have been described. Less attention has been paid to the social determinants of aging and the possible mechanism by which calorie restriction might influence social behavior. The purpose of this review is to discuss current knowledge in the interdisciplinary field of geroscience—immunosenescence, inflamm-aging, and metainflammation—which makes a significant contribution to aging. A substantial part of the review is devoted to frontiers in the brain insulin resistance in relation to neuroinflammation. In addition, we summarize new data on potential mechanisms of calorie restriction that influence as a lifestyle intervention on the social brain. This knowledge can be used to initiate successful aging and slow the onset of neurodegenerative diseases.

in Frontiers in Neuroscience: Neurodegeneration on January 14, 2021 12:00 AM.

• #### Multi-Hops Functional Connectivity Improves Individual Prediction of Fusiform Face Activation via a Graph Neural Network

Brain connectivity plays an important role in determining the brain region’s function. Previous researchers proposed that the brain region’s function is characterized by that region’s input and output connectivity profiles. Following this proposal, numerous studies have investigated the relationship between connectivity and function. However, this proposal only utilizes direct connectivity profiles and thus is deficient in explaining individual differences in the brain region’s function. To overcome this problem, we proposed that a brain region’s function is characterized by that region’s multi-hops connectivity profile. To test this proposal, we used multi-hops functional connectivity to predict the individual face activation of the right fusiform face area (rFFA) via a multi-layer graph neural network and showed that the prediction performance is essentially improved. Results also indicated that the two-layer graph neural network is the best in characterizing rFFA’s face activation and revealed a hierarchical network for the face processing of rFFA.

in Frontiers in Neuroscience: Brain Imaging Methods on January 14, 2021 12:00 AM.

• #### MicroRNA-138 Overexpression Alters Aβ42 Levels and Behavior in Wildtype Mice

in Frontiers in Neuroscience: Neurodegeneration on January 14, 2021 12:00 AM.

• #### Can We Push the “Quasi-Perfect Artifact Rejection” Even Closer to Perfection?

in Frontiers in Neuroinformatics on January 14, 2021 12:00 AM.

• #### Editorial: Visual Timing Impairments in Developmental, Acquired, and Age-Related Neurological Conditions

in Frontiers in Human Neuroscience on January 14, 2021 12:00 AM.

• #### Windows of Integration Hypothesis Revisited

In the ongoing research of the functions of consciousness, special emphasis has been put on integration of information: the ability to combine different signals into a coherent, unified one. Several theories of consciousness hold that this ability depends on – or at least goes hand in hand with – conscious processing. Yet some empirical findings have suggested otherwise, claiming that integration of information could take place even without awareness. Trying to reconcile this apparent contradiction, the “windows of integration” (WOI) hypothesis claims that conscious access enables signal processing over large integration windows. The hypothesis applies to integration windows defined either temporally, spatially, or semantically. In this review, we explain the hypothesis and re-examine it in light of new studies published since it was suggested. In line with the hypothesis, these studies provide compelling evidence for unconscious integration, but also demonstrate its limits with respect to time, space, and semantic distance. The review further highlights open questions that still need to be pursued to demonstrate the applicability of the WOI hypothesis as a guiding principle for understanding the depth and scope of unconscious processes.

in Frontiers in Human Neuroscience on January 14, 2021 12:00 AM.

• #### More Than Words: Extra-Sylvian Neuroanatomic Networks Support Indirect Speech Act Comprehension and Discourse in Behavioral Variant Frontotemporal Dementia

Indirect speech acts—responding “I forgot to wear my watch today” to someone who asked for the time—are ubiquitous in daily conversation, but are understudied in current neurobiological models of language. To comprehend an indirect speech act like this one, listeners must not only decode the lexical-semantic content of the utterance, but also make a pragmatic, bridging inference. This inference allows listeners to derive the speaker’s true, intended meaning—in the above dialog, for example, that the speaker cannot provide the time. In the present work, we address this major gap by asking non-aphasic patients with behavioral variant frontotemporal dementia (bvFTD, n = 21) and brain-damaged controls with amnestic mild cognitive impairment (MCI, n = 17) to judge simple question-answer dialogs of the form: “Do you want some cake for dessert?” “I’m on a very strict diet right now,” and relate the results to structural and diffusion MRI. Accuracy and reaction time results demonstrate that subjects with bvFTD, but not MCI, are selectively impaired in indirect relative to direct speech act comprehension, due in part to their social and executive limitations, and performance is related to caregivers’ judgment of communication efficacy. MRI imaging associates the observed impairment in bvFTD to cortical thinning not only in traditional language-associated regions, but also in fronto-parietal regions implicated in social and executive cerebral networks. Finally, diffusion tensor imaging analyses implicate white matter tracts in both dorsal and ventral projection streams, including superior longitudinal fasciculus, frontal aslant, and uncinate fasciculus. These results have strong implications for updated neurobiological models of language, and emphasize a core, language-mediated social disorder in patients with bvFTD.

in Frontiers in Human Neuroscience on January 14, 2021 12:00 AM.

• #### Causal Inferences in Repetitive Transcranial Magnetic Stimulation Research: Challenges and Perspectives

in Frontiers in Human Neuroscience on January 14, 2021 12:00 AM.

• #### Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders

Autism spectrum disorder (ASD) is comprised of several conditions characterized by alterations in social interaction, communication, and repetitive behaviors. Genetic and environmental factors contribute to the heterogeneous development of ASD behaviors. Several rodent models display ASD-like phenotypes, including repetitive behaviors. In this review article, we discuss the potential neural mechanisms involved in repetitive behaviors in rodent models of ASD and related neuropsychiatric disorders. We review signaling pathways, neural circuits, and anatomical alterations in rodent models that display robust stereotypic behaviors. Understanding the mechanisms and circuit alterations underlying repetitive behaviors in rodent models of ASD will inform translational research and provide useful insight into therapeutic strategies for the treatment of repetitive behaviors in ASD and other neuropsychiatric disorders.

in Frontiers in Cellular Neuroscience on January 14, 2021 12:00 AM.

• #### Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse

The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor that binds over 40 potential ligands and is involved in processes such as cell differentiation, proliferation, and survival. LRP1 is ubiquitously expressed in the organism and enriched among others in blood vessels, liver, and the central nervous system (CNS). There, it is strongly expressed by neurons, microglia, immature oligodendrocytes, and astrocytes. The constitutive LRP1 knockout leads to embryonic lethality. Therefore, previous studies focused on conditional LRP1-knockout strategies and revealed that the deletion of LRP1 causes an increased differentiation of neural stem and precursor cells into astrocytes. Furthermore, astrocytic LRP1 is necessary for the degradation of Aβ and the reduced accumulation of amyloid plaques in Alzheimer’s disease. Although the role of LRP1 in neurons has intensely been investigated, the function of LRP1 with regard to the differentiation and maturation of astrocytes and their functionality is still unknown. To address this question, we generated an inducible conditional transgenic mouse model, where LRP1 is specifically deleted from GLAST-positive astrocyte precursor cells. The recombination with resulting knockout events was visualized by the simultaneous expression of the fluorescent reporter tdTomato. We observed a significantly increased number of GLT-1 expressing astrocytes in LRP1-depleted astrocytic cultures in comparison to control astrocytes. Furthermore, we investigated the influence of astrocytic LRP1 on neuronal activity and synaptogenesis using the co-culture of hippocampal neurons with control or LRP1-depleted astrocytes. These analyses revealed that the LRP1-deficient astrocytes caused a decreased number of single action potentials as well as a negatively influenced neuronal network activity. Moreover, the proportion of pre- and postsynaptic structures was significantly altered in neurons co-cultured with LPR1-depleted astrocytes. However, the number of structural synapses was not affected. Additionally, the supernatant of hippocampal neurons co-cultured with LRP1-deficient astrocytes showed an altered set of cytokines in comparison to the control condition, which potentially contributed to the altered neuronal transmission and synaptogenesis. Our results suggest astrocytic LRP1 as a modulator of synaptic transmission and synaptogenesis by altering the expression of the glutamate transporter on the cell surface on astrocytes and the release of cytokines in vitro.

in Frontiers in Cellular Neuroscience on January 14, 2021 12:00 AM.

• #### NeuroExercise: The Effect of a 12-Month Exercise Intervention on Cognition in Mild Cognitive Impairment—A Multicenter Randomized Controlled Trial

Exercise intervention studies in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), have demonstrated inconsistent yet promising results. Addressing the limitations of previous studies, this trial investigated the effects of a 12-month structured exercise program on the progression of MCI. The NeuroExercise study is a multicenter randomized controlled trial across three European countries (Ireland, Netherlands, Germany). Hundred and eighty-three individuals with amnestic MCI were included and were randomized to a 12-month exercise intervention (3 units of 45 min) of either aerobic exercise (AE; n = 60), stretching and toning exercise (ST; n = 65) or to a non-exercise control group (CG; n = 58). The primary outcome, cognitive performance, was determined by an extensive neuropsychological test battery. For the primary complete case (CC) analyses, between-group differences were analyzed with analysis of covariance under two conditions: (1) the exercise group (EG = combined AE and ST groups) compared to the CG and (2) AE compared to ST. Primary analysis of the full cohort (n = 166, 71.5 years; 51.8% females) revealed no between-group differences in composite cognitive score [mean difference (95% CI)], 0.12 [(−0.03, 0.27), p = 0.13] or in any cognitive domain or quality of life. VO2 peak was significantly higher in the EG compared to the CG after 12 months [−1.76 (−3.39, −0.10), p = 0.04]. Comparing the two intervention groups revealed a higher VO2peak level in the aerobic exercise compared to the stretching and toning group, but no differences for the other outcomes. A 12-month exercise intervention did not change cognitive performance in individuals with amnestic MCI in comparison to a non-exercise CG. An intervention effect on physical fitness was found, which may be an important moderator for long term disease progression and warrants long-term follow-up investigations.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT02913053, identifier: NCT02913053.

in Frontiers in Ageing Neuroscience on January 14, 2021 12:00 AM.

• #### Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice

Isoflurane, a widely used volatile anesthetic, induces neuronal apoptosis and memory impairments in various animal models. However, the potential mechanisms and effective pharmacologic agents are still not fully understood. The p38MAPK/ATF-2 pathway has been proved to regulate neuronal cell survival and inflammation. Besides, atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts neuroprotective effects. Thus, this study aimed to explore the influence of atorvastatin on isoflurane-induced neurodegeneration and underlying mechanisms. Aged C57BL/6 mice (20 months old) were exposed to isoflurane (1.5%) anesthesia for 6 h. Atorvastatin (5, 10, or 20 mg/kg body weight) was administered to the mice for 7 days. Atorvastatin attenuated the isoflurane-induced generation of ROS and apoptosis. Western blotting revealed a decrease in cleaved caspase-9 and caspase-3 expression in line with ROS levels. Furthermore, atorvastatin ameliorated the isoflurane-induced activation of p38MAPK/ATF-2 signaling. In a cellular study, we proved that isoflurane could induce oxidative stress and inflammation by activating the p38MAPK/ATF-2 pathway in BV-2 microglia cells. In addition, SB203580, a selected p38MAPK inhibitor, inhibited the isoflurane-induced inflammation, oxidative stress, and apoptosis. The results implied that p38MAPK/ATF-2 was a potential target for the treatment of postoperative cognitive dysfunction.

in Frontiers in Ageing Neuroscience on January 14, 2021 12:00 AM.

• #### Estimating Brain Functional Networks Based on Adaptively-Weighted fMRI Signals for MCI Identification

in Frontiers in Ageing Neuroscience on January 14, 2021 12:00 AM.

• #### FTY720 Prevents Spatial Memory Impairment in a Rat Model of Chronic Cerebral Hypoperfusion via a SIRT3-Independent Pathway

Vascular dementia (VD) and Alzheimer's disease (AD) are the most prevalent types of late-life dementia. Chronic cerebral hypoperfusion (CCH) contributes to both AD and VD. Recently, accumulating evidence has indicated that fingolimod (FTY720) is neuroprotective in acute cerebral ischemic stroke animal models, and the drug is now being used in clinical translation studies. However, fewer studies have addressed the role of FTY720 in chronic cerebral hypoperfusion (CCH)-related brain damage. In the present study, to investigate whether FTY720 can improve CCH-induced spatial memory loss and its underlying mechanism, two-vessel occlusion (2VO) rats were administered intraperitoneal FTY720 (1 mg/kg) for 7 consecutive weeks from post-operative day 8. Spatial memory was tested using the Morris Water Maze (MWM), and the rats' brains were harvested to allow molecular, biochemical, and pathological tests. We found that FTY720 treatment significantly reduced the escape latency and increased the target quadrant swimming time of the 2VO rats in the MWM task. The improvement in memory performance paralleled lower levels of pro-inflammatory cytokines and Iba-1 positive cells in the hippocampus of the 2VO rats, indicating that FTY720 had a beneficial effect in mitigating neuroinflammation. Furthermore, we found that FTY720 alleviated mitochondrial dysfunction in 2VO rats, as manifested by lower malondialdehyde levels, higher ATP content, and upregulation of ATP synthase activity in the hippocampus after treatment. FTY720 had no effect on the CCH-induced decrease in the activity of hippocampal Sirtuin-3, a master regulator of mitochondrial function and neuroinflammation. In summary, the results showed that FTY720 can improve CCH-induced spatial memory loss. The mechanism may involve Sirtuin-3-independent regulation of mitochondrial dysfunction and neuroinflammation in the hippocampus. The present study provides new clues to the pathological mechanism of CCH-induced cognitive impairment.

in Frontiers in Ageing Neuroscience on January 14, 2021 12:00 AM.

• #### Repetitive Transcranial Magnetic Stimulation for Improving Cognitive Function in Patients With Mild Cognitive Impairment: A Systematic Review

Background: Mild cognitive impairment (MCI) is an early stage of Alzheimer's disease. Repetitive transcranial magnetic stimulation (rTMS) has been widely employed in MCI research. However, there is no reliable systematic evidence regarding the effects of rTMS on MCI. The aim of this review was to evaluate the efficacy and safety of rTMS in the treatment of MCI.

Methods: A comprehensive literature search of nine electronic databases was performed to identify articles published in English or Chinese before June 20, 2019. The identified articles were screened, data were extracted, and the methodological quality of the included trials was assessed. The meta-analysis was performed using the RevMan 5.3 software. We used the GRADE approach to rate the quality of the evidence.

Results: Nine studies comprising 369 patients were included. The meta-analysis showed that rTMS may significantly improve global cognitive function (standardized mean difference [SMD] 2.09, 95% confidence interval [CI] 0.94 to 3.24, p = 0.0004, seven studies, n = 296; low-quality evidence) and memory (SMD 0.44, 95% CI 0.16 to 0.72, p = 0.002, six studies, n = 204; moderate-quality evidence). However, there was no significant improvement in executive function and attention (p > 0.05). Subgroup analyses revealed the following: (1) rTMS targeting the left hemisphere significantly enhanced global cognitive function, while rTMS targeting the bilateral hemispheres significantly enhanced global cognitive function and memory; (2) high-frequency rTMS significantly enhanced global cognitive function and memory; and (3) a high number of treatments ≥20 times could improve global cognitive function and memory. There was no significant difference in dropout rate (p > 0.05) between the rTMS and control groups. However, patients who received rTMS had a higher rate of mild adverse effects (risk ratio 2.03, 95% CI 1.16 to 3.52, p = 0.01, seven studies, n = 317; moderate-quality evidence).

Conclusions: rTMS appears to improve global cognitive function and memory in patients with MCI and may have good acceptability and mild adverse effects. Nevertheless, these results should be interpreted cautiously due to the relatively small number of trials, particularly for low-frequency rTMS.

in Frontiers in Ageing Neuroscience on January 14, 2021 12:00 AM.

## Abstract

We investigated synaptic mechanisms in the hippocampus that could explain how loss of circadian timing leads to impairments in spatial and recognition memory. Experiments were performed in hippocampal slices from Siberian hamsters (Phodopus sungorus) because, unlike mice and rats, their circadian rhythms are easily eliminated without modifications to their genome and without surgical manipulations, thereby leaving neuronal circuits intact. Recordings of excitatory postsynaptic field potentials and population spikes in area CA1 and dentate gyrus granule cells revealed no effect of circadian arrhythmia on basic functions of synaptic circuitry, including long‐term potentiation. However, dentate granule cells from circadian‐arrhythmic animals maintained a more depolarized resting membrane potential than cells from circadian‐intact animals; a significantly greater proportion of these cells depolarized in response to the cholinergic agonist carbachol (10 μM), and did so by increasing their membrane potential three‐fold greater than cells from the control (entrained) group. Dentate granule cells from arrhythmic animals also exhibited higher levels of tonic inhibition, as measured by the frequency of spontaneous inhibitory postsynaptic potentials. Carbachol also decreased stimulus‐evoked synaptic excitation in dentate granule cells from both intact and arrhythmic animals as expected, but reduced stimulus‐evoked synaptic inhibition only in cells from control hamsters. These findings show that loss of circadian timing is accompanied by greater tonic inhibition, and increased synaptic inhibition in response to muscarinic receptor activation in dentate granule cells. Increased inhibition would likely attenuate excitation in dentate‐CA3 microcircuits, which in turn might explain the spatial memory deficits previously observed in circadian‐arrhythmic hamsters.

in Hippocampus on January 13, 2021 03:42 PM.

• #### Putting the axonal periodic scaffold in order

Publication date: August 2021

Source: Current Opinion in Neurobiology, Volume 69

Author(s): Christophe Leterrier

in Current Opinion in Neurobiology on January 13, 2021 02:00 PM.

• #### Identification of 3′ UTR motifs required for mRNA localization to myelin sheaths in vivo

by Katie M. Yergert, Caleb A. Doll, Rebecca O’Rouke, Jacob H. Hines, Bruce Appel

Myelin is a specialized membrane produced by oligodendrocytes that insulates and supports axons. Oligodendrocytes extend numerous cellular processes, as projections of the plasma membrane, and simultaneously wrap multiple layers of myelin membrane around target axons. Notably, myelin sheaths originating from the same oligodendrocyte are variable in size, suggesting local mechanisms regulate myelin sheath growth. Purified myelin contains ribosomes and hundreds of mRNAs, supporting a model that mRNA localization and local protein synthesis regulate sheath growth and maturation. However, the mechanisms by which mRNAs are selectively enriched in myelin sheaths are unclear. To investigate how mRNAs are targeted to myelin sheaths, we tested the hypothesis that transcripts are selected for myelin enrichment through consensus sequences in the 3′ untranslated region (3′ UTR). Using methods to visualize mRNA in living zebrafish larvae, we identified candidate 3′ UTRs that were sufficient to localize mRNA to sheaths and enriched near growth zones of nascent membrane. We bioinformatically identified motifs common in 3′ UTRs from 3 myelin-enriched transcripts and determined that these motifs are required and sufficient in a context-dependent manner for mRNA transport to myelin sheaths. Finally, we show that 1 motif is highly enriched in the myelin transcriptome, suggesting that this sequence is a global regulator of mRNA localization during developmental myelination.

in PLoS Biology on January 13, 2021 02:00 PM.

• #### Axon guidance at the spinal cord midline – a live imaging perspective

We describe a novel method to culture the intact spinal cord of the chicken embryo for live imaging of axon guidance at the midline. The stability of this ex vivo method allowed us to characterize key aspects of midline crossing such as, axonal growth, timing of crossing, dynamic morphological changes of the growth cones and growth cone‐floor plate cell interactions. .

## Abstract

During neural circuit formation, axons navigate several choice points to reach their final target. At each one of these intermediate targets, growth cones need to switch responsiveness from attraction to repulsion in order to move on. Molecular mechanisms that allow for the precise timing of surface expression of a new set of receptors that support the switch in responsiveness are difficult to study in vivo. Mostly, mechanisms are inferred from the observation of snapshots of many different growth cones analyzed in different preparations of tissue harvested at distinct time points. However, to really understand the behavior of growth cones at choice points, a single growth cone should be followed arriving at and leaving the intermediate target.

Existing ex vivo preparations, like cultures of an ‘open‐book’ preparation of the spinal cord have been successfully used to study floor‐plate entry and exit, but artefacts prevent the analysis of growth cone behavior at the floor‐plate exit site. Here, we describe a novel spinal cord preparation that allows for live imaging of individual axons during navigation in their intact environment. When comparing growth cone behavior in our ex vivo system with snapshots from in vivo navigation, we do not see any differences. The possibility to observe the dynamics of single growth cones navigating their intermediate target allows for measuring growth speed, changes in morphology, or aberrant behavior, like stalling and wrong turning. Moreover, observation of the intermediate target – the floor plate – revealed its active participation and interaction with commissural axons during midline crossing.

in Journal of Comparative Neurology on January 13, 2021 10:18 AM.

• #### A novel telencephalon‐opto‐hypothalamic morphogenetic domain coexpressing Foxg1 and Otp produces most of the glutamatergic neurons of the medial extended amygdala

This study shows that most glutamatergic neurons of the mouse medial extended amygdala originate in a novel telencephalon‐opto‐hypothalamic embryonic domain (TOH), which produces Otp‐lineage neurons expressing the telencephalic marker Foxg1 during development. These glutamatergic cells include a subpopulation of projection neurons, which activation has been previously shown to promote autistic‐like behavior. Our data open new venues for studying the implication of these neurons in neurodevelopmental disorders producing social deficits.

## Abstract

Deficits in social cognition and behavior are a hallmark of many psychiatric disorders. The medial extended amygdala, including the medial amygdala and the medial bed nucleus of the stria terminalis, is a key component of functional networks involved in sociality. However, this nuclear complex is highly heterogeneous and contains numerous GABAergic and glutamatergic neuron subpopulations. Deciphering the connections of different neurons is essential in order to understand how this structure regulates different aspects of sociality, and it is necessary to evaluate their differential implication in distinct mental disorders. Developmental studies in different vertebrates are offering new venues to understand neuronal diversity of the medial extended amygdala and are helping to establish a relation between the embryonic origin and molecular signature of distinct neurons with the functional subcircuits in which they are engaged. These studies have provided many details on the distinct GABAergic neurons of the medial extended amygdala, but information on the glutamatergic neurons is still scarce. Using an Otp‐eGFP transgenic mouse and multiple fluorescent labeling, we show that most glutamatergic neurons of the medial extended amygdala originate in a distinct telencephalon‐opto‐hypothalamic embryonic domain (TOH), located at the transition between telencephalon and hypothalamus, which produces Otp‐lineage neurons expressing the telencephalic marker Foxg1 but not Nkx2.1 during development. These glutamatergic cells include a subpopulation of projection neurons of the medial amygdala, which activation has been previously shown to promote autistic‐like behavior. Our data open new venues for studying the implication of this neuron subtype in neurodevelopmental disorders producing social deficits.

in Journal of Comparative Neurology on January 13, 2021 10:01 AM.

• #### Publisher Correction: DeepCell Kiosk: scaling deep learning–enabled cellular image analysis with Kubernetes

Nature Methods, Published online: 13 January 2021; doi:10.1038/s41592-021-01059-w

Publisher Correction: DeepCell Kiosk: scaling deep learning–enabled cellular image analysis with Kubernetes

in Nature Methods on January 13, 2021 12:00 AM.

• #### Corrigendum: T Cell Responses to Neural Autoantigens Are Similar in Alzheimer's Disease Patients and Age-Matched Healthy Controls

in Frontiers in Neuroscience: Neurodegeneration on January 13, 2021 12:00 AM.

• #### Implications of Glycosylation in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions of people worldwide, and no cure is currently available. The major pathological hallmarks of AD are considered to be amyloid beta plaques and neurofibrillary tangles, generated by respectively APP processing and Tau phosphorylation. Recent evidence imply that glycosylation of these proteins, and a number of other AD-related molecules is altered in AD, suggesting a potential implication of this process in disease pathology. In this review we summarize the understanding of glycans in AD pathogenesis, and discuss how glycobiology can contribute to early diagnosis and treatment of AD, serving as potential biomarkers and therapeutic targets. Furthermore, we look into the potential link between the emerging topic neuroinflammation and glycosylation, combining two interesting, and until recent years, understudied topics in the scope of AD. Lastly, we discuss how new model platforms such as induced pluripotent stem cells can be exploited and contribute to a better understanding of a rather unexplored area in AD.

in Frontiers in Neuroscience: Neurodegeneration on January 13, 2021 12:00 AM.

• #### LatLRR-FCNs: Latent Low-Rank Representation With Fully Convolutional Networks for Medical Image Fusion

Medical image fusion, which aims to derive complementary information from multi-modality medical images, plays an important role in many clinical applications, such as medical diagnostics and treatment. We propose the LatLRR-FCNs, which is a hybrid medical image fusion framework consisting of the latent low-rank representation (LatLRR) and the fully convolutional networks (FCNs). Specifically, the LatLRR module is used to decompose the multi-modality medical images into low-rank and saliency components, which can provide fine-grained details and preserve energies, respectively. The FCN module aims to preserve both global and local information by generating the weighting maps for each modality image. The final weighting map is obtained using the weighted local energy and the weighted sum of the eight-neighborhood-based modified Laplacian method. The fused low-rank component is generated by combining the low-rank components of each modality image according to the guidance provided by the final weighting map within pyramid-based fusion. A simple sum strategy is used for the saliency components. The usefulness and efficiency of the proposed framework are thoroughly evaluated on four medical image fusion tasks, including computed tomography (CT) and magnetic resonance (MR), T1- and T2-weighted MR, positron emission tomography and MR, and single-photon emission CT and MR. The results demonstrate that by leveraging the LatLRR for image detail extraction and the FCNs for global and local information description, we can achieve performance superior to the state-of-the-art methods in terms of both objective assessment and visual quality in some cases. Furthermore, our method has a competitive performance in terms of computational costs compared to other baselines.

in Frontiers in Neuroscience: Brain Imaging Methods on January 13, 2021 12:00 AM.

• #### Hemisphere-Specific Functional Remodeling and Its Relevance to Tumor Malignancy of Cerebral Glioma Based on Resting-State Functional Network Analysis

Background: Functional remodeling may vary with tumor aggressiveness of glioma. Investigation of the functional remodeling is expected to provide scientific relevance of tumor characterization and disease management of glioma. In this study, we aimed to investigate the functional remodeling of the contralesional hemisphere and its utility in predicting the malignant grade of glioma at the individual level with multivariate logistic regression (MLR) analysis. Subjects and Methods: One hundred and twenty-six right-handed subjects with histologically confirmed cerebral glioma were included with 80 tumors located in the left hemisphere (LH) and 46 tumors located in the right hemisphere (RH). Resting-state functional networks of the contralesional hemisphere were constructed using the human brainnetome atlas based on resting-state fMRI data. Functional connectivity and topological features of functional networks were quantified. The performance of functional features in predicting the glioma grade was evaluated using area under (AUC) the receiver operating characteristic curve (ROC). The dataset was divided into training and validation datasets. Features with high AUC values in malignancy classification in the training dataset were determined as predictive features. An MLR model was constructed based on predictive features and its classification performance was evaluated on the training and validation datasets with 10-fold cross validation. Results: Predictive functional features showed apparent hemispheric specifications. MLR classification models constructed with age and predictive functional connectivity features (AUC of 0.853 ± 0.079 and 1.000 ± 0.000 for LH and RH group, respectively) and topological features (AUC of 0.788 ± 0.150 and 0.897 ± 0.165 for LH and RH group, respectively) achieved efficient performance in predicting the malignant grade of gliomas. Conclusion: Functional remodeling of the contralesional hemisphere was hemisphere-specific and highly predictive of the malignant grade of glioma. Network approach provides a novel pathway that may innovate glioma characterization and management at the individual level.

in Frontiers in Neuroscience: Brain Imaging Methods on January 13, 2021 12:00 AM.

• #### Alternation of Resting-State Functional Connectivity Between Visual Cortex and Hypothalamus in Guinea Pigs With Experimental Glucocorticoid Enhanced Myopia After the Treatment of Electroacupuncture

Excessive glucocorticoids (GC) may lead to the aggravation of several basic diseases including myopia, due to plasma hormone imbalances associated with the hypothalamic–pituitary–adrenal axis (HPAA). Electroacupuncture (EA) is an effective therapeutic method to treat many diseases, although it remains unclear whether EA at acupoints on the foot or back would be effective in treating eye diseases. It was recently found that visual cortex activity for responses to visual stimuli with spatial frequency and resting-state functional connectivity (FC) between the supramarginal gyrus and rostrolateral prefrontal cortex was significantly reduced in patients with high myopia. The present study aims to investigate the role of the alternation of resting-state FC among the bilateral visual cortex and hypothalamus in exerting anti-myopia effects of EA in GC-enhanced lens-induced myopic (LIM) guinea pigs such that the mechanisms of EA to treat GC-enhanced myopia at Shenshu (BL23) acupoints can be probed. To confirm the effects of EA, ocular parameters including axial length and GC-associated physiological parameters such as animal appearance, behavior, bodyweight, and levels of four HPAA-associated plasma hormones [free triiodothyronine (FT3), free thyroxine (FT4), estradiol (E2), and testosterone (T)] were also collected. Increased resting-state FC between the left and right visual cortex was detected in GC-enhanced lens-induced myopic guinea pigs with EA at BL23 acupoints (LIM+GC+EA) guinea pigs compared to GC-enhanced lens-induced myopic guinea pigs with EA at sham acupoints (LIM+GC+Sham) guinea pigs, as well as suppressed myopia and recovery of symptoms initially caused by overdose of GC. Recovered symptoms included improved animal appearance, behavior, bodyweight, and HPAA-associated plasma hormone levels were observed after 4 weeks of EA treatment. In contrast, the LIM+GC+Sham group showed decreased FC with elongation of axial length for myopization as compared to the control group and LIM group and exhibited a deterioration in physiological parameters including reduced body weight and balance disruption in the four measured HPAA-associated plasma hormones. Our findings suggest that EA could effectively treat GC-enhanced myopia by increasing resting-state FC between the left and right visual cortices, which may be pivotal to further understanding the application and mechanisms of EA in treating GC-enhanced myopia.

in Frontiers in Neuroinformatics on January 13, 2021 12:00 AM.

• #### webTDat: A Web-Based, Real-Time, 3D Visualization Framework for Mesoscopic Whole-Brain Images

The popularity of mesoscopic whole-brain imaging techniques has increased dramatically, but these techniques generate teravoxel-sized volumetric image data. Visualizing or interacting with these massive data is both necessary and essential in the bioimage analysis pipeline; however, due to their size, researchers have difficulty using typical computers to process them. The existing solutions do not consider applying web visualization and three-dimensional (3D) volume rendering methods simultaneously to reduce the number of data copy operations and provide a better way to visualize 3D structures in bioimage data. Here, we propose webTDat, an open-source, web-based, real-time 3D visualization framework for mesoscopic-scale whole-brain imaging datasets. webTDat uses an advanced rendering visualization method designed with an innovative data storage format and parallel rendering algorithms. webTDat loads the primary information in the image first and then decides whether it needs to load the secondary information in the image. By performing validation on TB-scale whole-brain datasets, webTDat achieves real-time performance during web visualization. The webTDat framework also provides a rich interface for annotation, making it a useful tool for visualizing mesoscopic whole-brain imaging data.

in Frontiers in Neuroinformatics on January 13, 2021 12:00 AM.

• #### Novel Non-invasive Strategy for Spinal Neuromodulation to Control Human Locomotion

in Frontiers in Human Neuroscience on January 13, 2021 12:00 AM.

• #### Interpersonal Agreement and Disagreement During Face-to-Face Dialogue: An fNIRS Investigation

Although the neural systems that underlie spoken language are well-known, how they adapt to evolving social cues during natural conversations remains an unanswered question. In this work we investigate the neural correlates of face-to-face conversations between two individuals using functional near infrared spectroscopy (fNIRS) and acoustical analyses of concurrent audio recordings. Nineteen pairs of healthy adults engaged in live discussions on two controversial topics where their opinions were either in agreement or disagreement. Participants were matched according to their a priori opinions on these topics as assessed by questionnaire. Acoustic measures of the recorded speech including the fundamental frequency range, median fundamental frequency, syllable rate, and acoustic energy were elevated during disagreement relative to agreement. Consistent with both the a priori opinion ratings and the acoustic findings, neural activity associated with long-range functional networks, rather than the canonical language areas, was also differentiated by the two conditions. Specifically, the frontoparietal system including bilateral dorsolateral prefrontal cortex, left supramarginal gyrus, angular gyrus, and superior temporal gyrus showed increased activity while talking during disagreement. In contrast, talking during agreement was characterized by increased activity in a social and attention network including right supramarginal gyrus, bilateral frontal eye-fields, and left frontopolar regions. Further, these social and visual attention networks were more synchronous across brains during agreement than disagreement. Rather than localized modulation of the canonical language system, these findings are most consistent with a model of distributed and adaptive language-related processes including cross-brain neural coupling that serves dynamic verbal exchanges.

in Frontiers in Human Neuroscience on January 13, 2021 12:00 AM.

• #### Recognition of Consumer Preference by Analysis and Classification EEG Signals

Neuromarketing has gained attention to bridge the gap between conventional marketing studies and electroencephalography (EEG)-based brain-computer interface (BCI) research. It determines what customers actually want through preference prediction. The performance of EEG-based preference detection systems depends on a suitable selection of feature extraction techniques and machine learning algorithms. In this study, We examined preference detection of neuromarketing dataset using different feature combinations of EEG indices and different algorithms for feature extraction and classification. For EEG feature extraction, we employed discrete wavelet transform (DWT) and power spectral density (PSD), which were utilized to measure the EEG-based preference indices that enhance the accuracy of preference detection. Moreover, we compared deep learning with other traditional classifiers, such as k-nearest neighbor (KNN), support vector machine (SVM), and random forest (RF). We also studied the effect of preference indicators on the performance of classification algorithms. Through rigorous offline analysis, we investigated the computational intelligence for preference detection and classification. The performance of the proposed deep neural network (DNN) outperforms KNN and SVM in accuracy, precision, and recall; however, RF achieved results similar to those of the DNN for the same dataset.

in Frontiers in Human Neuroscience on January 13, 2021 12:00 AM.

• #### International Legal Approaches to Neurosurgery for Psychiatric Disorders

Neurosurgery for psychiatric disorders (NPD), also sometimes referred to as psychosurgery, is rapidly evolving, with new techniques and indications being investigated actively. Many within the field have suggested that some form of guidelines or regulations are needed to help ensure that a promising field develops safely. Multiple countries have enacted specific laws regulating NPD. This article reviews NPD-specific laws drawn from North and South America, Asia and Europe, in order to identify the typical form and contents of these laws and to set the groundwork for the design of an optimal regulation for the field. Key challenges for this design that are revealed by the review are how to define the scope of the law (what should be regulated), what types of regulations are required (eligibility criteria, approval procedures, data collection, and oversight mechanisms), and how to approach international harmonization given the potential migration of researchers and patients.

in Frontiers in Human Neuroscience on January 13, 2021 12:00 AM.

• #### Extrinsic Factors Regulating Dendritic Patterning

Stereotypic dendrite arborizations are key morphological features of neuronal identity, as the size, shape and location of dendritic trees determine the synaptic input fields and how information is integrated within developed neural circuits. In this review, we focus on the actions of extrinsic intercellular communication factors and their effects on intrinsic developmental processes that lead to dendrite patterning. Surrounding neurons or supporting cells express adhesion receptors and secreted proteins that respectively, act via direct contact or over short distances to shape, size, and localize dendrites during specific developmental stages. The different ligand-receptor interactions and downstream signaling events appear to direct dendrite morphogenesis by converging on two categorical mechanisms: local cytoskeletal and adhesion modulation and global transcriptional regulation of key dendritic growth components, such as lipid synthesis enzymes. Recent work has begun to uncover how the coordinated signaling of multiple extrinsic factors promotes complexity in dendritic trees and ensures robust dendritic patterning.

in Frontiers in Cellular Neuroscience on January 13, 2021 12:00 AM.

• #### Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain

Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca2+ signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.

in Frontiers in Cellular Neuroscience on January 13, 2021 12:00 AM.

• #### Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder

Autism spectrum disorder (ASD) is characterized by impaired social interaction, language delay and repetitive or restrictive behaviors. With increasing prevalence, ASD is currently estimated to affect 0.5–2.0% of the global population. However, its etiology remains unclear due to high genetic and phenotypic heterogeneity. Copy number variations (CNVs) are implicated in several forms of syndromic ASD and have been demonstrated to contribute toward ASD development by altering gene dosage and expression. Increasing evidence points toward the p-arm of chromosome 3 (chromosome 3p) as an ASD risk locus. Deletions occurring at chromosome 3p result in 3p-deletion syndrome (Del3p), a rare genetic disorder characterized by developmental delay, intellectual disability, facial dysmorphisms and often, ASD or ASD-associated behaviors. Therefore, we hypothesize that overlapping molecular mechanisms underlie the pathogenesis of Del3p and ASD. To investigate which genes encoded in chromosome 3p could contribute toward Del3p and ASD, we performed a comprehensive literature review and collated reports investigating the phenotypes of individuals with chromosome 3p CNVs. We observe that high frequencies of CNVs occur in the 3p26.3 region, the terminal cytoband of chromosome 3p. This suggests that CNVs disrupting genes encoded within the 3p26.3 region are likely to contribute toward the neurodevelopmental phenotypes observed in individuals affected by Del3p. The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4). CNVs disrupting these neuronal IgCAMs may contribute toward ASD phenotypes as they have been associated with key roles in neurodevelopment. CHL1, CNTN6, and CNTN4 have been observed to promote neurogenesis and neuronal survival, and regulate neuritogenesis and synaptic function. Furthermore, there is evidence that these neuronal IgCAMs possess overlapping interactomes and participate in common signaling pathways regulating axon guidance. Notably, mouse models deficient for these neuronal IgCAMs do not display strong deficits in axonal migration or behavioral phenotypes, which is in contrast to the pronounced defects in neuritogenesis and axon guidance observed in vitro. This suggests that when CHL1, CNTN6, or CNTN4 function is disrupted by CNVs, other neuronal IgCAMs may suppress behavioral phenotypes by compensating for the loss of function.

in Frontiers in Cellular Neuroscience on January 13, 2021 12:00 AM.

• #### P2RX7 in Dopaminergic Neurons of Ventral Periaqueductal Gray Mediates HTWP Acupuncture-Induced Consciousness in Traumatic Brain Injury

The induction of a coma by traumatic brain injury (TBI) is a crucial factor for poor clinical prognoses. We report that acupuncture at the hand 12 Jing-Well points (HTWP) improved consciousness and neurologic function in TBI rats. Gene chip analyses showed that HTWP acupuncture mostly activated genes modulating neuronal projections (P2rx7, P2rx3, Trpv1, Tacr1, and Cacna1d), protein secretion (Exoc1, Exoc3l1, Fgb, and Fgr), and dopamine (DA) receptor D3 (Drd3) in the ventral periaqueductal gray (vPAG), among which the expression rate of P2rx7 was the most obviously increased. Acupuncture also increased the expression and excitability of DA and P2RX7 neurons, and the DA neurons expressed P2RX7, P2RX3, and TRPV1 in the vPAG. Intracerebroventricular administration of P2RX7, P2RX3, or TRPV1 antagonists blocked acupuncture-induced consciousness, and the subsequent injection of a P2RX7 antagonist into the vPAG nucleus also inhibited this effect. Our findings provide evidence that acupuncture alleviates TBI-induced comas via DA neurons expressing P2RX7 in the vPAG, so as to reveal the cellular and molecular mechanisms of the improvement of TBI clinical outcomes by HTWP acupuncture.

in Frontiers in Cellular Neuroscience on January 13, 2021 12:00 AM.

• #### Fluoxetine Promotes Hippocampal Oligodendrocyte Maturation and Delays Learning and Memory Decline in APP/PS1 Mice

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2′3′cyclic nucleotide 3′-phosphodiesterase (CNPase)+ and newborn CNPase+ oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10)+ cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR+ oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3β (GSK3β) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3β through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3β on oligodendrocyte maturation in the hippocampus of an AD mouse model.

in Frontiers in Ageing Neuroscience on January 13, 2021 12:00 AM.

• #### Do High Mental Demands at Work Protect Cognitive Health in Old Age via Hippocampal Volume? Results From a Community Sample

As higher mental demands at work are associated with lower dementia risk and a key symptom of dementia is hippocampal atrophy, the study aimed at investigating the association between mental demands at work and hippocampal volume. We analyzed data from the population-based LIFE-Adult-Study in Leipzig, Germany (n = 1,409, age 40–80). Hippocampal volumes were measured via three-dimensional Magnetic resonance imaging (MRI; 3D MP-RAGE) and mental demands at work were classified via the O*NET database. Linear regression analyses adjusted for gender, age, education, APOE e4-allele, hypertension, and diabetes revealed associations between higher demands in “language and knowledge,” “information processing,” and “creativity” at work on larger white and gray matter volume and better cognitive functioning with “creativity” having stronger effects for people not yet retired. Among retired individuals, higher demands in “pattern detection” were associated with larger white matter volume as well as larger hippocampal subfields CA2/CA3, suggesting a retention effect later in life. There were no other relevant associations with hippocampal volume. Our findings do not support the idea that mental demands at work protect cognitive health via hippocampal volume or brain volume. Further research may clarify through what mechanism mentally demanding activities influence specifically dementia pathology in the brain.

in Frontiers in Ageing Neuroscience on January 13, 2021 12:00 AM.

• #### Deviations in Hippocampal Subregion in Older Adults With Cognitive Frailty

Background

Cognitive frailty is a particular state of cognitive vulnerability toward dementia with neuropathological hallmarks. The hippocampus is a complex, heterogeneous structure closely relates to the cognitive impairment in elderly which is composed of 12 subregions. Atrophy of these subregions has been implicated in a variety of neurodegenerative diseases. The aim of this study was to explore the changes in hippocampal subregions in older adults with cognitive frailty and the relationship between subregions and cognitive impairment as well as physical frailty.

Methods

Twenty-six older adults with cognitive frailty and 26 matched healthy controls were included in this study. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) scale (Fuzhou version) and Wechsler Memory Scale-Revised Chinese version (WMS-RC), while physical frailty was tested with the Chinese version of the Edmonton Frailty Scale (EFS) and grip strength. The volume of the hippocampal subregions was measured with structural brain magnetic resonance imaging. Partial correlation analysis was carried out between the volumes of hippocampal subregions and MoCA scores, Wechsler’s Memory Quotient and physical frailty indexes.

Results

A significant volume decrease was found in six hippocampal subregions, including the bilateral presubiculum, the left parasubiculum, molecular layer of the hippocampus proper (molecular layer of the HP), and hippocampal amygdala transition area (HATA), and the right cornu ammonis subfield 1 (CA1) area, in older adults with cognitive frailty, while the proportion of brain parenchyma and total number of white matter fibers were lower than those in the healthy controls. Positive correlations were found between Wechsler’s Memory Quotient and the size of the left molecular layer of the HP and HATA and the right presubiculum. The sizes of the left presubiculum, molecular of the layer HP, and HATA and right CA1 and presubiculum were found to be positively correlated with MoCA score. The sizes of the left parasubiculum, molecular layer of the HP and HATA were found to be negatively correlated with the physical frailty index.

Conclusion

Significant volume decrease occurs in hippocampal subregions of older adults with cognitive frailty, and these changes are correlated with cognitive impairment and physical frailty. Therefore, the atrophy of hippocampal subregions could participate in the pathological progression of cognitive frailty.

in Frontiers in Ageing Neuroscience on January 13, 2021 12:00 AM.

• #### The Neuroimmunology of Guillain-Barré Syndrome and the Potential Role of an Aging Immune System

Guillain-Barré syndrome (GBS) is a paralyzing autoimmune condition affecting the peripheral nervous system (PNS). Within GBS there are several variants affecting different aspects of the peripheral nerve. In general, there appears to be a role for T cells, macrophages, B cells, and complement in initiating and perpetuating attacks on gangliosides of Schwann cells and axons. Of note, GBS has an increased prevalence and severity with increasing age. In addition, there are alterations in immune cell functioning that may play a role in differences in GBS with age alongside general age-related declines in reparative processes (e.g., delayed de-differentiation of Schwann cells and decline in phagocytic ability of macrophages). The present review will explore the immune response in GBS as well as in animal models of several variants of the disorder. In addition, the potential involvement of an aging immune system in contributing to the increased prevalence and severity of GBS with age will be theorized.

in Frontiers in Ageing Neuroscience on January 13, 2021 12:00 AM.

• #### A Comprehensive Phenotype of Non-motor Impairments and Distribution of Alpha-Synuclein Deposition in Parkinsonism-Induced Mice by a Combination Injection of MPTP and Probenecid

Parkinson’s disease (PD) is characterized by non-motor symptoms as well as motor deficits. The non-motor symptoms rarely appear individually and occur simultaneously with motor deficits or independently. However, a comprehensive research on the non-motor symptoms using an experimental model of PD remains poorly understood. The aim of the current study is to establish a chronic mouse model of PD mimicking the comprehensive non-motor symptoms of human PD by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid (MPTP/p). The non-motor and motor symptoms were evaluated by performing buried food, short-term olfactory memory, hot plate, open field, tail suspension, Y maze, novel object recognition, bead expulsion, one-h stool collection, rotarod, rearing, catalepsy, and akinesia tests after 10 injections of MPTP/p into mice. The expression levels of α-synuclein, glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) or DJ-1 were analyzed by Western blotting or immunostaining. MPTP/p-treated mice achieved to reproduce the key features of non-motor symptoms including olfactory deficit, thermal hyperalgesia, anxiety, depression, cognitive decline, and gastrointestinal dysfunction in addition to motor deficits. The MPTP/p-treated mice also showed the high levels of α-synuclein and low levels of TH and DJ-1 in striatum, substantia nigra, olfactory bulb, hippocampus, amygdala, prefrontal cortex, locus coeruleus, or colon. In addition, the expression levels of phosphorylated-α-synuclein and GFAP were elevated in the striatum and substantia nigra in the MPTP/p-treated mice. Taken together, our study clarifies that the chronic MPTP/p-treated mice have a variety of non-motor dysfunctions as well as motor abnormalities by α-synuclein overexpression and dopaminergic depletion. Therefore, the study of comprehensive phenotypes of non-motor symptoms in one PD model would advance in-depth understandings of neuropathological alternations and contribute to future strategies for PD treatment.

in Frontiers in Ageing Neuroscience on January 13, 2021 12:00 AM.

• #### Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

in Frontiers in Ageing Neuroscience on January 13, 2021 12:00 AM.

• #### Creating and concentrating quantum resource states in noisy environments using a quantum neural network

Publication date: Available online 12 January 2021

Source: Neural Networks

Author(s): Tanjung Krisnanda, Sanjib Ghosh, Tomasz Paterek, Timothy C.H. Liew

in Neural Networks on January 12, 2021 07:00 PM.

## Abstract

The cetacean visual system is a product of selection pressures favoring underwater vision, yet relatively little is known about it across taxa. Previous studies report several mutations in the opsin genetic sequence in cetaceans, suggesting the evolutionary complete or partial loss of retinal cone photoreceptor function in mysticete and odontocete lineages, respectively. Despite this, limited anatomical evidence suggests cone structures are partially maintained but with absent outer and inner segments in the bowhead retina. The functional consequence and anatomical distributions associated with these unique cone morphologies remain unclear. The current study further investigates the morphology and distribution of cone photoreceptors in the bowhead whale and beluga retina and evaluates the potential functional capacity of these cells' alternative to photoreception. Refined histological and advanced microscopic techniques revealed two additional cone morphologies in the bowhead and beluga retina that have not been previously described. Two proteins involved in magnetosensation were present in these cone structures suggesting the possibility for an alternative functional role in responding to changes in geomagnetic fields. These findings highlight a revised understanding of the unique evolution of cone and gross retinal anatomy in cetaceans, and provide prefatory evidence of potential functional reassignment of these cells.

in Journal of Comparative Neurology on January 12, 2021 03:20 PM.

• #### Post‐training stimulation of the right dorsolateral prefrontal cortex impairs working memory training performance

We delivered transcranial direct current stimulation over the right dorsolateral prefrontal cortex before, during, or after working memory training in order to assess the optimal stimulation timing to maximize learning. Although our procedure did not end up eliciting learning benefits, we did find that stimulation immediately after training impaired performance.

## Abstract

Research investigating transcranial direct current stimulation (tDCS) to enhance cognitive training augments both our understanding of its long‐term effects on cognitive plasticity as well as potential applications to strengthen cognitive interventions. Previous work has demonstrated enhancement of working memory training while applying concurrent tDCS to the dorsolateral prefrontal cortex (DLPFC). However, the optimal stimulation parameters are still unknown. For example, the timing of tDCS delivery has been shown to be an influential variable that can interact with task learning. In the present study, we used tDCS to target the right DLPFC while participants trained on a visuospatial working memory task. We sought to compare the relative efficacy of online stimulation delivered during training to offline stimulation delivered either immediately before or afterwards. We were unable to replicate previously demonstrated benefits of online stimulation; however, we did find evidence that offline stimulation delivered after training can actually be detrimental to training performance relative to sham. We interpret our results in light of evidence suggesting a role of the right DLPFC in promoting memory interference, and conclude that while tDCS may be a promising tool to influence the results of cognitive training, more research and an abundance of caution are needed before fully endorsing its use for cognitive enhancement. This work suggests that effects can vary substantially in magnitude and direction between studies, and may be heavily dependent on a variety of intervention protocol parameters such as the timing and location of stimulation delivery, about which our understanding is still nascent.

in Journal of Neuroscience Research on January 12, 2021 03:04 PM.

• #### Investigating the mitochondrial genomic landscape of <i>Arabidopsis thaliana</i> by long-read sequencing

by Bansho Masutani, Shin-ichi Arimura, Shinichi Morishita

Plant mitochondrial genomes have distinctive features compared to those of animals; namely, they are large and divergent, with sizes ranging from hundreds of thousands of to a few million bases. Recombination among repetitive regions is thought to produce similar structures that differ slightly, known as “multipartite structures,” which contribute to different phenotypes. Although many reference plant mitochondrial genomes represent almost all the genes in mitochondria, the full spectrum of their structures remains largely unknown. The emergence of long-read sequencing technology is expected to yield this landscape; however, many studies aimed to assemble only one representative circular genome, because properly understanding multipartite structures using existing assemblers is not feasible. To elucidate multipartite structures, we leveraged the information in existing reference genomes and classified long reads according to their corresponding structures. We developed a method that exploits two classic algorithms, partial order alignment (POA) and the hidden Markov model (HMM) to construct a sensitive read classifier. This method enables us to represent a set of reads as a POA graph and analyze it using the HMM. We can then calculate the likelihood of a read occurring in a given cluster, resulting in an iterative clustering algorithm. For synthetic data, our proposed method reliably detected one variation site out of 9,000-bp synthetic long reads with a 15% sequencing-error rate and produced accurate clustering. It was also capable of clustering long reads from six very similar sequences containing only slight differences. For real data, we assembled putative multipartite structures of mitochondrial genomes of Arabidopsis thaliana from nine accessions sequenced using PacBio Sequel. The results indicated that there are recurrent and strain-specific structures in A. thaliana mitochondrial genomes.

in PLoS Computational Biology on January 12, 2021 02:00 PM.

• #### Characteristics of the neural coding of causality

Author(s): Yang Tian and Pei Sun

While causality processing is an essential cognitive capacity of the neural system, a systematic understanding of the neural coding of causality is still elusive. We propose a physically fundamental analysis of this issue and demonstrate that the neural dynamics encodes the original causality betwee...

[Phys. Rev. E 103, 012406] Published Tue Jan 12, 2021

in Physical Review E: Biological physics on January 12, 2021 10:00 AM.

• #### Integer topological defects of cell monolayers: Mechanics and flows

Author(s): Carles Blanch-Mercader, Pau Guillamat, Aurélien Roux, and Karsten Kruse

Monolayers of anisotropic cells exhibit long-ranged orientational order and topological defects. During the development of organisms, orientational order often influences morphogenetic events. However, the linkage between the mechanics of cell monolayers and topological defects remains largely unexp...

[Phys. Rev. E 103, 012405] Published Tue Jan 12, 2021

in Physical Review E: Biological physics on January 12, 2021 10:00 AM.

## Abstract

Episodic memory depends on the computational process of pattern separation in order to establish distinct memory representations of similar episodes. Studies of pattern separation in humans rely on mnemonic discrimination tasks, which have been shown to tax hippocampal‐dependent pattern separation. Although previous neuroimaging research has focused on hippocampal processing, little is known about how other brain regions, known to be involved in recognition memory performance, are involved in mnemonic discrimination tasks. Conversely, neuroimaging studies of pattern separation with whole‐brain coverage lack spatial resolution to localize activation to hippocampal subfields. In this study, 48 healthy young adult participants underwent whole‐brain high‐resolution functional MRI (fMRI) scanning while completing a mnemonic discrimination task. A priori region‐of‐interest analyses revealed activation patterns consistent with pattern separation in distinct hippocampal subregions, particularly in the subiculum. Connectivity analyses revealed a network of cortical regions consistent with the memory retrieval network where fMRI activation was correlated with hippocampal activation. An exploratory whole‐brain analysis revealed widespread activation differentially associated with performance of the mnemonic discrimination task. Taken together, these results suggest that a network of brain regions contribute to mnemonic discrimination performance, with the hippocampus and parahippocampal cortex as a hub in the network displaying clear signals consistent with pattern separation and regions such as the dorsal medial prefrontal cortex particularly important for successful lure discrimination.

in Hippocampus on January 12, 2021 09:14 AM.

## Abstract

Adult‐born granule cells (abGCs) integrate into the hippocampus and form connections with dentate gyrus parvalbumin‐positive (PV+) interneurons, a circuit important for modulating plasticity. Many of these interneurons are surrounded by perineuronal nets (PNNs), extracellular matrix structures known to participate in plasticity. We compared abGC projections to PV+ interneurons with negative‐to‐low intensity PNNs to those with high intensity PNNs using retroviral and 3R‐Tau labeling in adult mice, and found that abGC mossy fibers and boutons are more frequently located near PV+ interneurons with high intensity PNNs. These results suggest that axons of new neurons preferentially stabilize near target cells with intense PNNs. Next, we asked whether the number of abGCs influences PNN formation around PV+ interneurons, and found that near complete ablation of abGCs produced a decrease in the intensity and number of PV+ neurons with PNNs, suggesting that new neuron innervation may enhance PNN formation. Experience‐driven changes in adult neurogenesis did not produce consistent effects, perhaps due to widespread effects on plasticity. Our study identifies abGC projections to PV+ interneurons with PNNs, with more presumed abGC mossy fiber boutons found near the cell body of PV+ interneurons with strong PNNs.

in Hippocampus on January 12, 2021 09:11 AM.

• #### Shifting computational boundaries for complex organic materials

Nature Physics, Published online: 12 January 2021; doi:10.1038/s41567-020-01135-6

Methodology adapted from data science sparked the field of materials informatics, and materials databases are at the heart of it. Applying artificial intelligence to these databases will allow the prediction of the properties of complex organic crystals.

in Nature Physics on January 12, 2021 12:00 AM.

• #### Author Correction: Stable pure-blue hyperfluorescence organic light-emitting diodes with high-efficiency and narrow emission

Nature Photonics, Published online: 12 January 2021; doi:10.1038/s41566-021-00759-1

Author Correction: Stable pure-blue hyperfluorescence organic light-emitting diodes with high-efficiency and narrow emission

in Nature Photomics on January 12, 2021 12:00 AM.

• #### Isoflurane-Induced Burst Suppression Is a Thalamus-Modulated, Focal-Onset Rhythm With Persistent Local Asynchrony and Variable Propagation Patterns in Rats

Background: Inhalational anesthetic-induced burst suppression (BS) is classically considered a bilaterally synchronous rhythm. However, local asynchrony has been predicted in theoretical studies and reported in patients with pre-existing focal pathology.

Method: We used high-speed widefield calcium imaging to study the spatiotemporal dynamics of isoflurane-induced BS in rats.

Results: We found that isoflurane-induced BS is not a globally synchronous rhythm. In the neocortex, neural activity first emerged in a spatially shifting, variably localized focus. Subsequent propagation across the whole cortex was rapid, typically within <100 milliseconds, giving the superficial resemblance to global synchrony. Neural activity remained locally asynchronous during the bursts, forming complex recurrent propagating waves. Despite propagation variability, spatial sequences of burst propagation were largely preserved between the hemispheres, and neural activity was highly correlated between the homotopic areas. The critical role of the thalamus in cortical burst initiation was demonstrated by using unilateral thalamic tetrodotoxin injection.

Conclusion: The classical impression that anesthetics-induced BS is a state of global brain synchrony is inaccurate. Bursts are a series of shifting local cortical events facilitated by thalamic projection that unfold as rapid, bilaterally asynchronous propagating waves.

in Frontiers in Systems Neuroscience on January 12, 2021 12:00 AM.

• #### The Role of Cathepsin B in the Degradation of Aβ and in the Production of Aβ Peptides Starting With Ala2 in Cultured Astrocytes

Astrocytes may not only be involved in the clearance of Amyloid beta peptides (Aβ) in Alzheimer's disease (AD), but appear to produce N-terminally truncated Aβ (Aβn−x) independently of BACE1, which generates the N-Terminus of Aβ starting with Asp1 (Aβ1−x). A candidate protease for the generation of Aβn−x is cathepsin B (CatB), especially since CatB has also been reported to degrade Aβ, which could explain the opposite roles of astrocytes in AD. In this study, we investigated the influence of CatB inhibitors and the deletion of the gene encoding CatB (CTSB) using CRISPR/Cas9 technology on Aβ2−x and Aβ1−x levels in cell culture supernatants by one- and two-dimensional Urea-SDS-PAGE followed by immunoblot. While the cell-permeant inhibitors E64d and CA-074 Me did not significantly affect the Aβ1−x levels in supernatants of cultured chicken and human astrocytes, they did reduce the Aβ2−x levels. In the glioma-derived cell line H4, the Aβ2−x levels were likewise decreased in supernatants by treatment with the more specific, but cell-impermeant CatB-inhibitor CA-074, by CA-074 Me treatment, and by CTSB gene deletion. Additionally, a more than 2-fold increase in secreted Aβ1−x was observed under the latter two conditions. The CA-074 Me-mediated increase of Aβ1−x, but not the decrease of Aβ2−x, was influenced by concomitant treatment with the vacuolar H+-ATPase inhibitor Bafilomycin A1. This indicated that non-lysosomal CatB mediated the production of Aβ2−x in astrocytes, while the degradation of Aβ1−x seemed to be dependent on lysosomal CatB in H4 cells, but not in primary astrocytes. These findings highlight the importance of considering organelle targeting in drug development to promote Aβ degradation.

in Frontiers in Molecular Neuroscience on January 12, 2021 12:00 AM.

• #### An Integrative Approach to Study Structural and Functional Network Connectivity in Epilepsy Using Imaging and Signal Data

A key area of research in epilepsy neurological disorder is the characterization of epileptic networks as they form and evolve during seizure events. In this paper, we describe the development and application of an integrative workflow to analyze functional and structural connectivity measures during seizure events using stereotactic electroencephalogram (SEEG) and diffusion weighted imaging data (DWI). We computed structural connectivity measures using electrode locations involved in recording SEEG signal data as reference points to filter fiber tracts. We used a new workflow-based tool to compute functional connectivity measures based on non-linear correlation coefficient, which allows the derivation of directed graph structures to represent coupling between signal data. We applied a hierarchical clustering based network analysis method over the functional connectivity data to characterize the organization of brain network into modules using data from 27 events across 8 seizures in a patient with refractory left insula epilepsy. The visualization of hierarchical clustering values as dendrograms shows the formation of connected clusters first within each insulae followed by merging of clusters across the two insula; however, there are clear differences between the network structures and clusters formed across the 8 seizures of the patient. The analysis of structural connectivity measures showed strong connections between contacts of certain electrodes within the same brain hemisphere with higher prevalence in the perisylvian/opercular areas. The combination of imaging and signal modalities for connectivity analysis provides information about a patient-specific dynamical functional network and examines the underlying structural connections that potentially influences the properties of the epileptic network. We also performed statistical analysis of the absolute changes in correlation values across all 8 seizures during a baseline normative time period and different seizure events, which showed decreased correlation values during seizure onset; however, the changes during ictal phases were varied.

in Frontiers in Integrative Neuroscience on January 12, 2021 12:00 AM.

• #### Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

Brain organoids, or cerebral organoids, have become widely used to study the human brain in vitro. As pluripotent stem cell-derived structures capable of self-organization and recapitulation of physiological cell types and architecture, brain organoids bridge the gap between relatively simple two-dimensional human cell cultures and non-human animal models. This allows for high complexity and physiological relevance in a controlled in vitro setting, opening the door for a variety of applications including development and disease modeling and high-throughput screening. While technologies such as single cell sequencing have led to significant advances in brain organoid characterization and understanding, improved functional analysis (especially electrophysiology) is needed to realize the full potential of brain organoids. In this review, we highlight key technologies for brain organoid development and characterization, then discuss current electrophysiological methods for brain organoid analysis. While electrophysiological approaches have improved rapidly for two-dimensional cultures, only in the past several years have advances been made to overcome limitations posed by the three-dimensionality of brain organoids. Here, we review major advances in electrophysiological technologies and analytical methods with a focus on advances with applicability for brain organoid analysis.

in Frontiers in Neuroscience: Neural Technology on January 12, 2021 12:00 AM.

• #### Safety and Efficacy of Magnetic Resonance-Guided Focused Ultrasound Surgery With Autofocusing Echo Imaging

Objective

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) lesioning is a new treatment for brain disorders. However, the skull is a major barrier of ultrasound sonication in MRgFUS because it has an irregular surface and varies its size and shape among individuals. We recently developed the concept of skull density ratio (SDR) to select candidates for MRgFUS from among patients with essential tremor (ET). However, SDR is not the only factor contributing to successful MRgFUS lesioning treatment—refining the target through exact measurement of the ultrasonic echo in the transducer also improves treatment efficacy. In the present study, we carried out MRgFUS lesioning using an autofocusing echo imaging technique. We aimed to evaluate the safety and efficacy of this new approach, especially in patients with low SDR in whom previous focusing methods have failed.

Methods

From December 2019 to March 2020, we recruited 10 patients with ET or Parkinson’s disease (PD) who had a low SDR. Two patients dropped out of the trial due to the screening failure of other medical diseases. In total, eight patients were included: six with ET who underwent MRgFUS thalamotomy and two with PD who underwent MRgFUS pallidotomy. The autofocusing echo imaging technique was used in all cases.

Results

The mean SDR of the patients with ET was 0.34 (range: 0.29–0.39), while that of the patients with PD was 0.41 (range: 0.38–0.44). The mean skull volume of patients with ET was 280.57 cm3 (range: 227–319 cm3), while that of the patients with PD was 287.13 cm3 (range: 271–303 cm3). During MRgFUS, a mean of 15 sonications were performed, among which a mean of 5.63 used the autofocusing technique. The mean maximal temperature (Tmax) achieved was 55.88°C (range: 52–59°C), while the mean energy delivered was 34.75 kJ (range: 20–42 kJ) among all patients. No serious adverse events occurred during or after treatment. Tmax or sonication factors (skull volume, SDR, sonication number, autofocusing score, similarity score, energy range, and power) were not correlated with autofocusing technique (p > 0.05, autofocusing score showed a p-value of 0.071).

Conclusion

Using autofocusing echo imaging lesioning, a safe and efficient MRgFUS treatment, is available even for patients with a low SDR. Therefore, the indications for MRgFUS lesioning could be expanded to include patients with ET who have an SDR < 0.4 and those with PD who have an SDR < 0.45.

Clinical Trial Registration

clinicaltrials.gov, identifier: NCT03935581.

in Frontiers in Neuroscience: Neural Technology on January 12, 2021 12:00 AM.

• #### Is Brain Dynamics Preserved in the EEG After Automated Artifact Removal? A Validation of the Fingerprint Method and the Automatic Removal of Cardiac Interference Approach Based on Microstate Analysis

The assessment of a method for removing artifacts from electroencephalography (EEG) datasets often disregard verifying that global brain dynamics is preserved. In this study, we verified that the recently introduced optimized fingerprint method and the automatic removal of cardiac interference (ARCI) approach not only remove physiological artifacts from EEG recordings but also preserve global brain dynamics, as assessed with a new approach based on microstate analysis. We recorded EEG activity with a high-resolution EEG system during two resting-state conditions (eyes open, 25 volunteers, and eyes closed, 26 volunteers) known to exhibit different brain dynamics. After signal decomposition by independent component analysis (ICA), the independent components (ICs) related to eyeblinks, eye movements, myogenic interference, and cardiac electromechanical activity were identified with the optimized fingerprint method and ARCI approach and statistically compared with the outcome of the expert classification of the ICs by visual inspection. Brain dynamics in two different groups of denoised EEG signals, reconstructed after having removed the artifactual ICs identified by either visual inspection or the automated methods, was assessed by calculating microstate topographies, microstate metrics (duration, occurrence, and coverage), and directional predominance (based on transition probabilities). No statistically significant differences between the expert and the automated classification of the artifactual ICs were found (p > 0.05). Cronbach’s α values assessed the high test–retest reliability of microstate parameters for EEG datasets denoised by the automated procedure. The total EEG signal variance explained by the sets of global microstate templates was about 80% for all denoised EEG datasets, with no significant differences between groups. For the differently denoised EEG datasets in the two recording conditions, we found that the global microstate templates and the sequences of global microstates were very similar (p < 0.01). Descriptive statistics and Cronbach’s α of microstate metrics highlighted no significant differences and excellent consistency between groups (p > 0.5). These results confirm the ability of the optimized fingerprint method and the ARCI approach to effectively remove physiological artifacts from EEG recordings while preserving global brain dynamics. They also suggest that microstate analysis could represent a novel approach for assessing the ability of an EEG denoising method to remove artifacts without altering brain dynamics.

in Frontiers in Neuroscience: Brain Imaging Methods on January 12, 2021 12:00 AM.

• #### A Fiber Alginate Co-culture Platform for the Differentiation of mESC and Modeling of the Neural Tube

Alginate hydrogels are a commonly used substrate for in vitro 3D cell culture. These naturally derived biomaterials are highly tunable, biocompatible, and can be designed to mimic the elastic modulus of the adult brain at 1% w/v solution. Recent studies show that the molecular weight of the alginate can affect cell viability and differentiation. The relationship between the molecular weight, viscosity and ratio of G:M monomers of alginate hydrogels is complex, and the balance between these factors must be carefully considered when deciding on a suitable alginate hydrogel for stem cell research. This study investigates the formation of embryoid bodies (EB) from mouse embryonic stem cells, using low molecular weight (LMW) and high molecular weight (HMW) alginates. The cells are differentiated using a retinoic acid-based protocol, and the resulting aggregates are sectioned and stained for the presence of stem cells and the three germ layers (endoderm, mesoderm, and ectoderm). The results highlight that aggregates within LMW and HMW alginate are true EBs, as demonstrated by positive staining for markers of the three germ layers. Using tubular alginate scaffolds, formed with an adapted gradient maker protocol, we also propose a novel 3D platform for the patterned differentiation of mESCs, based on gradients of retinoic acid produced in situ by lateral motor column (LMC) motor neurons. The end product of our platform will be of great interest as it can be further developed into a powerful model of neural tube development.

in Frontiers in Neuroscience: Neural Technology on January 12, 2021 12:00 AM.

• #### Comparison of Facial Muscle Activation Patterns Between Healthy and Bell’s Palsy Subjects Using High-Density Surface Electromyography

Facial muscle activities are essential for the appearance and communication of human beings. Therefore, exploring the activation patterns of facial muscles can help understand facial neuromuscular disorders such as Bell’s palsy. Given the irregular shape of the facial muscles as well as their different locations, it should be difficult to detect the activities of whole facial muscles with a few electrodes. In this study, a high-density surface electromyogram (HD sEMG) system with 90 electrodes was used to record EMG signals of facial muscles in both healthy and Bell’s palsy subjects when they did different facial movements. The electrodes were arranged in rectangular arrays covering the forehead and cheek regions of the face. The muscle activation patterns were shown on maps, which were constructed from the Root Mean Square (RMS) values of all the 90-channel EMG recordings. The experimental results showed that the activation patterns of facial muscles were distinct during doing different facial movements and the activated muscle regions could be clearly observed. Moreover, two features of the activation patterns, 2D correlation coefficient (corr2) and Centre of Gravity (CG) were extracted to quantify the spatial symmetry and the location of activated muscle regions respectively. Furthermore, the deviation of activated muscle regions on the paralyzed side of a face compared to the