• #### Experimental Brain Research

in Experimental Brain Research on October 01, 2020 12:00 AM.

• #### The Cerebellum

in The Cerebellum on October 01, 2020 12:00 AM.

• #### Journal of Molecular Neuroscience

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

• #### Neuroinformatics

in Neuroinformatics on October 01, 2020 12:00 AM.

### Abstract

PSEN1 gene is considered to be the most common gene, which is responsible for the development of an autosomal dominant Alzheimer disease with early onset and sometimes broad phenotype. We present a patient with a spinocerebellar ataxia (SCA)-like phenotype who was found to carry an M233V mutation. General and neurological exam was carried out. Brain MRI as well as genetic testing for SCAs 1, 2, 3, 6, and 17 were performed. The patient was then referred for a next-generation sequencing-based gene panel test with 723 genes included. A 26-year-old man of an Azerbaijani origin presented with a progressive impairment of coordination followed by memory impairment. Family history was positive for a similar disorder suggesting autosomal dominant inheritance. Brain MRI showed bilateral hippocampal atrophy (more pronounced in the left), as well as mild atrophy of the left temporoparietal cortex. Tests for SCAs 1, 2, 3, 6, and 17 came negative. Gene panel test showed c.697A > G heterozygous variant in the PSEN1 gene leading to a M233V amino acid change, which was validated by a Sanger sequencing. So far, M233V mutation has not been associated with a combination of cerebellar and cognitive features at onset. Our case contributes to a better characterization of the PSEN1 mutations and expands the phenotype of the M233V carriers. We propose to consider PSEN1 mutations in patients presenting with an SCA-like phenotype but negative for common types of SCA.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

A prompt diagnosis and treatment of patients with autoimmune cerebellar ataxia (CA) with antibodies against glutamic acid decarboxylase (GAD-Abs) may lead to a better prognosis. Herein, we report prodromal transient neurological symptoms that should raise clinical suspicion of CA with GAD-Abs. We initially identified a 70-year-old man who presented a first acute episode of vertigo, diplopia, and ataxia lasting 2 weeks. Two months later, he experienced a similar episode along with new-onset gaze-evoked nystagmus. After 4 months, downbeat nystagmus, left limb dysmetria, and gait ataxia progressively appeared, and an autoimmune CA was diagnosed based on the positivity of GAD-Abs in serum and cerebrospinal fluid (CSF). We searched retrospectively for similar presentations in a cohort of 31 patients diagnosed with CA and GAD-Abs. We found 11 (35.4%) patients (all women, median age 62 years; 8/11 [72.7%] with autoimmune comorbidities) with transient neurological symptoms antedating CA onset by a median of 3 months, including vertigo in 9 (81.8%; described as paroxysmal in 8) and fluctuating diplopia in 3 (27.3%) patients. The identification of transient neurological symptoms of unknown etiology, such as paroxysmal vertigo and fluctuating diplopia, should lead to GAD-Abs testing in serum and CSF, especially in patients with autoimmune comorbidities.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Niemann-Pick type C (NPC) is a rare autosomal recessive disorder characterized by storage of unesterified glycolipids and cholesterol in lysosome. NPC’s clinical presentation is highly heterogeneous, depending on the time of onset. It encompasses visceral, neurological, and/or psychiatric manifestations. As the motor findings are so important and devastating in this disease, there is a lack of description about non-motor symptoms, even though they play important role in quality of life of NPC patients. We described the most common non-motor findings in NPC like cognitive dysfunction, neuroimaging, psychiatric symptoms, sleep disorders, seizures, hearing problems, respiratory and other systemic features, bladder and fecal dysfunction, hypersalivation, and malnutrition. In this review, we highlighted the importance of these undervalued symptoms and their management. Specific measures of all aforementioned clinical features may work as relevant biomarkers in order to evaluate successful therapies in future clinical trials.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Spinocerebellar ataxias (SCAs) represent a large group of heredodegenerative diseases, with great phenotypic and genotypic heterogeneity. However, in the clinical neurological practice, some symptoms and signs might help differentiate the SCAs. This study’s aims were to evaluate the frequency of upward gaze palsy (UGP) and investigate its role in assisting in the clinical differentiation of SCAs. We included 419 patients with SCAs (248 with SCA3, 95 with SCA10, 38 with SCA2, 22 with SCA1, 12 with SCA7, and 4 with SCA6). This study compared UGP with other known markers of disease severity—age of onset, disease duration, SARA score, and size of CAG expansion, and also other semiologic features, as bulging eyes. This sign was significantly more prevalent in SCA3 (64.11%), compared with SCA10 (3.16%; p < 0.001) and other SCAs (SCA1, SCA2, SCA7–11.84%; p < 0.001). UGP showed very high sensibility ins SCA3 (92.9), although lacking of specificity (64.1%). The odds ratio (OR) of UGP were also very high, 23.52 (95% CI 12.38–44.69), and was significantly correlated with larger CAG expansions, age, and disease duration in SCA3 patients, but not with age of onset or severity of the ataxic syndrome. This study showed that UGP is highly suggestive of SCA3 and has high sensitivity for the differential diagnosis among SCAs, and it could be of great value for bedside semiologic tool.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Communication difficulties have considerable impact on people with progressive ataxia, yet there are currently no evidence-based treatments. LSVT LOUD® focuses on the production of healthy vocal loudness whilst also improving breath support, vocal quality, loudness and articulation in participating patients. This study aimed to investigate whether Lee Silverman Voice Treatment (LSVT LOUD®) can improve communication effectiveness in these patients. We performed a rater-blinded, single-arm study investigating LSVT LOUD® treatment in a population of patients with progressive ataxia including Friedreich’s ataxia (n = 18), spinocerebellar ataxia type 6 (n = 1), idiopathic cerebellar ataxia (n = 1), and spastic paraplegia 7 (n = 1). Twenty-one patients were recruited to the study, with 19 completing treatment. Sessions were administered via Skype in the LSVT-X format, meaning two sessions per week over a period of 8 weeks. Assessments included two baseline and two post-treatment measures and focused on outcome measures covering aspects ranging from physiological function to impact and participation. Results indicate improvements in patient-perceived outcomes for 14 of the 19 participants, in both speech and psychosocial domains. Speech data furthermore demonstrate significant improvements in prolonged vowel duration, and voice quality measures. Intelligibility and naturalness evaluations showed no change post-treatment. Patients reported high acceptability of the treatment itself, as well as administration by Skype. This is the largest treatment study for people with progressive ataxia published to date. It provides an indication that LSVT LOUD® can have a positive impact on communication in this patient group and could form the basis for larger-scale trials.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Immune-mediated ataxias account for a substantial number of sporadic otherwise idiopathic ataxias. Despite some well-characterised entities such as paraneoplastic cerebellar degeneration where diagnostic markers exist, the majority of immune ataxias remained undiagnosed and untreated. We present here our experience in the treatment of suspected primary autoimmune cerebellar ataxia (PACA) using mycophenolate. All patients reported attend the Sheffield Ataxia Centre on a regular basis and had undergone extensive investigations, including genetic testing using next-generation sequencing, with other causes of ataxia excluded. The diagnosis of PACA was strongly suspected based on investigations, pattern of disease progression, and cerebellar involvement. Patients were treated with mycophenolate and monitored using MR spectroscopy of the cerebellar vermis. Thirty patients with PACA are reported here. Of these, 22 received mycophenolate (group 1). The remaining 8 were not on treatment (group 2-control group). Out of the 22 treated patients, 4 underwent serial MR spectroscopy prior to starting treatment and thus were used as controls making the total number of patients in the control group 12. The mean change of the MRS within the vermis (NAA/Cr area ratio) in the treatment group was + 0.144 ± 0.09 (improved) and in the untreated group − 0.155 ± 0.06 (deteriorated). The difference was significant. We also demonstrated a strong correlation between the spectroscopy and the SARA score. We have demonstrated the effectiveness of mycophenolate in the treatment of PACA. The results suggest that immune-mediated ataxias are potentially treatable, and that there is a need for early diagnosis to prevent permanent neurological deficit. The recently published diagnostic criteria for PACA would hopefully aid the diagnosis and treatment of this entity.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Speech production relies on motor control and cognitive processing and is linked to cerebellar function. In diseases where the cerebellum is impaired, such as multiple sclerosis (MS), speech abnormalities are common and can be detected by instrumental assessments. However, the potential of speech assessments to be used to monitor cerebellar impairment in MS remains unexplored. The aim of this study is to build an objectively measured speech score that reflects cerebellar function, pathology and quality of life in MS. Eighty-five people with MS and 21 controls participated in the study. Speech was independently assessed through objective acoustic analysis and blind expert listener ratings. Cerebellar function and overall disease disability were measured through validated clinical scores; cerebellar pathology was assessed via magnetic resonance imaging, and validated questionnaires informed quality of life. Selected speech variables were entered in a regression model to predict cerebellar function. The resulting model was condensed into one composite speech score and tested for prediction of abnormal 9-hole peg test (9HPT), and for correlations with the remaining cerebellar scores, imaging measurements and self-assessed quality of life. Slow rate of syllable repetition and increased free speech pause percentage were the strongest predictors of cerebellar impairment, complemented by phonatory instability. Those variables formed the acoustic composite score that accounted for 54% of variation in cerebellar function, correlated with cerebellar white matter volume (r = 0.3, p = 0.017), quality of life (r = 0.5, p < 0.001) and predicted an abnormal 9HPT with 85% accuracy. An objective multi-feature speech metric was highly representative of motor cerebellar impairment in MS.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Machado-Joseph disease (MJD) is relatively prevalent among the Yemenite Jewish subpopulation living in Israel. Currently, there is no treatment able to modify the disease progression. Trehalose is a disaccharide with protein-stabilizing and autophagy-enhancing properties. In animal models of MJD, trehalose showed reduction of cerebellar lesion size and improved motor function. This study was designed to be a proof-of-concept, phase 2 study lasting 6 to 12 months, to determine the safety, tolerability, and efficacy of weekly IV administration of 15 g or 30 g 10% trehalose solution in 14 MJD patients. Primary endpoints were safety and tolerability, which were assessed by various clinical and laboratory tests. Secondary endpoints were changes in the Scale for Assessment and Rating of Ataxia (SARA) score, Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), time to do 9-hole peg test (9HPT), time to do 8-meter walk (8MW), and quality of life assessed by the World Health Organization Quality-of-Life Questionnaire-BREF (WHOQoL-BREF). Trehalose was well tolerated, and no serious drug-related adverse events were noted. The average SARA score, NESSCA, and time to do 9HPT and 8MW and the WHOQoL-BREF for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests. IV trehalose seems to be safe in humans and probably effective to stabilize neurological impairment in MJD.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Corticomuscular and intermuscular coherence (CMC, IMC) reflect connectivity between neuronal activity in the motor cortex measured by electroencephalography (EEG) and muscular activity measured by electromyography (EMG), or between activity in different muscles, respectively. There is an ongoing debate on the appropriateness of EMG rectification prior to coherence estimation. This work examines the effects of EMG rectification in CMC and IMC estimation in 20 spinocerebellar ataxia type 2 (SCA2) patients, 16 prodromal SCA2 gene mutation carriers, and 26 healthy controls during a repetitive upper or lower limb motor task. Coherence estimations were performed using the non-rectified raw EMG signal vs. the rectified EMG signal. EMG rectification decreases the level of significance of lower beta-frequency band CMC and IMC values in SCA2 patients and prodromal SCA2 mutation carriers vs. healthy controls, and also results in overall lower coherence values. EMG rectification is detrimental for beta-frequency band CMC and IMC estimation. One likely reason for this effect is distortion of coherence estimation in high-frequency signals, where the level of amplitude cancelation is high.

in The Cerebellum on October 01, 2020 12:00 AM.

• #### Cerebellar White Matter Structural Correlates of Locomotor Adaptation. Do They Reflect Neural Adaptation?

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

The cerebellum plays a critical role in promoting learning of new motor tasks, which is an essential function for motor recovery. Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can be used to enhance learning. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol, on visuo-motor learning in a sample of hemiparetic patients due to recent stroke in the territory of the contralateral middle cerebral artery. Eight stroke patients were enrolled for the purposes of the study in the chronic stage of recovery (i.e., at least 6 months after stroke). In two sessions, Patients were randomly assigned to treatment with real or sham c-iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side. c-iTBS was applied immediately before the learning phase of a visuo-motor adaptation task. Real, but not sham, c-iTBS improved visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation task. Moreover, we also found that real but not sham c-iTBS induced a sustained improvement in the re-adaptation of the recently learned skill (i.e., when patients were re-tested after 30 min). Taken together, these data point to c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Chromosomal microarray analysis is commonly used as screening test for children with neurodevelopmental issues, also in case of complex neurological phenotypes. Developmental delay/intellectual disability is a common presentation sign in pediatric ataxias, diseases with high clinical and genetic heterogeneity. In order to determine the diagnostic yield of Array-CGH in such conditions, all the tests performed in the last 10-year activity of a single referral center in children who present, besides the neurodevelopmental impairment, cerebellar abnormalities have been systematically gathered. The study demonstrates that, except for Dandy-Walker malformation or poly-malformative phenotypes, chromosomal microarray analysis should be discouraged as first-line diagnostic test in pediatric ataxias with neurodevelopmental disability.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

We sought to assess structural and functional patterns of cerebellum in multiple system atrophy (cerebellar type), and investigate the associations of structural and functional cerebellar gray matter abnormalities. We collected magnetic resonance imaging data of 18 patients with multiple system atrophy (cerebellar type) and 18 health control subjects. The gray matter loss across the motor and cognitive cerebellar territories in patients was assessed using voxel-based morphometry. And change in the connectivity between the cerebellum and large-scale cortical networks was assessed using resting-state functional MRI analysis. Furthermore, we assessed the relationship between the extent of cerebellar atrophy and reduced-activation in the cerebellar-cortical and subthalamo-cerebellar functional connectivities. We confirmed the gray matter loss across the motor and cognitive cerebellar territories in patients and found that the extent of cerebellar atrophy was correlated with decreased connectivity between the cerebellum and large-scale cortical networks, including the default, frontal parietal, and sensorimotor networks. The volume reduction in the motor cerebellum was closely associated with the clinical motor severity. A post hoc analysis showed reduced-activation in the subthalamo-cerebellar functional connectivity without the subthalamic nucleus atrophy. These results emphasized significant atrophy in the cerebellar subsystem and its association with the large-scale cortical networks in multiple system atrophy (cerebellar type), which may improve our understanding of the neural pathophysiology mechanisms of disease.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Cerebellar volume, in particular vermal lobule areas VI–VII, have been extensively researched in individuals with autism spectrum disorder (ASD), although findings are often unclear. The aim of the present study is to consolidate all existing cerebellar and age data of individuals with ASD, and compare this data to typically developing (TD) controls. Raw data, or the means and standard deviations of cerebellar volume and age, were obtained from 17 studies (NCerebellum: 421 ASD and 370 TD participants; NVI–VII: 506 ASD and 290 TD participants). Total cerebellar volume, or VI–VII area, was plotted against age and lines of fit of ASD and TD data were compared. Mean differences in cerebellar volume and VI–VII area between participants with ASD and TD participants were then compared via ANCOVA analyses. Findings revealed multiple differences in VI–VII area between participants with ASD and TD participants below 18 years of age. Additionally, cerebellar volume was greater in males with ASD than TD males between 2 and 4 years. In the present study, cerebellar volume and VI–VII area show different rates of change across age for those with autism compared with those without. These morphological differences provide a neurobiological justification to investigate related behavioural correlates.

in The Cerebellum on October 01, 2020 12:00 AM.

### Abstract

Cerebellar granule neuron progenitors (CGNPs) give rise to the cerebellar granule neurons in the developing cerebellum. Generation of large number of these neurons is made possible by the high proliferation rate of CGNPs in the external granule layer (EGL) in the dorsal cerebellum. Here, we show that upregulation of β-catenin can maintain murine CGNPs in a state of proliferation. Further, we show that β-catenin mRNA and protein levels can be regulated by the mitogen Sonic hedgehog (Shh). Shh signaling led to an increase in the level of the transcription factor N-myc. N-myc was found to bind the β-catenin promoter, and the increase in β-catenin mRNA and protein levels could be prevented by blocking N-myc upregulation downstream of Shh signaling. Furthermore, blocking Wingless-type MMTV integration site (Wnt) signaling by Wnt signaling pathway inhibitor Dickkopf 1 (Dkk-1) in the presence of Shh did not prevent the upregulation of β-catenin. We propose that in culture, Shh signaling regulates β-catenin expression through N-myc and results in increased CGNP proliferation.

in The Cerebellum on October 01, 2020 12:00 AM.

• #### Correction to: Escin, a Novel Triterpene, Mitigates Chronic MPTP/P-Induced Dopaminergic Toxicity by Attenuating Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis

The original version of this article unfortunately contains an error in Figs. 8 and 9.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Alzheimer’s disease (AD) represents one of the main forms of dementia that afflicts our society. The expression of several genes has been associated with disease development. Despite this, the number of genes known to be capable of discriminating between AD patients according to sex remains deficient. In our study, we performed a transcriptomes meta-analysis on a large court of brains of healthy control subjects (n = 2139) (NDHC) and brains of AD patients (n = 1170). Our aim was to verify the brain expression levels of CHI3L2 and its correlation with genes associated with microglia-mediated neuroinflammation (IBA1), alteration of the blood–brain barrier (PECAM1), and neuronal damage (CALB1). We showed that the CHI3L2, IBA1, PECAM1, and CALB1 expression levels were modulated in the brains of patients with AD compared to NDHC subjects. Furthermore, both in NDHC and in AD patient’s brains, the CHI3L2 expression levels were directly correlated with IBA1 and PECAM1 and inversely with CALB1. Additionally, the expression levels of CHI3L2, PECAM1, and CALB1 but not of IBA1 were sex-depended. By stratifying the samples according to age and sex, correlation differences emerged between the expression levels of CHI3L2, IBA1, PECAM1, and CALB1 and the age of NDHC subjects and AD patients. CHI3L2 represents a promising gene potentially involved in the key processes underlying Alzheimer’s disease. Its expression in the brains of sex-conditioned AD patients opens up new possible sex therapeutic strategies aimed at controlling imbalance in disease progression.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

To explore plasma protein panels as potential biomarkers to screen for mild cognitive impairment (MCI) among elderly Chinese individuals with different educational backgrounds. Forty-four illiterate, 36 lower education (1–6 years), and 55 higher education (7 years or more) elderly individuals were included in the present study. Among all subjects, 67 were healthy individuals and 68 were diagnosed with MCI. Fifty plasma proteins in blood samples collected from these subjects were analyzed via the Luminex assay. Binary logistic regression was utilized to explore diagnostic models for MCI among the three educational subgroups. Then, receiver operating characteristic (ROC) curves were conducted for the clinical validity of the MCI models. Among the analyzed proteins, clusterin was used in the model of MCI among the total sample with a sensitivity (se) of 67.6%, a specificity (sp) of 59.7%, and a classification rate of 63.68%. The MCI model for the illiterate group included cystatin C, plasminogen activator inhibitor-1, and apolipoprotein A-I (se: 71.4%, sp.: 82.6%, accuracy: 77.25%). The sensitivity, specificity, and classification rate of the diagnostic model of MCI in elderly adults with lower education (human serum albumin) were each 75.0%. Additionally, the sensitivity, specificity, and accuracy rate of the diagnostic model for MCI elderly individuals with higher education (alpha-acid glycoprotein + soluble intercellular adhesion molecule-1 + pancreatic polypeptide) were 77.8%, 89.3%, and 83.60%, respectively. The performance of diagnostic models for MCI based on different educational levels is superior to that of diagnostic models for MCI without grouping by educational level.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

• #### Correction to: MicroRNA-351 Promotes the Proliferation and Invasion of Glioma Cells through Downregulation of NAIF1

The original version of this article unfortunately contained mistakes in the Affiliation section.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Recent studies have shown contribution of long non-coding RNAs (lncRNAs) in the pathogenesis of immune-related disorders including multiple sclerosis (MS). Based on the role of these transcripts in the regulation of immune response, peripheral levels of lncRNAs can reflect the level of immune activation. In the present study, we quantified expression of four lncRNAs namely SPRY4-IT1, HOXA-AS2, LINC-ROR, and MEG3 in venous blood of MS patients and controls using quantitative real-time PCR method. Relative expressions of SPRY4-IT1, HOXA-AS2, LINC-ROR, and MEG3 were significantly lower in female MS patients compared with female healthy subjects. For MEG3, this pattern of expression was also observed in male subjects. However, for other lncRNAs, no significant difference was detected between male patients and male controls. Expression of HOXA-AS2 was correlated with progression index (r = 0.36, P < 0.001). Besides, there was a significant correlation between expression of this lncRNA and expression of LINC-ROR in MS patients (r = 0.44, P < 0.0001). There was no other correlation between expression of lncRNAs and clinical data in MS patients. In control group, expressions of none of lncRNAs were correlated with age of persons. Notably, significant correlations were demonstrated between expression levels of all lncRNAs in healthy subjects with r values ranging from 0.23 to 0.42. The current investigation shows dysregulation of lncRNAs in MS patients in a sex-specific manner and warrants further studies to unravel the clinical and therapeutic implications of such dysregulation.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Glioblastoma (GBM) is the most serious brain tumor and shows a high rate of drug resistance. Wnt signaling is a very important pathway in GBM that can activate/inhibit other pathways, such as apoptosis and autophagy. In this study, we evaluated the efficacy of a combination of temozolomide (TMZ) plus curcumin or nanomicellar-curcumin on the inhibition of GBM growth in vitro, via effects on autophagy, apoptosis, and the Wnt signaling pathway. Two concentrations of curcumin and nanomicellar-curcumin (i.e., 20 μM and 50 μM) alone, and in combination with TMZ (50 μM) were used to induce cytotoxicity in the U87 GBM cell line. Wnt signaling–, autophagy-, and apoptosis-related genes were assessed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blots. All treatments (except 20 μM curcumin alone) significantly decreased the viability of U87 cells compared to controls. Curcumin (50 μM), nanomicellar-curcumin alone and in combination with TMZ significantly decreased the invasion and migration of U87 cells. Autophagy-related proteins (Beclin 1, LC3-I, LC3-II) were significantly increased. Apoptosis-related proteins (Bcl-2 and caspase 8) were also significantly increased, while Bax protein was significantly decreased. The expression levels of Wnt pathway–associated genes (β-catenin, cyclin D1, Twist, and ZEB1) were significantly reduced.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Serine Incorporator 2 (SERINC2) is a transmembrane protein that incorporates serine into membrane lipids. The function of SERINC2 in tumors has been reported, but the role of SERINC2 in gliomas is not fully understood. RNA-sequencing data from The Cancer Genome Atlas (TCGA) (530 cases of low-grade glioma (LGG) and 173 cases of glioblastoma multiforme (GBM)) and microarray data from Gene Expression Omnibus (GEO) (Accession No. GSE16011, 284 cases gliomas were included) were acquired. Bioinformatics analysis was performed as the primary method to examine the function of SERINC2 and its correlated genes in glioma. SERINC2 was highly expressed in GBM compared with LGG and normal brain tissues. Elevated SERINC2 expression predicted shorter 5-, 10-, and 15-year overall survival (OS) of LGG patients and isocitrate dehydrogenase-1 (IDH-1) mutation-type LGG patients but had no effect on the OS of GBM patients. Cox regression analysis showed that SERINC2 was an independent factor in LGG OS. Methylation analysis found that 13 CpG methylation sites (methylation450k) correlated with SERINC2 expression in LGG. The mRNA expression level of SERINC2 was significant lower in the DNA deletion group than in the intact and amplification groups. A total of 390 copositive and 244 conegative correlation genes with SERINC2 were obtained from LGG in TCGA-LGG and GSE16011. Gene ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the copositive correlation genes were primarily enriched in the mitotic process and cell cycle. Combining the results from the protein-protein interaction (PPI) network of SERINC2 correlation genes and CytoHubba led to the selection of 10 hub genes (CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE). OncoLnc analysis confirmed that high expression levels of these hub genes were associated with poor OS in LGG. Our results suggested that aberrant SERINC2 expression existed in glioma and that its expression might be a potential prognostic marker in LGG patients. CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE may be potential biomarkers and therapeutic targets for LGG.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Pancreatic cancer is one of the most aggressive and deadly malignancies with a very poor prognosis. Pancreatic cancer-induced visceral pain is very common and is generally presented among the initial symptoms in patients; such pain is strongly associated with poor quality of life, impaired functional activity, and decreased survival. However, the principal neurobiological mechanisms of pain caused by pancreatic cancer have not been fully elucidated. Accumulating studies have shown that miRNAs play a major role in chronic pain by suppressing key molecules involved in nociception. In the present study, we report that microRNA (miR)-330 is highly expressed in the spinal dorsal horn (SDH) of nude mice with pancreatic cancer pain. Mimicking pancreatic carcinoma-induced SDH miR-330 upregulation by microinjection of miR-330 mimic into the SDH significantly induced abdominal mechanical allodynia in normal nude mice. Additionally, we found that the expression of GABABR2 was significantly decreased in the SDH of nude mice with pancreatic cancer pain and was regulated directly by miR-330 both in vitro and in vivo. Furthermore, inhibition of miR-330 rescued the expression of GABABR2 and alleviated pancreatic carcinoma-induced abdominal pain hypersensitivity in nude mice with pancreatic carcinoma. These results show that miR-330 participates in the genesis of pancreatic carcinoma-induced pain hypersensitivity by inhibiting GABABR2 expression in the SDH and might be a potential therapeutic target for pancreatic cancer pain.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Alzheimer’s disease (AD), the most prevalent representation of dementia, is a neurodegenerative disease resulting from the degenerative disturbance of the central nervous system. Previous studies have indicated that miR-107 is reduced in the brain neocortex of patients with AD; however, its underlying mechanism is not clear. Therefore, the objective of this study was to explore the question of whether miR-107 participates in AD development. The study confirmed that the miR-107 expression levels were dramatically decreased in patients with AD and in beta-amyloid (Aβ) (Aβ)-treated SH-SY5Y cells compared with control groups. Upregulation of miR-107 reversed the inhibitory role of Aβ on cell proliferation and viability. In addition, miR-107 upregulation also ameliorated the Aβ-induced inflammation and apoptosis of SH-SY5Y cells. Furthermore, using bioinformatic prediction, dual-luciferase reporter assay (DLRA), quantitative polymerase chain reaction (qPCR), and Western blot (WB), miR-107 was confirmed to reduce the expression level of FGF7, and it subsequently deactivated the FGFR2/PI3K/Akt pathway. Moreover, FGF7 overexpression counteracted the role of miR-107 in the viability, proliferation, inflammation, and apoptosis of Aβ-induced SH-SY5Y cells.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Vascular cognitive impairment (VCI) is the second most common type of dementia that accounts for 15 to 30%. To date, VCI still lacks an effective therapeutic strategy and an objective diagnostic tool. MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression at the post-translational level, playing an essential role in the pathogenesis of VCI. Moreover, accumulating evidence has indicated that miRNAs could be used as therapeutic strategies and diagnostic biomarkers of diseases. In this review, we summarize various mechanisms of miRNA-based therapeutics and candidate miRNAs for clinical diagnosis in VCI. Results showed that miRNAs participate in VCI via different mechanisms, including neuronal death, inflammation, oxidative stress, blood-brain barrier permeability, and synaptic translation. Circulating miRNAs of VCI have been detected in serum, plasma, and cerebrospinal fluid with various diagnostic power. Taking together, miRNAs are a potential biomarker for being a therapeutic agent and a diagnostic tool of VCI.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

### Abstract

Mutations in the dystrophin gene could cause Duchenne muscular dystrophy (DMD), which is the most common muscular disorder in pediatrics. Considering the growing evidence on appropriateness of gene therapies for DMD, precise genetic diagnosis seems essential. Hence, we conducted a study to determine mutational patterns in Iranian children with DMD. To detect all probable large mutations in the dystrophin gene, 314 DMD patients were evaluated using the multiplex ligation-dependent probe amplification (MLPA). Subjects who were MLPA-negative underwent the next generation sequencing (NGS) to identify potential point mutations. MLPA detected deletions (79.93%) and duplications (5.41%) along the dystrophin gene of 268 patients. Distribution of large mutations was heterogeneous and followed hotspot pattern throughout the gene. From 46 patients who were MLPA-negative, 43 exhibited point mutations including nonsense in 7.64%, frameshifts in 4.77%, splicing in 0.96%, and missense variations in 0.32% of participants. Most of the point mutations were located between exons 19 and 40. In three patients (1%), no mutation was found using either MLPA or NGS. Two subjects had novel nonsense mutations (L1675X and E1199X) in their dystrophin gene, which were considered as the possible reason for elimination of major domains of the gene. The results of this study provided invaluable information regarding the distribution of various large and small mutations in Iranian individuals with DMD. Besides, the novel nonsense mutations L1675X and E1199X were identified within the highly conserved residues, leading to elimination of significant domains of the dystrophin gene.

in Journal of Molecular Neuroscience on October 01, 2020 12:00 AM.

• #### GP-GAN: Brain tumor growth prediction using stacked 3D generative adversarial networks from longitudinal MR Images

Publication date: Available online 17 September 2020

Source: Neural Networks

Author(s): Ahmed Elazab, Changmiao Wang, Syed Jamal Safdar Gardezi, Hongmin Bai, Qingmao Hu, Tianfu Wang, Chunqi Chang, Baiying Lei

in Neural Networks on September 18, 2020 06:00 PM.

• #### AMD-GAN: Attention encoder and multi-branch structure based generative adversarial networks for fundus disease detection from scanning laser ophthalmoscopy images

Publication date: Available online 17 September 2020

Source: Neural Networks

Author(s): Hai Xie, Haijun Lei, Xianlu Zeng, Yejun He, Guozhen Chen, Ahmed Elazab, Guanghui Yue, Jiantao Wang, Guoming Zhang, Baiying Lei

in Neural Networks on September 18, 2020 06:00 PM.

• #### Self-grouping convolutional neural networks

Publication date: Available online 17 September 2020

Source: Neural Networks

Author(s): Qingbei Guo, Xiao-Jun Wu, Josef Kittler, Zhiquan Feng

in Neural Networks on September 18, 2020 06:00 PM.

## Abstract

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

in Hippocampus on September 18, 2020 01:04 PM.

• #### The brain of the African wild dog. IV. The visual system

Lateral view of the brain of the African wild dog showing the location of the various visual cortical areas and regions identified anatomically in the current study. We could identify the four occipital visual areas 17, 18, 19 and 21, as well as suprasylvian, parietal and temporal regions likely comprised of multiple cortical areas. Scale bar = 1 cm.

## Abstract

The variegated pelage and social complexity of the African wild dog (Lycaon pictus) hint at the possibility of specializations of the visual system. Here, using a range of architectural and immunohistochemical stains, we describe the systems‐level organization of the image‐forming, nonimage forming, oculomotor, and accessory optic, vision‐associated systems in the brain of one representative individual of the African wild dog. For all of these systems, the organization, in terms of location, parcellation and topology (internal and external), is very similar to that reported in other carnivores. The image‐forming visual system consists of the superior colliculus, visual dorsal thalamus (dorsal lateral geniculate nucleus, pulvinar and lateral posterior nucleus) and visual cortex (occipital, parietal, suprasylvian, temporal and splenial visual regions). The nonimage forming visual system comprises the suprachiasmatic nucleus, ventral lateral geniculate nucleus, pretectal nuclear complex and the Edinger–Westphal nucleus. The oculomotor system incorporates the oculomotor, trochlear and abducens cranial nerve nuclei as well as the parabigeminal nucleus, while the accessory optic system includes the dorsal, lateral and medial terminal nuclei. The extent of similarity to other carnivores in the systems‐level organization of these systems indicates that the manner in which these systems process visual information is likely to be consistent with that found, for example, in the well‐studied domestic cat. It would appear that the sociality of the African wild dog is dependent upon the processing of information extracted from the visual system in the higher‐order cognitive and affective neural systems.

in Journal of Comparative Neurology on September 18, 2020 09:15 AM.

## Objectives

Adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology by their fifth decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo MRI‐based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross‐sectional relationship with age, beta‐amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.

## Methods

Participants from the Biomarkers of Alzheimer’s Disease in Down Syndrome (ADDS) study (n=138; 50±7 years; 39% women) with MRI data and a subset (n=90) with amyloid PET were included. We derived MRI‐based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET‐based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment‐DS (MCI‐DS), possible AD dementia, or definite AD dementia based on in‐depth assessments of cognition, function, and health status.

## Results

There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the fifth decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS<MCI‐DS<possible AD dementia<definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.

## Interpretation

The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity.

in Annals of Neurology on September 18, 2020 08:01 AM.

• #### Evolutionary Selective Imitation: Interpretable Agents by Imitation Learning Without a Demonstrator. (arXiv:2009.08403v1 [cs.NE])

We propose a new method for training an agent via an evolutionary strategy (ES), in which we iteratively improve a set of samples to imitate: Starting with a random set, in every iteration we replace a subset of the samples with samples from the best trajectories discovered so far. The evaluation procedure for this set is to train, via supervised learning, a randomly initialised neural network (NN) to imitate the set and then execute the acquired policy against the environment. Our method is thus an ES based on a fitness function that expresses the effectiveness of imitating an evolving data subset. This is in contrast to other ES techniques that iterate over the weights of the policy directly. By observing the samples that the agent selects for learning, it is possible to interpret and evaluate the evolving strategy of the agent more explicitly than in NN learning. In our experiments, we trained an agent to solve the OpenAI Gym environment Bipedalwalker-v3 by imitating an evolutionarily selected set of only 25 samples with a NN with only a few thousand parameters. We further test our method on the Procgen game Plunder and show here as well that the proposed method is an interpretable, small, robust and effective alternative to other ES or policy gradient methods.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Computational models in Electroencephalography. (arXiv:2009.08385v1 [q-bio.NC])

Computational models lie at the intersection of basic neuroscience and healthcare applications because they allow researchers to test hypotheses \textit{in silico} and predict the outcome of experiments and interactions that are very hard to test in reality. Yet, what is meant by "computational model" is understood in many different ways by researchers in different fields of neuroscience and psychology, hindering communication and collaboration. In this review, we point out the state of the art of computational modeling in Electroencephalography (EEG) and outline how these models can be used to integrate findings from electrophysiology, network-level models, and behavior. On the one hand, computational models serve to investigate the mechanisms that generate brain activity, for example measured with EEG, such as the transient emergence of oscillations at different frequency bands and/or with different spatial topographies. On the other hand, computational models serve to design experiments and test hypotheses \emph{in silico}. The final purpose of computational models of EEG is to obtain a comprehensive understanding of the mechanisms that underlie the EEG signal. This is crucial for an accurate interpretation of EEG measurements that may ultimately serve in the development of novel clinical applications.

in arXiv: Quantitative Biology: Neurons and Cognition on September 18, 2020 01:30 AM.

• #### EventProp: Backpropagation for Exact Gradients in Spiking Neural Networks. (arXiv:2009.08378v1 [q-bio.NC])

We derive the backpropagation algorithm for spiking neural networks composed of leaky integrate-and-fire neurons operating in continuous time. This algorithm, EventProp, computes the exact gradient of an arbitrary loss function of spike times and membrane potentials by backpropagating errors in time. For the first time, by leveraging methods from optimal control theory, we are able to backpropagate errors through spike discontinuities and avoid approximations or smoothing operations. EventProp can be applied to spiking networks with arbitrary connectivity, including recurrent, convolutional and deep feed-forward architectures. While we consider the leaky integrate-and-fire neuron model in this work, our methodology to derive the gradient can be applied to other spiking neuron models. As errors are backpropagated in an event-based manner (at spike times), EventProp requires the storage of state variables only at these times, providing favorable memory requirements. We demonstrate learning using gradients computed via EventProp in a deep spiking network using an event-based simulator and a non-linearly separable dataset encoded using spike time latencies. Our work supports the rigorous study of gradient-based methods to train spiking neural networks while providing insights toward the development of learning algorithms in neuromorphic hardware.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Modeling human visual search: A combined Bayesian searcher and saliency map approach for eye movement guidance in natural scenes. (arXiv:2009.08373v1 [cs.AI])

Finding objects is essential for almost any daily-life visual task. Saliency models have been useful to predict fixation locations in natural images, but are static, i.e., they provide no information about the time-sequence of fixations. Nowadays, one of the biggest challenges in the field is to go beyond saliency maps to predict a sequence of fixations related to a visual task, such as searching for a given target. Bayesian observer models have been proposed for this task, as they represent visual search as an active sampling process. Nevertheless, they were mostly evaluated on artificial images, and how they adapt to natural images remains largely unexplored.

Here, we propose a unified Bayesian model for visual search guided by saliency maps as prior information. We validated our model with a visual search experiment in natural scenes recording eye movements. We show that, although state-of-the-art saliency models perform well in predicting the first two fixations in a visual search task, their performance degrades to chance afterward. This suggests that saliency maps alone are good to model bottom-up first impressions, but are not enough to explain the scanpaths when top-down task information is critical. Thus, we propose to use them as priors of Bayesian searchers. This approach leads to a behavior very similar to humans for the whole scanpath, both in the percentage of target found as a function of the fixation rank and the scanpath similarity, reproducing the entire sequence of eye movements.

in arXiv: Quantitative Biology: Neurons and Cognition on September 18, 2020 01:30 AM.

• #### Unsupervised Image Classification Through Time-Multiplexed Photonic Multi-Layer Spiking Convolutional Neural Network. (arXiv:2009.08309v1 [q-bio.NC])

We present results of a deep photonic spiking convolutional neural network, based on two-section VCSELs, targeting image classification. Training is based on unsupervised spike-timing dependent plasticity, whereas neuron time-multiplexing and ultra-fast response are exploited towards a a reduction of the physical neuron count by 90%

in arXiv: Quantitative Biology: Neurons and Cognition on September 18, 2020 01:30 AM.

• #### The relationship between dynamic programming and active inference: the discrete, finite-horizon case. (arXiv:2009.08111v1 [cs.AI])

Active inference is a normative framework for generating behaviour based upon the free energy principle, a global theory of self-organisation. This framework has been successfully used to solve reinforcement learning and stochastic control problems, yet, the formal relation between active inference and reward maximisation has not been fully explicated. In this paper, we consider the relation between active inference and dynamic programming under the Bellman equation, which underlies many approaches to reinforcement learning and control. Our contribution shows that, on finite-horizon partially observed Markov decision processes, dynamic programming is a limiting case of active inference. In active inference, agents select actions in order to maximise expected free energy. In the absence of ambiguity about the latent causes of outcomes, this reduces to matching a target distribution encoding the agent's preferences. When these target states correspond to rewarding states, this minimises risk or maximises expected reward, as in reinforcement learning. When states are partially observed or ambiguous, an active inference agent will choose the action that minimises both risk and ambiguity. This allows active inference agents to supplement their reward maximising (or exploitative) behaviour with novelty-seeking (or exploratory) behaviour. This speaks to the unifying potential of active inference, as the functional optimised during action selection subsumes many important quantities used in decision-making in the physical, engineering, and life sciences.

in arXiv: Quantitative Biology: Neurons and Cognition on September 18, 2020 01:30 AM.

• #### Attracting Sets in Perceptual Networks. (arXiv:2009.08101v1 [q-bio.NC])

This document gives a specification for the model used in [1]. It presents a simple way of optimizing mutual information between some input and the attractors of a (noisy) network, using a genetic algorithm. The nodes of this network are modeled as simplified versions of the structures described in the "interface theory of perception" [2]. Accordingly, the system is referred to as a "perceptual network".

The present paper is an edited version of technical parts of [1] and serves as accompanying text for the Python implementation PerceptualNetworks, freely available under [3].

1. Prentner, R., and Fields, C.. Using AI methods to Evaluate a Minimal Model for Perception. OpenPhilosophy 2019, 2, 503-524.

2. Hoffman, D. D., Prakash, C., and Singh, M.. The Interface Theory of Perception. Psychonomic Bulletin and Review 2015, 22, 1480-1506.

3. Prentner, R.. PerceptualNetworks. https://github.com/RobertPrentner/PerceptualNetworks. (accessed September 17 2020)

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Distributional Generalization: A New Kind of Generalization. (arXiv:2009.08092v1 [cs.LG])

We introduce a new notion of generalization-- Distributional Generalization-- which roughly states that outputs of a classifier at train and test time are close *as distributions*, as opposed to close in just their average error. For example, if we mislabel 30% of dogs as cats in the train set of CIFAR-10, then a ResNet trained to interpolation will in fact mislabel roughly 30% of dogs as cats on the *test set* as well, while leaving other classes unaffected. This behavior is not captured by classical generalization, which would only consider the average error and not the distribution of errors over the input domain. This example is a specific instance of our much more general conjectures which apply even on distributions where the Bayes risk is zero. Our conjectures characterize the form of distributional generalization that can be expected, in terms of problem parameters (model architecture, training procedure, number of samples, data distribution). We verify the quantitative predictions of these conjectures across a variety of domains in machine learning, including neural networks, kernel machines, and decision trees. These empirical observations are independently interesting, and form a more fine-grained characterization of interpolating classifiers beyond just their test error.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Using Sensory Time-cue to enable Unsupervised Multimodal Meta-learning. (arXiv:2009.07879v1 [cs.CV])

As data from IoT (Internet of Things) sensors become ubiquitous, state-of-the-art machine learning algorithms face many challenges on directly using sensor data. To overcome these challenges, methods must be designed to learn directly from sensors without manual annotations. This paper introduces Sensory Time-cue for Unsupervised Meta-learning (STUM). Different from traditional learning approaches that either heavily depend on labels or on time-independent feature extraction assumptions, such as Gaussian distribution features, the STUM system uses time relation of inputs to guide the feature space formation within and across modalities. The fact that STUM learns from a variety of small tasks may put this method in the camp of Meta-Learning. Different from existing Meta-Learning approaches, STUM learning tasks are composed within and across multiple modalities based on time-cue co-exist with the IoT streaming data. In an audiovisual learning example, because consecutive visual frames usually comprise the same object, this approach provides a unique way to organize features from the same object together. The same method can also organize visual object features with the object's spoken-name features together if the spoken name is presented with the object at about the same time. This cross-modality feature organization may further help the organization of visual features that belong to similar objects but acquired at different location and time. Promising results are achieved through evaluations.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### A Privacy-Preserving-Oriented DNN Pruning and Mobile Acceleration Framework. (arXiv:2003.06513v2 [cs.LG] UPDATED)

Weight pruning of deep neural networks (DNNs) has been proposed to satisfy the limited storage and computing capability of mobile edge devices. However, previous pruning methods mainly focus on reducing the model size and/or improving performance without considering the privacy of user data. To mitigate this concern, we propose a privacy-preserving-oriented pruning and mobile acceleration framework that does not require the private training dataset. At the algorithm level of the proposed framework, a systematic weight pruning technique based on the alternating direction method of multipliers (ADMM) is designed to iteratively solve the pattern-based pruning problem for each layer with randomly generated synthetic data. In addition, corresponding optimizations at the compiler level are leveraged for inference accelerations on devices. With the proposed framework, users could avoid the time-consuming pruning process for non-experts and directly benefit from compressed models. Experimental results show that the proposed framework outperforms three state-of-art end-to-end DNN frameworks, i.e., TensorFlow-Lite, TVM, and MNN, with speedup up to 4.2X, 2.5X, and 2.0X, respectively, with almost no accuracy loss, while preserving data privacy.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Optimization of Convolutional Neural Network Using the Linearly Decreasing Weight Particle Swarm Optimization. (arXiv:2001.05670v2 [cs.NE] UPDATED)

Convolutional neural network (CNN) is one of the most frequently used deep learning techniques. Various forms of models have been proposed and improved for learning at CNN. When learning with CNN, it is necessary to determine the optimal hyperparameters. However, the number of hyperparameters is so large that it is difficult to do it manually, so much research has been done on automation. A method that uses metaheuristic algorithms is attracting attention in research on hyperparameter optimization. Metaheuristic algorithms are naturally inspired and include evolution strategies, genetic algorithms, antcolony optimization and particle swarm optimization. In particular, particle swarm optimization converges faster than genetic algorithms, and various models have been proposed. In this paper, we propose CNN hyperparameter optimization with linearly decreasing weight particle swarm optimization (LDWPSO). In the experiment, the MNIST data set and CIFAR-10 data set, which are often used as benchmark data sets, are used. By optimizing CNN hyperparameters with LDWPSO, learning the MNIST and CIFAR-10 datasets, we compare the accuracy with a standard CNN based on LeNet-5. As a result, when using the MNIST dataset, the baseline CNN is 94.02% at the 5th epoch, compared to 98.95% for LDWPSO CNN, which improves accuracy. When using the CIFAR-10 dataset, the Baseline CNN is 28.07% at the 10th epoch, compared to 69.37% for the LDWPSO CNN, which greatly improves accuracy.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Genetic Neural Architecture Search for automatic assessment of human sperm images. (arXiv:1909.09432v2 [cs.LG] UPDATED)

Male infertility is a disease which affects approximately 7% of men. Sperm morphology analysis (SMA) is one of the main diagnosis methods for this problem. Manual SMA is an inexact, subjective, non-reproducible, and hard to teach process. As a result, in this paper, we introduce a novel automatic SMA based on a neural architecture search algorithm termed Genetic Neural Architecture Search (GeNAS). For this purpose, we used a collection of images called MHSMA dataset contains 1,540 sperm images which have been collected from 235 patients with infertility problems. GeNAS is a genetic algorithm that acts as a meta-controller which explores the constrained search space of plain convolutional neural network architectures. Every individual of the genetic algorithm is a convolutional neural network trained to predict morphological deformities in different segments of human sperm (head, vacuole, and acrosome), and its fitness is calculated by a novel proposed method named GeNAS-WF especially designed for noisy, low resolution, and imbalanced datasets. Also, a hashing method is used to save each trained neural architecture fitness, so we could reuse them during fitness evaluation and speed up the algorithm. Besides, in terms of running time and computation power, our proposed architecture search method is far more efficient than most of the other existing neural architecture search algorithms. Additionally, other proposed methods have been evaluated on balanced datasets, whereas GeNAS is built specifically for noisy, low quality, and imbalanced datasets which are common in the field of medical imaging. In our experiments, the best neural architecture found by GeNAS has reached an accuracy of 91.66%, 77.33%, and 77.66% in the vacuole, head, and acrosome abnormality detection, respectively. In comparison to other proposed algorithms for MHSMA dataset, GeNAS achieved state-of-the-art results.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 18, 2020 01:30 AM.

• #### Editorial Expression of Concern: Living annulative π-extension polymerization for graphene nanoribbon synthesis

Nature, Published online: 18 September 2020; doi:10.1038/s41586-020-2756-0

Editorial Expression of Concern: Living annulative π-extension polymerization for graphene nanoribbon synthesis

in Nature on September 18, 2020 12:00 AM.

• #### Author Correction: Coupling dinitrogen and hydrocarbons through aryl migration

Nature, Published online: 18 September 2020; doi:10.1038/s41586-020-2722-x

Author Correction: Coupling dinitrogen and hydrocarbons through aryl migration

in Nature on September 18, 2020 12:00 AM.

• #### Three-dimensional strain dynamics govern the hysteresis in heterogeneous catalysis

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18622-2

Direct visualisation of site-specific strain variations of catalysts is needed to better understand catalytic properties. Here, the authors determine with attojoule precision that the well-known catalytic hysteresis phenomenon occurs at single particle level and involves three-dimensional strain field.

in Nature Communications on September 18, 2020 12:00 AM.

• #### Realization of acoustic spin transport in metasurface waveguides

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18599-y

Spin angular momenta play a crucial role in topological phases of matter, in acoustic waves they have been demonstrated recently. Here, the authors present a symmetry-breaking metasurface waveguide that assists backscattering suppression of acoustic waves, because of tight spin-momentum coupling.

in Nature Communications on September 18, 2020 12:00 AM.

• #### Ultrasensitive and visual detection of SARS-CoV-2 using all-in-one dual CRISPR-Cas12a assay

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18575-6

Rapid and early detection of SARS-CoV-2 will aid intervention to stop disease spread. Here the authors present a one-pot CRISPR-based rapid detection system with visual readout.

in Nature Communications on September 18, 2020 12:00 AM.

• #### SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18549-8

Cancer stem cells can evade treatment. Here, the authors perform an in vitro screen to identify proteins that are involved in protecting glioma cancer stem cells from therapy and find that SPT6 increases BRCA1 expression and drives error-free DNA repair, thereby ensuring the survival of the cells.

in Nature Communications on September 18, 2020 12:00 AM.

• #### Structural and mechanistic basis of capsule O-acetylation in Neisseria meningitidis serogroup A

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18464-y

Neisseria meningitidis capsular polysaccharide (CPS) is a major virulence factor and vaccine formulations against Neisseria meningitidis serogroup A (NmA) contain O-acetylated CPS. Here, the authors provide mechanistic insights into CPS O-acetylation in NmA by determining the crystal structure of the O-acetyltransferase CsaC and NMR measurements further reveal that the CsaC-mediated reaction is regioselective for O3 and that the O4 modification results from spontaneous O-acetyl migration.

in Nature Communications on September 18, 2020 12:00 AM.

• #### Retrieving functional pathways of biomolecules from single-particle snapshots

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18403-x

There is a great interest in retrieving functional pathways from cryo-EM single-particle data. Here, the authors present an approach that combines cryo-EM with advanced data-analytical methods and molecular dynamics simulations to reveal the functional pathways traversed on experimentally derived energy landscapes using the ryanodine receptor type 1 as an example.

in Nature Communications on September 18, 2020 12:00 AM.

• #### Hot electrons in a nanowire hard X-ray detector

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18384-x

Designing efficient nanowire chip-based electrical and optical devices remains a challenge. Here, the authors present an axial p-n junction GaAs nanowire X-ray detector that enables achieving a spatial resolution of 200 nm; probing the internal electrical field and observing hot electron effects at the nanoscale.

in Nature Communications on September 18, 2020 12:00 AM.

• #### DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Nature Communications, Published online: 18 September 2020; doi:10.1038/s41467-020-18304-z

DsbA-L upregulation prevents lipid-induced renal injury in diabetic nephropathy. Here, the authors show that DsbA-L knockout attenuates tubulointerstitial fibrosis in mice, and show that this occurs via activation of Smad3 and p53, which result in modulation of CTGF, a regulator of kidney fibrosis.

in Nature Communications on September 18, 2020 12:00 AM.

• #### Daily briefing: Genes map how the Vikings spread across Europe

Nature, Published online: 18 September 2020; doi:10.1038/d41586-020-02693-8

Genetics reveals which Vikings went where during the influential Viking Age. Plus, how to get a COVID-19 vaccine to those who need it most and what happens when you read a paper every single day.

in Nature on September 18, 2020 12:00 AM.

• #### Microscopy illuminates charcoal’s sketchy origins

Nature, Published online: 18 September 2020; doi:10.1038/d41586-020-02672-z

A large volume of charcoal sold in Europe comes from tropical forests and is often incorrectly labelled, raising questions about whether it was logged illegally.

in Nature on September 18, 2020 12:00 AM.

• #### COVID research updates: Musicians and a monk are tied to superspreading in Hong Kong

Nature, Published online: 18 September 2020; doi:10.1038/d41586-020-00502-w

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

in Nature on September 18, 2020 12:00 AM.

• #### A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For TSC1, few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet TSC1 has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in TSC1, R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse TSC1. We found these variants complemented a known phenotype caused by loss of TSC1, increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some TSC1 missense variants and provide an in vivo system to assess TSC1 variants’ neurological impact better.

in Frontiers in Molecular Neuroscience on September 18, 2020 12:00 AM.

• #### Anterograde Axonal Transport in Neuronal Homeostasis and Disease

Neurons are highly polarized cells with an elongated axon that extends far away from the cell body. To maintain their homeostasis, neurons rely extensively on axonal transport of membranous organelles and other molecular complexes. Axonal transport allows for spatio-temporal activation and modulation of numerous molecular cascades, thus playing a central role in the establishment of neuronal polarity, axonal growth and stabilization, and synapses formation. Anterograde and retrograde axonal transport are supported by various molecular motors, such as kinesins and dynein, and a complex microtubule network. In this review article, we will primarily discuss the molecular mechanisms underlying anterograde axonal transport and its role in neuronal development and maturation, including the establishment of functional synaptic connections. We will then provide an overview of the molecular and cellular perturbations that affect axonal transport and are often associated with axonal degeneration. Lastly, we will relate our current understanding of the role of axonal trafficking concerning anterograde trafficking of mRNA and its involvement in the maintenance of the axonal compartment and disease.

in Frontiers in Molecular Neuroscience on September 18, 2020 12:00 AM.

• #### Home-Based Transcranial Direct Current Stimulation (tDCS) to Prevent and Treat Symptoms Related to Stress: A Potential Tool to Remediate the Behavioral Consequences of the COVID-19 Isolation Measures?

in Frontiers in Integrative Neuroscience on September 18, 2020 12:00 AM.

• #### Evidence of Progenitor Cell Lineage Rerouting in the Adult Mouse Hippocampus After Status Epilepticus

Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that 3 days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus (DG) co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Unilateral intrahippocampal administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) triggered epileptiform discharges and led to a significant increase in the number of GFP+ cells in both ipsi and contralateral DG. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. We also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, suggesting that some Dcx-progenitors could regress to a multipotent stage. The boosted neurogenesis and astrogliogenesis observed in the Dcx-lineage following chemoconvulsants administration correlated, respectively, with preservation or degeneration of the parvalbuminergic plexus in the DG. Increased inflammatory response, by contrast, was observed both in the DG showing increased neurogenesis or astrogliogenesis. Altogether, our data support the view that cell lineage progression in the adult hippocampus is not unidirectional and could be modulated by local network activity and GABA-mediated signaling.

in Frontiers in Neuroscience: Neurogenesis on September 18, 2020 12:00 AM.

• #### Snowball ICA: A Model Order Free Independent Component Analysis Strategy for Functional Magnetic Resonance Imaging Data

In independent component analysis (ICA), the selection of model order (i.e., number of components to be extracted) has crucial effects on functional magnetic resonance imaging (fMRI) brain network analysis. Model order selection (MOS) algorithms have been used to determine the number of estimated components. However, simulations show that even when the model order equals the number of simulated signal sources, traditional ICA algorithms may misestimate the spatial maps of the signal sources. In principle, increasing model order will consider more potential information in the estimation, and should therefore produce more accurate results. However, this strategy may not work for fMRI because large-scale networks are widely spatially distributed and thus have increased mutual information with noise. As such, conventional ICA algorithms with high model orders may not extract these components at all. This conflict makes the selection of model order a problem. We present a new strategy for model order free ICA, called Snowball ICA, that obviates these issues. The algorithm collects all information for each network from fMRI data without the limitations of network scale. Using simulations and in vivo resting-state fMRI data, our results show that component estimation using Snowball ICA is more accurate than traditional ICA. The Snowball ICA software is available at https://github.com/GHu-DUT/Snowball-ICA.

in Frontiers in Neuroscience: Brain Imaging Methods on September 18, 2020 12:00 AM.

• #### BCIAUT-P300: A Multi-Session and Multi-Subject Benchmark Dataset on Autism for P300-Based Brain-Computer-Interfaces

There is a lack of multi-session P300 datasets for Brain-Computer Interfaces (BCI). Publicly available datasets are usually limited by small number of participants with few BCI sessions. In this sense, the lack of large, comprehensive datasets with various individuals and multiple sessions has limited advances in the development of more effective data processing and analysis methods for BCI systems. This is particularly evident to explore the feasibility of deep learning methods that require large datasets. Here we present the BCIAUT-P300 dataset, containing 15 autism spectrum disorder individuals undergoing 7 sessions of P300-based BCI joint-attention training, for a total of 105 sessions. The dataset was used for the 2019 IFMBE Scientific Challenge organized during MEDICON 2019 where, in two phases, teams from all over the world tried to achieve the best possible object-detection accuracy based on the P300 signals. This paper presents the characteristics of the dataset and the approaches followed by the 9 finalist teams during the competition. The winner obtained an average accuracy of 92.3% with a convolutional neural network based on EEGNet. The dataset is now publicly released and stands as a benchmark for future P300-based BCI algorithms based on multiple session data.

in Frontiers in Neuroscience: Neural Technology on September 18, 2020 12:00 AM.

• #### Low-Temperature Atomic Layer Deposited Oxide on Titanium Nitride Electrodes Enables Culture and Physiological Recording of Electrogenic Cells

The performance of electrode arrays insulated by low-temperature atomic layer deposited (ALD) titanium dioxide (TiO2) or hafnium dioxide (HfO2) for culture of electrogenic cells and for recording of extracellular action potentials is investigated. If successful, such insulation may be considered to increase the stability of future neural implants. Here, insulation of titanium nitride electrodes of microelectrode arrays (MEAs) was performed using ALD of nanometer-sized TiO2 or hafnium oxide at low temperatures (100–200°C). The electrode properties, impedance, and leakage current were measured and compared. Although electrode insulation using ALD oxides increased the electrode impedance, it did not prevent stable, physiological recordings of electrical activity from electrogenic cells (cardiomyocytes and neurons). The insulation quality, estimated from leakage current measurements, was less than 100 nA/cm2 in a range of 3 V. Cardiomyocytes were successfully cultured and recorded after 5 days on the insulated MEAs with signal shapes similar to the recordings obtained using uncoated electrodes. Light-induced electrical activity of retinal ganglion cells was recorded using a complementary metal-oxide semiconductor-based MEA insulated with HfO2 without driving the recording electrode into saturation. The presented results demonstrate that low-temperature ALD-deposited TiO2 and hafnium oxide are biocompatible and biostable and enable physiological recordings. Our results indicate that nanometer-sized ALD insulation can be used to protect electrodes for long-term biological applications.

in Frontiers in Neuroscience: Neural Technology on September 18, 2020 12:00 AM.

• #### Molecular Imaging of Striatal Dopaminergic Neuronal Loss and the Neurovascular Unit in Parkinson Disease

Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by loss of nigrostriatal dopaminergic neurons. Impairment of the neurovascular unit (NVU) has been hypothesized to play a critical role in early PD pathophysiology, and to precede neurodegenerative mechanisms. [C-11]-PE2I (N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane) (PE2I) is a PET radiotracer targeting neuronal dopamine transporters (DaT) with high specificity, allowing for highly accurate and specific DaT quantification. We investigated NVU integrity using arterial spin labeling (ASL) MRI in a prospective cohort of 26 patients with PD, and correlated our findings with analysis of striatal DaT density using PE2I PET in a subcohort of 17 patients. Analysis was performed in FreeSurfer to obtain rCBF and mean standardized regional PET avidity. Pearson correlations and Mann–Whitney tests were performed. Significantly lower mean normalized striatal PE2I SUV values were seen in multiple regions in patients with greater disease duration (p < 0.05). PET uptake in the putamen correlated with disease duration independent of patient age. Stratifying patients based on Montreal Cognitive Assessment (MoCA) scores (stratified into ≥ 27 vs. < 27), there was statistically significantly lower PE2I PET avidity in the higher MoCA score group in both more and less affected sides of the caudate, putamen and pallidum (p < 0.05). A moderate negative correlation between MDS-UPDRS part 3 (motor) “off” and rCBF values was also seen in the L and R cerebellum WM (r = −0.43 and −0.47, p < 0.05). A statistically significant negative correlation was found between dominant hand pegboard test results and rCBF in the less affected pallidum (r = −0.41; p = 0.046). A statistically significant negative correlation of ASL MRI with [11C]-PE2I PET was also found (r = −0.53 to −0.58; p-value 0.017–0.033) between left cerebral WM rCBF and more and less affected striatal PET regions. Our ROI-based analyses suggest that longer disease duration is associated with lower rCBF and lower PE2I mean SUV, implying greater NVU dysfunction and dopaminergic neuronal loss, respectively. Combined ASL MRI and PE2I PET imaging could inform future prospective clinical trials providing an improved mechanistic understanding of the disease, laying the foundation for the development of early disease biomarkers and potential therapeutic targets.

in Frontiers in Neuroscience: Brain Imaging Methods on September 18, 2020 12:00 AM.

• #### Dynamic Neural Network Changes Revealed by Voxel-Based Functional Connectivity Strength in Left Basal Ganglia Ischemic Stroke

Objective

This study intends to track whole-brain functional connectivity strength (FCS) changes and the lateralization index (LI) in left basal ganglia (BG) ischemic stroke patients.

Methods

Twenty-five patients (N = 25; aged 52.73 ± 10.51 years) with five visits at <7, 14, 30, 90, and 180 days and 26 healthy controls (HCs; N = 26; 51.84 ± 8.06 years) were examined with resting-state functional magnetic resonance imaging (rs-fMRI) and motor function testing. FCS and LI were calculated through constructing the voxel-based brain functional network. One-way analysis of covariance (ANOVA) was first performed to obtain longitudinal FCS and LI changes in patients among the five visits (Bonferroni corrected, P < 0.05). Then, pairwise comparisons of FCS and LI were obtained during the five visits, and the two-sample t test was used to examine between-group differences in FCS [family-wise error (FWE) corrected, P < 0.05] and LI. Correlations between connectivity metrics (FCS and LI) and motor function were further assessed.

Results

Compared to HCs, decreased FCS in the patients localized in the calcarine and inferior occipital gyrus (IOG), while increased FCS gathered in the middle prefrontal cortex (MPFC), middle frontal gyrus, and insula (P < 0.05). The LI and FCS of patients first decreased and then increased, which showed significant differences compared with HCs (P < 0.05) and demonstrated a transition at the 30-day visit. Additionally, LI at the third visit was significantly different from those at the other visits (P < 0.05). No significant longitudinal correlations were observed between motor function and FCS or LI (P > 0.05).

Conclusion

Focal ischemic stroke in the left BG leads to extensive alterations in the FCS. Strong plasticity in the functional networks could be reorganized in different temporal dynamics to facilitate motor recovery after BG stroke, contribute to diagnosing the disease course, and estimate the intervention treatment.

in Frontiers in Neuroscience: Brain Imaging Methods on September 18, 2020 12:00 AM.

• #### Penetrating Ballistic-Like Brain Injury Leads to MicroRNA Dysregulation, BACE1 Upregulation, and Amyloid Precursor Protein Loss in Lesioned Rat Brain Tissues

Severe traumatic brain injury (TBI) is a risk factor for neurodegenerative diseases. Yet, the molecular events involving dysregulated miRNAs that may be associated with protein degradation in the brain remains elusive. Quantitation of more than 800 miRNAs was conducted using rat ipsilateral coronal brain tissues collected 1, 3, or 7 days after penetrating ballistic-like brain injury (PBBI). As a control for each time-point, Sham-operated animals received craniotomy alone. Microarray and systems biology analysis indicated that the amplitude and complexity of miRNAs affected were greatest 7 day after PBBI. Arrays and Q-PCR inferred that dysregulation of miR-135a, miR-328, miR-29c, and miR-21 were associated with altered levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), PSEN1, PSEN2, and amyloid precursor protein (APP) genes. These events were followed by increased levels of mature BACE1 protein and concomitant loss of full length APP within 3–7 days, then elevation of amyloid beta (Aβ)-40 7 days after PBBI. This study indicates that miRNA arrays, coupled with systems biology, may be used to guide study design prior validation of miRNA dysregulation. Associative analysis of miRNAs, mRNAs, and proteins within a proposed pathway are poised for further validation as biomarkers and therapeutic targets relevant to TBI-induced APP loss and subsequent Aβ peptide generation during neurodegeneration.

in Frontiers in Neuroscience: Neurodegeneration on September 18, 2020 12:00 AM.

• #### Early Prediction of Cognitive Deficit in Very Preterm Infants Using Brain Structural Connectome With Transfer Learning Enhanced Deep Convolutional Neural Networks

Up to 40% of very preterm infants (≤32 weeks’ gestational age) were identified with a cognitive deficit at 2 years of age. Yet, accurate clinical diagnosis of cognitive deficit cannot be made until early childhood around 3–5 years of age. Recently, brain structural connectome that was constructed by advanced diffusion tensor imaging (DTI) technique has been playing an important role in understanding human cognitive functions. However, available annotated neuroimaging datasets with clinical and outcome information are usually limited and expensive to enlarge in the very preterm infants’ studies. These challenges hinder the development of neonatal prognostic tools for early prediction of cognitive deficit in very preterm infants. In this study, we considered the brain structural connectome as a 2D image and applied established deep convolutional neural networks to learn the spatial and topological information of the brain connectome. Furthermore, the transfer learning technique was utilized to mitigate the issue of insufficient training data. As such, we developed a transfer learning enhanced convolutional neural network (TL-CNN) model for early prediction of cognitive assessment at 2 years of age in very preterm infants using brain structural connectome. A total of 110 very preterm infants were enrolled in this work. Brain structural connectome was constructed using DTI images scanned at term-equivalent age. Bayley III cognitive assessments were conducted at 2 years of corrected age. We applied the proposed model to both cognitive deficit classification and continuous cognitive score prediction tasks. The results demonstrated that TL-CNN achieved improved performance compared to multiple peer models. Finally, we identified the brain regions most discriminative to the cognitive deficit. The results suggest that deep learning models may facilitate early prediction of later neurodevelopmental outcomes in very preterm infants at term-equivalent age.

in Frontiers in Neuroscience: Brain Imaging Methods on September 18, 2020 12:00 AM.

• #### The International Neuromodulation Registry: An Informatics Framework Supporting Cohort Discovery and Analysis

Background

Neuromodulation therapies, such as deep brain stimulation (DBS), spinal cord stimulation (SCS), responsive neurostimulation (RNS), transcranial magnetic stimulation (TMS), transcranial direct stimulation (tDCS), and vagus nerve stimulation (VNS) are used to treat neurological and psychiatric conditions for patients who have failed to benefit from other treatment approaches. Although generally effective, seemingly similar cases often have very different levels of effectiveness. While there is ongoing interest in developing predictors, it can be difficult to aggregate the necessary data from limited cohorts of patients at individual treatment centers.

Objective

In order to increase the predictive power in neuromodulation studies, we created an informatics platform called the International Neuromodulation Registry (INR). The INR platform has a data flow process that will allow researchers to pool data across multiple centers to enable population health research.

Methods

This custom informatics platform has a Neo4j graph database and includes a harmonization process that allows data from different studies to be aggregated and compared. Users of the INR can download deidentified patient imaging, patient demographic data, device settings, and medical rating scales. The INR supports complex network analysis and patient timeline visualization.

Results

The INR currently houses and allows visualization of deidentified imaging and clinical data from hundreds of patients with a wide range of diagnoses and neuromodulation therapies.

Conclusion

Ultimately, we believe that widespread adoption of the INR platform will improve population health research in neuromodulation therapy.

in Frontiers in Neuroinformatics on September 18, 2020 12:00 AM.

• #### Musical Tension Associated With Violations of Hierarchical Structure

Tension is one of the core principles of emotion evoked by music, linking objective musical events and subjective experience. The present study used continuous behavioral rating and electroencephalography (EEG) to investigate the dynamic process of tension generation and its underlying neurocognitive mechanisms; specifically, tension induced by structural violations at different music hierarchical levels. In the experiment, twenty-four musicians were required to rate felt tension continuously in real-time, while listening to music sequences with either well-formed structure, phrase violations, or period violations. The behavioral data showed that structural violations gave rise to increasing and accumulating tension experience as the music unfolded; tension was increased dramatically by structural violations. Correspondingly, structural violations elicited N5 at GFP peaks, and induced decreasing neural oscillations power in the alpha frequency band (8–13 Hz). Furthermore, compared to phrase violations, period violations elicited larger N5 and induced a longer-lasting decrease of power in the alpha band, suggesting a hierarchical manner of musical processing. These results demonstrate the important role of musical structure in the generation of the experience of tension, providing support to the dynamic view of musical emotion and the hierarchical manner of tension processing.

in Frontiers in Human Neuroscience on September 18, 2020 12:00 AM.

• #### Neural Correlates of Repetition Priming: A Coordinate-Based Meta-Analysis of fMRI Studies

Repetition priming is a form of implicit memory, whereby classification or identification of a stimulus is improved by prior presentation of the same stimulus. Repetition priming is accompanied with a deceased fMRI signal for primed vs. unprimed stimuli in various brain regions, often called “repetition suppression,” or RS. Previous studies proposed that RS in posterior regions is associated with priming of perceptual processes, whereas RS in more anterior (prefrontal) regions is associated with priming of conceptual processes. To clarify which regions exhibit reliable RS associated with perceptual and conceptual priming, we conducted a quantitative meta-analysis using coordinate-based activation likelihood estimation. This analysis included 65 fMRI studies that (i) employed visual repetition priming during either perceptual or conceptual tasks, (ii) demonstrated behavioral priming, and (iii) reported the results from whole-brain analyses. Our results showed that repetition priming was mainly associated with RS in left inferior frontal gyrus and fusiform gyrus. Importantly, RS in these regions was found for both perceptual and conceptual tasks, and no regions show RS that was selective to one of these tasks. These results question the simple distinction between conceptual and perceptual priming, and suggest consideration of other factors such as stimulus-response bindings.

in Frontiers in Human Neuroscience on September 18, 2020 12:00 AM.

• #### Bi-Dimensional Approach Based on Transfer Learning for Alcoholism Pre-disposition Classification via EEG Signals

Recent statistics have shown that the main difficulty in detecting alcoholism is the unreliability of the information presented by patients with alcoholism; this factor confusing the early diagnosis and it can reduce the effectiveness of treatment. However, electroencephalogram (EEG) exams can provide more reliable data for analysis of this behavior. This paper proposes a new approach for the automatic diagnosis of patients with alcoholism and introduces an analysis of the EEG signals from a two-dimensional perspective according to changes in the neural activity, highlighting the influence of high and low-frequency signals. This approach uses a two-dimensional feature extraction method, as well as the application of recent Computer Vision (CV) techniques, such as Transfer Learning with Convolutional Neural Networks (CNN). The methodology to evaluate our proposal used 21 combinations of the traditional classification methods and 84 combinations of recent CNN architectures used as feature extractors combined with the following classical classifiers: Gaussian Naive Bayes, K-Nearest Neighbor (k-NN), Multilayer Perceptron (MLP), Random Forest (RF) and Support Vector Machine (SVM). CNN MobileNet combined with SVM achieved the best results in Accuracy (95.33%), Precision (95.68%), F1-Score (95.24%), and Recall (95.00%). This combination outperformed the traditional methods by up to 8%. Thus, this approach is applicable as a classification stage for computer-aided diagnoses, useful for the triage of patients, and clinical support for the early diagnosis of this disease.

in Frontiers in Human Neuroscience on September 18, 2020 12:00 AM.

• #### The Dynamics of Functional Brain Networks Associated With Depressive Symptoms in a Nonclinical Sample

Brain function depends on the flexible and dynamic coordination of functional subsystems within distributed neural networks operating on multiple scales. Recent progress has been made in the characterization of functional connectivity (FC) at the whole-brain scale from a dynamic, rather than static, perspective, but its validity for cognitive sciences remains under debate. Here, we analyzed brain activity recorded with functional Magnetic Resonance Imaging from 71 healthy participants evaluated for depressive symptoms after a relationship breakup based on the conventional Major Depression Inventory (MDI). We compared both static and dynamic FC patterns between participants reporting high and low depressive symptoms. Between-group differences in static FC were estimated using a standard pipeline for network-based statistic (NBS). Additionally, FC was analyzed from a dynamic perspective by characterizing the occupancy, lifetime, and transition profiles of recurrent FC patterns. Recurrent FC patterns were defined by clustering the BOLD phase-locking patterns obtained using leading eigenvector dynamics analysis (LEiDA). NBS analysis revealed a brain subsystem exhibiting significantly lower within-subsystem correlation values in more depressed participants (high MDI). This subsystem predominantly comprised connections between regions of the default mode network (i.e., precuneus) and regions outside this network. On the other hand, LEiDA results showed that high MDI participants engaged more in a state connecting regions of the default mode, memory retrieval, and frontoparietal network (p-FDR = 0.012); and less in a state connecting mostly the visual and dorsal attention systems (p-FDR = 0.004). Although both our analyses on static and dynamic FC implicate the role of the precuneus in depressive symptoms, only including the temporal evolution of BOLD FC helped to disentangle over time the distinct configurations in which this region plays a role. This finding further indicates that a holistic understanding of brain function can only be gleaned if the temporal dynamics of FC is included.

in Frontiers in Neural Circuits on September 18, 2020 12:00 AM.

• #### Phenotyping CCL2 Containing Central Amygdala Neurons Controlling Alcohol Withdrawal-Induced Anxiety

Chemokines such as chemokine (C-C motif) ligand 2 (CCL2) play a role in several behaviors, including anxiety-like behavior, but whether neurons are an important source of CCL2 for behavior and how neuronal CCL2 may work to affect behavior are still debated. When a herpes simplex virus (HSV) vector was used to knockdown CCL2 mRNA in neurons of the central nucleus of the amygdala (CeA) in rats experiencing multiple withdrawals from low dose ethanol, anxiety-like behavior appeared in the social interaction task. To examine this finding further Fractalkine (CX3CL1), a chemokine that is often found to have an opposing function to CCL2 was measured in these rats. Both alcohol withdrawal and CCL2 knockdown increased the levels of the anti-inflammatory protein CX3CL1. The combination of alcohol withdrawal and CCL2 knockdown decreased CX3CL1 and may alter pro-inflammatory/anti-inflammatory balance, and thus highlights the potential importance of CCL2 and CCL2/CX3CL1 balance in anxiety. To find a mechanism by which neuronal chemokines like CCL2 could affect behavior, retrograde tracing with fluorescent nanobeads was done in two brain regions associated with anxiety the bed nucleus of the stria terminalis (BNST) and the ventral periaqueductal gray (VPAG). These studies identified CeA projection neurons to these brain regions that contain CCL2. To demonstrate that CCL2 can be transported via axons to downstream brain regions, the axonal transport blocker, colchicine, was given and 24 h later, the accumulation of CCL2 in CeA neuronal cell bodies was found. Finally, CCL2 in CeA neurons was localized to the synapse using confocal microscopy with enhanced resolution following deconvolution and electron microscopy, which along with the other evidence suggests that CCL2 may be transported down axons in CeA neurons and released from nerve terminals perhaps into brain regions like the BNST and VPAG to affect behaviors such as anxiety. These results suggest that neurons are an important target for chemokine research related to behavior.

in Frontiers in Cellular Neuroscience on September 18, 2020 12:00 AM.

• #### A Dual Nanosensor Approach to Determine the Cytosolic Concentration of ATP in Astrocytes

Adenosine triphosphate (ATP) is the central energy carrier of all cells and knowledge on the dynamics of the concentration of ATP ([ATP]) provides important insights into the energetic state of a cell. Several genetically encoded fluorescent nanosensors for ATP were developed, which allow following the cytosolic [ATP] at high spatial and temporal resolution using fluorescence microscopy. However, to calibrate the fluorescent signal to [ATP] has remained challenging. To estimate basal cytosolic [ATP] ([ATP]0) in astrocytes, we here took advantage of two ATP nanosensors of the ATeam-family (ATeam1.03; ATeam1.03YEMK) with different affinities for ATP. Altering [ATP] by external stimuli resulted in characteristic pairs of signal changes of both nanosensors, which depend on [ATP]0. Using this dual nanosensor strategy and epifluorescence microscopy, [ATP]0 was estimated to be around 1.5 mM in primary cultures of cortical astrocytes from mice. Furthermore, in astrocytes in acutely isolated cortical slices from mice expressing both nanosensors after stereotactic injection of AAV-vectors, 2-photon microscopy revealed [ATP]0 of 0.7 mM to 1.3 mM. Finally, the change in [ATP] induced in the cytosol of cultured cortical astrocytes by application of azide, glutamate, and an increased extracellular concentration of K+ were calculated as −0.50 mM, −0.16 mM, and 0.07 mM, respectively. In summary, the dual nanosensor approach adds another option for determining the concentration of [ATP] to the increasing toolbox of fluorescent nanosensors for metabolites. This approach can also be applied to other metabolites when two sensors with different binding properties are available.

in Frontiers in Cellular Neuroscience on September 18, 2020 12:00 AM.

• #### Microglial Immunometabolism in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. In response to Aβ and tau aggregates, microglia, the primary innate immune cells of the central nervous system (CNS), facilitate Aβ and tau clearance and contribute to neuroinflammation that damages neurons. Microglia also perform a wide range of other functions, e.g., synaptic pruning, within the CNS that require a large amount of energy. Glucose appears to be the primary energy source, but microglia can utilize several other substrates for energy production including other sugars and ketone bodies. Recent studies have demonstrated that changes in the metabolic profiles of immune cells, including macrophages, are important in controlling their activation and effector functions. Additional studies have focused on the role of metabolism in neuron and astrocyte function while until recently microglia metabolism has been considerably less well understood. Considering many neurological disorders, such as neurodegeneration associated with AD, are associated with chronic inflammation and alterations in brain energy metabolism, it is hypothesized that microglial metabolism plays a significant role in the inflammatory responses of microglia during neurodegeneration. Here, we review the role of microglial immunometabolism in AD.

in Frontiers in Cellular Neuroscience on September 18, 2020 12:00 AM.

• #### Lower Thalamic Blood Flow Is Associated With Slower Stride Velocity in Older Adults

Background

Gait deficits are associated with brain atrophy and white matter hyperintensities (WMH) – both markers of underlying cerebral small vessel disease (SVD). Given reduced subcortical cerebral blood flow (CBF) is prevalent in SVD, we tested the hypothesis that regional CBF is positively associated with gait performance among older adults.

Methods

Thirty-two older adults (55–80 years) with at least one vascular risk factor were recruited. We assessed gait during 2 consecutive walking sequences using a GAITRite system: (1) at a self-selected pace, and (2) while performing a serial subtraction dual-task challenge. We quantified CBF using pseudo-continuous arterial spin labeling MRI within 4 regions of interest: putamen, pallidum, thalamus, and hippocampus. We investigated associations between gait characteristics and overall CBF adjusting for age, sex, and height in an omnibus approach using multivariate analysis of variance, followed by regression analysis with each individual region. We also conducted further regression analyses to investigate associations between gait characteristics and frontal lobe CBF. Sensitivity analyses examined how the observed associations were modified by WMH, executive function, and depressive symptoms. A change of 10% in the model’s adjusted r2 and effect size was considered as a threshold for confounding.

Results

Overall subcortical CBF was not associated with self-paced gait. When examining individual ROI, gait velocity was directly related to thalamic CBF (p = 0.026), and across all gait variables the largest effect sizes were observed in relation to thalamic CBF. In the dual-task condition, gait variables were not related to CBF in either the omnibus approach or individual multiple regressions. Furthermore, no significant associations were observed between frontal CBF and gait variables in either the self-paced or dual-task condition. Sensitivity analyses which were restricted to examine the association of velocity and thalamic CBF identified a cofounding effect of depressive symptoms which increased the effect size of the CBF-gait association by 12%.

Conclusion

Subcortical hypoperfusion, particularly in regions that comprise central input/output tracts to the cortical tissue, may underlie the association between gait deficits and brain aging.

in Frontiers in Ageing Neuroscience on September 18, 2020 12:00 AM.

• #### The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.

in Frontiers in Ageing Neuroscience on September 18, 2020 12:00 AM.

• #### Cell-cycle-gated feedback control mediates desensitization to interferon stimulation

Cells use molecular circuits to interpret and respond to extracellular cues, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the type I interferon (IFN)-responsive regulatory network operates in single human cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on input durations. These effects are governed by a regulatory network composed of a fast-acting positive feedback loop and a delayed negative feedback loop, mediated by upregulation of ubiquitin-specific peptidase 18 (USP18). We further revealed that USP18 upregulation can only be initiated at the G1/early S phases of cell cycle upon the treatment onset, resulting in heterogeneous and delayed induction kinetics in single cells. This cell cycle gating provides a temporal compartmentalization of feedback loops, enabling duration-dependent desensitization to repetitive stimulations.

in eLife on September 18, 2020 12:00 AM.

• #### External location of touch is constructed post-hoc based on limb choice

When humans indicate on which hand a tactile stimulus occurred, they often err when their hands are crossed. This finding seemingly supports the view that the automatically determined touch location in external space affects limb assignment: the crossed right hand is localized in left space, and this conflict presumably provokes hand assignment errors. Here, participants judged on which hand the first of two stimuli, presented during a bimanual movement, had occurred, and then indicated its external location by a reach-to-point movement. When participants incorrectly chose the hand stimulated second, they pointed to where that hand had been at the correct, first time point, though no stimulus had occurred at that location. This behavior suggests that stimulus localization depended on hand assignment, not vice versa. It is, thus, incompatible with the notion of automatic computation of external stimulus location upon occurrence. Instead, humans construct external touch location post-hoc and on demand.

in eLife on September 18, 2020 12:00 AM.

• #### Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances learning of cue-reward contingency

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency. BLA CaMKIIα neuron activity followed reward retrieval and moved to the reward-predictive cue after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers led to quicker acquisition of the cue-reward contingency. These results indicate BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli.

in eLife on September 18, 2020 12:00 AM.

• #### WDR90 is a centriolar microtubule wall protein important for centriole architecture integrity

Centrioles are characterized by a nine-fold arrangement of microtubule triplets held together by an inner protein scaffold. These structurally robust organelles experience strenuous cellular processes such as cell division or ciliary beating while performing their function. However, the molecular mechanisms underlying the stability of microtubule triplets, as well as centriole architectural integrity remain poorly understood. Here, using ultrastructure expansion microscopy for nanoscale protein mapping, we reveal that POC16 and its human homolog WDR90 are components of the microtubule wall along the central core region of the centriole. We further found that WDR90 is an evolutionary microtubule associated protein. Finally, we demonstrate that WDR90 depletion impairs the localization of inner scaffold components, leading to centriole structural abnormalities in human cells. Altogether, this work highlights that WDR90 is an evolutionary conserved molecular player participating in centriole architecture integrity.

in eLife on September 18, 2020 12:00 AM.

• #### A novel DNA primase-helicase pair encoded by SCCmec elements

Mobile genetic elements (MGEs) are a rich source of new enzymes, and conversely, understanding the activities of MGE-encoded proteins can elucidate MGE function. Here we biochemically characterize 3 proteins encoded by a conserved operon carried by the Staphylococcal Cassette Chromosome (SCCmec), an MGE that confers methicillin resistance to Staphylococcus aureus, creating MRSA strains. The first of these proteins, CCPol, is an active A-family DNA polymerase. The middle protein, MP, binds tightly to CCPol and confers upon it the ability to synthesize DNA primers de novo. The CCPol-MP complex is therefore a unique primase-polymerase enzyme unrelated to either known primase family. The third protein, Cch2, is a 3'-to-5' helicase. Cch2 additionally binds specifically to a dsDNA sequence downstream of its gene that is also a preferred initiation site for priming by CCPol-MP. Taken together, our results suggest that this is a functional replication module for SCCmec.

in eLife on September 18, 2020 12:00 AM.

• #### The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.

in eLife on September 18, 2020 12:00 AM.

• #### Differential Emergence and Stability of Sensory and Temporal Representations in Context-Specific Hippocampal Sequences

Taxidis et al. demonstrate that odor-specific spiking sequences in the hippocampus combine robust and stable encoding of olfactory stimuli with highly dynamic temporal codes that increase during learning of a working memory task. This combination allows the linking of fixed external elements and their variable temporal relationships in memory space.

in Neuron: In press on September 18, 2020 12:00 AM.

• #### Relating neural oscillations to laminar fMRI connectivity

Laminar fMRI can non-invasively study brain activation and potentially connectivity at the laminar level in humans. In a previous simultaneous laminar fMRI/EEG experiment, we observed that attention effects in alpha, beta and gamma band EEG power relate to attention effects in fMRI activation in V1/V2/V3 at distinct cortical depths: alpha and gamma band EEG attention effects related to fMRI effects in superficial layers, whereas beta attention effects related to deep layers. Here we reanalyzed these data to investigate how EEG-attention effects relate to changes in connectivity between regions. We computed the fMRI-based attention effect on laminar connectivity between regions within a hemisphere and connectivity between layers within brain regions. We observed that the beta band strongly relates to laminar specific changes in connectivity. Our results indicate that the attention-related decrease in beta power relates to an increase in deep-to-deep layer connectivity between regions and deep/middle to superficial layer connectivity within brain regions. The attention related alpha power increase predominantly relates to increases in connectivity between deep and superficial layers within brain regions. We observed no strong relation between laminar connectivity and gamma band oscillations. These results indicate that especially beta band oscillations, and to a lesser extent alpha band oscillations relate to laminar specific changes in connectivity as measured by laminar fMRI. Together, the effects for the alpha and beta bands suggest a complex picture of possibly co-occurring neural processes that can differentially affect laminar connectivity.

in bioRxiv: Neuroscience on September 18, 2020 12:00 AM.

• #### Age-specific gene signatures underlying the transcriptomes and functional connectomes of human cerebral cortex

The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method TCA (Transcriptome-connectome Correlation Analysis), which integrates the brain functional MR magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood, and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets.

in bioRxiv: Neuroscience on September 18, 2020 12:00 AM.

• #### Genetic grouping of SARS-CoV-2 coronavirus sequences using informative subtype markers for pandemic spread visualization

by Zhengqiao Zhao, Bahrad A. Sokhansanj, Charvi Malhotra, Kitty Zheng, Gail L. Rosen

We propose an efficient framework for genetic subtyping of SARS-CoV-2, the novel coronavirus that causes the COVID-19 pandemic. Efficient viral subtyping enables visualization and modeling of the geographic distribution and temporal dynamics of disease spread. Subtyping thereby advances the development of effective containment strategies and, potentially, therapeutic and vaccine strategies. However, identifying viral subtypes in real-time is challenging: SARS-CoV-2 is a novel virus, and the pandemic is rapidly expanding. Viral subtypes may be difficult to detect due to rapid evolution; founder effects are more significant than selection pressure; and the clustering threshold for subtyping is not standardized. We propose to identify mutational signatures of available SARS-CoV-2 sequences using a population-based approach: an entropy measure followed by frequency analysis. These signatures, Informative Subtype Markers (ISMs), define a compact set of nucleotide sites that characterize the most variable (and thus most informative) positions in the viral genomes sequenced from different individuals. Through ISM compression, we find that certain distant nucleotide variants covary, including non-coding and ORF1ab sites covarying with the D614G spike protein mutation which has become increasingly prevalent as the pandemic has spread. ISMs are also useful for downstream analyses, such as spatiotemporal visualization of viral dynamics. By analyzing sequence data available in the GISAID database, we validate the utility of ISM-based subtyping by comparing spatiotemporal analyses using ISMs to epidemiological studies of viral transmission in Asia, Europe, and the United States. In addition, we show the relationship of ISMs to phylogenetic reconstructions of SARS-CoV-2 evolution, and therefore, ISMs can play an important complementary role to phylogenetic tree-based analysis, such as is done in the Nextstrain project. The developed pipeline dynamically generates ISMs for newly added SARS-CoV-2 sequences and updates the visualization of pandemic spatiotemporal dynamics, and is available on Github at https://github.com/EESI/ISM (Jupyter notebook), https://github.com/EESI/ncov_ism (command line tool) and via an interactive website at https://covid19-ism.coe.drexel.edu/.

in PLoS Computational Biology on September 17, 2020 09:00 PM.

• #### Ten simple rules for writing scientific op-ed articles

by Hoe-Han Goh, Philip Bourne

in PLoS Computational Biology on September 17, 2020 09:00 PM.

• #### A new Graph Gaussian embedding method for analyzing the effects of cognitive training

by Mengjia Xu, Zhijiang Wang, Haifeng Zhang, Dimitrios Pantazis, Huali Wang, Quanzheng Li

Identifying heterogeneous cognitive impairment markers at an early stage is vital for Alzheimer’s disease diagnosis. However, due to complex and uncertain brain connectivity features in the cognitive domains, it remains challenging to quantify functional brain connectomic changes during non-pharmacological interventions for amnestic mild cognitive impairment (aMCI) patients. We present a quantitative method for functional brain network analysis of fMRI data based on the multi-graph unsupervised Gaussian embedding method (MG2G). This neural network-based model can effectively learn low-dimensional Gaussian distributions from the original high-dimensional sparse functional brain networks, quantify uncertainties in link prediction, and discover the intrinsic dimensionality of brain networks. Using the Wasserstein distance to measure probabilistic changes, we discovered that brain regions in the default mode network and somatosensory/somatomotor hand, fronto-parietal task control, memory retrieval, and visual and dorsal attention systems had relatively large variations during non-pharmacological training, which might provide distinct biomarkers for fine-grained monitoring of aMCI cognitive alteration. An important finding of our study is the ability of the new method to capture subtle changes for individual patients before and after short-term intervention. More broadly, the MG2G method can be used in studying multiple brain disorders and injuries, e.g., in Parkinson’s disease or traumatic brain injury (TBI), and hence it will be useful to the wider neuroscience community.

in PLoS Computational Biology on September 17, 2020 09:00 PM.

• #### Response nonlinearities in networks of spiking neurons

by Alessandro Sanzeni, Mark H. Histed, Nicolas Brunel

Combining information from multiple sources is a fundamental operation performed by networks of neurons in the brain, whose general principles are still largely unknown. Experimental evidence suggests that combination of inputs in cortex relies on nonlinear summation. Such nonlinearities are thought to be fundamental to perform complex computations. However, these non-linearities are inconsistent with the balanced-state model, one of the most popular models of cortical dynamics, which predicts networks have a linear response. This linearity is obtained in the limit of very large recurrent coupling strength. We investigate the stationary response of networks of spiking neurons as a function of coupling strength. We show that, while a linear transfer function emerges at strong coupling, nonlinearities are prominent at finite coupling, both at response onset and close to saturation. We derive a general framework to classify nonlinear responses in these networks and discuss which of them can be captured by rate models. This framework could help to understand the observed diversity of non-linearities observed in cortical networks.

in PLoS Computational Biology on September 17, 2020 09:00 PM.

• #### The relative contributions of infectious and mitotic spread to HTLV-1 persistence

by Daniel J. Laydon, Vikram Sunkara, Lies Boelen, Charles R. M. Bangham, Becca Asquith

Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection. However, in light of recent high-throughput data on the abundance of HTLV-1 clones, and recent estimates of HTLV-1 clonal diversity that are substantially higher than previously thought (typically between 104 and 105 HTLV-1+ T cell clones in the body of an asymptomatic carrier or patient with HTLV-1-associated myelopathy/tropical spastic paraparesis), ongoing infectious spread during chronic infection remains possible. We estimate the ratio of infectious to mitotic spread using a hybrid model of deterministic and stochastic processes, fitted to previously published HTLV-1 clonal diversity estimates. We investigate the robustness of our estimates using three alternative estimators. We find that, contrary to previous belief, infectious spread persists during chronic infection, even after HTLV-1 proviral load has reached its set point, and we estimate that between 100 and 200 new HTLV-1 clones are created and killed every day. We find broad agreement between all estimators. The risk of HTLV-1-associated malignancy and inflammatory disease is strongly correlated with proviral load, which in turn is correlated with the number of HTLV-1-infected clones, which are created by de novo infection. Our results therefore imply that suppression of de novo infection may reduce the risk of malignant transformation.

in PLoS Computational Biology on September 17, 2020 09:00 PM.

• #### CombiANT: Antibiotic interaction testing made easy

by Nikos Fatsis-Kavalopoulos, Roderich Roemhild, Po-Cheng Tang, Johan Kreuger, Dan I. Andersson

Antibiotic combination therapies are important for the efficient treatment of many types of infections, including those caused by antibiotic-resistant pathogens. Combination treatment strategies are typically used under the assumption that synergies are conserved across species and strains, even though recent results show that the combined treatment effect is determined by specific drug–strain interactions that can vary extensively and unpredictably, both between and within bacterial species. To address this problem, we present a new method in which antibiotic synergy is rapidly quantified on a case-by-case basis, allowing for improved combination therapy. The novel CombiANT methodology consists of a 3D-printed agar plate insert that produces defined diffusion landscapes of 3 antibiotics, permitting synergy quantification between all 3 antibiotic pairs with a single test. Automated image analysis yields fractional inhibitory concentration indices (FICis) with high accuracy and precision. A technical validation with 3 major pathogens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, showed equivalent performance to checkerboard methodology, with the advantage of strongly reduced assay complexity and costs for CombiANT. A synergy screening of 10 antibiotic combinations for 12 E. coli urinary tract infection (UTI) clinical isolates illustrates the need for refined combination treatment strategies. For example, combinations of trimethoprim (TMP) + nitrofurantoin (NIT) and TMP + mecillinam (MEC) showed synergy, but only for certain individual isolates, whereas MEC + NIT combinations showed antagonistic interactions across all tested strains. These data suggest that the CombiANT methodology could allow personalized clinical synergy testing and large-scale screening. We anticipate that CombiANT will greatly facilitate clinical and basic research of antibiotic synergy.

in PLoS Biology on September 17, 2020 09:00 PM.

## Abstract

Place and grid cells in the hippocampal formation are commonly thought to support a unified and coherent cognitive map of space. This mapping mechanism faces a challenge when a navigator is placed in a familiar environment that has been deformed from its original shape. Under such circumstances, many transformations could plausibly serve to map a navigator's familiar cognitive map to the deformed space. Previous empirical results indicate that the firing fields of rodent place and grid cells stretch or compress in a manner that approximately matches the environmental deformation, and human spatial memory exhibits similar distortions. These effects have been interpreted as evidence that reshaping a familiar environment elicits an analogously reshaped cognitive map. However, recent work has suggested an alternative explanation, whereby deformation‐induced distortions of the grid code are attributable to a mechanism that dynamically anchors grid fields to the most recently experienced boundary, thus causing history‐dependent shifts in grid phase. This interpretation raises the possibility that human spatial memory will exhibit similar history‐dependent dynamics. To test this prediction, we taught participants the locations of objects in a virtual environment and then probed their memory for these locations in deformed versions of this environment. Across three experiments with variable access to visual and vestibular cues, we observed the predicted pattern, whereby the remembered locations of objects were shifted from trial to trial depending on the boundary of origin of the participant's movement trajectory. These results provide evidence for a dynamic anchoring mechanism that governs both neuronal firing and spatial memory.

in Hippocampus on September 17, 2020 07:00 PM.

• #### Real-time gun detection in CCTV: An open problem

Publication date: Available online 17 September 2020

Source: Neural Networks

Author(s): Jose Luis Salazar González, Carlos Zaccaro, Juan A. Álvarez-García, Luis M. Soria Morillo, Fernando Sancho Caparrini

in Neural Networks on September 17, 2020 01:00 PM.

• #### Developmental Distribution of Primary Cilia in the Retinofugal Visual Pathway

In this study we show that both the number of primary cilia and the number of ciliated neurons declines with age in major retinorecipient targets. Our data suggests that the maturation timing of neuronal and non‐neural cilia differs with maturation of neuronal cilia occurring over a longer postnatal period.

## Abstract

The mammalian visual system is composed of circuitry connecting sensory input from the retina to the processing core of the visual cortex. The two main retinorecipient brain targets, the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN), bridge retinal input and visual output. The primary cilium is a conserved organelle increasingly viewed as a critical sensor for the regulation of developmental and homeostatic pathways in most mammalian cell types. Moreover, cilia have been described as crucial for neurogenesis, neuronal maturation, and survival in the cortex and retina. However, cilia in the visual relay center remain to be fully described. In this study, we characterized the ciliation profile of the SC and dLGN and found that the overall number of ciliated cells declined during development. Interestingly, shorter ciliated cells in both regions were identified as neurons, whose numbers remained stable over time, suggesting that cilia retention is a critical feature for optimal neuronal function in SC and dLGN. Our study suggests that primary cilia are important for neuronal maturation and function in cells of the SC and dLGN.

in Journal of Comparative Neurology on September 17, 2020 08:30 AM.

• #### Boundary Mittag-Leffler stabilization of fractional reaction–diffusion cellular neural networks

Publication date: December 2020

Source: Neural Networks, Volume 132

Author(s): Xiao-Zhen Liu, Ze-Tao Li, Kai-Ning Wu

in Neural Networks on September 17, 2020 07:00 AM.

• #### Analysis of the transferability and robustness of GANs evolved for Pareto set approximations

Publication date: Available online 16 September 2020

Source: Neural Networks

Author(s): Unai Garciarena, Alexander Mendiburu, Roberto Santana

in Neural Networks on September 17, 2020 07:00 AM.

• #### Computational tool to study high dimensional dynamic in NMM. (arXiv:2009.07479v1 [q-bio.NC])

Neuroscience has shown great progress in recent years. Several of the theoretical bases have arisen from the examination of dynamic systems, using Neural Mass Models (NMMs). Due to the largescale brain dynamics of NMMs and the difficulty of studying nonlinear systems, the local linearization approach to discretize the state equation was used via an algebraic formulation, as it intervenes favorably in the speed and efficiency of numerical integration. To study the spacetime organization of the brain and generate more complex dynamics, three structural levels (cortical unit, population and system) were defined and assumed, in which the new assumed representation for conduction delays and new ways of connecting were defined. This is a new time-delay NMM, which can simulate several types of EEG activities since kinetics information was considered at three levels of complexity. Results obtained in this analysis provide additional theoretical foundations and indicate specific characteristics for understanding neurodynamic.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 17, 2020 01:30 AM.

• #### An Extensive Experimental Evaluation of Automated Machine Learning Methods for Recommending Classification Algorithms (Extended Version). (arXiv:2009.07430v1 [cs.LG])

This paper presents an experimental comparison among four Automated Machine Learning (AutoML) methods for recommending the best classification algorithm for a given input dataset. Three of these methods are based on Evolutionary Algorithms (EAs), and the other is Auto-WEKA, a well-known AutoML method based on the Combined Algorithm Selection and Hyper-parameter optimisation (CASH) approach. The EA-based methods build classification algorithms from a single machine learning paradigm: either decision-tree induction, rule induction, or Bayesian network classification. Auto-WEKA combines algorithm selection and hyper-parameter optimisation to recommend classification algorithms from multiple paradigms. We performed controlled experiments where these four AutoML methods were given the same runtime limit for different values of this limit. In general, the difference in predictive accuracy of the three best AutoML methods was not statistically significant. However, the EA evolving decision-tree induction algorithms has the advantage of producing algorithms that generate interpretable classification models and that are more scalable to large datasets, by comparison with many algorithms from other learning paradigms that can be recommended by Auto-WEKA. We also observed that Auto-WEKA has shown meta-overfitting, a form of overfitting at the meta-learning level, rather than at the base-learning level.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 17, 2020 01:30 AM.

• #### Recurrence Quantification Analysis of Dynamic Brain Networks. (arXiv:2001.03761v2 [q-bio.NC] UPDATED)

Evidence suggests that brain network dynamics is a key determinant of brain function and dysfunction. Here we propose a new framework to assess the dynamics of brain networks based on recurrence analysis. Our framework uses recurrence plots and recurrence quantification analysis to characterize dynamic networks. For resting-state magnetoencephalographic dynamic functional networks (dFNs), we have found that functional networks recur more quickly in people with epilepsy than healthy controls. This suggests that recurrence of dFNs may be used as a biomarker of epilepsy. For stereo electroencephalography data, we have found that dFNs involved in epileptic seizures emerge before seizure onset, and recurrence analysis allows us to detect seizures. We further observe distinct dFNs before and after seizures, which may inform neurostimulation strategies to prevent seizures. Our framework can also be used for understanding dFNs in healthy brain function and in other neurological disorders besides epilepsy.

in arXiv: Quantitative Biology: Neurons and Cognition on September 17, 2020 01:30 AM.

• #### Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

Nature, Published online: 17 September 2020; doi:10.1038/s41586-020-2772-0

Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

in Nature on September 17, 2020 12:00 AM.

• #### Locus coeruleus: a new look at the blue spot

Nature Reviews Neuroscience, Published online: 17 September 2020; doi:10.1038/s41583-020-0360-9

Major compelling questions about the functional role of the locus coeruleus nucleus that had been difficult to answer, given its remote location and diminutive size, have now become accessible via new neuroscience tools. In this Perspective, 14 investigators provide a historical context for recent discoveries and outline new vistas for investigation.

in Nature Reviews on September 17, 2020 12:00 AM.

• #### Publisher Correction: Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18719-8

Publisher Correction: Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

in Nature Communications on September 17, 2020 12:00 AM.

• #### mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18504-7

mTORC1 is a key mediator of drug resistance and also regulates autophagy. In this study, the authors demonstrate that cancer cells with acquired drug resistance exibit metabolic vulnerabilities mediated by high levels of mTORC1 and the consequent inhibition of autophagy.

in Nature Communications on September 17, 2020 12:00 AM.

• #### Porous cage-derived nanomaterial inks for direct and internal three-dimensional printing

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18495-5

3D printing of nanomaterials generates opportunities to create advanced materials but printing of nanoparticles with intrinsic porosity has gained only little attention. Here, the authors demonstrate printing of silica nanocages using digital light processing to fabricate hierarchically porous parts with tunable internal structure and complex shapes.

in Nature Communications on September 17, 2020 12:00 AM.

• #### Ring-opening polymerization-induced crystallization-driven self-assembly of poly-L-lactide-block-polyethylene glycol block copolymers (ROPI-CDSA)

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18460-2

A key challenge in the self-assembly of block copolymers is obtaining independent control over molecular structure and hierarchical structure in all dimensions using scalable one-pot chemistry. Here the authors show the ring opening polymerization-induced crystallization-driven self-assembly of poly-L-lactide-block-polyethylene glycol block copolymers into 1D, 2D and 3D nanostructures.

in Nature Communications on September 17, 2020 12:00 AM.

• #### A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18450-4

Antibody mediated immunity to SARS-CoV-2 will affect future transmission and disease severity. This systematic review on antibody response to coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and endemic coronaviruses provides insights into kinetics, correlates of protection, and association with disease severity.

in Nature Communications on September 17, 2020 12:00 AM.

• #### Carbon pricing and planetary boundaries

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18342-7

In the light of nine Earth System Processes (ESPs) and the corresponding planetary boundaries, here the authors assessed the global environmental impact of a global carbon pricing in a multi-boundary world. They show that a global carbon tax would relieve pressure on most ESPs and it is therefore stronger in a multi-boundary world than when considering climate change in isolation.

in Nature Communications on September 17, 2020 12:00 AM.

• #### Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18330-x

Yeast exhibit oscillations that share features with circadian rhythms. The authors show that bioenergetic constraints promote oscillatory behaviour: resources are stored until supplies can support translational bursting, this is licensed by ion transport and release from membrane-less compartments.

in Nature Communications on September 17, 2020 12:00 AM.

• #### Chemical engineering of quasicrystal approximants in lanthanide-based coordination solids

Nature Communications, Published online: 17 September 2020; doi:10.1038/s41467-020-18328-5

Tessellation of self-assembling molecular building blocks is attractive for accessing metal-organic materials with geometric frustration, however such motifs are rare. Here the authors use ytterbium(II) as a five-vertex node to assemble an Archimedean tessellation in a bulk, molecule-based material.

in Nature Communications on September 17, 2020 12:00 AM.

• #### Daily briefing: We still don’t fully understand fire

Nature, Published online: 17 September 2020; doi:10.1038/d41586-020-02686-7

Despite our intimate familiarity with fire, we still struggle with a complete understanding of it. Plus, fast antigen coronavirus tests and increasingly impenetrable papers.

in Nature on September 17, 2020 12:00 AM.

• #### Who gets a COVID vaccine first? Access plans are taking shape

Nature, Published online: 17 September 2020; doi:10.1038/d41586-020-02684-9

Advisory groups around the world release guidance to prioritize health-care workers and those in front-line jobs.

in Nature on September 17, 2020 12:00 AM.

• #### How the giant stinging tree of Australia can inflict months of agony

Nature, Published online: 17 September 2020; doi:10.1038/d41586-020-02668-9

A new type of peptide produces pain so intense that sometimes even morphine cannot quell it.

in Nature on September 17, 2020 12:00 AM.

• #### Revisiting the Idea That Amyloid-β Peptide Acts as an Agonist for P2X7

The P2X7 receptor (P2X7) is a cell surface ligand-gated ion channel, activated by its physiological nucleotide agonist ATP and a synthetic analog (BzATP). However, it has also been suggested that there may be structurally unrelated, non-nucleotide agonists such as the amyloidogenic β peptide. Here we aimed to reassess the effect of amyloid β peptides in various in vitro cell models, namely HEK293 overexpressing human P2X7, the microglial BV-2 cell line, and BV-2 cells lacking P2X7. We measured YO-PRO-1 dye uptake in response to full-length amyloid β peptide (1–42) or the shorter amyloid β peptide (25–35) and there was a concentration-dependent increase in YO-PRO-1 dye uptake in HEK-hP2X7 cells. However, these amyloid β peptide-induced increases in YO-PRO-1 dye uptake were also identical in non-transfected HEK-293 cells. We could observe small transient increases in [Ca2+]i induced by amyloid β peptides in BV-2 cells, however these were identical in BV-2 cells lacking P2X7. Furthermore, our metabolic viability and LDH release experiments suggest no significant change in viability or cell membrane damage in HEK-hP2X7 cells. In the BV-2 cells we found that high concentrations of amyloid β peptides (1–42) and (25–35) could reduce cell viability by up to 35% but this was also seen in BV-2 cells lacking P2X7. We found no evidence of LDH release by amyloid β peptides. In summary, we found no evidence that amyloid β peptides act as agonists of P2X7 in our in vitro models. Our study raises the possibility that amyloid β peptides simply mimic features of P2X7 activation.

in Frontiers in Molecular Neuroscience on September 17, 2020 12:00 AM.

• #### Early Disruption of Cortical Sleep-Related Oscillations in a Mouse Model of Dementia With Lewy Bodies (DLB) Expressing Human Mutant (A30P) Alpha-Synuclein

Changes in sleep behavior and sleep-related cortical activity have been reported in conditions associated with abnormal alpha-synuclein (α-syn) expression, in particular Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Notably, changes can occur in patients years before the onset of cognitive decline. Sleep-related network oscillations play a key role in memory function, but how abnormal α-syn impacts the generation of such activity is currently unclear. To determine whether early changes in sleep-related network activity could also be observed, prior to any previously reported cognitive dysfunction, we used mice that over-express human mutant α-syn (A30P). Recordings in vivo were performed under urethane anesthesia in the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus in young male (2.5 – 4 months old) A30P and age-matched wild type (WT) mice. We found that the slow oscillation (SO) < 1 Hz frequency was significantly faster in both the mPFC and hippocampus in A30P mice, and Up-state-associated fast oscillations at beta (20 – 30 Hz) and gamma (30 – 80 Hz) frequencies were delayed relative to the onset of the Up-state. Spindle (8 – 15 Hz) activity in the mPFC was also altered in A30P mice, as spindles were shorter in duration and had reduced density compared to WT. These changes demonstrate that dysregulation of sleep-related oscillations occurs in young A30P mice long before the onset of cognitive dysfunction. Our data suggest that, as seen in patients, changes in sleep-related oscillations are an early consequence of abnormal α-syn aggregation in A30P mice.

in Frontiers in Neuroscience: Neurodegeneration on September 17, 2020 12:00 AM.

• #### Mapping the Interactive Effects of ApoE Gene Polymorphism on Caudate Functional Connectivity in Mild Cognitive Impairment Associated With Parkinson’s Disease

Introduction

Cognitive impairment (CI) is a frequent non-motor symptom of Parkinson’s disease (PD). Caudate and Apolipoprotein E (ApoE) are biomarkers linked to CI in PD. There is little known about whether ApoE affects caudate in mild CI of PD (PD-MCI). We investigated the possible interactive effect of ApoE genotypes on caudate functional connectivity (FC) in PD-MCI.

Methods

A total of 95 PD-MCI patients and 99 matched healthy controls underwent extensive neuropsychological assessment and magnetic resonance imaging. The two groups were separated into three subgroups according to their genotyping. Functional data were analyzed with FC analysis.

Results

Decreased FC between the caudate and the bilateral inferior orbit frontal gyrus and bilateral middle occipital gyrus (MOG) was found between groups, along with poor performance in general, executive, episodic memory, language, and visual–spatial function. Decreased FC between the caudate and right MOG, right middle temporal gyrus, and right superior occipital gyrus was found as an interaction effect. The FC values of ε4 carriers with PD-MCI were much lower than the other carriers, and FC was positively correlated with the impairment of global and language function.

Conclusion

These results support the idea that altered FC between the bilateral caudate and posterior cortical regions was interactively influenced by ApoE genotype and PD-MCI status, and the ε4 subtype associated with underlying pathology of global cognitive decline and semantic fluency impairment in an interactive manner. Gene-based imaging approaches might strengthen the credibility in imaging genetic associations, which might provide new powerful insights into the neural mechanisms underlying PD-MCI.

in Frontiers in Neuroscience: Neurodegeneration on September 17, 2020 12:00 AM.

• #### Identification and Classification of Alzheimer’s Disease Patients Using Novel Fractional Motion Model

in Frontiers in Neuroscience: Brain Imaging Methods on September 17, 2020 12:00 AM.

• #### A Machine-Based Prediction Model of ADHD Using CPT Data

in Frontiers in Human Neuroscience on September 17, 2020 12:00 AM.

• #### Abnormal Spatial Patterns of Intrinsic Brain Activity in Osteonecrosis of the Femoral Head: A Resting-State Functional Magnetic Resonance Imaging Study

Objective: Osteonecrosis of the femoral head (ONFH) is a common condition that is encountered in clinical practice, and yet, little is known about its characteristics and manifestations in the brain. Therefore, in this study, we aimed to use resting-state functional magnetic resonance imaging (rs-fMRI) to investigate the spatial patterns of spontaneous brain activity in the brain of ONFH patients.

Methods: The study included ONFH patients and healthy controls. The pattern of intrinsic brain activity was measured by examining the amplitude of low-frequency fluctuations (ALFF) of blood oxygen level-dependent signals using rs-fMRI. Meanwhile, we also used Harris hip scores to evaluate the functional performance of ONFH patients and healthy controls.

Result: Ten ONFH patients and 10 health controls were investigated. We found global ALFF differences between the two groups throughout the occipital, parietal, frontal, prefrontal, and temporal cortices. In the ONFH patients, altered brain activity was found in the brain regions in the sensorimotor network, pain-related network, and emotion and cognition network. The results of the correlation investigations also demonstrated that the regions with ALFF changes had significant correlations with the functional performance of the patients evaluated by Harris hip scores.

Conclusions: Our study has revealed the abnormal pattern of brain activity in ONFH patients, and our findings could be used to aid in understanding the mechanisms behind the gait abnormality and intractable pain associated with ONFH at the central level.

in Frontiers in Human Neuroscience on September 17, 2020 12:00 AM.

• #### K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na+ channels and hyperpolarization-activated cyclic nucleotide–gated (HCN) channels. K+ channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (Kv1.1, 1.2), A-channels (Kv1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (Kv7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (KIR6.2), Ca2+-activated K+ channels (KCa1.1, 2.1, 2.2, 2.3, and 3.1), Na+-activated K+ channels (KCa4.1 and 4.2) and two pore domain leak channels (K2p; TWIK related channels). Function of all K+ channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K+ channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K+ channel can produce signs of pain in vivo. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K+ channel function. Despite the current state of knowledge, attempts to target K+ channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K+ channel activators.

in Frontiers in Cellular Neuroscience on September 17, 2020 12:00 AM.

• #### Integration of Within-Cell Experimental Data With Multi-Compartmental Modeling Predicts H-Channel Densities and Distributions in Hippocampal OLM Cells

Determining biophysical details of spatially extended neurons is a challenge that needs to be overcome if we are to understand the dynamics of brain function from cellular perspectives. Moreover, we now know that we should not average across recordings from many cells of a given cell type to obtain quantitative measures such as conductance since measures can vary multiple-fold for a given cell type. In this work we examine whether a tight combination of experimental and computational work can address this challenge. The oriens-lacunosum/moleculare (OLM) interneuron operates as a “gate” that controls incoming sensory and ongoing contextual information in the CA1 of the hippocampus, making it essential to understand how its biophysical properties contribute to memory function. OLM cells fire phase-locked to the prominent hippocampal theta rhythms, and we previously used computational models to show that OLM cells exhibit high or low theta spiking resonance frequencies that depend respectively on whether their dendrites have hyperpolarization-activated cation channels (h-channels) or not. However, whether OLM cells actually possess dendritic h-channels is unknown at present. We performed a set of whole-cell recordings of OLM cells from mouse hippocampus and constructed three multi-compartment models using morphological and electrophysiological parameters extracted from the same OLM cell, including per-cell pharmacologically isolated h-channel currents. We found that the models best matched experiments when h-channels were present in the dendrites of each of the three model cells created. This strongly suggests that h-channels must be present in OLM cell dendrites and are not localized to their somata. Importantly, this work shows that a tight integration of model and experiment can help tackle the challenge of characterizing biophysical details and distributions in spatially extended neurons. Full spiking models were built for two of the OLM cells, matching their current clamp cell-specific electrophysiological recordings. Overall, our work presents a technical advancement in modeling OLM cells. Our models are available to the community to use to gain insight into cellular dynamics underlying hippocampal function.

in Frontiers in Cellular Neuroscience on September 17, 2020 12:00 AM.

• #### Correction: Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase

in eLife on September 17, 2020 12:00 AM.

• #### A dual role for Cav1.4 Ca2+ channels in the molecular and structural organization of the rod photoreceptor synapse

Synapses are fundamental information processing units that rely on voltage-gated Ca2+ (Cav) channels to trigger Ca2+-dependent neurotransmitter release. Cav channels also play Ca2+-independent roles in other biological contexts, but whether they do so in axon terminals is unknown. Here, we addressed this unknown with respect to the requirement for Cav1.4 L-type channels for the formation of rod photoreceptor synapses in the retina. Using a mouse strain expressing a non-conducting mutant form of Cav1.4, we report that the Cav1.4 protein, but not its Ca2+ conductance, is required for the molecular assembly of rod synapses; however, Cav1.4 Ca2+ signals are needed for the appropriate recruitment of postsynaptic partners. Our results support a model in which presynaptic Cav channels serve both as organizers of synaptic building blocks and as sources of Ca2+ ions in building the first synapse of the visual pathway and perhaps more broadly in the nervous system.

in eLife on September 17, 2020 12:00 AM.

• #### Alkylative damage of mRNA leads to ribosome stalling and rescue by trans translation in bacteria

Similar to DNA replication, translation of the genetic code by the ribosome is hypothesized to be exceptionally sensitive to small chemical changes to its template mRNA. Here we show that addition of common alkylating agents to growing cultures of E. coli leads to accumulation of several adducts within RNA, including N(1)-methyladenosine (m1A). As expected, the introduction of m1A to model mRNAs was found to reduce the rate of peptide-bond formation by three orders of magnitude in a well-defined in vitro system. These observations suggest that alkylative stress is likely to stall translation in vivo and necessitates activation of ribosome-rescue pathways. Indeed, the addition of alkylation agents was found to robustly activate the transfer-messenger RNA system, even when transcription was inhibited. Our findings suggest that bacteria carefully monitor the chemical integrity of their mRNA and they evolved rescue pathways to cope with its effect on translation.

in eLife on September 17, 2020 12:00 AM.

• #### Antibody escape by polyomavirus capsid mutation facilitates neurovirulence

JCPyV polyomavirus, a member of the human virome, causes Progressive Multifocal Leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation.

in eLife on September 17, 2020 12:00 AM.

• #### MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression

A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained–but not pulsatile–ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.

in eLife on September 17, 2020 12:00 AM.

• #### Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

The differentiation of neuronal stem cells into polarized neurons is a well-coordinated process which has mostly been studied in classical non-human model systems, but to what extent these findings are recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured hiPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. The neuron transcriptome and proteome shows extensive remodeling, with differential expression profiles of ~1100 transcripts and ~2200 proteins during neuronal differentiation and polarization. We also identified a distinct axon developmental stage marked by the relocation of axon initial segment proteins and increased microtubule remodeling from the distal (stage 3a) to the proximal (stage 3b) axon. This developmental transition coincides with action potential maturation. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.

in eLife on September 17, 2020 12:00 AM.

• #### miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions

Cortical lesions represent a hallmark of multiple sclerosis and are proposed as a predictor of disease severity. microRNAs are suggested to be important players in the disease pathogenesis and the experimental autoimmune encephalomyelitis animal model. We implemented a mouse model recapitulating more closely the human pathology as it is characterized by both an autoimmune heterogeneity and the presence of cortical lesions, two parameters missing in experimental autoimmune encephalomyelitis. In our model, mice clustered in two groups displaying high or low clinical scores. Upon cortical cytokine injection, lesions appeared with a specific topography while cortical miRNA profiles were altered. These two features differed according to disease severity. We evidenced changes in miRNA regulators and targets suggesting that miRNA alteration had functional repercussions that could explain the differences in cortical lesions. This model represents a crucial tool for the study of both miRNA involvement and cortical lesion formation in disease pathogenesis.

in eLife on September 17, 2020 12:00 AM.

• #### Training deep neural density estimators to identify mechanistic models of neural dynamics

Mechanistic modeling in neuroscience aims to explain observed phenomena in terms of underlying causes. However, determining which model parameters agree with complex and stochastic neural data presents a significant challenge. We address this challenge with a machine learning tool which uses deep neural density estimators- trained using model simulations- to carry out Bayesian inference and retrieve the full space of parameters compatible with raw data or selected data features. Our method is scalable in parameters and data features, and can rapidly analyze new data after initial training. We demonstrate the power and flexibility of our approach on receptive fields, ion channels, and Hodgkin-Huxley models. We also characterize the space of circuit configurations giving rise to rhythmic activity in the crustacean stomatogastric ganglion, and use these results to derive hypotheses for underlying compensation mechanisms. Our approach will help close the gap between data-driven and theory-driven models of neural dynamics.

in eLife on September 17, 2020 12:00 AM.

• #### A whole-brain connectivity map of mouse insular cortex

The insular cortex (IC) plays key roles in emotional and regulatory brain functions and is affected across psychiatric diseases. However, the brain-wide connections of the mouse IC have not been comprehensively mapped. Here we traced the whole-brain inputs and outputs of the mouse IC across its rostro-caudal extent. We employed cell-type specific monosynaptic rabies virus tracings to characterize afferent connections onto either excitatory or inhibitory IC neurons, and adeno-associated viral tracings to label excitatory efferent axons. While the connectivity between the IC and other cortical regions was highly bidirectional, the IC connectivity with subcortical structures was often unidirectional, revealing prominent cortical-to-subcortical or subcortical-to-cortical pathways. The posterior and medial IC exhibited resembling connectivity patterns, while the anterior IC connectivity was distinct, suggesting two major functional compartments. Our results provide insights into the anatomical architecture of the mouse IC and thus a structural basis to guide investigations into its complex functions.

in eLife on September 17, 2020 12:00 AM.

• #### Topological constraints in early multicellularity favor reproductive division of labor

Reproductive division of labor (e.g., germ-soma specialization) is a hallmark of the evolution of multicellularity, signifying the emergence of a new type of individual and facilitating the evolution of increased organismal complexity. A large body of work from evolutionary biology, economics, and ecology has shown that specialization is beneficial when further division of labor produces an accelerating increase in absolute productivity (i.e., productivity is a convex function of specialization). Here we show that reproductive specialization is qualitatively different from classical models of resource sharing, and can evolve even when the benefits of specialization are saturating (i.e., productivity is a concave function of specialization). Through analytical theory and evolutionary individual-based simulations, we demonstrate that reproductive specialization is strongly favored in sparse networks of cellular interactions that reflect the morphology of early, simple multicellular organisms, highlighting the importance of restricted social interactions in the evolution of reproductive specialization.

in eLife on September 17, 2020 12:00 AM.

• #### Attention-related modulation of caudate neurons depends on superior colliculus activity

Recent work has implicated the primate basal ganglia in visual perception and attention, in addition to their traditional role in motor control. The basal ganglia, especially the caudate nucleus 'head' (CDh) of the striatum, receive indirect anatomical connections from the superior colliculus, a midbrain structure that is known to play a crucial role in the control of visual attention. To test the possible functional relationship between these subcortical structures, we recorded CDh neuronal activity of macaque monkeys before and during unilateral superior colliculus (SC) inactivation in a spatial attention task. SC inactivation significantly altered the attention-related modulation of CDh neurons and strongly impaired the classification of task epochs based on CDh activity. Only inactivation of SC on the same side of the brain as recorded CDh neurons, not the opposite side, had these effects. These results demonstrate a novel interaction between SC activity and attention-related visual processing in the basal ganglia.

in eLife on September 17, 2020 12:00 AM.

• #### This Is Your Brain on (Low) Glucose

Brain functioning and high-order cognitive functions critically rely on glucose as a metabolic substrate. In a recent study, Kealy et al. investigated the impact of glucose availability on sickness behavior and delirium in mice and humans. They identified disrupted brain carbohydrate metabolism as a key mechanistic driver of these behaviors.

in Trends in Neurosciences: In press on September 17, 2020 12:00 AM.

• #### Wireless Programmable Recording and Stimulation of Deep Brain Activity in Freely Moving Humans

Topalovic et al. present a mobile deep brain recording and stimulation (Mo-DBRS) research platform that enables wireless and programmable intracranial electroencephalographic recording and electrical stimulation integrated and synchronized with virtual reality/augmented reality (VR/AR) and wearable sensors capable of external measurements.

in Neuron: In press on September 17, 2020 12:00 AM.

• #### Neural Sequences as an Optimal Dynamical Regime for the Readout of Time

By recording in the striatum and premotor cortex during a two-interval timing task, Zhou et al. show that, while both areas encode time, the dynamics in the striatum is more sequential. These neural sequences provide an ideal code for downstream areas to read out time in a biologically plausible manner.

in Neuron: In press on September 17, 2020 12:00 AM.

• #### NGF receptors and PI3K/AKT pathway involved in glucose fluctuation-induced damage to neurons and α-lipoic acid treatment

Glucose fluctuation promotes neuronal apoptosis, which plays a central role in diabetic encephalopathy (DE). Nerve growth factor (NGF), and its interaction with high-affinity (TrkA) and low-affinity (p75NTR) r...

in BMC Neuroscience on September 17, 2020 12:00 AM.

• #### The organization and developmental establishment ofcortical interneuron presynaptic circuits

Sensory and cognitive functions are processed in discrete cortical areas and depend upon the integration of long range cortical and subcortical inputs. PV and SST inhibitory interneurons (cINs) gate these inputs and failure to do so properly is implicated in many neurodevelopmental disorders.The logic by which these interneuron populations are integrated into cortical circuits and how these vary across sensory versus associative cortical areas is unknown. To answer this question, we began by surveying the breadth of afferents impinging upon PV and SST cINs within distinct cortical areas. We found that presynaptic inputs to both cIN populations are similar and primarily dictated by their areal location. By contrast, the timing of when they receive these afferents is cell-type specific. In sensory regions, both SST and PV cINs initially receive thalamocortical first order inputs. While by adulthood PV cINs remain heavily skewed towards first order inputs, SST cINs receive an equal balance of first and higher order thalamic afferents. Remarkably, while perturbations to sensory experience affect PV cIN thalamocortical connectivity, SST cIN connectivity is disrupted in a model of fragile X syndrome (Fmr1 loss of function) but not a model of ASD (Shank3B loss of function). Altogether, these data provide a comprehensive map of cIN afferents within different functional cortical areas and reveal the region-specific logic by which PV and SST cIN circuits are established.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Overt and covert prosody are reflected in neurophysiological responses previously attributed to grammatical processing

Recent neurophysiological research suggests that slow cortical activity tracks hierarchical syntactic structure during online sentence processing (e.g., Ding, Melloni, Zhang, Tian, & Poeppel, 2016). Here we tested an alternative hypothesis: electrophysiological activity peaks at sentence constituent frequencies reflect cortical tracking of overt or covert (implicit) prosodic grouping. In three experiments, participants listened to series of sentences while electroencephalography (EEG) was recorded. First, prosodic cues in the sentence materials were neutralized. We found an EEG spectral power peak elicited at a frequency that only "tagged" covert prosodic change, but not any major syntactic constituents. In the second experiment, participants listened to a series of sentences with overt prosodic grouping cues that either aligned or misaligned with the syntactic phrasing in the sentences (initial overt prosody trials). Immediately after each overt prosody trial, participants were presented with a second series of sentences (covert prosody trial) with all overt prosodic cues neutralized and asked to imagine the prosodic contour present in the previous, overt prosody trial. The EEG responses reflected an interactive relationship between syntactic processing and prosodic tracking at the frequencies of syntactic constituents (sentences and phrases): alignment of syntax and prosody boosted EEG responses, whereas their misalignment had an opposite effect. This was true for both overt and covert (imagined) prosody. We conclude that processing of both overt and covert prosody is reflected in the frequency tagged neural responses at sentence constituent frequencies, whereas identifying neural markers that are narrowly reflective of syntactic processing remains difficult and controversial.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Disordered phasic relationships between hippocampal place cells, theta, and gamma rhythms in the Ts65Dn mouse model of Down Syndrome

Down Syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS have shown changes in spectral coherence in the field potentials of hippocampus and regions important for executive function such as prefrontal cortex. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from Medial Septum (MS) to regions such as hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in the Ts65Dn mouse model of DS in comparison to their non-trisomic 2N littermates. We find changes in hippocampal phenomenology that suggest that MS output, which drives theta rhythm in the hippocampus, is strongly altered. Moreover, we find that this change affects the phasic relationship of both CA1 place cells and gamma rhythms to theta. Since the phasic relationship of both of these aspects of hippocampal phenomenology to theta are thought to be critical for the segregation of encoding and retrieval epochs within hippocampus, it is likely that these changes are the neural substrates of the learning and memory deficits seen both in human DS and animal models such as Ts65Dn.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Activation of group II metabotropic receptors attenuates cortical E-I imbalance in a 15q13.3 microdeletion mouse model

Animal models reflecting human risk for schizophrenia are essential research tools for gaining further insight into the convergence of CNS pathology and clinical biomarkers. Amongst the variety of animal models that display schizophrenia-related neuronal network deficits, transgenic mice for rare and highly penetrant copy number variants (CNVs) provide a unique opportunity to study pathological correlates in models with strong construct validity. The Df(h15q13)/+ mouse model of the human 15q13.3 microdeletion CNV has been shown to mimic deficits in parvalbumin positive (PV+) interneuron and cortical network function. However, the corresponding changes in synapse density and activity within the medial prefrontal cortex (mPFC) have not been described. Using high-content immunofluorescence imaging, we have shown a reduced density of PV+ neurons and inhibitory synapses in the mPFC of Df(h15q13)/+ mice. We found that the reduced detection of PV+ synapses were accompanied by changes in spontaneous inhibitory and excitatory synaptic activity onto layer 2/3 pyramidal neurons. The aberrant cortical function was also evident in awake animals by a reduced high frequency auditory steady-state responses (ASSR), reliably monitored by EEG. Importantly, the imbalance of excitatory to inhibitory function could be attenuated on a cellular and cortical network level by activation of mGlu2/3 receptors, indicating the relevance of excessive excitatory transmission to the cortical network deficit in the Df(15q13)/+ mouse model. Our findings highlight the preclinical value of genetic risk and in particular CNV models such as the Df(15q13)/+ mice to investigate pathological network correlates of schizophrenia risk and to probe therapeutic opportunities based on clinically relevant biomarkers.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Novel genetic variants associated with brain functional networks in 18,445 adults from the UK Biobank

This is the first study investigating the genetics of weighted functional brain network graph theory measures from 18,445 participants of the UK Biobank (44-80 years). The eighteen measures studied showed low heritability (mean h2SNP =0.12) and were highly genetically correlated. Genome-wide association studies for these measures observed 14 significant variants associated with strength of somatomotor and limbic networks. These intergenic variants were located near the PAX8 gene on chromosome 2. Gene-based analyses identified five significantly associated genes for five of the network measures, which have been implicated in sleep duration, neuronal differentiation/development, cancer, and susceptibility to neurodegenerative diseases. Genetic correlations with other traits were examined and significant correlations were observed with sleep measures and psychiatric symptoms. Further analysis found that somatomotor network strength was phenotypically associated with sleep duration and insomnia. Single nucleotide polymorphism (SNP) and gene level associations with functional network measures were identified, which may help uncover novel biological pathways relevant to human brain functional network integrity and diseases that affect it.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Circuit mechanisms of top-down attentional control in a thalamic reticular model

The thalamus is a key brain structure engaged in attentional functions, such as selectively amplifying task-relevant signals of one sensory modality while filtering distractors of another. To investigate computational mechanisms of attentional modulation, we developed a biophysically grounded thalamic reticular circuit model, comprising excitatory thalamocortical and inhibitory reticular neurons, which captures characteristic neurophysiological observations from the alert behaving animals. Top-down attentional control inputs onto reticular neurons effectively modulate thalamic gain and enhance downstream readout, to improve performance across detection, discrimination, and cross-modal task paradigms. Heterogeneity of thalamic responses plays an essential role in downstream decoding during attentional modulation. Dynamical systems analysis explains why reticular neurons are an especially potent site for top-down control, as implicated by experiments. Perturbation analysis reveals excitation-inhibition ratio as an effective parameter governing thalamic processing. These findings establish experimentally testable circuit mechanisms for attentional control in thalamus, with implications for distributed neural control of cognitive processing.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Electro-optical mechanically flexible coaxial microprobes for minimally invasive interfacing with intrinsic neural circuits

Central to advancing our understanding of neural circuits is the development of minimally invasive, multi-modal interfaces capable of simultaneously recording and modulating neural activity. Recent devices have focused on matching the mechanical compliance of tissue to reduce inflammatory responses. However, reductions in the size of multi-modal interfaces are needed to further improve biocompatibility and long-term recording capabilities. Here we demonstrate a multi-modal coaxial microprobe design with a minimally invasive footprint (8-12 m diameter over millimeter lengths) that enables efficient electrical and optical interrogation of neural networks. In the brain, the probes allowed robust electrical measurement and optogenetic stimulation. Scalable fabrication strategies can be used with various electrical and optical materials, making the probes highly customizable to experimental requirements, including length, diameter, and mechanical properties. Given their negligible inflammatory response, these probes promise to enable a new generation of readily tunable multi-modal devices for minimally invasive interfacing with neural circuits.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Rotational dynamics versus sequence-like responses

In a recent review, Vyas et al. commented on our previous observations regarding the presence of response sequences in the activity of cortical neuronal population and the contribution of such sequences to rotational dynamics patterns revealed with jPCA. Vyas et al. suggested that rotations generated from sequence-like responses are different from the ones arising from empirical neuronal patterns, which are highly heterogeneous across motor conditions in terms of response timing and shape. Here we clarify our previous findings and present new results showing that empirical population data contain plentiful neuronal responses whose temporal structure persists across conditions. The more complex, heterogeneous responses also contain temporal structure that persists within clusters of conditions. Both consistent and heterogeneous responses contribute to rotational dynamics; therefore, these contributions should be considered when interpreting population rotations. Overall, we do not see any principal contradiction between the neural population dynamics framework and our results pertaining to sequence-like responses. Yet, questions remain regarding the conclusions that can be drawn from the analysis of low-dimensional representations of neuronal population data.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Functional dynamics of de-afferented early visual cortex in glaucoma

fMRI studies in macular degeneration (MD) and retinitis pigmentosa (RP) demonstrated that responses in the lesion projection zones (LPZ) of V1 are task related, indicating significant limits of bottom-up visual system plasticity in MD and RP. In advanced glaucoma (GL), a prevalent eye disease and leading cause of blindness, the scope of visual system plasticity is currently unknown. We performed 3T fMRI in patients with extensive visual field defects due to GL (n=5), RP (n=2) and healthy controls (n=7; with simulated defects). Participants viewed contrast patterns drifting in 8 directions alternating with uniform gray and performed 3 tasks: (1) passive viewing (PV), (2) one-back task (OBT) and (3) fixation-dot task (FDT). During PV, they passively viewed the stimulus with central fixation, during OBT they reported the succession of the same two motion directions, and during FDT a change in the fixation color. In GL, LPZ responses of the early visual cortex (V1, V2 and V3) shifted from negative during PV to positive for OBT [p (corrected): V1(0.006); V2(0.04); V3(0.008)], while they were negative in the controls' simulated LPZ for all stimulation conditions. For RP a similar pattern as for GL was observed. Consequently, activity in the de-afferented visual cortex in glaucoma is, similar to MD and RP, task-related. In conclusion, the lack of bottom-up plasticity appears to be a general feature of the human visual system. These insights are of importance for the development of treatment and rehabilitation schemes in glaucoma. Keywords: Visual cortex, Lesion projection zone, fMRI, Task-dependent activity, glaucoma, plasticity Highlights: 1. Functional dynamics of early visual cortex LPZ depend on task demands in glaucoma 2. Brain activity in deprived visual cortex suggests absence of large-scale remapping 3. Limited scope of bottom-up plasticity is a general feature of human visual system 4. Visual system stability and plasticity is of relevance for therapeutic advances

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### A method to remove the influence of fixative concentration on post-mortem T2 maps using a Kinetic Tensor model

Formalin fixation has been shown to substantially reduce T2 estimates when performing post-mortem imaging, primarily driven by the presence of bulk fixative in tissue. Prior to scanning, post-mortem tissue samples are often placed into a fluid that has more favourable imaging properties, such as matched magnetic susceptibility. This study investigates whether there is any evidence for a change in T2 in regions close to the tissue surface in post-mortem T2 maps due to fixative outflux into this surrounding fluid. Furthermore, we investigate whether a simulated spatial map of fixative concentration can be used as a confound regressor to reduce T2 inhomogeneity. To achieve this, T2 maps and diffusion tensor estimates were obtained in 14 whole, formalin fixed post-mortem brains placed in fluorinert approximately 48 hours prior to scanning. This consisted of 7 brains fixed with 10% formalin and 7 brains fixed with 10% neutral buffered formalin (NBF). Fixative outflux was modelled using a Kinetic Tensor (KT) model, which incorporates voxelwise diffusion tensor estimates to account for diffusion anisotropy and tissue-specific diffusion coefficients. Brains fixed with 10% NBF revealed a spatial T2 pattern consistent with the modelled fixative outflux. Confound regression of fixative concentration reduced T2 inhomogeneity across both white and grey matter, with the greatest reduction attributed to the KT model vs simpler models of fixative outflux. No such effect was observed in brains fixed with 10% formalin. Correlations with ferritin and myelin proteolipid protein (PLP) histology lead to an increased similarity for the relationship between T2 and PLP for the two fixative types after KT correction. Only small correlations were identified between T2 and ferritin before and after KT correction.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Orientation of Directional Deep Brain Stimulation Leads on CT: Resolving the Ambiguity

While directional deep brain stimulation (DBS) shows promising clinical effects by providing a new degree of freedom in programming, precise knowledge of the lead position and orientation is necessary to mitigate the resulting increased complexity. Two methods for orientation assessment based on postoperative CT imaging have become available, but neither of them is currently able to resolve the respective 180{degrees} artifact symmetry. Both rely on information about the intended orientation and assume that a deviation of more than {+/-} 90{degrees} is very unlikely. Our aim was to develop an enhanced algorithm capable of detecting asymmetries in the CT data and to thus eliminate the need for user interaction. Two different approaches are presented: one based on the lead marker's center of mass (COM) and one based on asymmetric sampling of the marker's intensity profile (ASM). Both were tested on a total of 98 scans of 2 lead phantoms, resulting in 165 measurements with a large variety of lead implantation and orientation angles. The 180{degrees} ambiguity was correctly resolved in 99.4% of cases by COM and in 96.4% of cases by ASM. These results demonstrate the substantial and currently unused asymmetry in CT and the potential for a truly automated workflow.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Effective connectivity and spatial selectivity-dependent fMRI changes elicited by microstimulation of pulvinar and LIP

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Mobile EEG reveals functionally dissociable dynamic processes supporting real-world ambulatory obstacle avoidance: Evidence for early proactive control

The ability to safely negotiate the world on foot takes years to develop in human infants, reflecting the huge cognitive demands associated with real-time dynamic planning and control of walking. Despite the importance of walking, surprisingly little is known about the neural and cognitive processes that support ambulatory motor control in humans. In particular, methodological limitations have, to date, largely prevented study of the neural processes involved in detecting and avoiding obstacles during walking. Here, using mobile EEG during real-world ambulatory obstacle avoidance, we captured the dynamic oscillatory response to changes in the environment. Time-frequency analysis of EEG data revealed clear neural markers of proactive and reactive forms of movement control (occurring before and after crossing an obstacle), visible as increases in frontal theta and centro-parietal beta power respectively. Critically, the temporal profile of changes in frontal theta allowed us to arbitrate between early selection and late correction mechanisms of proactive control: our data show that motor plans are updated as soon as an upcoming obstacle appears, rather than when the obstacle is reached, as previously thought. In addition, regardless of whether motor plans required updating, a clear beta rebound was present after obstacles were crossed, reflecting the resetting of the motor system. Overall, our use of mobile EEG during real-world walking provides novel insight into the cognitive and neural basis of dynamic motor control in humans, suggesting new routes to the monitoring and rehabilitation of motor disorders such as dyspraxia and Parkinsons disease.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Time course of homeostatic structural plasticity in response to optogenetic stimulation in mouse anterior cingulate cortex

Synapse formation and network rewiring is key to build neural circuits during development and has been widely observed in adult brains. Maintaining neural activity with the help of synaptic plasticity is essential to enable normal brain function. The model of homeostatic structural plasticity (HSP) was proposed to reflect the homeostatic regulation of neural activity and explain structural changes seen after perturbations. However, the specific temporal profile of such plastic responses has not yet been elucidated in experiments. To address this issue, we combined computational modeling and mouse optogenetic stimulation experiments. Our model predicted that within 48h post-stimulation, neural activity returns to baseline, while the connectivity among stimulated neurons follows a very specific transient increase and decrease. To capture such dynamics experimentally in vivo, we activated the pyramidal neurons in the anterior cingulate cortex of mice and harvested their brains at 1.5h, 24h, and 48h post-stimulation. Cortical hyperactivity as demonstrated by robust c-Fos expression persisted up to 1.5h and decayed to baseline after 24h. However, spine density and spine head volume were increased at 24h and decreased at 48h. Synaptic proteins VGLUT1 and PSD-95 were also upregulated and downregulated at 24h and 48h, respectively, while the calmodulin-binding protein neurogranin was translocated from the soma to the dendrite. Additionally, lasting astrocyte reactivation and microglia proliferation were observed, suggesting a role of neuron-glia interaction. All this corroborates the interpretation of our experimental results in terms of homeostatic structural plasticity. Our results bring important insights of how external stimulation modulates synaptic plasticity and behaviors.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### A cortical circuit mechanism for coding and updating task structural knowledge in inference-based decision-making

Making decisions based on knowledge about causal environmental structures is a hallmark of higher cognition in mammalian brains. Despite mounting work in psychological and cognitive sciences, how the brain implements knowledge-based decision-making at neuronal circuit level remains a terra incognita. Here we established an inference-based auditory categorization task, where mice performed within-session re-categorization of stimuli by inferring the changing task rules. Using a belief-state reinforcement learning (BS-RL) model, we quantified the hidden variable associated with task knowledge. Using simultaneous two-photon population imaging and projection-specific optogenetics, we found that a subpopulation of auditory cortex (ACx) neurons encoded the hidden task-rule variable, which depended on the feedback input from orbitofrontal cortex (OFC). Chemogenetic silencing of the OFC-ACx projection specifically disrupted re-categorization performance. Finally, imaging from OFC axons within ACx revealed task state-related value signals in line with the modeled updating mechanism. Our results provide a cortical circuit mechanism underlying inference-based decision-making.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Reciprocal connectivity of the periaqueductal gray with the ponto-medullary respiratory network in rat.

Synaptic activities of the periaqueductal gray (PAG) can modulate or appropriate the respiratory motor activities in the context of behavior and emotion via descending projections to nucleus retroambiguus. However, alternative anatomical pathways for the mediation of PAG-evoked respiratory modulation via core nuclei of the brainstem respiratory network remains only partially described. We injected the retrograde tracer Cholera toxin subunit B (CT-B) in the pontine Kolliker-Fuse nucleus (KFn, n=5), medullary Botzinger (BotC, n=3) and pre-Botzinger complexes (pre-BotC; n=3), and the caudal raphe nuclei (n=3), and quantified the ascending and descending connectivity of the PAG. CT-B injections in the KFn, pre-BotC, and caudal raphe, but not in the BotC, resulted in CT-B-labeled neurons that were predominantly located in the lateral and ventrolateral PAG columns. In turn, CT-B injections into the lateral and ventrolateral PAG columns (n=4) yield the highest numbers of CT-B-labeled neurons in the KFn and far fewer numbers of labeled neurons in the pre-BotC and caudal raphe. Analysis of the relative projection strength revealed that the KFn shares the densest reciprocal connectivity with the PAG (ventrolateral and lateral columns, in particular). Overall, our data imply that the PAG may engage a distributed respiratory rhythm and pattern generating network beyond the nucleus retroambiguus to mediate downstream modulation of breathing. However, the reciprocal connectivity of the KFn and PAG suggests specific roles for synaptic interaction between these two nuclei that are most likely related to the regulation of upper airway patency during vocalization or other volitional orofacial behaviors.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Conductance-Based Structural Brain Connectivity in Aging and Dementia

Structural brain connectivity has been shown to be sensitive to the changes that the brain undergoes during Alzheimer's disease (AD) progression. In this work, we use our recently proposed structural connectivity quantification measure derived from diffusion MRI, which accounts for both direct and indirect pathways, to quantify brain connectivity in dementia. We analyze data from the ADNI-2 and OASIS-3 datasets to derive relevant information for the study of the changes that the brain undergoes in AD. We also compare these datasets to the HCP dataset, as a reference. Our analysis shows expected trends of mean conductance with respect to age and cognitive scores, significant age prediction values in aging data, and regional effects centered among subcortical regions, and cingulate and temporal cortices. Results indicate that the conductance measure has prediction potential, especially for age, that age and cognitive scores largely overlap, and that this measure could be used to study effects such as anti-correlation in structural connections.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### A clock in mouse cones contributes to the retinal oscillator network and to synchronization of the circadian system

Multiple circadian clocks dynamically regulate mammalian physiology. In retina, rhythmic gene expression serves to align vision and tissue homeostasis with daily light changes. Photic input is relayed to the suprachiasmatic nucleus to entrain the master clock, which matches behaviour to environmental changes. Circadian organization of the mouse retina involves coordinated, layer-specific oscillators, but so far little is known about the cone photoreceptor clock and its role in the circadian system. Using the cone-only Nrl-/- mouse model we show that cones contain a functional self-sustained molecular clockwork. By bioluminescence-combined imaging we also show that cones provide substantial input to the retinal clock network. Furthermore, we found that light entrainment and negative masking in cone-only mice are subtly altered and that constant light displayed profound effects on their central clock. Thus, our study demonstrates the contribution of cones to retinal circadian organisation and their role in finely tuning behaviour to environmental conditions.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### Unraveling the Developmental Dynamic of Visual Exploration of Social Interactions in Autism

Atypical deployment of social gaze is present early on in toddlers with autism spectrum disorders (ASDs). Yet, studies characterizing the developmental dynamic behind it are scarce. Here we used a data-driven method to delineate the developmental change in visual exploration of social interaction over childhood years in autism. Longitudinal eye-tracking data were acquired as children with ASD and their typically developing (TD) peers freely explored complex animated scene. We found divergent moment-to moment gaze patterns in children with ASD compared to their TD peers. This divergence was particularly evident in sequences that displayed social interactions between characters, and even more so in the children with lower developmental and functional levels. Basic visual properties of the animated scene did not accounted for the enhanced divergence. Over childhood years, these differences dramatically increased to become more idiosyncratic. Taken together, these findings suggest that social attention should be targeted early in clinical treatments.

in bioRxiv: Neuroscience on September 17, 2020 12:00 AM.

• #### DeepHE: Accurately predicting human essential genes based on deep learning

by Xue Zhang, Wangxin Xiao, Weijia Xiao

Accurately predicting essential genes using computational methods can greatly reduce the effort in finding them via wet experiments at both time and resource scales, and further accelerate the process of drug discovery. Several computational methods have been proposed for predicting essential genes in model organisms by integrating multiple biological data sources either via centrality measures or machine learning based methods. However, the methods aiming to predict human essential genes are still limited and the performance still need improve. In addition, most of the machine learning based essential gene prediction methods are lack of skills to handle the imbalanced learning issue inherent in the essential gene prediction problem, which might be one factor affecting their performance. We propose a deep learning based method, DeepHE, to predict human essential genes by integrating features derived from sequence data and protein-protein interaction (PPI) network. A deep learning based network embedding method is utilized to automatically learn features from PPI network. In addition, 89 sequence features were derived from DNA sequence and protein sequence for each gene. These two types of features are integrated to train a multilayer neural network. A cost-sensitive technique is used to address the imbalanced learning problem when training the deep neural network. The experimental results for predicting human essential genes show that our proposed method, DeepHE, can accurately predict human gene essentiality with an average performance of AUC higher than 94%, the area under precision-recall curve (AP) higher than 90%, and the accuracy higher than 90%. We also compare DeepHE with several widely used traditional machine learning models (SVM, Naïve Bayes, Random Forest, and Adaboost) using the same features and utilizing the same cost-sensitive technique to against the imbalanced learning issue. The experimental results show that DeepHE significantly outperforms the compared machine learning models. We have demonstrated that human essential genes can be accurately predicted by designing effective machine learning algorithm and integrating representative features captured from available biological data. The proposed deep learning framework is effective for such task.

in PLoS Computational Biology on September 16, 2020 09:00 PM.

• #### Discovering functional sequences with RELICS, an analysis method for CRISPR screens

by Patrick C. Fiaux, Hsiuyi V. Chen, Poshen B. Chen, Aaron R. Chen, Graham McVicker

CRISPR screens are a powerful technology for the identification of genome sequences that affect cellular phenotypes such as gene expression, survival, and proliferation. By targeting non-coding sequences for perturbation, CRISPR screens have the potential to systematically discover novel functional sequences, however, a lack of purpose-built analysis tools limits the effectiveness of this approach. Here we describe RELICS, a Bayesian hierarchical model for the discovery of functional sequences from CRISPR screens. RELICS specifically addresses many of the challenges of non-coding CRISPR screens such as the unknown locations of functional sequences, overdispersion in the observed single guide RNA counts, and the need to combine information across multiple pools in an experiment. RELICS outperforms existing methods with higher precision, higher recall, and finer-resolution predictions on simulated datasets. We apply RELICS to published CRISPR interference and CRISPR activation screens to predict and experimentally validate novel regulatory sequences that are missed by other analysis methods. In summary, RELICS is a powerful new analysis method for CRISPR screens that enables the discovery of functional sequences with unprecedented resolution and accuracy.

in PLoS Computational Biology on September 16, 2020 09:00 PM.

• #### Diet choice: The two-factor host acceptance system of silkworm larvae

by Kana Tsuneto, Haruka Endo, Fumika Shii, Ken Sasaki, Shinji Nagata, Ryoichi Sato

Many herbivorous insects are mono- or oligophagous, having evolved to select a limited range of host plants. They specifically identify host-plant leaves using their keen sense of taste. Plant secondary metabolites and sugars are thought to be key chemical cues that enable insects to identify host plants and evaluate their quality as food. However, the neuronal and behavioral mechanisms of host-plant recognition are poorly understood. Here, we report a two-factor host acceptance system in larvae of the silkworm Bombyx mori, a specialist on several mulberry species. The first step is controlled by a chemosensory organ, the maxillary palp (MP). During palpation at the leaf edge, the MP detects trace amounts of leaf-surface compounds, which enables host-plant recognition without biting. Chemosensory neurons in the MP are tuned with ultrahigh sensitivity (thresholds of attomolar to femtomolar) to chlorogenic acid (CGA), quercetin glycosides, and β-sitosterol (βsito). Only if these 3 compounds are detected does the larva make a test bite, which is evaluated in the second step. Low-sensitivity neurons in another chemosensory organ, the maxillary galea (MG), mainly detect sucrose in the leaf sap exuded by test biting, allowing larvae to accept the leaf and proceed to persistent biting (feeding). The two-factor host acceptance system reported here may commonly underlie stereotyped feeding behavior in many phytophagous insects and determine their feeding habits.

in PLoS Biology on September 16, 2020 09:00 PM.

• #### Morphological and physiological properties of Rohon‐Beard neurons along the zebrafish spinal cord

Primary mechanosensory afferents serve as the first level of signal processing at the somatosensory periphery and provide information about behaviorally relevant stimulus features. Here, we show that the mechanosensory Rohon‐Beard (RB) neurons in larval zebrafish are rapidly adapting cells that can signal stimulus onset and offset and encode stimulus intensity implementing rate and temporal coding mechanisms. We also revealed a rostrocaudal variation in both morphology and physiology within the RB neuron population, which offers insights on what signals RBs carry into central circuits and on their role in locomotor behaviors.

## ABSTRACT

Primary mechanosensory neurons play an important role in converting mechanical forces into the sense of touch. In zebrafish, Rohon‐Beard (RB) neurons serve this role at embryonic and larval stages of development. Here we examine the morphology and physiology of RBs in larval zebrafish to better understand how mechanosensory stimuli are represented along the spinal cord. We report that the morphology of RB neurons differs along the rostrocaudal body axis. Rostral RB neurons arborize in the skin near the cell body whereas caudal cells arborize at a distance posterior to their cell body. Using a novel electrophysiological approach, we also found longitudinal differences in the mechanosensitivity and physiological properties of RB neurons. Rostral RB neurons respond to mechanical stimulations close to the soma and produce up to three spikes with increasing stimulus intensity, whereas caudal cells respond at more distal locations and can produce four or more spikes when the intensity of the mechanical stimulus increases. The mechanosensory properties of RB neurons are consistent with those of rapidly adapting mechanoreceptors and can signal the onset, offset and intensity of mechanical stimulation. This is the first report of the intensity encoding properties of RB neurons, where an increase in spike number and a decrease in spike latency are observed with increasing stimulation intensity. This study reveals an unappreciated complexity of the larval zebrafish mechanosensory system and demonstrates how differences in the morphological and physiological properties of RBs related to their rostrocaudal location, which can influence the signals that enter the spinal cord.

in Journal of Comparative Neurology on September 16, 2020 07:24 PM.

• #### Sympathetic innervation of inguinal white adipose tissue in the mouse

Pre‐and postganglionic sympathetic iWAT inputs are anatomically distinct from iBAT

Dorsolumbar and inguinal iWAT portions are innervated by anatomically distinct sympathetic nerves

Sympathetic postganglionic iWAT innervation reaches its target organ via lateral cutaneous rami of intercostal nerves T11‐L1 and anterior cutaneous femoral nerve (as part of the lumbar plexus, L1)

White adipocytes are sparsely innervated (sparse varicosities), while brown adipocytes (beige islands) show dense innervation (dense varicosities) in iWAT

## Abstract

Adipose tissue plays an important role in metabolic homeostasis and its prominent role as endocrine organ is now well‐recognized. Adipose tissue is controlled via the sympathetic nervous system. New viral, molecular‐genetic tools will soon allow a more detailed study of adipose tissue innervation in metabolic function, yet, the precise anatomical extent of pre‐and postganglionic inputs to the inguinal white adipose tissue (iWAT) is limited. Furthermore, several viral, molecular‐genetic tools will require the use of cre/loxP mouse models, while the available studies on sympathetic iWAT innervation were established in larger species. In this study, we generated a detailed map for the sympathetic innervation of iWAT in male and female mice. We adapted iDISCO tissue clearing to process large, whole‐body specimens for an unprecedented view of the natural abdominal sympathetic nervous system. Combined with pseudorabies virus retrograde tracing from the iWAT, we defined the pre‐and postganglionic sympathetic input to iWAT. We used fluorescence‐guided anatomical dissections of sympathetic nerves in reporter mice to further clarify that postganglionic axons connect to iWAT via lateral cutaneous rami (dorsolumbar iWAT portion) and the lumbar plexus (inguinal iWAT portion). Importantly, these rami carry axons that branch to iWAT, as well as axons that travel further to innervate the skin and vasculature, and their functional impact will require consideration in denervation studies. Our study may serve as a comprehensive map for future experiments that employ virally‐driven neuromodulation techniques to predict anatomy‐based viral labeling.

in Journal of Comparative Neurology on September 16, 2020 07:00 PM.

• #### Differential development of myelin in zebra finch song nuclei

The forebrain song nuclei in adult songbirds exhibit distinct myelination patterns, yet little is known about myelin development. We demonstrate different developmental rates and final levels of myelination across five major song nuclei. This differential myelin development could contribute to different aspects of song acquisition and production.

## Abstract

Songbirds learn vocalizations by hearing and practicing songs. As song develops, the tempo becomes faster and more precise. In the songbird brain, discrete nuclei form interconnected myelinated circuits that control song acquisition and production. The myelin sheath increases the speed of action potential propagation by insulating the axons of neurons and by reducing membrane capacitance. As the brain develops, myelin increases in density, but the time course of myelin development across discrete song nuclei has not been systematically studied in a quantitative fashion. We tested the hypothesis that myelination develops differentially across time and song nuclei. We examined myelin development in the brains of the zebra finch (Taeniopygia guttata) from chick at posthatch day (d) 8 to adult (up to 147 d) in five major song nuclei: HVC (proper name), robust nucleus of the arcopallium (RA), Area X, lateral magnocellular nucleus of the anterior nidopallium, and medial portion of the dorsolateral thalamic nucleus (DLM). All of these nuclei showed an increase in the density of myelination during development but at different rates and to different final degrees. Exponential curve fits revealed that DLM showed earlier myelination than other nuclei, and HVC showed the slowest myelination of song nuclei. Together, these data show differential maturation of myelination in different portions of the song system. Such differential maturation would be well placed to play a role in regulating the development of learned song.

in Journal of Comparative Neurology on September 16, 2020 07:00 PM.

## Purpose

In acute ischemic stroke with unknown time of onset, MR‐based diffusion‐weighted imaging (DWI) and fluid‐attenuated inversion recovery (FLAIR) estimates lesion age to guide intravenous thrombolysis. CT‐based quantitative net water uptake (NWU) may be a potential alternative. The purpose of this study was to directly compare CT‐based NWU to MRI at identifying patients with lesion age <4.5h from symptom onset.

## Methods

50 acute anterior circulation stroke patients were analyzed with both imaging modalities at admission between 0.5h‐8.0h after known symptom onset. DWI‐FLAIR lesion mismatch was rated and NWU was measured in admission‐CT. An established NWU‐threshold (11.5%) was used to classify patients within and beyond 4.5h. Multiparametric MRI signal was compared to NWU using logistic regression analyses. The empirical distribution of NWU was analyzed in a consecutive cohort of wake‐up stroke patients.

## Results

The median time between CT and MRI was 35 minutes (IQR: 24‐50). The accuracy of DWI‐FLAIR mismatch was 68.8% (95%CI: 53.7‐81.3%) with a sensitivity of 58% and specificity of 82%. The accuracy of NWU‐threshold was 86.0% (95%CI: 73.3‐94.2%) with a sensitivity of 91% and specificity of 78%. The AUC of multiparametric MRI to classify lesion age <4.5h was 0.86 (95%CI: 0.64‐0.97), and the AUC of quantitative NWU was 0.91 (95%CI: 0.78‐0.98). Among 87 wake‐up stroke patients, 46 patients (53%) showed low NWU (<11.5%).

## Conclusion

The predictive power of CT‐based lesion water imaging to identify patients within the time window of thrombolysis was comparable to multiparametric DWI‐FLAIR MRI. A significant proportion of wake‐up stroke patients with low NWU may be potentially suitable for thrombolysis.

in Annals of Neurology on September 16, 2020 04:10 PM.

## Objective

A recessive biallelic repeat expansion, (AAGGG)exp, in the RFC1 gene has been reported to be a frequent cause of late‐onset ataxia. For cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG)exp genotype was present in approximately 92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA) which shared a spectrum of symptoms with CANVAS.

## Methods

In this study, we screened the pathogenic (AAGGG)exp repeat and five other PNRs in Chinese 104 sporadic adult‐onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients and 203 unaffected individuals. Multiple molecular genetic tests were used, including long‐range PCR, RP‐PCR, Sanger sequencing and Southern blot. Comprehensive clinical assessments were conducted including neurological examination, neuroimaging, nerve electrophysiology and vestibular function examination.

## Results

We identified biallelic (AAGGG)exp in one SAOA patient and three MSA patients. Additionally, an MSA patient had the (AAGGG)exp/(AAAGG)exp genotype with uncertain pathogenicity. The carrier frequency for different PNRs in our cohorts was also described. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG)exp in RFC1 could be associated with MSA and should be screened routinely in the MSA diagnostic workflow.

## Interpretation

Our results expanded the clinical phenotypic spectrum of RFC1‐related disorders and raised the possibility that MSA might share the same genetic background with CANVAS, which was crucial for re‐evaluating the current CANVAS and MSA diagnostic criteria.

in Annals of Neurology on September 16, 2020 03:56 PM.

• #### Concerning Vision Therapy and Ocular Motor Training in Mild Traumatic Brain Injury

in Annals of Neurology on September 16, 2020 11:16 AM.

## Objective

Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity.

## Methods

We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD.

## Results

We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory‐motor, lateral sensory‐motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = −0.760 [95% CI = −1.297, −0.224]), default mode (p = 0.012, parameter estimate = −0.417 [95% CI = −0.731, −0.104]), and cingulo‐opercular (p = 0.009, parameter estimate = −0.883 [95% CI = −1.517, −0.250]) networks decreased.

## Interpretation

We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020

in Annals of Neurology on September 16, 2020 11:15 AM.

• #### Nontrivial amplification below the threshold for excitable cell signaling

Author(s): Emma Iverson, Minjing Yang, Hongyong Zhang, and Jonathan H. McCoy

It has long been known that transients in many excitable systems can be dramatically amplified, even when resulting from perturbations that are too small to excite spikes. The authors study noise amplification in three types of excitable systems commonly studied in mathematical biology. They find general conditions for dramatic amplification of fluctuations that are insensitive to system details.

[Phys. Rev. E 102, 032409] Published Wed Sep 16, 2020

in Physical Review E: Biological physics on September 16, 2020 10:00 AM.

• #### Diffusion of antibiotics through a biofilm in the presence of diffusion and absorption barriers

Author(s): Tadeusz Kosztołowicz and Ralf Metzler

We propose a model of antibiotic diffusion through a bacterial biofilm when diffusion and/or absorption barriers develop in the biofilm. The idea of this model is: We deduce details of the diffusion process in a medium in which direct experimental study is difficult, based on probing diffusion in ex...

[Phys. Rev. E 102, 032408] Published Wed Sep 16, 2020

in Physical Review E: Biological physics on September 16, 2020 10:00 AM.

• #### Softening of DNA near melting as disappearance of an emergent property

Author(s): Debjyoti Majumdar and Somendra M. Bhattacharjee

Near the melting transition the bending elastic constant $\kappa$, an emergent property of double-stranded DNA (dsDNA), is shown not to follow the rodlike scaling for small-length $N$. The reduction in $\kappa$ with temperature is determined by the denatured bubbles for a continuous transition, e.g., when the two s...

[Phys. Rev. E 102, 032407] Published Wed Sep 16, 2020

in Physical Review E: Biological physics on September 16, 2020 10:00 AM.

• #### Flexibility of brain regions during working memory curtails cognitive consequences to lack of sleep. (arXiv:2009.07233v1 [q-bio.NC])

Previous research has shown a clear relationship between sleep and memory, examining the impact of sleep deprivation on key cognitive processes over very short durations or in special populations. Here, we show, in a longitudinal 16 week study, that naturalistic, unfettered sleep modulations in healthy adults have significant impacts on the brain. Using a dynamic networks approach combined with hierarchical statistical modelling, we show that the flexibility of particular brain regions that span a large network including regions in occipital, temporal, and frontal cortex increased when participants performed a working memory task following low sleep episodes. Critically, performance itself did not change as a function of sleep, implying adaptability in brain networks to compensate for having a poor night's sleep by recruiting the necessary resources to complete the task. We further explore whether this compensatory effect is driven by a (i) increase in the recruitment of network resources over time and/or (ii) an expansion of the network itself. Our results add to the literature linking sleep and memory, provide an analytical framework in which to investigate compensatory modulations in the brain, and highlight the brain's resilience to day-to-day fluctuations of external pressures to performance.

in arXiv: Quantitative Biology: Neurons and Cognition on September 16, 2020 01:30 AM.

• #### Approximate spectral clustering using both reference vectors and topology of the network generated by growing neural gas. (arXiv:2009.07101v1 [cs.LG])

Spectral clustering (SC) is one of the most popular clustering methods and often outperforms traditional clustering methods. SC uses the eigenvectors of a Laplacian matrix calculated from a similarity matrix of a dataset. SC has serious drawbacks that are the significant increase in the computational complexity derived from the eigendecomposition and the memory space complexities to store the similarity matrix. To address the issues, I develop a new approximate spectral clustering using the network generated by growing neural gas (GNG), called ASC with GNG in this study. The proposed method uses not only reference vectors for vector quantization but also the topology of the network for extraction of the topological relationship between data points in a dataset. The similarity matrix used by ASC with GNG is made from both the reference vectors and the topology of the network generated by GNG. Using the network generated from a dataset by GNG, we achieve to reduce the computational and space complexities and to improve clustering quality. This paper demonstrates that the proposed method effectively reduces the computational time. Moreover, the results of this study show that the proposed method displays equal to or better performance of clustering than SC.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 16, 2020 01:30 AM.

• #### Co-evolution of Functional Brain Network at Multiple Scales during Early Infancy. (arXiv:2009.06899v1 [q-bio.NC])

The human brains are organized into hierarchically modular networks facilitating efficient and stable information processing and supporting diverse cognitive processes during the course of development. While the remarkable reconfiguration of functional brain network has been firmly established in early life, all these studies investigated the network development from a "single-scale" perspective, which ignore the richness engendered by its hierarchical nature. To fill this gap, this paper leveraged a longitudinal infant resting-state functional magnetic resonance imaging dataset from birth to 2 years of age, and proposed an advanced methodological framework to delineate the multi-scale reconfiguration of functional brain network during early development. Our proposed framework is consist of two parts. The first part developed a novel two-step multi-scale module detection method that could uncover efficient and consistent modular structure for longitudinal dataset from multiple scales in a completely data-driven manner. The second part designed a systematic approach that employed the linear mixed-effect model to four global and nodal module-related metrics to delineate scale-specific age-related changes of network organization. By applying our proposed methodological framework on the collected longitudinal infant dataset, we provided the first evidence that, in the first 2 years of life, the brain functional network is co-evolved at different scales, where each scale displays the unique reconfiguration pattern in terms of modular organization.

in arXiv: Quantitative Biology: Neurons and Cognition on September 16, 2020 01:30 AM.

• #### Ensemble learning of diffractive optical networks. (arXiv:2009.06869v1 [cs.NE])

A plethora of research advances have emerged in the fields of optics and photonics that benefit from harnessing the power of machine learning. Specifically, there has been a revival of interest in optical computing hardware, due to its potential advantages for machine learning tasks in terms of parallelization, power efficiency and computation speed. Diffractive Deep Neural Networks (D2NNs) form such an optical computing framework, which benefits from deep learning-based design of successive diffractive layers to all-optically process information as the input light diffracts through these passive layers. D2NNs have demonstrated success in various tasks, including e.g., object classification, spectral-encoding of information, optical pulse shaping and imaging, among others. Here, we significantly improve the inference performance of diffractive optical networks using feature engineering and ensemble learning. After independently training a total of 1252 D2NNs that were diversely engineered with a variety of passive input filters, we applied a pruning algorithm to select an optimized ensemble of D2NNs that collectively improve their image classification accuracy. Through this pruning, we numerically demonstrated that ensembles of N=14 and N=30 D2NNs achieve blind testing accuracies of 61.14% and 62.13%, respectively, on the classification of CIFAR-10 test images, providing an inference improvement of >16% compared to the average performance of the individual D2NNs within each ensemble. These results constitute the highest inference accuracies achieved to date by any diffractive optical neural network design on the same dataset and might provide a significant leapfrog to extend the application space of diffractive optical image classification and machine vision systems.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 16, 2020 01:30 AM.

• #### Short-term synaptic plasticity optimally models continuous environments. (arXiv:2009.06808v1 [cs.NE])

Biological neural networks operate with extraordinary energy efficiency, owing to properties such as spike-based communication and synaptic plasticity driven by local activity. When emulated in silico, such properties also enable highly energy-efficient machine learning and inference systems. However, it is unclear whether these mechanisms only trade off performance for efficiency or rather they are partly responsible for the superiority of biological intelligence. Here, we first address this theoretically, proving rigorously that indeed the optimal prediction and inference of randomly but continuously transforming environments, a common natural setting, relies on adaptivity through short-term spike-timing dependent plasticity, a hallmark of biological neural networks. Secondly, we assess this theoretical optimality via simulations and also demonstrate improved artificial intelligence (AI). For the first time, a largely biologically modelled spiking neural network (SNN) surpasses state-of-the-art artificial neural networks (ANNs) in all relevant aspects, in an example task of recognizing video frames transformed by moving occlusions. The SNN recognizes the frames more accurately, even if trained on few, still, and untransformed images, with unsupervised and synaptically-local learning, binary spikes, and a single layer of neurons - all in contrast to the deep-learning-trained ANNs. These results indicate that on-line adaptivity and spike-based computation may optimize natural intelligence for natural environments. Moreover, this expands the goal of exploiting biological neuro-synaptic properties for AI, from mere efficiency, to computational supremacy altogether.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 16, 2020 01:30 AM.

• #### Variable Binding for Sparse Distributed Representations: Theory and Applications. (arXiv:2009.06734v1 [cs.NE])

Symbolic reasoning and neural networks are often considered incompatible approaches. Connectionist models known as Vector Symbolic Architectures (VSAs) can potentially bridge this gap. However, classical VSAs and neural networks are still considered incompatible. VSAs encode symbols by dense pseudo-random vectors, where information is distributed throughout the entire neuron population. Neural networks encode features locally, often forming sparse vectors of neural activation. Following Rachkovskij (2001); Laiho et al. (2015), we explore symbolic reasoning with sparse distributed representations. The core operations in VSAs are dyadic operations between vectors to express variable binding and the representation of sets. Thus, algebraic manipulations enable VSAs to represent and process data structures in a vector space of fixed dimensionality. Using techniques from compressed sensing, we first show that variable binding between dense vectors in VSAs is mathematically equivalent to tensor product binding between sparse vectors, an operation which increases dimensionality. This result implies that dimensionality-preserving binding for general sparse vectors must include a reduction of the tensor matrix into a single sparse vector. Two options for sparsity-preserving variable binding are investigated. One binding method for general sparse vectors extends earlier proposals to reduce the tensor product into a vector, such as circular convolution. The other method is only defined for sparse block-codes, block-wise circular convolution. Our experiments reveal that variable binding for block-codes has ideal properties, whereas binding for general sparse vectors also works, but is lossy, similar to previous proposals. We demonstrate a VSA with sparse block-codes in example applications, cognitive reasoning and classification, and discuss its relevance for neuroscience and neural networks.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 16, 2020 01:30 AM.

• #### Prokaryotic viperins produce diverse antiviral molecules

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2762-2

Prokaryotic viperins produce diverse antiviral molecules

in Nature on September 16, 2020 12:00 AM.

• #### Author Correction: Molecular architecture of lineage allocation and tissue organization in early mouse embryo

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2755-1

Author Correction: Molecular architecture of lineage allocation and tissue organization in early mouse embryo

in Nature on September 16, 2020 12:00 AM.

• #### Reprogramming roadmap reveals route to human induced trophoblast stem cells

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2734-6

Single-cell transcriptomics roadmap of human dermal fibroblasts reprogrammed to primed and naive pluripotency reveals a route for the direct reprogramming of somatic cells into induced trophoblast stem cells.

in Nature on September 16, 2020 12:00 AM.

• #### Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2732-8

The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions.

in Nature on September 16, 2020 12:00 AM.

• #### Deep posteromedial cortical rhythm in dissociation

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2731-9

Dissociative states in mouse and human brains are traced to low-frequency rhythmic neural activity—with distinct molecular, cellular and physiological properties—in the deep retrosplenial cortex and the posteromedial cortex.

in Nature on September 16, 2020 12:00 AM.

• #### Stimulus-specific hypothalamic encoding of a persistent defensive state

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2728-4

Persistent neural activity in the mouse hypothalamus encodes aversive emotional states related to specific threatening stimuli.

in Nature on September 16, 2020 12:00 AM.

• #### Red blood cell tension protects against severe malaria in the Dantu blood group

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2726-6

The rare blood group Dantu is known to protect against severe malaria, and a mechanism is proposed here: Dantu red blood cells have a high membrane tension that prevents invasion by malaria parasites.

in Nature on September 16, 2020 12:00 AM.

• #### Bridging of DNA breaks activates PARP2–HPF1 to modify chromatin

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2725-7

The PARP2–HPF1 histone-modifying complex bridges two nucleosomes to align broken DNA ends for ligation, initiating conformational changes that activate PARP2 and enable DNA damage repair.

in Nature on September 16, 2020 12:00 AM.

• #### Homeostatic mini-intestines through scaffold-guided organoid morphogenesis

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2724-8

Miniature gut tubes grown in vitro from mouse intestinal stem cells are perfusable, can be colonized with microorganisms and exhibit a similar arrangement and diversity of specialized cell types to intestines in vivo.

in Nature on September 16, 2020 12:00 AM.

• #### Metabolic trait diversity shapes marine biogeography

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2721-y

A tight coupling between metabolic rate, efficacy of oxygen supply and the temperature sensitivities of marine animals predicts a variety of geographical niches that better aligns with the distributions of species than models of either temperature or oxygen alone.

in Nature on September 16, 2020 12:00 AM.

• #### Evolution of the endothelin pathway drove neural crest cell diversification

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2720-z

CRISPR–Cas9-mediated disruption of the endothelin-signalling pathway in the sea lamprey Petromyzon marinus and the frog Xenopus laevis were used to delineate ancient and lineage-specific roles of endothelin signalling and provide insights into vertebrate evolution.

in Nature on September 16, 2020 12:00 AM.

• #### A giant planet candidate transiting a white dwarf

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2713-y

A giant planet candidate roughly the size of Jupiter but more than 14 times as massive is observed by TESS and other instruments to be transiting the white dwarf star WD 1856+534.

in Nature on September 16, 2020 12:00 AM.

• #### Reverse and forward engineering of Drosophila corneal nanocoatings

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2707-9

The building blocks of the nanostructures observed on Drosophila corneas are determined, and then used to create artificial nanostructures with anti-reflective and anti-adhesive properties.

in Nature on September 16, 2020 12:00 AM.

• #### Slow compression of crystalline ice at low temperature

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2697-7

Slow compression of crystalline ice at low temperature

in Nature on September 16, 2020 12:00 AM.

• #### Population genomics of the Viking world

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2688-8

Ancient DNA analyses reveal that Viking Age migrations from Scandinavia resulted in differential influxes of ancestry to different parts of Europe, and the increased presence of non-local ancestry within Scandinavia.

in Nature on September 16, 2020 12:00 AM.

• #### The superconducting quasicharge qubit

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2687-9

A fundamental superconducting qubit is introduced: ‘blochnium’ is dual to the transmon, relies on a circuit element called hyperinductance, and its fundamental physical variable is the quasicharge of the Josephson junction.

in Nature on September 16, 2020 12:00 AM.

• #### A submicrometre silicon-on-insulator resonator for ultrasound detection

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2685-y

The widely available silicon-on-insulator technology is used to develop a miniaturized ultrasound detector, which is 200 times smaller than the wavelengths of sound that it can detect.

in Nature on September 16, 2020 12:00 AM.

• #### Plasmonic enhancement of stability and brightness in organic light-emitting devices

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2684-z

Plasmonic effects in organic light-emitting devices, which are normally considered a source of energy loss, are harnessed to enhance the stability of these devices while maintaining operational efficiency.

in Nature on September 16, 2020 12:00 AM.

• #### Array programming with NumPy

Nature, Published online: 16 September 2020; doi:10.1038/s41586-020-2649-2

NumPy is the primary array programming library for Python; here its fundamental concepts are reviewed and its evolution into a flexible interoperability layer between increasingly specialized computational libraries is discussed.

in Nature on September 16, 2020 12:00 AM.

• #### Turning twenty

Nature Reviews Neuroscience, Published online: 16 September 2020; doi:10.1038/s41583-020-0371-6

Nature Reviews Neuroscience was first published in October 2000. In this issue, we therefore mark the 20th anniversary of the journal.

in Nature Reviews on September 16, 2020 12:00 AM.

• #### Author Correction: Identification and characterization of Cardiac Glycosides as senolytic compounds

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18714-z

Author Correction: Identification and characterization of Cardiac Glycosides as senolytic compounds

in Nature Communications on September 16, 2020 12:00 AM.

• #### Author Correction: Targeting QKI-7 in vivo restores endothelial cell function in diabetes

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18712-1

Author Correction: Targeting QKI-7 in vivo restores endothelial cell function in diabetes

in Nature Communications on September 16, 2020 12:00 AM.

• #### IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18519-0

The pathogenic mechanisms of cardiorenal syndrome type 4 (CRS4) remain unclear. Here, the authors identify IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling as a contributor to CRS4 pathogenesis, thus providing potential new targets for reducing cardiovascular events in CKD patients.

in Nature Communications on September 16, 2020 12:00 AM.

• #### Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18483-9

Mutations in RAS-MAPK pathway genes are implicated in Noonan-spectrum, yet up to 20% of cases have unknown cause. Here, the authors identify RREB1 underlying a 6p microdeletion RASopathy-like syndrome and show that RREB1, SIN3A and KDM1A form a transcriptional repressive complex to control methylation of MAPK pathway genes.

in Nature Communications on September 16, 2020 12:00 AM.

• #### Improved haplotype inference by exploiting long-range linking and allelic imbalance in RNA-seq datasets

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18320-z

Haplotype reconstruction of distant genetic variants is problematic in short-read sequencing. Here, the authors describe HapTree-X, a probabilistic framework that uses differential allele-specific expression to better reconstruct paternal haplotypes from diploid and polyploid genomes.

in Nature Communications on September 16, 2020 12:00 AM.

• #### Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18276-0

Diabetic foot ulcers (DFU) represent a complex disease with limited treatment options. Here, the authors compare human RNASeq patient data from DFU, oral mucosa and skin acute wounds, identifying FOXM1 as a mediator of macrophage and neutrophil recruitment, which contributes to disease pathogenesis and is dysregulated in patients.

in Nature Communications on September 16, 2020 12:00 AM.

• #### Reductions in commuting mobility correlate with geographic differences in SARS-CoV-2 prevalence in New York City

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18271-5

New York City is one of the areas most affected by the SARS-CoV-2 pandemic in the United States, and there has been large variation in rates of hospitalisation and death by city borough. Here, the authors show that boroughs with the largest reduction in daily commutes also had the lowest SARS-CoV-2 prevalence.

in Nature Communications on September 16, 2020 12:00 AM.

• #### Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Nature Communications, Published online: 16 September 2020; doi:10.1038/s41467-020-18189-y

Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.

in Nature Communications on September 16, 2020 12:00 AM.

• #### Daily briefing: World fails to meet every UN biodiversity goal

Nature, Published online: 16 September 2020; doi:10.1038/d41586-020-02664-z

We have not met any of the 20 Aichi Biodiversity Targets agreed in 2010 — but there are hopeful signs to build on. Plus, how COVID-19 can damage the brain and a visually sumptuous tour of the latest dinosaur discoveries.

in Nature on September 16, 2020 12:00 AM.

• #### Fast coronavirus tests: what they can and can't do

Nature, Published online: 16 September 2020; doi:10.1038/d41586-020-02661-2

Rapid antigen tests are designed to tell in a few minutes whether someone is infectious. Will they be game changers?

in Nature on September 16, 2020 12:00 AM.

• #### Synchronization and resilience in the Kuramoto white matter network model with adaptive state-dependent delays

White matter pathways form a complex network of myelinated axons that regulate signal transmission in the nervous system and play a key role in behaviour and cognition. Recent evidence reveals that white matte...

in The Journal of Mathematical Neuroscience on September 16, 2020 12:00 AM.

• #### Paramagnetic Metal Accumulation in the Deep Gray Matter Nuclei Is Associated With Neurodegeneration in Wilson’s Disease

Background

Neuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson’s disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied in vivo. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients.

Methods

Seventeen neurological WD patients and 20 healthy controls were recruited for the study. Mean bulk susceptibility values and volumes of DGM were obtained from quantitative susceptibility mapping (QSM). Regions of interest including the head of the caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, red nucleus, and dentate nucleus were manually segmented. The susceptibility values and volumes of DGM in different groups were compared using a linear regression model. Correlations between susceptibility values and volumes of DGM and Unified Wilson’s Disease Rating Scale (UWDRS) neurological subscores were investigated.

Results

The susceptibility values of all examined DGM in WD patients were higher than those in healthy controls (P < 0.05). Volume reductions were observed in the head of the caudate nucleus, globus pallidus, putamen, thalamus, and substantia nigra of WD patients (P < 0.001). Susceptibility values were negatively correlated with the volumes of the head of the caudate nucleus (rp = −0.657, P = 0.037), putamen (rp = −0.667, P = 0.037), and thalamus (rp = −0.613, P = 0.046) in WD patients. UWDRS neurological subscores were positively correlated with the susceptibility values of all examined DGM. The susceptibility values of putamen, head of the caudate nucleus, and dentate nucleus could well predict UWDRS neurological subscores.

Conclusion

Our study provided in vivo evidence that paramagnetic metal accumulation in the DGM was associated with DGM atrophy and neurological impairment. The susceptibility of DGM could be used as a biomarker to assess the severity of neurodegeneration in WD.

in Frontiers in Neuroscience: Neurodegeneration on September 16, 2020 12:00 AM.

• #### Initial Experience of Challenge-Free MRI-Based Oxygen Extraction Fraction Mapping of Ischemic Stroke at Various Stages: Comparison With Perfusion and Diffusion Mapping

MRI-based oxygen extraction fraction imaging has a great potential benefit in the selection of clinical strategies for ischemic stroke patients. This study aimed to evaluate the performance of a challenge-free oxygen extraction fraction (OEF) mapping in a cohort of acute and subacute ischemic stroke patients. Consecutive ischemic stroke patients (a total of 30 with 5 in the acute stage, 19 in the early subacute stage, and 6 in the late subacute stage) were recruited. All subjects underwent MRI including multi-echo gradient echo (mGRE), diffusion weighted imaging (DWI), and 3D-arterial spin labeling (ASL). OEF maps were generated from mGRE phase + magnitude data, which were processed using quantitative susceptibility mapping (QSM) + quantitative blood oxygen level-dependent (qBOLD) imaging with cluster analysis of time evolution. Cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) maps were reconstructed from 3D-ASL and DWI, respectively. Further, cerebral metabolic rate of oxygen (CMRO2) was calculated as the product of CBF and OEF. OEF, CMRO2, CBF, and ADC values in the ischemic cores (absolute values) and their contrasts to the contralateral regions (relative values) were evaluated. One-way analysis of variance (ANOVA) was used to compare OEF, CMRO2, CBF, and ADC values and their relative values among different stroke stages. The OEF value of infarct core showed a trend of decrease from acute, to early subacute, and to late subacute stages of ischemic stroke. Significant differences among the three stroke stages were only observed in the absolute OEF (F = 6.046, p = 0.005) and relative OEF (F = 5.699, p = 0.009) values of the ischemic core, but not in other measurements (absolute and relative CMRO2, CBF, ADC values, all values of p > 0.05). In conclusion, the challenge-free QSM + qBOLD-generated OEF mapping can be performed on stroke patients. It can provide more information on tissue viability that was not available with CBF and ADC and, thus, may help to better manage ischemic stroke patients.

in Frontiers in Neuroscience: Brain Imaging Methods on September 16, 2020 12:00 AM.

• #### Movement Kinematics and Interjoint Coordination Are Influenced by Target Location and Arm in 6-Year-Old Children

Rapid aiming movements are typically used to study upper limb motor control and development. Despite the large corpus of work in this area, few studies have examined kinematic manual asymmetries in children who have just started formal schooling and until now, none have characterized how children coordinate their joints to complete these movements (i.e., interjoint coordination). In the present study, manual asymmetries in kinematics and interjoint coordination in strongly right-handed 6-year-old children were investigated when reaching for ipsilateral and contralateral targets with their dominant right arm and the non-dominant left arm. Overall, manual asymmetries in interjoint coordination are apparent for both 6-year-old children and young adults, although young children completed the task by adopting a different strategy than adults. Also, control strategies employed by 6-year-old children were influenced by both the location of the target as well as the arm used to perform the task. Specifically, compared to all other conditions, children’s trajectories were more curved when performing contralateral movements with the non-dominant left arm, which were driven by smaller shoulder excursions combined with larger elbow excursions for this condition. Based on these results, we argue that the differences in interjoint coordination reflect the stage of development of 6-year-old children, the origin of which derives from maturational (e.g., hand dominance) and environmental factors (e.g., school-based experience).

in Frontiers in Human Neuroscience on September 16, 2020 12:00 AM.

• #### Sex Differences in Dendritic Spine Formation in the Hippocampus and Animal Behaviors in a Mouse Model of Hyperthyroidism

Thyroid hormones are critical for the regulation of development and differentiation of neurons and glial cells in the central nervous system (CNS). We have previously reported the sex-dependent changes of glial morphology in the brain under the state of hyperthyroidism. Here, we examined sex-dependent changes in spine structure of granule neurons in the dentate gyrus of hippocampus in male and female mice with hyperthyroidism. Using FIB/SEM (focused ion beam/scanning electron microscopy), three-dimensional reconstructed structures of dendritic spines in dentate granule cells were analyzed. Dendritic spine density in granule cells increased significantly in both male and female mice with hyperthyroidism. The decrease in spine volume was observed only in female mice. These findings suggest that hyperthyroidism induces the formation of spines with normal size in male mice but the formation of spines with small size in female mice. To evaluate an outcome of neuronal and previously observed glial changes, behavioral tests were performed. Male mice with hyperthyroidism showed increased locomotor activity in the open field test, while female mice showed elevated immobility time in the tail suspension test, reflecting depression-like behavior. Although direct link between changes in spine and behavioral modifications requires further analysis, our results may help to understand gender-dependent neurological and psychological symptoms observed in patients with hyperthyroidism.

in Frontiers in Cellular Neuroscience on September 16, 2020 12:00 AM.

• #### Morphologic Characterization of Trigeminothalamic Terminal Arbors Arising From the Principal Nucleus in the Macaque

The ventral posterior medial nucleus (VPM) is amandatory relay for orofacial sensory information targeting the primary somatosensory cortex. We characterized the morphology of VPM axons arising in the principal trigeminal sensory nucleus (pV) through injections of biotinylated dextran amine (BDA) placed in pV of Macaca fascicularis and mulatta monkeys. Labeled terminals formed a patchy bilateral distribution. Within contralateral VPM, patches were found primarily, but not exclusively, within the laterally located, vertical segment, and in ipsilateral VPM, primarily, but not exclusively, in the medially located, horizontal segment. Two fiber types were labeled: thin and thick. Thin fibers were poorly branched and diffusely distributed. They were studded with small en passant boutons. Most labeled fibers were thick and they branched extensively to form distinctive terminal arbors decorated with numerous boutons that varied in size and shape. Quantitative analysis of thick fiber arbor features showed little difference between the sides, although contralateral boutons were significantly larger than ipsilateral ones. Bouton distribution with respect to counterstained somata suggests that proximal dendrites are their main target. Indeed, ultrastructural examination demonstrated that they provide large diameter dendrites with numerous contacts. Direct comparison of thick fiber terminal arbors to cytochrome oxidase (CO) staining revealed that these arbors are much smaller than individual CO-rich patches believed to designate rods containing discrete body area representations. Thus, each terminal arbor appears to heavily innervate a small number of VPM neurons within a rod. This relationship would serve to maintain relatively small receptive fields within the topographic representation of the face.

in Frontiers in Neuroanatomy on September 16, 2020 12:00 AM.

• #### White Matter Integrity Is Associated With the Amount of Physical Activity in Older Adults With Super-aging

Previous studies have introduced the concept of “SuperAgers,” defined as older adults with youthful memory performance associated with the increased cortical thickness of the anterior cingulate cortex. Given that age-related structural brain changes are observed earlier in the white matter (WM) than in the cortical areas, we investigated whether WM integrity is different between the SuperAgers (SA) and typical agers (TA) and whether it is associated with superior memory performance as well as a healthy lifestyle. A total of 35 SA and 55 TA were recruited for this study. Further, 3.0-T magnetic resonance imaging (MRI), neuropsychological tests, and lifestyle factors related to cognitive function, such as physical activity and duration of sleep, were evaluated in all participants. SA was defined as individuals demonstrating the youthful performance of verbal and visual memory, as measured by the Seoul Verbal Learning Test (SVLT) and the Rey-Osterrieth Complex Figure Test (RCFT), respectively. Tract-based spatial statistics (TBSS) analysis was used to compare the diffusion values such as fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) between the SA and TA. SA exhibited better performance in memory, attention, visuospatial, and frontal executive functions than the TA did. SA also exhibited greater amounts of physical activity than the TA did. As compared to TA, SA demonstrated higher FA with lower MD, RD, and AD in the corpus callosum and higher FA and lower RD in the right superior longitudinal fasciculus (SLF), which is significantly associated with memory function. Interestingly, FA values of the body of corpus callosum were correlated with the amount of physical activity. Our findings suggest that WM integrity of the corpus callosum is associated with superior memory function and a higher level of physical activities in SA compared to TA.

in Frontiers in Ageing Neuroscience on September 16, 2020 12:00 AM.

• #### Reading the epigenetic code for exchanging DNA

Three independent studies show that a protein called ZCWPW1 is able to recognize the histone modifications that initiate the recombination of genetic information during meiosis.

in eLife on September 16, 2020 12:00 AM.

• #### Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein

Heterotrimeric G-proteins are signal transducers involved in mediating the action of many natural extracellular stimuli as well as of many therapeutic agents. Non-invasive approaches to manipulate the activity of G-proteins with high precision are crucial to understand their regulation in space and time. Here, we developed LOV2GIVe, an engineered modular protein that allows the activation of heterotrimeric G-proteins with blue light. This optogenetic construct relies on a versatile design that differs from tools previously developed for similar purposes, i.e. metazoan opsins, which are light-activated GPCRs. Instead, LOV2GIVe consists of the fusion of a G-protein activating peptide derived from a non-GPCR regulator of G-proteins to a small plant protein domain, such that light uncages the G-protein activating module. Targeting LOV2GIVe to cell membranes allowed for light-dependent activation of Gi proteins in different experimental systems. In summary, LOV2GIVe expands the armamentarium and versatility of tools available to manipulate heterotrimeric G-protein activity.

in eLife on September 16, 2020 12:00 AM.

• #### IER5, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55a subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.

in eLife on September 16, 2020 12:00 AM.

• #### The Wnt effector TCF7l2 promotes oligodendroglial differentiation by repressing autocrine BMP4-mediated signaling

Promoting oligodendrocyte differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector TCF7l2 was upregulated in MS lesions and had been proposed to inhibit oligodendrocyte differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP4)-mediated signaling. Disrupting TCF7l2 results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo. Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested oligodendrocyte differentiation elicited by TCF7l2 disruption in vivo. Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Rhythmic expression of Neurofibromin 1 in mushroom body neurons mediates circadian wake drive through activating cAMP-PKA signaling

Various behavioral and cognitive states exhibit circadian variations in animals across phyla including Drosophila, in which only [~]0.1% of the entire brain neurons contain circadian clocks. This suggests that clock neurons communicate with a plethora of non-clock neurons to transmit the timing information to gate various behavioral outputs in Drosophila. Here, we address the molecular underpinning of this phenomenon by performing circadian RNA-seq analysis of non-clock neurons that constitute the mushroom body (MB), the center of information processing and sleep regulation. We identify hundreds of genes rhythmically expressed in the MB, including the Drosophila ortholog of Neurofibromin 1 (Nf1), the gene responsible for neurofibromatosis type 1 (NF1). Rhythmic expression of Nf1 promotes daytime wakefulness by activating cAMP-PKA signaling and increasing excitability of the MB. These findings reveal the pervasive, non-cell-autonomous circadian regulation of gene expression in the brain and its role in sleep, with implications in the pathology of NF1.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Endogenous memory reactivation during sleep in humans is clocked by slow oscillation-spindle complexes.

Sleep is thought to support memory consolidation via reactivation of prior experiences, with particular electrophysiological sleep signatures (slow oscillations (SOs) and sleep spindles) gating the information flow between relevant brain areas. However, empirical evidence for a role of endogenous memory reactivation (i.e., without experimentally delivered memory cues) for consolidation in humans is lacking. Here, we devised a paradigm in which participants acquired associative memories before taking a nap. Multivariate decoding was then used to capture endogenous memory reactivation during non-rapid eye movement (NREM) sleep. Results revealed reactivation of learning material during SO-spindle complexes, with the precision of SO-spindle coupling predicting reactivation strength. Critically, reactivation strength in turn predicted the level of consolidation across participants. These results elucidate the memory function of sleep in humans and emphasize the importance of SOs and spindles in clocking endogenous consolidation processes.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Mimicry is associated with procedural learning, not social bonding, neural systems in autism

Mimicry facilitates social bonding throughout the lifespan. Mimicry impairments in autism spectrum conditions (ASC) are widely reported, including differentiation of the brain networks associated with its social bonding and learning functions. This study examined associations between volumes of brain regions associated with social bonding versus procedural skill learning, and mimicry of gestures during a naturalistic interaction in ASC and neurotypical (NT) children. Consistent with predictions, results revealed reduced mimicry in ASC relative to the NT children. Mimicry frequency was negatively associated with autism symptom severity. Mimicry was predicted predominantly by the volume of procedural skill learning regions in ASC, and by bonding regions in NT. Further, bonding regions contributed significantly less to mimicry in ASC than in NT, while the contribution of learning regions was not different across groups. These findings suggest that associating mimicry with skill learning, rather than social bonding, may partially explain observed communication difficulties in ASC.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Mean-field modeling of brain-scale dynamics for the evaluation of EEG source-space networks

Understanding the dynamics of brain-scale functional networks at rest and during cognitive tasks is the subject of intense research efforts to unveil fundamental principles of brain functions. To estimate these large-scale brain networks, the emergent method called "electroencephalography (EEG) source connectivity" has generated increasing interest in the network neuroscience community, due to its ability to identify cortical brain networks with good spatio-temporal resolution, while reducing mixing and volume conduction effects. However, the method is still immature and several methodological issues should be carefully accounted for to avoid pitfalls. Therefore, optimizing the EEG source connectivity pipelines is required, which involves the evaluation of several parameters. One key issue to address those evaluation aspects is the availability of a ground truth. In this paper, we show how a recently developed large-scale model of brain-scale activity, named COALIA, can provide to some extent such ground truth by providing realistic simulations (epileptiform activity) of source-level and scalp-level activity. Using a bottom-up approach, the model bridges cortical micro-circuitry and large-scale network dynamics. Here, we provide an example of the potential use of COALIA to analyze the effect of three key factors involved in the "EEG source connectivity" pipeline: (i) EEG sensors density, (ii) algorithm used to solve the inverse problem, and (iii) functional connectivity measure. Results show that a high electrode density (at least 64 channels) is needed to accurately estimate cortical networks. Regarding the inverse solution/connectivity measure combination, the best performance at high electrode density was obtained using the weighted minimum norm estimate (wMNE) combined with the weighted phase lag index (wPLI). The COALIA model and the simulations used in this paper are freely available and made accessible for the community. We believe that this model-based approach will help researchers to address some current and future cognitive and clinical neuroscience questions, and ultimately transform EEG brain network imaging into a mature technology.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Alpha fluctuations regulate the accrual of visual information to awareness

Endogenous brain processes play a paramount role in shaping up perceptual phenomenology, as illustrated by the alternations experienced by humans (and other animals) when watching perceptually ambiguous, static images. Here, we hypothesised that endogenous alpha fluctuations in the visual cortex pace the accumulation of sensory information leading to perceptual outcomes. We addressed this hypothesis using binocular rivalry combined with visual entrainment and electroencephalography in humans (42 female, 40 male). The results revealed a correlation between the individual frequency of alpha oscillations in the occipital cortex and perceptual alternation rates experienced during binocular rivalry. In subsequent experiments we show that regulating endogenous brain activity via entrainment produced corresponding changes in perceptual alternation rate, which were observed only in the alpha range but not at lower entrainment frequencies. Overall, rhythmic alpha stimulation resulted in faster perceptual alternation rates, compared to arrhythmic or no stimulation. These findings support the notion that visual information is accumulated via alpha cycles to promote the emergence of conscious perceptual representations. We suggest that models of binocular rivalry incorporating posterior alpha as a pacemaker can provide an important advance in the comprehension of the dynamics of visual awareness. Significance statementMainstream theories in cognitive neuroscience agree that endogenous brain processes play a paramount role in shaping our perceptual experience of sensory inputs. In vision, endogenous fluctuations in the alpha rhythm have been pointed out to regulate visual inputs to perception. In support of this hypothesis, here we used EEG recordings and visual entrainment to demonstrate that inter-individual differences in the speed of endogenous alpha fluctuations in the brain are causally related to the accrual of visual information to awareness. These findings provide, for the first time, evidence for alpha-gated regulation of the dynamics of alternations in conscious visual perception.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Disruption of Glial Ca2+ Oscillations at the Drosophila Blood-Brain Barrier Predisposes to Seizure-Like Behavior

Glia play key roles in regulating multiple aspects of neuronal development and function from invertebrates to humans. We recently found microdomain Ca2+ signaling in Drosophila cortex glia and astrocytes regulate extracellular K+ buffering and neurotransmitter uptake, respectively. Here we identify a role for ER store-operated Ca2+ entry (SOCE) in perineurial glia (PG), a distinct population that contributes to the blood-brain barrier (BBB). PG show a diverse range of Ca2+ oscillatory activity that varies based on their locale within the brain. Unlike cortex glia and astrocytes, PG Ca2+ oscillations do not require extracellular Ca2+ and are blocked by inhibition of SOCE or gap junctions. Disruption of these components triggers heat shock and mechanical-induced seizure-like episodes without effecting PG morphology or large molecule BBB permeability. These findings indicate SOCE-mediated Ca2+ oscillations in PG increase the susceptibility of seizure-like episodes in Drosophila, providing an additional link between glial Ca2+ signaling and neuronal activity.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### Calcium imaging and the curse of negativity

The imaging of neuronal activity using calcium indicators has become a staple of modern neuroscience. However, without ground truths, there is a real risk of missing a significant portion of the real responses. Here, we show that a common assumption, the non-negativity of the neuronal responses as detected by calcium indicators, biases all levels of the frequently used analytical methods for these data. From the extraction of meaningful fluorescence changes to spike inference and the analysis of inferred spikes, each step risks missing real responses because of the assumption of non-negativity. We first show that negative deviations from baseline can exist in calcium imaging of neuronal activity. Then, we use simulated data to test three popular algorithms for image analysis, finding that suite2p may be the best suited to large datasets. Spike inference algorithms also showed their limitations in dealing with inhibited neurons, and new approaches may be needed to address this problem. We further suggest avoiding data analysis approaches that may ignore inhibited responses in favor of a first exploratory step to ensure that none are present. Taking these steps will ensure that inhibition, as well as excitation, is detected in calcium imaging datasets.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### TMS cortical mapping of multiple muscles: absolute and relative test-retest reliability

The spatial accuracy of TMS may be as small as a few millimeters. Despite such great potential, navigated TMS (nTMS) mapping is still underused for the assessment of motor plasticity, particularly in clinical settings. Here we investigate the within-limb somatotopy gradient as well as absolute and relative reliability of three hand muscle cortical representations (MCRs) using a comprehensive grid-based sulcus-informed nTMS motor mapping. We enrolled 22 young healthy male volunteers. Two nTMS mapping sessions were separated by 5-10 days. Motor evoked potentials were obtained from abductor pollicis brevis (APB), abductor digiti minimi, and extensor digitorum communis. In addition to individual MRI-based analysis, we studied MNI normalized MCRs. For the reliability assessment, we calculated intra-class correlation and the smallest detectable change. Our results revealed a somatotopy gradient reflected by APB MCR having the most lateral location. Reliability analysis showed that the commonly used metrics of MCRs, such as areas, volumes, centers of gravity (COGs), and hotspots had a high relative and low absolute reliability for all three muscles. For within-limb TMS somatotopy, the most common metrics such as the shifts between MCR COGs and hotspots had poor relative reliability. However, overlaps between different muscle MCRs were highly reliable. We thus provide novel evidence that inter-muscle MCR interaction can be reliably traced using MCR overlaps while shifts between the COGs and hotspots of different MCRs are not suitable for this purpose. Our results have implications for the interpretation of nTMS motor mapping results in healthy subjects and patients with neurological conditions.

in bioRxiv: Neuroscience on September 16, 2020 12:00 AM.

• #### A comparison of neuronal population dynamics measured with calcium imaging and electrophysiology

by Ziqiang Wei, Bei-Jung Lin, Tsai-Wen Chen, Kayvon Daie, Karel Svoboda, Shaul Druckmann

Calcium imaging with fluorescent protein sensors is widely used to record activity in neuronal populations. The transform between neural activity and calcium-related fluorescence involves nonlinearities and low-pass filtering, but the effects of the transformation on analyses of neural populations are not well understood. We compared neuronal spikes and fluorescence in matched neural populations in behaving mice. We report multiple discrepancies between analyses performed on the two types of data, including changes in single-neuron selectivity and population decoding. These were only partially resolved by spike inference algorithms applied to fluorescence. To model the relation between spiking and fluorescence we simultaneously recorded spikes and fluorescence from individual neurons. Using these recordings we developed a model transforming spike trains to synthetic-imaging data. The model recapitulated the differences in analyses. Our analysis highlights challenges in relating electrophysiology and imaging data, and suggests forward modeling as an effective way to understand differences between these data.

in PLoS Computational Biology on September 15, 2020 09:00 PM.

• #### MONET: Multi-omic module discovery by omic selection

by Nimrod Rappoport, Roy Safra, Ron Shamir

Recent advances in experimental biology allow creation of datasets where several genome-wide data types (called omics) are measured per sample. Integrative analysis of multi-omic datasets in general, and clustering of samples in such datasets specifically, can improve our understanding of biological processes and discover different disease subtypes. In this work we present MONET (Multi Omic clustering by Non-Exhaustive Types), which presents a unique approach to multi-omic clustering. MONET discovers modules of similar samples, such that each module is allowed to have a clustering structure for only a subset of the omics. This approach differs from most existent multi-omic clustering algorithms, which assume a common structure across all omics, and from several recent algorithms that model distinct cluster structures. We tested MONET extensively on simulated data, on an image dataset, and on ten multi-omic cancer datasets from TCGA. Our analysis shows that MONET compares favorably with other multi-omic clustering methods. We demonstrate MONET's biological and clinical relevance by analyzing its results for Ovarian Serous Cystadenocarcinoma. We also show that MONET is robust to missing data, can cluster genes in multi-omic dataset, and reveal modules of cell types in single-cell multi-omic data. Our work shows that MONET is a valuable tool that can provide complementary results to those provided by existent algorithms for multi-omic analysis.

in PLoS Computational Biology on September 15, 2020 09:00 PM.

• #### Centrioles are amplified in cycling progenitors of olfactory sensory neurons

by Kaitlin Ching, Tim Stearns

Olfaction in most animals is mediated by neurons bearing cilia that are accessible to the environment. Olfactory sensory neurons (OSNs) in chordates usually have multiple cilia, each with a centriole at its base. OSNs differentiate from stem cells in the olfactory epithelium, and how the epithelium generates cells with many centrioles is not yet understood. We show that centrioles are amplified via centriole rosette formation in both embryonic development and turnover of the olfactory epithelium in adult mice, and rosette-bearing cells often have free centrioles in addition. Cells with amplified centrioles can go on to divide, with centrioles clustered at each pole. Additionally, we found that centrioles are amplified in immediate neuronal precursors (INPs) concomitant with elevation of mRNA for polo-like kinase 4 (Plk4) and SCL/Tal1-interrupting locus gene (Stil), key regulators of centriole duplication. These results support a model in which centriole amplification occurs during a transient state characterized by elevated Plk4 and Stil in early INP cells. These cells then go on to divide at least once to become OSNs, demonstrating that cell division with amplified centrioles, known to be tolerated in disease states, can occur as part of a normal developmental program.

in PLoS Biology on September 15, 2020 09:00 PM.

• #### Imaging dendritic spines: molecular organization and signaling for plasticity

Publication date: April 2021

Source: Current Opinion in Neurobiology, Volume 67

Author(s): Swathi Shivaram Suratkal, Yu-Hsin Yen, Jun Nishiyama

in Current Opinion in Neurobiology on September 15, 2020 06:00 PM.

## OBJECTIVE

Perirolandic atrophy occurs in corticobasal syndrome (CBS) but is not specific vs. progressive supranuclear palsy (PSP). There is heterogeneity in the locations of atrophy outside perirolandic cortex and it remains unknown why atrophy in different locations would cause the same CBS‐specific symptoms. In prior work, we used a wiring diagram of the brain called the human connectome to localize lesion‐induced disorders to symptom‐specific brain networks. Here, we use a similar technique termed atrophy network mapping to localize single‐subject atrophy maps to symptom‐specific brain networks.

## METHODS

Single‐subject atrophy maps were generated by comparing cortical thickness in CBS patients vs. controls. Next, we performed seed‐based functional connectivity using a large normative connectome to determine brain regions functionally connected to each patient's atrophied locations.

## RESULTS

CBS patients had perirolandic atrophy vs. controls at the group level, but locations of atrophy in CBS were heterogeneous outside of perirolandic cortex at the single‐subject level (mean spatial correlation = 0.04). In contrast, atrophy occurred in locations functionally connected to the perirolandic cortex in all CBS patients (spatial correlation = 0.66). Compared with PSP, CBS patients had atrophy connected to a network of higher‐order sensorimotor regions beyond perirolandic cortex, matching a CBS atrophy network from a recent meta‐analysis. Finally, atrophy network mapping identified a symptom‐specific network for alien limb, matching a lesion‐induced alien limb network and a network associated with agency in normal subjects.

## INTERPRETATION

We identified a syndrome‐specific network for CBS and symptom‐specific network for alien limb using single‐subject atrophy maps and the human connectome.

in Annals of Neurology on September 15, 2020 05:29 PM.

• #### Correction to Supporting Information for Sun et al., Prevalent Eurasian avian-like H1N1 swine influenza virus with 2009 pandemic viral genes facilitating human infection [SI Corrections]

MICROBIOLOGY Correction to Supporting Information for “Prevalent Eurasian avian-like H1N1 swine influenza virus with 2009 pandemic viral genes facilitating human infection,” by Honglei Sun, Yihong Xiao, Jiyu Liu, Dayan Wang, Fangtao Li, Chenxi Wang, Chong Li, Junda Zhu, Jingwei Song, Haoran Sun, Zhimin Jiang, Litao Liu, Xin Zhang, Kai Wei,...

in PNAS on September 15, 2020 04:01 PM.

• #### Correction to Supporting Information for Roudnicky et al., Inducers of the endothelial cell barrier identified through chemogenomic screening in genome-edited hPSC-endothelial cells [SI Corrections]

APPLIED BIOLOGICAL SCIENCES Correction to Supporting Information for “Inducers of the endothelial cell barrier identified through chemogenomic screening in genome-edited hPSC-endothelial cells,” by Filip Roudnicky, Jitao David Zhang, Bo Kyoung Kim, Nikhil J. Pandya, Yanjun Lan, Lisa Sach-Peltason, Heloise Ragelle, Pamela Strassburger, Sabine Gruener, Mirjana Lazendic, Sabine Uhles, Franco Revelant,...

in PNAS on September 15, 2020 04:01 PM.

• #### Correction for Chen et al., Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia [Correction]

GENETICS Correction for “Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia,” by Bing Chen, Lu Jiang, Meng-Ling Zhong, Jian-Feng Li, Ben-Shang Li, Li-Jun Peng, Yu-Ting Dai, Bo-Wen Cui, Tian-Qi Yan, Wei-Na Zhang, Xiang-Qin Weng, Yin-Yin Xie, Jing Lu, Rui-Bao Ren, Su-Ning Chen, Jian-Da Hu,...

in PNAS on September 15, 2020 04:01 PM.

• #### Correction for de Beco et al., Endocytosis is required for E-cadherin redistribution at mature adherens junctions [Correction]

CELL BIOLOGY Correction for “Endocytosis is required for E-cadherin redistribution at mature adherens junctions,” by Simon de Beco, Charles Gueudry, François Amblard, and Sylvie Coscoy, which was first published April 28, 2009; 10.1073/pnas.0811253106 (Proc. Natl. Acad. Sci. U.S.A. 106, 7010–7015). The authors wish to note the following: “We have found...

in PNAS on September 15, 2020 04:01 PM.

• #### Kinetic profiling of metabolic specialists demonstrates stability and consistency of in vivo enzyme turnover numbers [Systems Biology]

Enzyme turnover numbers (kcats) are essential for a quantitative understanding of cells. Because kcats are traditionally measured in low-throughput assays, they can be inconsistent, labor-intensive to obtain, and can miss in vivo effects. We use a data-driven approach to estimate in vivo kcats using metabolic specialist Escherichia coli strains that...

in PNAS on September 15, 2020 04:01 PM.

• #### Fine-scale heterogeneity in Schistosoma mansoni force of infection measured through antibody response [Population Biology]

Schistosomiasis is among the most common parasitic diseases in the world, with over 142 million people infected in low- and middle-income countries. Measuring population-level transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected using stool microscopy, which is logistically difficult at program...

in PNAS on September 15, 2020 04:01 PM.

• #### Plant expression of NifD protein variants resistant to mitochondrial degradation [Plant Biology]

To engineer Mo-dependent nitrogenase function in plants, expression of the structural proteins NifD and NifK will be an absolute requirement. Although mitochondria have been established as a suitable eukaryotic environment for biosynthesis of oxygen-sensitive enzymes such as NifH, expression of NifD in this organelle has proven difficult due to cryptic...

in PNAS on September 15, 2020 04:01 PM.

• #### Femtosecond visible transient absorption spectroscopy of chlorophyll-f-containing photosystem II [Plant Biology]

The recently discovered, chlorophyll-f-containing, far-red photosystem II (FR-PSII) supports far-red light photosynthesis. Participation and kinetics of spectrally shifted far-red pigments are directly observable and separated from that of bulk chlorophyll-a. We present an ultrafast transient absorption study of FR-PSII, investigating energy transfer and charge separation processes. Results show a rapid...

in PNAS on September 15, 2020 04:01 PM.

• #### Supergene evolution via stepwise duplications and neofunctionalization of a floral-organ identity gene [Plant Biology]

Heterostyly represents a fascinating adaptation to promote outbreeding in plants that evolved multiple times independently. While l-morph individuals form flowers with long styles, short anthers, and small pollen grains, S-morph individuals have flowers with short styles, long anthers, and large pollen grains. The difference between the morphs is controlled by...

in PNAS on September 15, 2020 04:01 PM.

• #### Structures of Arabidopsis thaliana oxygen-sensing plant cysteine oxidases 4 and 5 enable targeted manipulation of their activity [Plant Biology]

In higher plants, molecular responses to exogenous hypoxia are driven by group VII ethylene response factors (ERF-VIIs). These transcriptional regulators accumulate in the nucleus under hypoxia to activate anaerobic genes but are destabilized in normoxic conditions through the action of oxygen-sensing plant cysteine oxidases (PCOs). The PCOs catalyze the reaction...

in PNAS on September 15, 2020 04:01 PM.

• #### The phosphatidylethanolamine-binding protein DTH1 mediates degradation of lipid droplets in Chlamydomonas reinhardtii [Plant Biology]

Lipid droplets (LDs) are intracellular organelles found in a wide range of organisms and play important roles in stress tolerance. During nitrogen (N) starvation, Chlamydomonas reinhardtii stores large amounts of triacylglycerols (TAGs) inside LDs. When N is resupplied, the LDs disappear and the TAGs are degraded, presumably providing carbon and...

in PNAS on September 15, 2020 04:01 PM.

• #### Cuscuta australis (dodder) parasite eavesdrops on the host plants’ FT signals to flower [Plant Biology]

Many plants use environmental cues, including seasonal changes of day length (photoperiod), to control their flowering time. Under inductive conditions, FLOWERING LOCUS T (FT) protein is synthesized in leaves, and FT protein is a mobile signal, which is able to travel to the shoot apex to induce flowering. Dodders (Cuscuta,...

in PNAS on September 15, 2020 04:01 PM.

• #### Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease [Physiology]

Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here...

in PNAS on September 15, 2020 04:01 PM.

• #### Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway [Pharmacology]

Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide’s classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide...

in PNAS on September 15, 2020 04:01 PM.

• #### Analysis of {beta}2AR-Gs and {beta}2AR-Gi complex formation by NMR spectroscopy [Pharmacology]

The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor (GPCR) that preferentially couples to the stimulatory G protein Gs and stimulates cAMP formation. Functional studies have shown that the β2AR also couples to inhibitory G protein Gi, activation of which inhibits cAMP formation [R. P. Xiao, Sci. STKE 2001,...

in PNAS on September 15, 2020 04:01 PM.

• #### Active vision shapes and coordinates flight motor responses in flies [Neuroscience]

Animals use active sensing to respond to sensory inputs and guide future motor decisions. In flight, flies generate a pattern of head and body movements to stabilize gaze. How the brain relays visual information to control head and body movements and how active head movements influence downstream motor control remains...

in PNAS on September 15, 2020 04:01 PM.

• #### CRL5-dependent regulation of the small GTPases ARL4C and ARF6 controls hippocampal morphogenesis [Neuroscience]

The small GTPase ARL4C participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The ARL4C signaling cascade starts by the recruitment of the ARF–GEF cytohesins to the plasma membrane, which, in turn, bind and activate the small GTPase ARF6. However, the role of ARL4C–cytohesin–ARF6...

in PNAS on September 15, 2020 04:01 PM.

• #### Finding the neural correlates of collaboration using a three-person fMRI hyperscanning paradigm [Neuroscience]

Humans have an extraordinary ability to interact and cooperate with others. Despite the social and evolutionary significance of collaboration, research on finding its neural correlates has been limited partly due to restrictions on the simultaneous neuroimaging of more than one participant (also known as hyperscanning). Several studies have used dyadic...

in PNAS on September 15, 2020 04:01 PM.

• #### Fusogen-mediated neuron-neuron fusion disrupts neural circuit connectivity and alters animal behavior [Neuroscience]

The 100-y-old neuron doctrine from Ramón y Cajal states that neurons are individual cells, rejecting the process of cell−cell fusion in the normal development and function of the nervous system. However, fusogens—specialized molecules essential and sufficient for the fusion of cells—are expressed in the nervous system of different species under...

in PNAS on September 15, 2020 04:01 PM.

• #### Mechanism for analogous illusory motion perception in flies and humans [Neuroscience]

Visual motion detection is one of the most important computations performed by visual circuits. Yet, we perceive vivid illusory motion in stationary, periodic luminance gradients that contain no true motion. This illusion is shared by diverse vertebrate species, but theories proposed to explain this illusion have remained difficult to test....

in PNAS on September 15, 2020 04:01 PM.

• #### Dark noise and retinal degeneration from D190N-rhodopsin [Neuroscience]

Numerous rhodopsin mutations have been implicated in night blindness and retinal degeneration, often with unclear etiology. D190N-rhodopsin (D190N-Rho) is a well-known inherited human mutation causing retinitis pigmentosa. Both higher-than-normal spontaneous-isomerization activity and misfolding/mistargeting of the mutant protein have been proposed as causes of the disease, but neither explanation has been...

in PNAS on September 15, 2020 04:01 PM.

• #### Low-dimensional dynamics for working memory and time encoding [Neuroscience]

Our decisions often depend on multiple sensory experiences separated by time delays. The brain can remember these experiences and, simultaneously, estimate the timing between events. To understand the mechanisms underlying working memory and time encoding, we analyze neural activity recorded during delays in four experiments on nonhuman primates. To disambiguate...

in PNAS on September 15, 2020 04:01 PM.

• #### Visual experience is not necessary for the development of face-selectivity in the lateral fusiform gyrus [Neuroscience]

The fusiform face area responds selectively to faces and is causally involved in face perception. How does face-selectivity in the fusiform arise in development, and why does it develop so systematically in the same location across individuals? Preferential cortical responses to faces develop early in infancy, yet evidence is conflicting...

in PNAS on September 15, 2020 04:01 PM.

• #### Developing a population-state decision system for intelligently reprogramming extracellular electron transfer in Shewanella oneidensis [Microbiology]

The unique extracellular electron transfer (EET) ability has positioned electroactive bacteria (EAB) as a major class of cellular chassis for genetic engineering aimed at favorable environmental, energy, and geoscience applications. However, previous efforts to genetically enhance EET ability have often impaired the basal metabolism and cellular growth due to the...

in PNAS on September 15, 2020 04:01 PM.

• #### Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies [Microbiology]

Antibodies may bind to bacterial pathogens or their toxins to control infections, and their effector activity is mediated through the recruitment of complement component C1q or the engagement with Fcγ receptors (FcγRs). For bacterial pathogens that rely on a single toxin to cause disease, immunity correlates with toxin neutralization. Most...

in PNAS on September 15, 2020 04:01 PM.

• #### Early evolutionary loss of the lipid A modifying enzyme PagP resulting in innate immune evasion in Yersinia pestis [Microbiology]

Immune evasion through membrane remodeling is a hallmark of Yersinia pestis pathogenesis. Yersinia remodels its membrane during its life cycle as it alternates between mammalian hosts (37 °C) and ambient (21 °C to 26 °C) temperatures of the arthropod transmission vector or external environment. This shift in growth temperature induces...

in PNAS on September 15, 2020 04:01 PM.

• #### Engineering carboxylic acid reductase for selective synthesis of medium-chain fatty alcohols in yeast [Microbiology]

Medium-chain fatty alcohols (MCFOHs, C6 to C12) are potential substitutes for fossil fuels, such as diesel and jet fuels, and have wide applications in various manufacturing processes. While today MCFOHs are mainly sourced from petrochemicals or plant oils, microbial biosynthesis represents a scalable, reliable, and sustainable alternative. Here, we aim...

in PNAS on September 15, 2020 04:01 PM.

• #### Avoiding ventilator-associated pneumonia: Curcumin-functionalized endotracheal tube and photodynamic action [Applied Physical Sciences]

Hospital-acquired infections are a global health problem that threatens patients’ treatment in intensive care units, causing thousands of deaths and a considerable increase in hospitalization costs. The endotracheal tube (ETT) is a medical device placed in the patient’s trachea to assist breathing and delivering oxygen into the lungs. However, bacterial...

in PNAS on September 15, 2020 04:01 PM.

• #### Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women [Medical Sciences]

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron...

in PNAS on September 15, 2020 04:01 PM.

• #### DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination [Immunology and Inflammation]

The DNA-dependent protein kinase (DNA-PK), which is composed of the KU heterodimer and the large catalytic subunit (DNA-PKcs), is a classical nonhomologous end-joining (cNHEJ) factor. Naïve B cells undergo class switch recombination (CSR) to generate antibodies with different isotypes by joining two DNA double-strand breaks at different switching regions via...

in PNAS on September 15, 2020 04:01 PM.

• #### Polyethylene glycol‐fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses

Innate and adaptive immune responses to sciatic nerve allografts treated with a polyethylene glycol (PEG)‐fusion repair protocol were compared to those in negative control allografts untreated by PEG. By 21 days PO, PEG‐fused allografts showed significantly reduced major histocompatibility complex class I expression and T cell (CD3) infiltration. PEG‐fused allografts more closely resembled unoperated nerves.

## Abstract

Ablation/segmental loss peripheral nerve injuries (PNIs) exhibit poor functional recovery due to slow and inaccurate outgrowth of regenerating axons. Viable peripheral nerve allografts (PNAs) as growth‐guide conduits are immunologically rejected and all anucleated donor/host axonal segments undergo Wallerian degeneration. In contrast, we report that ablation‐type sciatic PNIs repaired by neurorrhaphy of viable sciatic PNAs and a polyethylene glycol (PEG)‐fusion protocol using PEG immediately restored axonal continuity for many axons, reinnervated/maintained their neuromuscular junctions, and prevented much Wallerian degeneration. PEG‐fused PNAs permanently restored many sciatic‐mediated behaviors within 2–6 weeks. PEG‐fused PNAs were not rejected even though host/donors were neither immunosuppressed nor tissue‐matched in outbred female Sprague Dawley rats. Innate and adaptive immune responses to PEG‐fused sciatic PNAs were analyzed using electron microscopy, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction for morphological features, T cell and macrophage infiltration, major histocompatibility complex (MHC) expression, apoptosis, expression of cytokines, chemokines, and cytotoxic effectors. PEG‐fused PNAs exhibited attenuated innate and adaptive immune responses by 14–21 days postoperatively, as evidenced by (a) many axons and cells remaining viable, (b) significantly reduced infiltration of cytotoxic and total T cells and macrophages, (c) significantly reduced expression of inflammatory cytokines, chemokines, and MHC proteins, (d) consistently low apoptotic response. Morphologically and/or biochemically, PEG‐fused sciatic PNAs often resembled sciatic autografts or intact sciatic nerves. In brief, PEG‐fused PNAs are an unstudied, perhaps unique, example of immune tolerance of viable allograft tissue in a nonimmune‐privileged environment and could greatly improve the clinical outcomes for PNIs relative to current protocols.

in Journal of Neuroscience Research on September 15, 2020 12:57 PM.

• #### Disrupted brain functional networks in patients with end‐stage renal disease undergoing hemodialysis

Using graph theory‐based approach, we investigated the topological organization of functional brain networks in patients with end‐stage renal disease (ESRD) undergoing hemodialysis (HD). Disrupted brain functional networks were identified in patients with ESRD, and HD patients showed further disruptions in functional network organization compared with nondialysis patients.

## Abstract

Patterns of change in whole‐brain functional networks remain poorly understood in patients with end‐stage renal disease (ESRD) undergoing hemodialysis (HD). We conducted a prospective research to investigate the topological properties of whole‐brain functional networks in those patients using a graph‐based network analysis. Resting‐state functional magnetic resonance imaging was performed on 51 ESRD patients (25 HD and 26 nondialysis patients) and 36 healthy controls (HCs). We compared the topological properties of brain functional networks among the three groups, and analyzed the relationships between those significant parameters and clinical variables in ESRD patients. Progressively disrupted global topological organizations were observed from nondialysis patients to HD patients compared with HCs (all p < 0.05 after Bonferroni correction). HD patients, relative to HCs, showed significantly decreased nodal centralities in the left temporal pole: superior temporal gyrus, bilateral median cingulate and paracingulate gyri, bilateral hippocampus, bilateral parahippocampal gyrus, and bilateral amygdala, and showed increased nodal centralities in the orbital part of the bilateral middle frontal gyrus, left cuneus, and left superior occipital gyrus (all p < 0.05 after Bonferroni correction). Furthermore, nodal centralities in the bilateral hippocampus were significantly decreased in HD patients compared with nondialysis patients (p < 0.05 after Bonferroni correction). Dialysis duration negatively correlated with global efficiency in ESRD patients undergoing HD (r = −0.676, FDR q = 0.004). This study indicates that ESRD patients exhibit disruptions in brain functional networks, which are more severe in HD patients, and these alterations are correlated with cognitive performance and clinical markers.

in Journal of Neuroscience Research on September 15, 2020 12:25 PM.

## Abstract

Depression is a mental disorder that affects millions of people around the world. However, depressive symptoms can be seen in other psychiatric and medical conditions. Here, we investigate the effect of DHEA treatment on depressive symptoms in individuals with depression and/or other clinical conditions in which depressive symptoms are present. An electronic search was performed until October 2019, with no restrictions on language or year of publication in the following databases: Medline, EMBASE, LILACS, and Cochrane Library. Randomized controlled trials comparing DHEA versus placebo were included if the depressive symptoms were assessed. Fifteen studies with 853 female and male individuals were included in this review. To conduct the meta‐analysis, data were extracted from 14 studies. In comparison with placebo, DHEA improved depressive symptoms (standardized mean difference [SMD] −0.28, 95% (CI) −0.45 to −0.11, p =.001, 12 studies, 742 individuals (375 in the experimental group and 367 in the placebo group), I 2 = 24%), very low quality of evidence, 2 of 14 studies reporting this outcome were removed in a sensitivity analysis as they were strongly influencing heterogeneity between studies. No hormonal changes that indicated any risk to the participants' health were seen. Side effects observed were uncommon, mild, and transient, but commonly related to androgyny. In conclusion, DHEA was associated with a beneficial effect on depressive symptoms compared to placebo. However, these results should be viewed with caution, since the quality of evidence for this outcome was considered very low according to the GRADE criteria.

in Journal of Neuroscience Research on September 15, 2020 12:25 PM.

## Objective

To examine the association of the plasma neuroaxonal injury markers neurofilament light (NfL), total tau, glial fibrillary acid protein, and ubiquitin carboxyl‐terminal hydrolase L1 with delirium, delirium severity, and cognitive performance.

## Methods

Delirium case–no delirium control (n = 108) pairs were matched by age, sex, surgery type, cognition, and vascular comorbidities. Biomarkers were measured in plasma collected preoperatively (PREOP), and 2 days (POD2) and 30 days postoperatively (PO1MO) using Simoa technology (Quanterix, Lexington, MA). The Confusion Assessment Method (CAM) and CAM‐S (Severity) were used to measure delirium and delirium severity, respectively. Cognitive function was measured with General Cognitive Performance (GCP) scores.

## Results

Delirium cases had higher NfL on POD2 and PO1MO (median matched pair difference = 16.2pg/ml and 13.6pg/ml, respectively; p < 0.05). Patients with PREOP and POD2 NfL in the highest quartile (Q4) had increased risk for incident delirium (adjusted odds ratio [OR] = 3.7 [95% confidence interval (CI) = 1.1–12.6] and 4.6 [95% CI = 1.2–18.2], respectively) and experienced more severe delirium, with sum CAM‐S scores 7.8 points (95% CI = 1.6–14.0) and 9.3 points higher (95% CI = 3.2–15.5). At PO1MO, delirium cases had continued high NfL (adjusted OR = 9.7, 95% CI = 2.3–41.4), and those with Q4 NfL values showed a −2.3 point decline in GCP score (−2.3 points, 95% CI = −4.7 to −0.9).

## Interpretation

Patients with the highest PREOP or POD2 NfL levels were more likely to develop delirium. Elevated NfL at PO1MO was associated with delirium and greater cognitive decline. These findings suggest NfL may be useful as a predictive biomarker for delirium risk and long‐term cognitive decline, and once confirmed would provide pathophysiological evidence for neuroaxonal injury following delirium. ANN NEUROL 2020

in Annals of Neurology on September 15, 2020 11:54 AM.

• #### Heterogeneous expression of dopaminergic markers and Vglut2 in mouse mesodiencephalic dopaminergic nuclei A8–A13

Graph illustrating the heterogeneity within the mesodiencephalic dopaminergic nuclei, in the proportion of cells immunopositive for tyrosine hydroxylase (TH+) that expressed the vesicular glutamatergic transporter 2 (Vglut2) during their lifetime according to a cell fate mapping strategy. Each dot illustrates the proportion measured from one mouse.

## Abstract

Co‐transmission of glutamate by brain dopaminergic (DA) neurons was recently proposed as a potential factor influencing cell survival in models of Parkinson's disease. Intriguingly, brain DA nuclei are differentially affected in Parkinson's disease. Whether this is associated with different patterns of co‐expression of the glutamatergic phenotype along the rostrocaudal brain axis is unknown in mammals. We hypothesized that, as in zebrafish, the glutamatergic phenotype is present preferentially in the caudal mesodiencephalic DA nuclei. Here, we used in mice a cell fate mapping strategy based on reporter protein expression (ZsGreen) consecutive to previous expression of the vesicular glutamate transporter 2 (Vglut2) gene, coupled with immunofluorescence experiments against tyrosine hydroxylase (TH) or dopamine transporter (DAT). We found three expression patterns in DA cells, organized along the rostrocaudal brain axis. The first pattern (TH‐positive, DAT‐positive, ZsGreen‐positive) was found in A8–A10. The second pattern (TH‐positive, DAT‐negative, ZsGreen‐positive) was found in A11. The third pattern (TH‐positive, DAT‐negative, ZsGreen‐negative) was found in A12–A13. These patterns should help to refine the establishment of the homology of DA nuclei between vertebrate species. Our results also uncover that Vglut2 is expressed at some point during cell lifetime in DA nuclei known to degenerate in Parkinson's disease and largely absent from those that are preserved, suggesting that co‐expression of the glutamatergic phenotype in DA cells influences their survival in Parkinson's disease.

in Journal of Comparative Neurology on September 15, 2020 10:30 AM.

• #### Remodeling of projections from ventral hippocampus to prefrontal cortex in Alzheimer's mice

Axon terminal branches, originating from the ventral hippocampus and distributed in the prefrontal cortex, undergo more frequent bifurcation but bear less numerous varicosities, which are putative synaptic sites, in Alzheimer's than wild‐type mice. This projection appears to be more widely spread, with scantier synapses, and therefore diluted in Alzheimer's mice.

## Abstract

Emotional dysregulation often accompanies cognitive deficits in Alzheimer's disease (AD). The hippocampus, most notably damaged by AD pathology, is classified into the cognition‐bound posterior and emotion‐bound anterior hippocampi. Since the anterior hippocampus or its rodent counterpart, the ventral hippocampus (VH), sends dense afferents to the prefrontal cortex (PFC) and the basolateral amygdala (BLA), the two structures implicated in fear responses, we investigated whether these afferents are modified in 3xTg AD model mice. An anterograde dextrin tracer injected into VH revealed that axons in PFC were more ramified in 3xTg than wild‐type (WT) mice, with the synaptic density reduced. The VH projections to BLA were not affected. Intracellular accumulation of amyloid β (Aβ) or Aβ‐like immunoreactivity was found in PFC and BLA neurons alike. Behaviorally, in the 2‐way active avoidance test, the frequency of chamber change was higher, with the test performance better, in 3xTg than WT mice, suggesting a distorted contextual fear in the 3xTg group. Given the essential involvement of parts of PFC in contextual fear responses and that of BLA in fear responses in general, the observed remodeling of VH‐to‐PFC afferents and the accumulation of intracellular Aβ in BLA and PFC pyramidal cells might exercise critical influences on enhanced avoidance behavior in 3xTg mice.

in Journal of Comparative Neurology on September 15, 2020 10:04 AM.

• #### IEO: Intelligent Evolutionary Optimisation for Hyperparameter Tuning. (arXiv:2009.06390v1 [cs.LG])

Hyperparameter optimisation is a crucial process in searching the optimal machine learning model. The efficiency of finding the optimal hyperparameter settings has been a big concern in recent researches since the optimisation process could be time-consuming, especially when the objective functions are highly expensive to evaluate. In this paper, we introduce an intelligent evolutionary optimisation algorithm which applies machine learning technique to the traditional evolutionary algorithm to accelerate the overall optimisation process of tuning machine learning models in classification problems. We demonstrate our Intelligent Evolutionary Optimisation (IEO)in a series of controlled experiments, comparing with traditional evolutionary optimisation in hyperparameter tuning. The empirical study shows that our approach accelerates the optimisation speed by 30.40% on average and up to 77.06% in the best scenarios.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Adaptive Convolution Kernel for Artificial Neural Networks. (arXiv:2009.06385v1 [cs.CV])

Many deep neural networks are built by using stacked convolutional layers of fixed and single size (often 3$\times$3) kernels. This paper describes a method for training the size of convolutional kernels to provide varying size kernels in a single layer. The method utilizes a differentiable, and therefore backpropagation-trainable Gaussian envelope which can grow or shrink in a base grid. Our experiments compared the proposed adaptive layers to ordinary convolution layers in a simple two-layer network, a deeper residual network, and a U-Net architecture. The results in the popular image classification datasets such as MNIST, MNIST-CLUTTERED, CIFAR-10, Fashion, and Faces in the Wild'' showed that the adaptive kernels can provide statistically significant improvements on ordinary convolution kernels. A segmentation experiment in the Oxford-Pets dataset demonstrated that replacing a single ordinary convolution layer in a U-shaped network with a single 7$\times$7 adaptive layer can improve its learning performance and ability to generalize.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Reservoir Memory Machines as Neural Computers. (arXiv:2009.06342v1 [cs.LG])

Differentiable neural computers extend artificial neural networks with an explicit memory without interference, thus enabling the model to perform classic computation tasks such as graph traversal. However, such models are difficult to train, requiring long training times and large datasets. In this work, we achieve some of the computational capabilities of differentiable neural computers with a model that can be trained extremely efficiently, namely an echo state network with an explicit memory without interference. This extension raises the computation power of echo state networks from strictly less than finite state machines to strictly more than finite state machines. Further, we demonstrate experimentally that our model performs comparably to its fully-trained deep version on several typical benchmark tasks for differentiable neural computers.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Risk Bounds for Robust Deep Learning. (arXiv:2009.06202v1 [cs.LG])

It has been observed that certain loss functions can render deep-learning pipelines robust against flaws in the data. In this paper, we support these empirical findings with statistical theory. We especially show that empirical-risk minimization with unbounded, Lipschitz-continuous loss functions, such as the least-absolute deviation loss, Huber loss, Cauchy loss, and Tukey's biweight loss, can provide efficient prediction under minimal assumptions on the data. More generally speaking, our paper provides theoretical evidence for the benefits of robust loss functions in deep learning.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### AutoML for Multilayer Perceptron and FPGA Co-design. (arXiv:2009.06156v1 [cs.NE])

State-of-the-art Neural Network Architectures (NNAs) are challenging to design and implement efficiently in hardware. In the past couple of years, this has led to an explosion in research and development of automatic Neural Architecture Search (NAS) tools. AutomML tools are now used to achieve state of the art NNA designs and attempt to optimize for hardware usage and design. Much of the recent research in the auto-design of NNAs has focused on convolution networks and image recognition, ignoring the fact that a significant part of the workload in data centers is general-purpose deep neural networks. In this work, we develop and test a general multilayer perceptron (MLP) flow that can take arbitrary datasets as input and automatically produce optimized NNAs and hardware designs. We test the flow on six benchmarks. Our results show we exceed the performance of currently published MLP accuracy results and are competitive with non-MLP based results. We compare general and common GPU architectures with our scalable FPGA design and show we can achieve higher efficiency and higher throughput (outputs per second) for the majority of datasets. Further insights into the design space for both accurate networks and high performing hardware shows the power of co-design by correlating accuracy versus throughput, network size versus accuracy, and scaling to high-performance devices.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Simple Learning Rules Generate Complex Canonical Circuits. (arXiv:2009.06118v1 [q-bio.NC])

Cortical circuits are characterized by exquisitely complex connectivity patterns that emerge during development from undifferentiated networks. The development of these circuits is governed by a combination of precise molecular cues that dictate neuronal identity and location along with activity dependent mechanisms that help establish, refine, and maintain neuronal connectivity. Here we ask whether simple plasticity mechanisms can lead to assembling a cortical microcircuit with canonical inter-laminar connectivity, starting from a network with all-to-all connectivity. The target canonical microcircuit is based on the pattern of connections between cortical layers typically found in multiple cortical areas in rodents, cats and monkeys. We use a computational model as a proof-of-principle to demonstrate that classical and reverse spike-timing dependent plasticity rules lead to a formation of networks that resemble canonical microcircuits. The model converges to biologically reasonable solutions provided that there is a balance between potentiation and depression and enhanced inputs to layer 4, only for a small combination of plasticity rules. The model makes specific testable predictions about the learning computations operant across cortical layers and their dynamic deployment during development.

in arXiv: Quantitative Biology: Neurons and Cognition on September 15, 2020 01:30 AM.

• #### Simple Simultaneous Ensemble Learning in Genetic Programming. (arXiv:2009.06037v2 [cs.NE] UPDATED)

Learning ensembles by bagging can substantially improve the generalization performance of low-bias high-variance estimators, including those evolved by Genetic Programming (GP). Yet, the best way to learn ensembles in GP remains to be determined. This work attempts to fill the gap between existing GP ensemble learning algorithms, which are often either simple but expensive, or efficient but complex. We propose a new algorithm that is both simple and efficient, named Simple Simultaneous Ensemble Genetic Programming (2SEGP). 2SEGP is obtained by relatively minor modifications to fitness evaluation and selection of a classic GP algorithm, and its only drawback is an (arguably small) increase of the fitness evaluation cost from the classic $\mathcal{O}(n \ell)$ to $\mathcal{O}(n(\ell + \beta))$, with $n$ the number of observations and $\ell$/$\beta$ the estimator/ensemble size. Experimental comparisons on real-world datasets between supervised classification and regression show that, despite its simplicity, 2SEGP fares very well against state-of-the-art (ensemble and not) GP algorithms. We further provide insights into what matters in 2SEGP by (i) scaling $\beta$, (ii) ablating the proposed selection method, (iii) observing the evolvability induced by traditional subtree variation.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Extracting Optimal Solution Manifolds using Constrained Neural Optimization. (arXiv:2009.06024v1 [cs.NE])

Constrained Optimization solution algorithms are restricted to point based solutions. In practice, single or multiple objectives must be satisfied, wherein both the objective function and constraints can be non-convex resulting in multiple optimal solutions. Real world scenarios include intersecting surfaces as Implicit Functions, Hyperspectral Unmixing and Pareto Optimal fronts. Local or global convexification is a common workaround when faced with non-convex forms. However, such an approach is often restricted to a strict class of functions, deviation from which results in sub-optimal solution to the original problem. We present neural solutions for extracting optimal sets as approximate manifolds, where unmodified, non-convex objectives and constraints are defined as modeler guided, domain-informed $L_2$ loss function. This promotes interpretability since modelers can confirm the results against known analytical forms in their specific domains. We present synthetic and realistic cases to validate our approach and compare against known solvers for bench-marking in terms of accuracy and computational efficiency.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Iterative beam search algorithms for the permutation flowshop. (arXiv:2009.05800v1 [cs.AI])

We study an iterative beam search algorithm for the permutation flowshop (makespan and flowtime minimization). This algorithm combines branching strategies inspired by recent branch-and-bounds and a guidance strategy inspired by the LR heuristic. It obtains competitive results, reports many new-best-so-far solutions on the VFR benchmark (makespan minimization) and the Taillard benchmark (flowtime minimization) without using any NEH-based branching or iterative-greedy strategy. The source code is available at: https://gitlab.com/librallu/cats-pfsp.

in arXiv: Computer Science: Neural and Evolutionary Computing on September 15, 2020 01:30 AM.

• #### Publisher Correction: ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells

Nature Communications, Published online: 15 September 2020; doi:10.1038/s41467-020-18674-4

Publisher Correction: ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells

in Nature Communications on September 15, 2020 12:00 AM.

• #### A predictive index for health status using species-level gut microbiome profiling

Nature Communications, Published online: 15 September 2020; doi:10.1038/s41467-020-18476-8

A biologically-interpretable and robust metric that provides insight into one’s health status from a gut microbiome sample is an important clinical goal in current human microbiome research. Herein, the authors introduce a species-level index that predicts the likelihood of having a disease.

in Nature Communications on September 15, 2020 12:00 AM.

• #### Two-photon excited deep-red and near-infrared emissive organic co-crystals

Nature Communications, Published online: 15 September 2020; doi:10.1038/s41467-020-18431-7

Two-photon excited near-infrared fluorescence materials have garnered considerable attention because of their superior optical properties compared with other optical materials. Here, the authors use a convenient and efficient supramolecular approach to synthesize a two-photon excited near-infrared emissive co-crystalline material.

in Nature Communications on September 15, 2020 12:00 AM.

• #### Photoswitchable paclitaxel-based microtubule stabilisers allow optical control over the microtubule cytoskeleton

Nature Communications, Published online: 15 September 2020; doi:10.1038/s41467-020-18389-6

Light-based modulation of the microtubule (MT) cytoskeleton is an attractive goal for spatiotemporally-resolved MT studies. Here the authors develop a first generation photoswitchable small molecule MT stabiliser based on paclitaxel, allowing optical control over cellular MT dynamics.

in Nature Communications on September 15, 2020 12:00 AM.

• #### Uncovering temporal changes in Europe’s population density patterns using a data fusion approach

Nature Communications, Published online: 15 September 2020; doi:10.1038/s41467-020-18344-5

Official data on the distribution of human population often ignores the changing spatio-temporal densities resulting from mobility. Here, authors apply an approach combining official statistics and geospatial data to assess intraday and monthly population variations at continental scale at 1 km2 resolution.

in Nature Communications on September 15, 2020 12:00 AM.

• #### A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis

Nature Communications, Published online: 15 September 2020; doi:10.1038/s41467-020-18257-3

RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants.

in Nature Communications on September 15, 2020 12:00 AM.

• #### Mechanism of Zinc Excitotoxicity: A Focus on AMPK

Over the last 20 years, it has been shown that complex signaling cascades are involved in zinc excitotoxicity. Free zinc rapidly induces PKC activation, which causes reactive oxygen species (ROS) production at least in part through NADPH oxidase. It also promotes neuronal nitric oxide synthase, thereby increasing nitric oxide (NO) production. Extracellular signal-regulated kinase activation and Egr-1 transcription factor activity were quickly induced by zinc, too. These concurrent actions of kinases consequently produce oxygen free radical, ROS, and NO, which may cause severe DNA damage. Following the excessive activity of poly(ADP-ribose) polymerase-1 depletes NAD+/ATP in the cells. Zinc excitotoxicity exhibits distinct characteristics of apoptosis, too. Activation of caspase-3 is induced by liver kinase B1 (LKB1)-AMP-activated kinase (AMPK)-Bim cascade signaling and induction of p75NTR receptors and p75NTR-associated Death Executor. Thus, zinc excitotoxicity is a mechanism of neuronal cell death showing various cell death patterns. In addition to the above signaling cascades, individual intracellular organelles also play a crucial role in zinc excitotoxicity. Mitochondria and lysosomes function as zinc reservoirs, and as such, are capable of regulating zinc concentration in the cytoplasm. However, when loaded with too much zinc, they may undergo mitochondrial permeability transition pore (mPTP) opening, and lysosomal membrane permeabilization (LMP), both of which are well-established mechanisms of cell death. Since zinc excitotoxicity has been reported to be associated with acute brain injuries, including stroke, trauma, and epilepsy, we performed to find the novel AMPK inhibitors as therapeutic agents for these diseases. Since we thought acute brain injury has complicated neuronal death pathways, we tried to see the neuroprotection against zinc excitotoxicity, calcium-overload excitotoxicity, oxidative damage, and apoptosis. We found that two chemicals showed significant neuroprotection against all cellular neurotoxic models we tested. Finally, we observed the reduction of infarct volume in a rat model of brain injury after middle cerebral artery occlusion (MCAO). In this review, we introduced the AMPK-mediated cell death mechanism and novel strategy for the development of stroke therapeutics. The hope is that this understanding would provide a rationale for acute brain injury and eventually find new therapeutics.

in Frontiers in Neuroscience: Neurodegeneration on September 15, 2020 12:00 AM.

• #### The Role of Autophagy in Manganese-Induced Neurotoxicity

Manganese (Mn), an essential micronutrient, acts as a cofactor for multiple enzymes. Epidemiological investigations have shown that an excessive level of Mn is an important environmental factor involved in neurotoxicity. Frequent pollution of air and water by Mn is a serious threat to the health of the population. Overexposure to Mn is particularly detrimental to the central nervous system, leading to symptoms similar to several neurological disorders. Many different mechanisms have been implicated in Mn-induced neurotoxicity, including oxidative/nitrosative stress, toxic protein aggregation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, dysregulation of autophagy, and the apoptotic cascade, which together promote the progressive neurodegeneration of nerve cells. As a compensatory regulatory mechanism, autophagy plays dual roles in various biological activities under pathological stress conditions. Dysregulation of autophagy is involved in the development of neurodegenerative disorders, with recent emerging evidence indicating a strong, complex relationship between autophagy and Mn-induced neurotoxicity. This review discusses the connection between autophagy and Mn-induced neurotoxicity, especially alpha-synuclein oligomerization, ER stress, and aberrated protein S-nitrosylation, which will provide new insights to profoundly explore the precise mechanisms of Mn-induced neurotoxicity.

in Frontiers in Neuroscience: Neurodegeneration on September 15, 2020 12:00 AM.

• #### Cold Exposure After Exercise Impedes the Neuroprotective Effects of Exercise on Thermoregulation and UCP4 Expression in an MPTP-Induced Parkinsonian Mouse Model

Moderate exercise and mild hypothermia have protective effects against brain injury and neurodegeneration. Running in a cold environment alters exercise-induced hyperthermia and outcomes; however, evaluations of post-exercise cold exposure related to exercise benefits for the brain are relatively rare. We investigated the effects of 4°C cold exposure after exercise on exercise-induced thermal responses and neuroprotection in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinsonian mouse model. Male C57BL/6J mice were pretreated with MPTP for five consecutive days and follow-up treadmill exercise for 4 weeks. After 1-h running at a 22°C temperature, the mice were exposed to a 4°C environment for 2 h. An MPTP injection induced a transient drop in body and brain temperatures, while mild brain hypothermia was found to last for 4 weeks after MPTP treatment. Preventing brain hypothermia by exercise or 4°C exposure was associated with an improvement in MPTP-induced striatal uncoupling protein 4 (UCP4) downregulation and nigrostriatal dopaminergic neurodegeneration. However, 4°C exposure after exercise abrogated the exercise-induced beneficial effects and thermal responses in MPTP-treated mice, including a low amplitude of exercise-induced brain hyperthermia and body temperature while at rest after exercise. Our findings elucidate that post-exercise thermoregulation and UCP4 expression are important in the neuroprotective effects of exercise against MPTP toxicity.

in Frontiers in Neuroscience: Neurodegeneration on September 15, 2020 12:00 AM.

• #### Susceptibility and Volume Measures of the Mammillary Bodies Between Mild Cognitively Impaired Patients and Healthy Controls

Purpose

To investigate the baseline values and differences for susceptibility and volume of the mammillary bodies between mild cognitively impaired (MCI) patients and healthy controls (HCs), and further explore their differences in relation to gender, MCI subtypes and apolipoprotein E (APOE) genotypes.

Methods

T1-weighted and multi-echo gradient echo imaging sequences were acquired on a 3T MR scanner to evaluate the T1W based volume and susceptibility differences in the mammillary body for 47 MCI and 47 HCs. T-tests were performed to compare volume and susceptibility between groups, and right and left hemispheres. Correlation analysis was used to relate the volume and mean susceptibility as a function of age in MCI and HC groups separately, and to investigate the relationship of susceptibility with the neuro-psychological scales in the MCI group.

Results

Susceptibility was found to be elevated within the right mammillary body in MCI patients compared to HCs (p < 0.05). There were no differences for the mammillary body volumes between the MCI and HC groups, although there was a reduction in volume with age for the MCI group (p = 0.007). Women showed decreased mammillary body volume compared to men in the HC group (p = 0.004). No significant differences were found in relation to MCI subtypes and APOE genotypes. No significant correlations were observed between mammillary body susceptibility with neuro-psychological scales.

Conclusion

This work provides a quantitative baseline for both the volume and susceptibility of the mammillary body which can be used for future studies of cognitive impairment patients underlying the pathology of the Papez circuit.

in Frontiers in Neuroscience: Neurodegeneration on September 15, 2020 12:00 AM.

• #### Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

Dyskinesia associated with chronic levodopa treatment in Parkinson’s disease is associated with maladaptive striatal plasticity. The objective of this study was to examine whether macroscale structural changes, as captured by magnetic resonance imaging (MRI) accompany this plasticity and to identify plausible cellular contributors in a rodent model of levodopa-induced dyskinesia. Adult male Sprague-Dawley rats were rendered hemi-parkinsonian by stereotaxic injection of 6-hydroxydopamine into the left medial forebrain bundle prior to chronic treatment with saline (control) or levodopa to induce abnormal involuntary movements (AIMs), reflective of dyskinesia. Perfusion-fixed brains underwent ex vivo structural MRI before sectioning and staining for cellular markers. Chronic treatment with levodopa induced significant AIMs (p < 0.0001 versus saline). The absolute volume of the ipsilateral, lesioned striatum was increased in levodopa-treated rats resulting in a significant difference in percentage volume change when compared to saline-treated rats (p < 0.01). Moreover, a significant positive correlation was found between this volume change and AIMs scores for individual levodopa-treated rats (r = 0.96; p < 0.01). The density of Iba1+ cells was increased within the lesioned versus intact striatum (p < 0.01) with no difference between treatment groups. Conversely, Iba1+ microglia soma size was significantly increased (p < 0.01) in the lesioned striatum of levodopa-treated but not saline-treated rats. Soma size was not, however, significantly correlated with either AIMs or MRI volume change. Although GFAP+ astrocytes were elevated in the lesioned versus intact striatum (p < 0.001), there was no difference between treatment groups. No statistically significant effects of either lesion or treatment on RECA1, a marker for blood vessels, were observed. Collectively, these data suggest chronic levodopa treatment in 6-hydroxydopamine lesioned rats is associated with increased striatal volume that correlates with the development of AIMs. The accompanying increase in number and size of microglia, however, cannot alone explain this volume expansion. Further multi-modal studies are warranted to establish the brain-wide effects of chronic levodopa treatment.

in Frontiers in Neuroscience: Neurodegeneration on September 15, 2020 12:00 AM.

• #### Reproducibility of Glutamate, Glutathione, and GABA Measurements in vivo by Single-Voxel STEAM Magnetic Resonance Spectroscopy at 7-Tesla in Healthy Individuals

Background and Purpose

Derangements in brain glutamate, glutathione, and γ-amino butyric acid (GABA) are implicated in a range of neurological disorders. Reliable methods to measure these compounds non-invasively in vivo are needed. We evaluated the reproducibility of their measurements in brain regions involved in the default mode network using quantitative MRS at 7-Tesla in healthy individuals.

Methods

Ten right-handed healthy volunteers underwent 7-Tesla MRI scans on 2 separate days, not more than 2 weeks apart. On each day two scanning sessions took place, with a re-positioning break in between. High-resolution isotropic anatomical scans were acquired prior to each scan, followed by single-voxel 1H-MRS using the STEAM pulse sequence on an 8 mL midline cubic voxel, positioned over the posterior cingulate and precuneus regions. Concentrations were corrected for partial-volume effects.

Results

Maximal Cramér-Rao lower bounds for glutamate, glutathione, and GABA were 2.0, 8.0, and 14.0%, respectively. Mean coefficients of variation within sessions were 5.9 ± 4.8%, 9.3 ± 7.6%, and 11.5 ± 8.8%, and between sessions were 4.6 ± 4.5%, 8.3 ± 5.7%, and 9.2 ± 8.7%, respectively. The mean (±SD) Dice’s coefficient for voxel overlap was 90 ± 4% within sessions and 86 ± 7% between sessions.

Conclusion

Glutamate, glutathione, and GABA can be reliably quantified using STEAM MRS at 7-Tesla from the posterior cingulate and precuneus cortices of healthy human subjects. STEAM MRS at 7-Tesla may be used to study the metabolic behavior of this important resting-state hub in various disease states.

in Frontiers in Neuroscience: Brain Imaging Methods on September 15, 2020 12:00 AM.

• #### Electrophysiological and Neuroimaging Studies – During Resting State and Sensory Stimulation in Disorders of Consciousness: A Review

A severe brain injury may lead to a disorder of consciousness (DOC) such as coma, vegetative state (VS), minimally conscious state (MCS) or locked-in syndrome (LIS). Till date, the diagnosis of DOC relies only on clinical evaluation or subjective scoring systems such as Glasgow coma scale, which fails to detect subtle changes and thereby results in diagnostic errors. The high rate of misdiagnosis and inability to predict the recovery of consciousness for DOC patients have created a huge research interest in the assessment of consciousness. Researchers have explored the use of various stimulation and neuroimaging techniques to improve the diagnosis. In this article, we present the important findings of resting-state as well as sensory stimulation methods and highlight the stimuli proven to be successful in the assessment of consciousness. Primarily, we review the literature based on (a) application/non-use of stimuli (i.e., sensory stimulation/resting state-based), (b) type of stimulation used (i.e., auditory, visual, tactile, olfactory, or mental-imagery), (c) electrophysiological signal used (EEG/ERP, fMRI, PET, EMG, SCL, or ECG). Among the sensory stimulation methods, auditory stimulation has been extensively used, since it is easier to conduct for these patients. Olfactory and tactile stimulation have been less explored and need further research. Emotionally charged stimuli such as subject’s own name or narratives in a familiar voice or subject’s own face/family pictures or music result in stronger responses than neutral stimuli. Studies based on resting state analysis have employed measures like complexity, power spectral features, entropy and functional connectivity patterns to distinguish between the VS and MCS patients. Resting-state EEG and fMRI are the state-of-the-art techniques and have a huge potential in predicting the recovery of coma patients. Further, EMG and mental-imagery based studies attempt to obtain volitional responses from the VS patients and thus could detect their command-following capability. This may provide an effective means to communicate with these patients. Recent studies have employed fMRI and PET to understand the brain-activation patterns corresponding to the mental imagery. This review promotes our knowledge about the techniques used for the diagnosis of patients with DOC and attempts to provide ideas for future research.

in Frontiers in Neuroscience: Neural Technology on September 15, 2020 12:00 AM.

• #### Relationship Between Basic Properties of BOLD Fluctuations and Calculated Metrics of Complexity in the Human Connectome Project

Resting state functional MRI (rs-fMRI) creates a rich four-dimensional data set that can be analyzed in a variety of ways. As more researchers come to view the brain as a complex dynamical system, tools are increasingly being drawn from other fields to characterize the complexity of the brain’s activity. However, given that the signal measured with rs-fMRI arises from the hemodynamic response to neural activity, the extent to which complexity metrics reflect neural complexity as compared to signal properties related to image quality remains unknown. To provide some insight into this question, correlation dimension, approximate entropy and Lyapunov exponent were calculated for different rs-fMRI scans from the same subject to examine their reliability. The metrics of complexity were then compared to several properties of the rs-fMRI signal from each brain area to determine if basic signal features could explain differences in the complexity metrics. Differences in complexity across brain areas were highly reliable and were closely linked to differences in the frequency profiles of the rs-fMRI signal. The spatial distributions of the complexity and frequency metrics suggest that they are both influenced by location-dependent signal properties that can obscure changes related to neural activity.

in Frontiers in Neuroscience: Brain Imaging Methods on September 15, 2020 12:00 AM.

• #### Pyneal: Open Source Real-Time fMRI Software

Increasingly, neuroimaging researchers are exploring the use of real-time functional magnetic resonance imaging (rt-fMRI) as a way to access a participant’s ongoing brain function throughout a scan. This approach presents novel and exciting experimental applications ranging from monitoring data quality in real time, to delivering neurofeedback from a region of interest, to dynamically controlling experimental flow, or interfacing with remote devices. Yet, for those interested in adopting this method, the existing software options are few and limited in application. This presents a barrier for new users, as well as hinders existing users from refining techniques and methods. Here we introduce a free, open-source rt-fMRI package, the Pyneal toolkit, designed to address this limitation. The Pyneal toolkit is python-based software that offers a flexible and user friendly framework for rt-fMRI, is compatible with all three major scanner manufacturers (GE, Siemens, Phillips), and, critically, allows fully customized analysis pipelines. In this article, we provide a detailed overview of the architecture, describe how to set up and run the Pyneal toolkit during an experimental session, offer tutorials with scan data that demonstrate how data flows through the Pyneal toolkit with example analyses, and highlight the advantages that the Pyneal toolkit offers to the neuroimaging community.

in Frontiers in Neuroscience: Brain Imaging Methods on September 15, 2020 12:00 AM.

• #### Do Musicians Have Better Mnemonic and Executive Performance Than Actors? Influence of Regular Musical or Theater Practice in Adults and in the Elderly

The effects of musical practice on cognition are well established yet rarely compared with other kinds of artistic training or expertise. This study aims to compare the possible effect of musical and theater regular practice on cognition across the lifespan. Both of these artistic activities require many hours of individual or collective training in order to reach an advanced level. This process requires the interaction between higher-order cognitive functions and several sensory modalities (auditory, verbal, visual and motor), as well as regular learning of new pieces. This study included participants with musical or theater practice, and healthy controls matched for age (18–84 years old) and education. The objective was to determine whether specific practice in these activities had an effect on cognition across the lifespan, and a protective influence against undesirable cognitive outcomes associated with aging. All participants underwent a battery of cognitive tasks that evaluated processing speed, executive function, fluency, working memory, verbal and visual long-term memories, and non-verbal reasoning abilities. Results showed that music and theater artistic practices were strongly associated with cognitive enhancements. Participants with musical practice were better in executive functioning, working memory and non-verbal reasoning, whereas participants with regular acting practice had better long-term verbal memory and fluency performance. Thus, taken together, results suggest a differential effect of these artistic practices on cognition across the lifespan. Advanced age did not seem to reduce the benefit, so future studies should focus on the hypothetical protective effects of artistic practice against cognitive decline.

in Frontiers in Human Neuroscience on September 15, 2020 12:00 AM.

• #### A Simplified CNN Classification Method for MI-EEG via the Electrode Pairs Signals

A brain-computer interface (BCI) based on electroencephalography (EEG) can provide independent information exchange and control channels for the brain and the outside world. However, EEG signals come from multiple electrodes, the data of which can generate multiple features. How to select electrodes and features to improve classification performance has become an urgent problem to be solved. This paper proposes a deep convolutional neural network (CNN) structure with separated temporal and spatial filters, which selects the raw EEG signals of the electrode pairs over the motor cortex region as hybrid samples without any preprocessing or artificial feature extraction operations. In the proposed structure, a 5-layer CNN has been applied to learn EEG features, a 4-layer max pooling has been used to reduce dimensionality, and a fully-connected (FC) layer has been utilized for classification. Dropout and batch normalization are also employed to reduce the risk of overfitting. In the experiment, the 4 s EEG data of 10, 20, 60, and 100 subjects from the Physionet database are used as the data source, and the motor imaginations (MI) tasks are divided into four types: left fist, right fist, both fists, and both feet. The results indicate that the global averaged accuracy on group-level classification can reach 97.28%, the area under the receiver operating characteristic (ROC) curve stands out at 0.997, and the electrode pair with the highest accuracy on 10 subjects dataset is FC3-FC4, with 98.61%. The research results also show that this CNN classification method with minimal (2) electrode can obtain high accuracy, which is an advantage over other methods on the same database. This proposed approach provides a new idea for simplifying the design of BCI systems, and accelerates the process of clinical application.

in Frontiers in Human Neuroscience on September 15, 2020 12:00 AM.

• #### Oscillatory Bursting as a Mechanism for Temporal Coupling and Information Coding

Even the simplest cognitive processes involve interactions between cortical regions. To study these processes, we usually rely on averaging across several repetitions of a task or across long segments of data to reach a statistically valid conclusion. Neuronal oscillations reflect synchronized excitability fluctuations in ensembles of neurons and can be observed in electrophysiological recordings in the presence or absence of an external stimulus. Oscillatory brain activity has been viewed as sustained increase in power at specific frequency bands. However, this perspective has been challenged in recent years by the notion that oscillations may occur as transient burst-like events that occur in individual trials and may only appear as sustained activity when multiple trials are averaged together. In this review, we examine the idea that oscillatory activity can manifest as a transient burst as well as a sustained increase in power. We discuss the technical challenges involved in the detection and characterization of transient events at the single trial level, the mechanisms that might generate them and the features that can be extracted from these events to study single-trial dynamics of neuronal ensemble activity.

in Frontiers in Computational Neuroscience on September 15, 2020 12:00 AM.

• #### Editorial: Temporal Structure of Neural Processes Coupling Sensory, Motor and Cognitive Functions of the Brain

in Frontiers in Computational Neuroscience on September 15, 2020 12:00 AM.

• #### Raising the Connectome: The Emergence of Neuronal Activity and Behavior in Caenorhabditis elegans

The differentiation of neurons and formation of connections between cells is the basis of both the adult phenotype and behaviors tied to cognition, perception, reproduction, and survival. Such behaviors are associated with local (circuits) and global (connectome) brain networks. A solid understanding of how these networks emerge is critical. This opinion piece features a guided tour of early developmental events in the emerging connectome, which is crucial to a new view on the connectogenetic process. Connectogenesis includes associating cell identities with broader functional and developmental relationships. During this process, the transition from developmental cells to terminally differentiated cells is defined by an accumulation of traits that ultimately results in neuronal-driven behavior. The well-characterized developmental and cell biology of Caenorhabditis elegans will be used to build a synthesis of developmental events that result in a functioning connectome. Specifically, our view of connectogenesis enables a first-mover model of synaptic connectivity to be demonstrated using data representing larval synaptogenesis. In a first-mover model of Stackelberg competition, potential pre- and postsynaptic relationships are shown to yield various strategies for establishing various types of synaptic connections. By comparing these results to what is known regarding principles for establishing complex network connectivity, these strategies are generalizable to other species and developmental systems. In conclusion, we will discuss the broader implications of this approach, as what is presented here informs an understanding of behavioral emergence and the ability to simulate related biological phenomena.

in Frontiers in Cellular Neuroscience on September 15, 2020 12:00 AM.

• #### Corrigendum: Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System

in Frontiers in Neuroanatomy on September 15, 2020 12:00 AM.

• #### Changes in Metabolism and Proteostasis Drive Aging Phenotype in Aplysia californica Sensory Neurons

Aging is associated with cognitive declines that originate in impairments of function in the neurons that make up the nervous system. The marine mollusk Aplysia californica (Aplysia) is a premier model for the nervous system uniquely suited to investigation of neuronal aging due to uniquely identifiable neurons and molecular techniques available in this model. This study describes the molecular processes associated with aging in two populations of sensory neurons in Aplysia by applying RNA sequencing technology across the aging process (age 6–12 months). Differentially expressed genes clustered into four to five coherent expression patterns across the aging time series in the two neuron populations. Enrichment analysis of functional annotations in these neuron clusters revealed decreased expression of pathways involved in energy metabolism and neuronal signaling, suggesting that metabolic and signaling pathways are intertwined. Furthermore, increased expression of pathways involved in protein processing and translation suggests that proteostatic stress also occurs in aging. Temporal overlap of enrichment for energy metabolism, proteostasis, and neuronal function suggests that cognitive impairments observed in advanced age result from the ramifications of broad declines in energy metabolism.

in Frontiers in Ageing Neuroscience on September 15, 2020 12:00 AM.

• #### Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral–bacterial interactions

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.

in eLife on September 15, 2020 12:00 AM.

• #### Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races

Host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving ‘v1’ loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that the majority of mutations increase weak antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via a single adaptive substitution. Our results indicate that TRIM5α’s adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses.

in eLife on September 15, 2020 12:00 AM.

• #### Global landscape of phenazine biosynthesis and biodegradation reveals species-specific colonization patterns in agricultural soils and crop microbiomes

Phenazines are natural bacterial antibiotics that can protect crops from disease. However, for most crops it is unknown which producers and specific phenazines are ecologically relevant, and whether phenazine biodegradation can counter their effects. To better understand their ecology, we developed and environmentally-validated a quantitative metagenomic approach to mine for phenazine biosynthesis and biodegradation genes, applying it to >800 soil and plant-associated shotgun-metagenomes. We discover novel producer-crop associations and demonstrate that phenazine biosynthesis is prevalent across habitats and preferentially enriched in rhizospheres, whereas biodegrading bacteria are rare. We validate an association between maize and Dyella japonica, a putative producer abundant in crop microbiomes. D. japonica upregulates phenazine biosynthesis during phosphate limitation and robustly colonizes maize seedling roots. This work provides a global picture of phenazines in natural environments and highlights plant-microbe associations of agricultural potential. Our metagenomic approach may be extended to other metabolites and functional traits in diverse ecosystems.

in eLife on September 15, 2020 12:00 AM.

• #### Transport of DNA within cohesin involves clamping on top of engaged heads by Scc2 and entrapment within the ring by Scc3

In addition to extruding DNA loops, cohesin entraps within its SMC-kleisin ring (S-K) individual DNAs during G1 and sister DNAs during S-phase. All three activities require related hook-shaped proteins called Scc2 and Scc3. Using thiol-specific crosslinking we provide rigorous proof of entrapment activity in vitro. Scc2 alone promotes entrapment of DNAs in the E-S and E-K compartments, between ATP-bound engaged heads and the SMC hinge and associated kleisin, respectively. This does not require ATP hydrolysis nor is it accompanied by entrapment within S-K rings, which is a slower process requiring Scc3. Cryo-EM reveals that DNAs transported into E-S/E-K compartments are ‘clamped’ in a sub-compartment created by Scc2’s association with engaged heads whose coiled coils are folded around their elbow. We suggest that clamping may be a recurrent feature of cohesin complexes active in loop extrusion and that this conformation precedes the S-K entrapment required for sister chromatid cohesion.

in eLife on September 15, 2020 12:00 AM.

• #### SWELL1 regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism, however the molecular mechanosensor remains unknown. Here, we show that SWELL1 (Lrrc8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. LRRC8A over-expression in Lrrc8a KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle targeted Lrrc8a KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to WT mice. These results reveal that the LRRC8 complex regulates insulin-PI3K-AKT-mTOR signalling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.

in eLife on September 15, 2020 12:00 AM.

• #### Transmission of West Nile and five other temperate mosquito-borne viruses peaks at temperatures between 23°C and 26°C

The temperature-dependence of many important mosquito-borne diseases has never been quantified. These relationships are critical for understanding current distributions and predicting future shifts from climate change. We used trait-based models to characterize temperature-dependent transmission of 10 vector–pathogen pairs of mosquitoes (Culex pipiens, Cx. quinquefascsiatus, Cx. tarsalis, and others) and viruses (West Nile, Eastern and Western Equine Encephalitis, St. Louis Encephalitis, Sindbis, and Rift Valley Fever viruses), most with substantial transmission in temperate regions. Transmission is optimized at intermediate temperatures (23–26°C) and often has wider thermal breadths (due to cooler lower thermal limits) compared to pathogens with predominately tropical distributions (in previous studies). The incidence of human West Nile virus cases across US counties responded unimodally to average summer temperature and peaked at 24°C, matching model-predicted optima (24–25°C). Climate warming will likely shift transmission of these diseases, increasing it in cooler locations while decreasing it in warmer locations.

in eLife on September 15, 2020 12:00 AM.

• #### Meta Research: Questionable research practices may have little effect on replicability

This article examines why many studies fail to replicate statistically significant published results. We address this issue within a general statistical framework that also allows us to include various questionable research practices (QRPs) that are thought to reduce replicability. The analyses indicate that the base rate of true effects is the major factor that determines the replication rate of scientific results. Specifically, for purely statistical reasons, replicability is low in research domains where true effects are rare (e.g., search for effective drugs in pharmacology). This point is under-appreciated in current scientific and media discussions of replicability, which often attribute poor replicability mainly to QRPs.

in eLife on September 15, 2020 12:00 AM.

• #### Erasable labeling of neuronal activity using a reversible calcium marker

Understanding how the brain encodes and processes information requires the recording of neural activity that underlies different behaviors. Recent efforts in fluorescent protein engineering have succeeded in developing powerful tools for visualizing neural activity, in general by coupling neural activity to different properties of a fluorescent protein scaffold. Here, we take advantage of a previously unexploited class of reversibly switchable fluorescent proteins to engineer a new type of calcium sensor. We introduce rsCaMPARI, a genetically encoded calcium marker engineered from a reversibly switchable fluorescent protein that enables spatiotemporally precise marking, erasing, and remarking of active neuron populations under brief, user-defined time windows of light exposure. rsCaMPARI photoswitching kinetics are modulated by calcium concentration when illuminating with blue light, and the fluorescence can be reset with violet light. We demonstrate the utility of rsCaMPARI for marking and remarking active neuron populations in freely swimming zebrafish.

in eLife on September 15, 2020 12:00 AM.

• #### Performance of a deep learning based neural network in the selection of human blastocysts for implantation

Deep learning in in-vitro fertilization is currently being evaluated in the development of assistive tools for the determination of transfer order and implantation potential using time-lapse data collected through expensive imaging hardware. Assistive tools and algorithms that can work with static images, however, can help in improving the access to care by enabling their use with images acquired from traditional microscopes that are available to virtually all fertility centers. Here, we evaluated the use of a deep convolutional neural network (CNN), trained using single timepoint images of embryos collected at 113 hours post-insemination, in embryo selection amongst 97 clinical patient cohorts (742 embryos) and observed an accuracy of 90% in choosing the highest quality embryo available. Furthermore, a CNN trained to assess an embryo’s implantation potential directly using a set of 97 euploid embryos capable of implantation outperformed 15 trained embryologists (75.26% vs. 67.35%, P<0.0001) from 5 different fertility centers.

in eLife on September 15, 2020 12:00 AM.

• #### Efficient sampling and noisy decisions

Human decisions are based on finite information, which makes them inherently imprecise. But what determines the degree of such imprecision? Here, we develop an efficient coding framework for higher-level cognitive processes in which information is represented by a finite number of discrete samples. We characterize the sampling process that maximizes perceptual accuracy or fitness under the often-adopted assumption that full adaptation to an environmental distribution is possible, and show how the optimal process differs when detailed information about the current contextual distribution is costly. We tested this theory on a numerosity discrimination task, and found that humans efficiently adapt to contextual distributions, but in the way predicted by the model in which people must economize on environmental information. Thus, understanding decision behavior requires that we account for biological restrictions on information coding, challenging the often-adopted assumption of precise prior knowledge in higher-level decision systems.

in eLife on September 15, 2020 12:00 AM.

• #### Vasopressin Neurons: Master Integrators of Time and Homeostasis

A recent article by Gizowski and Bourque shows that vasopressinergic (VP) neurons within the suprachiasmatic nucleus (SCN) master circadian clock have the ability of encoding afferent input from osmosensors and generating appropriate homeostatic responses, suggesting that SCN neurons can integrate internal circadian time and acute changes in homeostatic markers.

in Trends in Neurosciences: In press on September 15, 2020 12:00 AM.

• #### Central Vestibular Tuning Arises from Patterned Convergence of Otolith Afferents

Though computational models predict how sensory inputs converge in central neurons, it is technically challenging to test these ideas experimentally. With whole-cell recordings in larval zebrafish in vivo, Liu et al. demonstrate that the convergence of similarly or differently tuned vestibular afferents produces more simple or complex postsynaptic tuning, respectively.

in Neuron: In press on September 15, 2020 12:00 AM.

• #### Toll-like Receptor 5 Activation by the CagY Repeat Domains of Helicobacter pylori

Tegtmeyer et al. identify the Helicobacter pylori protein CagY, a type IV secretion system (T4SS) core component and pilus-associated VirB10 ortholog, as an agonist for Toll-like receptor 5 (TLR5). This interaction is involved in crucial innate and adaptive immune responses by this gastric pathogen.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### The Natural Compound Notopterol Binds and Targets JAK2/3 to Ameliorate Inflammation and Arthritis

Wang et al. show that the natural compound notopterol alleviates arthritis by binding to JAK2 and JAK3 which inhibit the JAK-STAT pathway and reduce inflammatory cytokine and chemokine production.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Structural Basis for Regulation of the Opposing (p)ppGpp Synthetase and Hydrolase within the Stringent Response Orchestrator Rel

Pausch et al. report the structural and functional analysis of the bifunctional regulator of the (p)ppGpp-dependent stringent response in its free and ribosome-bound state. The study provides a detailed molecular view into the bacterial mechanism of stringent response repression in the absence of stress.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons

Evans et al. functionally map inhibitory inputs onto SNc dopamine neuron dendrites from genetically defined basal ganglia subpopulations. Using two-photon calcium imaging and computational modeling, they reveal a dendrite-specific striatonigral circuit that facilitates dopamine neuron rebound activity.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### A Bisulfite-free Approach for Base-Resolution Analysis of Genomic 5-Carboxylcytosine

Licyte et al. present a chemo-enzymatic approach for mapping 5-carboxylcytosine, which uses enzymatic removal of the carboxyl group from 5caCG sites and their detection via high-resolution sequencing. Profiling of 5caCGs in naive and primed pluripotent mouse ESCs demonstrates the state-specific distribution of 5caCGs and association with active gene expression.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Protein Stability Buffers the Cost of Translation Attenuation following eIF2α Phosphorylation

Here, we find that translation attenuation following eIF2α phosphorylation is not uniform, with long-lived proteins, including cytosolic and mitochondrial ribosomal subunits, being prominently downregulated. Because protein stability buffers the cost of translational attenuation, there is no measurable decrease of the targeted proteins. This reveals an evolutionary principle of cellular robustness.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Innate Lymphoid Cell Activation and Sustained Depletion in Blood and Tissue of Children Infected with HIV from Birth Despite Antiretroviral Therapy

ILCs are dysregulated during HIV-1 infection in adults, but their fate in children is unknown. Singh et al. demonstrate that circulating and tonsil-resident ILCs are depleted in children infected with HIV-1 since birth. Transcriptionally, ILCs exhibit cell-type- and compartment-specific activity in HIV-1 infected children compared to healthy controls.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Visual Sequences Drive Experience-Dependent Plasticity in Mouse Anterior Cingulate Cortex

Sidorov et al. demonstrate that patterned visual input can drive experience-dependent plasticity in the timing of neural responses in mouse anterior cingulate cortex.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

Chen et al. show that the rate of onset and maximal cellular Akt1 activity induced by mitogens was augmented by cyclin D1. Cyclin D1 bound and phosphorylated Akt1 at Ser473. These studies identify a novel extranuclear function of cyclin D1 to enhance proliferative functions via augmenting Akt1 phosphorylation at Ser473.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Astrocyte- and Neuron-Derived CXCL1 Drives Neutrophil Transmigration and Blood-Brain Barrier Permeability in Viral Encephalitis

Viral encephalitis results in brain injury despite effective anti-viral therapy. Michael et al. find that neutrophil entry into the brain drives morbidity in a mouse model of HSV-1 encephalitis. Neutrophil recruitment required CXCR2 and its ligand CXCL1, which represent attractive therapeutic targets to limit brain injury associated with encephalitis.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### PRC2 Acts as a Critical Timer That Drives Oligodendrocyte Fate over Astrocyte Identity by Repressing the Notch Pathway

Wang et al. show that the polycomb repressive complex PRC2 is required for the differentiation of oligodendrocyte precursors to myelinating oligodendrocytes. They further show that PRC2 promotes oligodendrocyte differentiation and inhibits erroneous astrocytic fate by repressing the Notch pathway.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

Using a comparative proteomic analysis of endogenous SUMO2/3 substrates, Theurillat et al. find a shift in the repertoire of SUMOylated proteins during cell differentiation. SUMO2/3 targets pluripotency and heterochromatin transactions in ESCs but general cellular functions and fibroblastic enhancer activity in MEFs.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Identification of a Core Module for Bone Mineral Density through the Integration of a Co-expression Network and GWAS Data

Sabik et al. describe a network-based approach for identifying genes with “core-like” characteristics for complex skeletal traits through the integration of a cell-type- and time-point-specific gene co-expression network for mineralizing osteoblasts and the results of genome-wide association studies for bone mineral density, a significant predictor of osteoporotic fracture.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### LIM-Homeodomain Transcription Factor LHX4 Is Required for the Differentiation of Retinal Rod Bipolar Cells and OFF-Cone Bipolar Subtypes

Dong et al. show that the loss of Lhx4 in mice results in the loss of rod bipolar cells and rod-connecting bipolar cells and in a visual defect resembling human congenital stationary night blindness. Lhx4, together with Isl1, acts upstream of Bhlhe23, Prdm8, Fezf2, and Lhx3 to regulate bipolar cell development.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### The Dorsal Lateral Habenula-Interpeduncular Nucleus Pathway Is Essential for Left-Right-Dependent Decision Making in Zebrafish

Cherng et al. show that zebrafish can exploit both directional and cued information for foraging to adapt flexibly to the changes of the imposed rules and that the habenular output pathway regulating the social dominance is specifically involved in direction-associated learning, suggesting the dual roles of this pathway.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Infection with Bacteroides Phage BV01 Alters the Host Transcriptome and Bile Acid Metabolism in a Common Human Gut Microbe

Integrative phages can have myriad effects on bacterial hosts. Campbell et al. find that integration of Bacteroides phage BV01 into Bacteroides vulgatus disrupts expression of TspO, reducing bile acid deconjugation. This is predicted to affect gut colonization and interactions with the human host. BV01 belongs to the Salyersviridae family.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion

Appropriate insulin secretion is governed through organ crosstalk. Drareni et al. show that GPS2 expression in adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance in obese mice.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### The GSK-3β-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function

Wirianto et al. find that the circadian E3 ligase FBXL21 drives rhythmic degradation of the sarcomeric protein TCAP in skeletal muscle. GSK-3β co-phosphorylates FBXL21 and TCAP and promotes SCF complex formation and phosphodegron-dependent TCAP turnover. Psttm mice, expressing a hypomorphic Fbxl21 mutant, show dysregulated TCAP degradation and impaired muscle function.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### A Chemogenetic Tool that Enables Functional Neural Circuit Analysis

Chemogenetics provides understanding of the function of specific neurons transduced to express an actuating receptor that is affected by global ligand administration. Ngo et al. generate a viral vector that induces neuronal expression and synaptic release of the inhibitory chemogenetic ligand, allatostatin, enabling circuit-based inhibition of allatostatin receptor-expressing neurons.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Visual Input into the Drosophila melanogaster Mushroom Body

Li et al. find that the dorsal accessory calyx of the Drosophila melanogaster mushroom body integrates visual input from the lobula and the posterior lateral protocerebrum.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Brain mRNA Expression Associated with Cortical Volume Alterations in Autism Spectrum Disorder

The genes related to cerebral cortex volume (CCV) abnormalities in autism spectrum disorder (ASD) remain largely unknown. Xie et al. identify 417 genes whose expressions are associated with CCV alterations in ASD and highlight a model whereby genetic risk impacts gene expression (downregulated), leading to CCV alterations in ASD

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### A Membrane-Associated DHH-DHHA1 Nuclease Degrades Type III CRISPR Second Messenger

Zhao et al. find that a metal-dependent and membrane-associated nuclease activity accelerates clearance of high-level cOA in Sulfolobus. They further show that a metal-dependent and membrane-associated DHH-DHHA1 family nuclease efficiently degrades cOA and deactivates type III CRISPR accessory nuclease.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Cell-Type- and Brain-Region-Resolved Mouse Brain Lipidome

Fitzner et al. perform extensive lipidome analyses on the mouse brain and its major cell types and integrate lipid with protein expression profiles to predict lipid pathways enriched in specific cells and brain regions. The study serves as a resource for better understanding of brain development and function.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Single Nucleotide Resolution Analysis Reveals Pervasive, Long-Lasting DNA Methylation Changes by Developmental Exposure to a Mitochondrial Toxicant

Lozoya et al. provide in vivo evidence of the epigenetic effects of mitochondrial dysfunction. Developmental-only exposure to rotenone through the mother’s diet inhibits mitochondrial complex I in the dams and results in lifelong nuclear DNA methylation and gene expression changes in the offspring. Aged offspring also show functional outcomes.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Generation of Human Renal Vesicles in Mouse Organ Niche Using Nephron Progenitor Cell Replacement System

Fujimoto et al. present a mouse model that enables tamoxifen-induced ablation of Six2-positive nephron progenitor cells (NPCs). Transplanted human induced NPCs differentiate into renal vesicles that connect to the host mouse ureteric bud. The potential regeneration of human kidneys via an NPC replacement system is demonstrated.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities

Nagahama et al. demonstrate that mimicking a de novo mutation of the schizophrenia-risk gene SETD1A in mice induces various abnormal behaviors relevant to schizophrenia. Setd1a in postsynaptic neurons positively regulates excitatory synaptic transmission and structure in the medial prefrontal cortex through histone modification and regulating the expression of diverse synaptic genes.

in Cell Reports: Current Issue on September 15, 2020 12:00 AM.

• #### Distributed causality in resting-state network connectivity in the acute and remitting phases of RRMS

Although previous studies have shown that intra-network abnormalities in brain functional networks are correlated with clinical/cognitive impairment in multiple sclerosis (MS), there is little information rega...

in BMC Neuroscience on September 15, 2020 12:00 AM.

• #### Kinetic modeling of H<sub>2</sub>O<sub>2</sub> dynamics in the mitochondria of HeLa cells

by Kassi T. Stein, Sun Jin Moon, Athena N. Nguyen, Hadley D. Sikes

Hydrogen peroxide (H2O2) promotes a range of phenotypes depending on its intracellular concentration and dosing kinetics, including cell death. While this qualitative relationship has been well established, the quantitative and mechanistic aspects of H2O2 signaling are still being elucidated. Mitochondria, a putative source of intracellular H2O2, have recently been demonstrated to be particularly vulnerable to localized H2O2 perturbations, eliciting a dramatic cell death response in comparison to similar cytosolic perturbations. We sought to improve our dynamic and mechanistic understanding of the mitochondrial H2O2 reaction network in HeLa cells by creating a kinetic model of this system and using it to explore basal and perturbed conditions. The model uses the most current quantitative proteomic and kinetic data available to predict reaction rates and steady-state concentrations of H2O2 and its reaction partners within individual mitochondria. Time scales ranging from milliseconds to one hour were simulated. We predict that basal, steady-state mitochondrial H2O2 will be in the low nM range (2–4 nM) and will be inversely dependent on the total pool of peroxiredoxin-3 (Prx3). Neglecting efflux of H2O2 to the cytosol, the mitochondrial reaction network is expected to control perturbations well up to H2O2 generation rates ~50 μM/s (0.25 nmol/mg-protein/s), above which point the Prx3 system would be expected to collapse. Comparison of these results with redox Western blots of Prx3 and Prx2 oxidation states demonstrated reasonable trend agreement at short times (≤ 15 min) for a range of experimentally perturbed H2O2 generation rates. At longer times, substantial efflux of H2O2 from the mitochondria to the cytosol was evidenced by peroxiredoxin-2 (Prx2) oxidation, and Prx3 collapse was not observed. A refined model using Monte Carlo parameter sampling was used to explore rates of H2O2 efflux that could reconcile model predictions of Prx3 oxidation states with the experimental observations.

in PLoS Computational Biology on September 14, 2020 09:00 PM.

• #### NuSeT: A deep learning tool for reliably separating and analyzing crowded cells

by Linfeng Yang, Rajarshi P. Ghosh, J. Matthew Franklin, Simon Chen, Chenyu You, Raja R. Narayan, Marc L. Melcher, Jan T. Liphardt

Segmenting cell nuclei within microscopy images is a ubiquitous task in biological research and clinical applications. Unfortunately, segmenting low-contrast overlapping objects that may be tightly packed is a major bottleneck in standard deep learning-based models. We report a Nuclear Segmentation Tool (NuSeT) based on deep learning that accurately segments nuclei across multiple types of fluorescence imaging data. Using a hybrid network consisting of U-Net and Region Proposal Networks (RPN), followed by a watershed step, we have achieved superior performance in detecting and delineating nuclear boundaries in 2D and 3D images of varying complexities. By using foreground normalization and additional training on synthetic images containing non-cellular artifacts, NuSeT improves nuclear detection and reduces false positives. NuSeT addresses common challenges in nuclear segmentation such as variability in nuclear signal and shape, limited training sample size, and sample preparation artifacts. Compared to other segmentation models, NuSeT consistently fares better in generating accurate segmentation masks and assigning boundaries for touching nuclei.

in PLoS Computational Biology on September 14, 2020 09:00 PM.

• #### Genetic buffering and potentiation in metabolism

by Juan F. Poyatos

Cells adjust their metabolism in response to mutations, but how this reprogramming depends on the genetic context is not well known. Specifically, the absence of individual enzymes can affect reprogramming, and thus the impact of mutations in cell growth. Here, we examine this issue with an in silico model of Saccharomyces cerevisiae’s metabolism. By quantifying the variability in the growth rate of 10000 different mutant metabolisms that accumulated changes in their reaction fluxes, in the presence, or absence, of a specific enzyme, we distinguish a subset of modifier genes serving as buffers or potentiators of variability. We notice that the most potent modifiers refer to the glycolysis pathway and that, more broadly, they show strong pleiotropy and epistasis. Moreover, the evidence that this subset depends on the specific growing condition strengthens its systemic underpinning, a feature only observed before in a toy model of a gene-regulatory network. Some of these enzymes also modulate the effect that biochemical noise and environmental fluctuations produce in growth. Thus, the reorganization of metabolism induced by mutations has not only direct physiological implications but also transforms the influence that other mutations have on growth. This is a general result with implications in the development of cancer therapies based on metabolic inhibitors.

in PLoS Computational Biology on September 14, 2020 09:00 PM.

• #### Effects of spatial heterogeneity on bacterial genetic circuits

by Carlos Barajas, Domitilla Del Vecchio

Intracellular spatial heterogeneity is frequently observed in bacteria, where the chromosome occupies part of the cell’s volume and a circuit’s DNA often localizes within the cell. How this heterogeneity affects core processes and genetic circuits is still poorly understood. In fact, commonly used ordinary differential equation (ODE) models of genetic circuits assume a well-mixed ensemble of molecules and, as such, do not capture spatial aspects. Reaction-diffusion partial differential equation (PDE) models have been only occasionally used since they are difficult to integrate and do not provide mechanistic understanding of the effects of spatial heterogeneity. In this paper, we derive a reduced ODE model that captures spatial effects, yet has the same dimension as commonly used well-mixed models. In particular, the only difference with respect to a well-mixed ODE model is that the association rate constant of binding reactions is multiplied by a coefficient, which we refer to as the binding correction factor (BCF). The BCF depends on the size of interacting molecules and on their location when fixed in space and it is equal to unity in a well-mixed ODE model. The BCF can be used to investigate how spatial heterogeneity affects the behavior of core processes and genetic circuits. Specifically, our reduced model indicates that transcription and its regulation are more effective for genes located at the cell poles than for genes located on the chromosome. The extent of these effects depends on the value of the BCF, which we found to be close to unity. For translation, the value of the BCF is always greater than unity, it increases with mRNA size, and, with biologically relevant parameters, is substantially larger than unity. Our model has broad validity, has the same dimension as a well-mixed model, yet it incorporates spatial heterogeneity. This simple-to-use model can be used to both analyze and design genetic circuits while accounting for spatial intracellular effects.

in PLoS Computational Biology on September 14, 2020 09:00 PM.

• #### A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway

by Gabriella J. Gerlach, Rachel Carrock, Robyn Stix, Elliott J. Stollar, K. Aurelia Ball

Protein-protein interactions are involved in a wide range of cellular processes. These interactions often involve intrinsically disordered proteins (IDPs) and protein binding domains. However, the details of IDP binding pathways are hard to characterize using experimental approaches, which can rarely capture intermediate states present at low populations. SH3 domains are common protein interaction domains that typically bind proline-rich disordered segments and are involved in cell signaling, regulation, and assembly. We hypothesized, given the flexibility of SH3 binding peptides, that their binding pathways include multiple steps important for function. Molecular dynamics simulations were used to characterize the steps of binding between the yeast Abp1p SH3 domain (AbpSH3) and a proline-rich IDP, ArkA. Before binding, the N-terminal segment 1 of ArkA is pre-structured and adopts a polyproline II helix, while segment 2 of ArkA (C-terminal) adopts a 310 helix, but is far less structured than segment 1. As segment 2 interacts with AbpSH3, it becomes more structured, but retains flexibility even in the fully engaged state. Binding simulations reveal that ArkA enters a flexible encounter complex before forming the fully engaged bound complex. In the encounter complex, transient nonspecific hydrophobic and long-range electrostatic contacts form between ArkA and the binding surface of SH3. The encounter complex ensemble includes conformations with segment 1 in both the forward and reverse orientation, suggesting that segment 2 may play a role in stabilizing the correct binding orientation. While the encounter complex forms quickly, the slow step of binding is the transition from the disordered encounter ensemble to the fully engaged state. In this transition, ArkA makes specific contacts with AbpSH3 and buries more hydrophobic surface. Simulating the binding between ApbSH3 and ArkA provides insight into the role of encounter complex intermediates and nonnative hydrophobic interactions for other SH3 domains and IDPs in general.

in PLoS Computational Biology on September 14, 2020 09:00 PM.

• #### Providing new insights on the biphasic lifestyle of the predatory bacterium <i>Bdellovibrio bacteriovorus</i> through genome-scale metabolic modeling

by Cristina Herencias, Sergio Salgado-Briegas, María A. Prieto, Juan Nogales

In this study we analyze the growth-phase dependent metabolic states of Bdellovibrio bacteriovorus by constructing a fully compartmented, mass and charge-balanced genome-scale metabolic model of this predatory bacterium (iCH457). Considering the differences between life cycle phases driving the growth of this predator, growth-phase condition-specific models have been generated allowing the systematic study of its metabolic capabilities. Using these computational tools, we have been able to analyze, from a system level, the dynamic metabolism of the predatory bacteria as the life cycle progresses. We provide computational evidences supporting potential axenic growth of B. bacteriovorus’s in a rich medium based on its encoded metabolic capabilities. Our systems-level analysis confirms the presence of “energy-saving” mechanisms in this predator as well as an abrupt metabolic shift between the attack and intraperiplasmic growth phases. Our results strongly suggest that predatory bacteria’s metabolic networks have low robustness, likely hampering their ability to tackle drastic environmental fluctuations, thus being confined to stable and predictable habitats. Overall, we present here a valuable computational testbed based on predatory bacteria activity for rational design of novel and controlled biocatalysts in biotechnological/clinical applications.

in PLoS Computational Biology on September 14, 2020 09:00 PM.

• #### The World Coral Conservatory: A Noah's ark for corals to support survival of reef ecosystems

by Didier Zoccola, Nadia Ounais, Dominique Barthelemy, Robert Calcagno, Françoise Gaill, Stephane Henard, Ove Hoegh-Guldberg, Max Janse, Jean Jaubert, Hollie Putnam, Bernard Salvat, Christian R. Voolstra, Denis Allemand

Global change causes widespread decline of coral reefs. In order to counter the anticipated disappearance of coral reefs by the end of this century, many initiatives are emerging, including creation of marine protected areas (MPAs), reef restoration projects, and assisted evolution initiatives. Such efforts, although critically important, are locally constrained. We propose to build a “Noah's Ark” biological repository for corals that taps into the network of the world’s public aquaria and coral reef scientists. Public aquaria will serve not only as a reservoir for the purpose of conservation, restoration, and research of reef-building corals but also as a laboratory for the implementation of operations for the selection of stress-resilient and resistant genotypes. The proposed project will provide a global dimension to coral reef education and protection as a result of the involvement of a network of public and private aquaria.

in PLoS Biology on September 14, 2020 09:00 PM.

• #### Two unequally redundant "helper" immune receptor families mediate <i>Arabidopsis thaliana</i> intracellular "sensor" immune receptor functions

by Svenja C. Saile, Pierre Jacob, Baptiste Castel, Lance M. Jubic, Isai Salas-Gonzalez, Marcel Bäcker, Jonathan D. G. Jones, Jeffery L. Dangl, Farid El Kasmi

Plant nucleotide-binding (NB) leucine-rich repeat (LRR) receptor (NLR) proteins function as intracellular immune receptors that perceive the presence of pathogen-derived virulence proteins (effectors) to induce immune responses. The 2 major types of plant NLRs that “sense” pathogen effectors differ in their N-terminal domains: these are Toll/interleukin-1 receptor resistance (TIR) domain-containing NLRs (TNLs) and coiled-coil (CC) domain-containing NLRs (CNLs). In many angiosperms, the RESISTANCE TO POWDERY MILDEW 8 (RPW8)-CC domain containing NLR (RNL) subclass of CNLs is encoded by 2 gene families, ACTIVATED DISEASE RESISTANCE 1 (ADR1) and N REQUIREMENT GENE 1 (NRG1), that act as “helper” NLRs during multiple sensor NLR-mediated immune responses. Despite their important role in sensor NLR-mediated immunity, knowledge of the specific, redundant, and synergistic functions of helper RNLs is limited. We demonstrate that the ADR1 and NRG1 families act in an unequally redundant manner in basal resistance, effector-triggered immunity (ETI) and regulation of defense gene expression. We define RNL redundancy in ETI conferred by some TNLs and in basal resistance against virulent pathogens. We demonstrate that, in Arabidopsis thaliana, the 2 RNL families contribute specific functions in ETI initiated by specific CNLs and TNLs. Time-resolved whole genome expression profiling revealed that RNLs and “classical” CNLs trigger similar transcriptome changes, suggesting that RNLs act like other CNLs to mediate ETI downstream of sensor NLR activation. Together, our genetic data confirm that RNLs contribute to basal resistance, are fully required for TNL signaling, and can also support defense activation during CNL-mediated ETI.

in PLoS Biology on September 14, 2020 09:00 PM.

## Objective

We report natural history data in a large cohort of 199 spinal muscular atrophy (SMA) type III patients assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number and functional status.

## Methods

HFMSE longitudinal changes were assessed using piecewise linear mixed‐effects models.

The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12‐month assessments.

## Results

A break point at age 7 was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type and ambulatory status were significantly associated with changes in mean HFMSE score while sex and SMN2 copy number were not.

The increase in response before the break point of age 7 is significant only for SMA IIIA (β = 1.79, p < .0001). After the break point the change in the rate of HFMSE score significantly decrease for both SMA IIIA (β = −1.15, p < .0001) and IIIB (β = −0.69, p = 0.002).

## Interpretation

Our findings contribute to the understanding of the natural history of type III SMA and will be helpful in the interpretation of the real‐world data of patients treated with commercially available drugs.

in Annals of Neurology on September 14, 2020 11:14 AM.

• #### The Journal of Comparative Neurology, Table of Content, Vol. 528, No. 16, November , 2020

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Cover Image, Volume 528, Issue 16

The cover image is based on the Original Article Region‐ and neuronal‐subtype‐specific expression of Na, K‐ATPase alpha and beta subunit isoforms in the mouse brain by Yugo Fukazawa et al., https://doi.org/10.1002/cne.24924.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### The connectome of the Caenorhabditis elegans pharynx

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

## Abstract

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

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Expression profiling of precuneus layer III cathepsin D‐immunopositive pyramidal neurons in mild cognitive impairment and Alzheimer's disease: Evidence for neuronal signaling vulnerability

Precuneus (PreC) layer III projection neurons, which contain lysosomal hydrolase cathepsin D (CatD) are dysfunctional in Alzheimer's disease (AD). Expression profiling of PreC CatD‐ positive layer III neurons revealed significant dysregulation of a mosaic of genes in tissue from subjects with mild cognitive impairment and AD that was not previously appreciated in terms of their indication of systems‐wide signaling defects in a key hub of the default mode memory network.

## Abstract

The precuneus (PreC; Brodmann area 7), a key hub within the default mode network (DMN) displays amyloid and tau‐containing neurofibrillary tangle (NFT) pathology during the onset of Alzheimer's disease (AD). PreC layer III projection neurons contain lysosomal hydrolase cathepsin D (CatD), a marker of neurons vulnerable to NFT pathology. Here we applied single population laser capture microdissection coupled with custom‐designed microarray profiling to determine the genetic signature of PreC CatD‐positive‐layer III neurons accrued from postmortem tissue obtained from the Rush Religious Orders Study (RROS) cases with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD. Expression profiling revealed significant differential expression of key transcripts in MCI and AD compared to NCI that underlie signaling defects, including dysregulation of genes within the endosomal‐lysosomal and autophagy pathways, cytoskeletal elements, AD‐related genes, ionotropic and metabotropic glutamate receptors, cholinergic enzymes and receptors, markers of monoamine neurotransmission as well as steroid‐related transcripts. Pervasive defects in both MCI and AD were found in select transcripts within these key gene ontology categories, underscoring the vulnerability of these corticocortical projection neurons during the onset and progression of dementia. Select PreC dysregulated genes detected via custom‐designed microarray analysis were validated using qPCR. In summary, expression profiling of PreC CatD ‐positive layer III neurons revealed significant dysregulation of a mosaic of genes in MCI and AD that were not previously appreciated in terms of their indication of systems‐wide signaling defects in a key hub of the DMN.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

## Abstract

Our prior studies showed bilateral gustatory cortex (GC) lesions significantly impair taste sensitivity to salts (NaCl and KCl) and quinine (“bitter”) but not to sucrose (“sweet”). The range of qualitative tastants tested here has been extended in a theoretically relevant way to include the maltodextrin, Maltrin, a preferred stimulus by rats thought to represent a unique taste quality, and the “sour” stimulus citric acid; NaCl was also included as a positive control. Male rats (Sprague–Dawley) with histologically confirmed neurotoxin‐induced bilateral (BGCX, n = 13), or right (RGCX, n = 13) or left (LGCX, n = 9) unilateral GC lesions and sham‐operated controls (SHAM, n = 16) were trained to discriminate a tastant from water in an operant two‐response detection task. A mapping system was used to determine placement, size, and symmetry (when bilateral) of the lesion. BGCX significantly impaired taste sensitivity to NaCl, as expected, but not to Maltrin or citric acid, emulating our prior results with sucrose. However, in the case of citric acid, there was some disruption in performance at higher concentrations. Interestingly, RGCX, but not LGCX, also significantly impaired taste sensitivity, but only to NaCl, suggesting some degree of lateralized function. Taken together with our prior findings, extensive bilateral lesions in GC do not disrupt basic taste signal detection to all taste stimuli uniformly. Moreover, GC lesions do not preclude the ability of rats to learn and perform the task, clearly demonstrating that, in its absence, other brain regions are able to maintain sensory‐discriminative taste processing, albeit with attenuated sensitivity for select stimuli.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Central afferents to the nucleus of the solitary tract in rats and mice

Rats and mice have similar patterns of retrogradely labeled neurons that project axons to the NTS. Afferent neurons in the hypothalamus are glutamatergic, while those in the amygdala are GABAergic. In the paraventricular hypothalamic nucleus, NTS afferent neurons are distinct from neuroendocrine neurons. Injecting retrograde tracers into the medial and lateral NTS subdivisions produce similar patterns of retrograde labeling.

## Abstract

The nucleus of the solitary tract (NTS) regulates life‐sustaining functions ranging from appetite and digestion to heart rate and breathing. It is also the brain's primary sensory nucleus for visceral sensations relevant to symptoms in medical and psychiatric disorders. To better understand which neurons may exert top‐down control over the NTS, here we provide a brain‐wide map of all neurons that project axons directly to the caudal, viscerosensory NTS, focusing on a medial subregion with aldosterone‐sensitive HSD2 neurons. Injecting an axonal tracer (cholera toxin b) into the NTS produces a similar pattern of retrograde labeling in rats and mice. The paraventricular hypothalamic nucleus (PVH), lateral hypothalamic area, and central nucleus of the amygdala (CeA) contain the densest concentrations of NTS‐projecting neurons. PVH afferents are glutamatergic (express Slc17a6/Vglut2) and are distinct from neuroendocrine PVH neurons. CeA afferents are GABAergic (express Slc32a1/Vgat) and are distributed largely in the medial CeA subdivision. Other retrogradely labeled neurons are located in a variety of brain regions, including the cerebral cortex (insular and infralimbic areas), bed nucleus of the stria terminalis, periaqueductal gray, Barrington's nucleus, Kölliker‐Fuse nucleus, hindbrain reticular formation, and rostral NTS. Similar patterns of retrograde labeling result from tracer injections into different NTS subdivisions, with dual retrograde tracing revealing that many afferent neurons project axon collaterals to both the lateral and medial NTS subdivisions. This information provides a roadmap for studying descending axonal projections that may influence visceromotor systems and visceral “mind–body” symptoms.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Perineuronal nets and subtypes of GABAergic cells differentiate auditory and multisensory nuclei in the intercollicular area of the midbrain

The intercollicular region, which lies between the inferior and superior colliculi in the midbrain, contains neurons that respond to auditory, visual, and somatosensory stimuli. Golgi studies have been used to parse this region into three distinct nuclei: the intercollicular tegmentum (ICt), the rostral pole of the inferior colliculus (ICrp), and the nucleus of the brachium of the IC (NBIC). Few reports have focused on these nuclei, especially the ICt and the ICrp, possibly due to lack of a marker that distinguishes these areas and is compatible with modern methods. Here, we show that staining for GABAergic cells (magenta) and perineuronal nets (green) differentiates these intercollicular nuclei in guinea pigs.

## Abstract

The intercollicular region, which lies between the inferior and superior colliculi in the midbrain, contains neurons that respond to auditory, visual, and somatosensory stimuli. Golgi studies have been used to parse this region into three distinct nuclei: the intercollicular tegmentum (ICt), the rostral pole of the inferior colliculus (ICrp), and the nucleus of the brachium of the IC (NBIC). Few reports have focused on these nuclei, especially the ICt and the ICrp, possibly due to lack of a marker that distinguishes these areas and is compatible with modern methods. Here, we found that staining for GABAergic cells and perineuronal nets differentiates these intercollicular nuclei in guinea pigs. Further, we found that the proportions of four subtypes of GABAergic cells differentiate intercollicular nuclei from each other and from adjacent inferior collicular subdivisions. Our results support earlier studies that suggest distinct morphology and functions for intercollicular nuclei, and provide staining methods that differentiate intercollicular nuclei and are compatible with most modern techniques. We hope that this will help future studies to further characterize the intercollicular region.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Deep hypothermia prevents striatal alterations produced by perinatal asphyxia: Implications for the prevention of dyskinesia and psychosis

GABAergic medium spiny neurons are the main neuronal population in the striatum. Calbindin is preferentially expressed in medium spiny neurons involved in the indirect pathway. The perinatal asphyxia (PA) group showed a significant decrease in calbindin neurons and a paradoxical increase in neurons estimated by NeuN staining. Moreover, calretinin+ cells, a specific subpopulation of GABAergic neurons, showed an increase caused by PA. Deep hypothermia reversed most of these alterations probably by protecting calbindin neurons.

## Abstract

GABAergic medium spiny neurons are the main neuronal population in the striatum. Calbindin is preferentially expressed in medium spiny neurons involved in the indirect pathway. The aim of the present work is to analyze the effect of perinatal asphyxia on different subpopulations of GABAergic neurons in the striatum and to assess the outcome of deep therapeutic hypothermia. The uterus of pregnant rats was removed by cesarean section and the fetuses were exposed to hypoxia by immersion in water (19 min) at 37°C (perinatal asphyxia). The hypothermic group was exposed to 10°C during 30 min after perinatal asphyxia. The rats were euthanized at the age of one month (adolescent/adult rats), their brains were dissected out and coronal sections were immunolabeled for calbindin, calretinin, NeuN, and reelin. Reelin+ cells showed no staining in the striatum besides subventricular zone. The perinatal asphyxia (PA) group showed a significant decrease in calbindin neurons and a paradoxical increase in neurons estimated by NeuN staining. Moreover, calretinin+ cells, a specific subpopulation of GABAergic neurons, showed an increase caused by PA. Deep hypothermia reversed most of these alterations probably by protecting calbindin neurons. Similarly, there was a reduction of the diameter of the anterior commissure produced by the asphyxia that was prevented by hypothermic treatment.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Region‐ and neuronal‐subtype‐specific expression of Na,K‐ATPase alpha and beta subunit isoforms in the mouse brain

Na,K‐ATPase comprises α (Atp1a), β (Atp1b), and FXYD subunits, and each subunit has isoforms. In situ hybridization for α and β subunit isoforms revealed regional‐ and neuronal‐subtype‐specific expression of the isoforms in the mouse brain. The photograph shows Atp1a1 (red) and Atp1a3 (green) expression in the hippocampal dentate gyrus (stained with DAPI, blue).

## Abstract

Na,K‐ATPase is a ubiquitous molecule contributing to the asymmetrical distribution of Na+ and K+ ions across the plasma membrane and maintenance of the membrane potential, a prerequisite of neuronal activity. Na,K‐ATPase comprises three subunits (α, β, and FXYD). The α subunit has four isoforms in mice, with three of them (α1, α2, and α3) expressed in the brain. However, the functional and biological significances of the different brain isoforms remain to be fully elucidated. Recent studies have revealed the association of Atp1a3, a gene encoding α3 subunit, with neurological disorders. To map the cellular distributions of the α subunit isoforms and their coexpression patterns, we evaluated the mRNA expression of Atp1a1, Atp1a2, and Atp1a3 by in situ hybridization in the mouse brain. Atp1a1 and Atp1a3 were expressed in neurons, whereas Atp1a2 was almost exclusively expressed in glial cells. Most neurons coexpressed Atp1a1 and Atp1a3, with highly heterogeneous expression levels across the brain regions and neuronal subtypes. We identified parvalbumin (PV)‐expressing GABAergic neurons in the hippocampus, somatosensory cortex, and retrosplenial cortex as an example of a neuronal subtype expressing low Atp1a1 and high Atp1a3. The expression of Atp1b isoforms was also heterogeneous across brain regions and cellular subtypes. The PV‐expressing neurons expressed a high level of Atp1b1 and a low level of Atp1b2 and Atp1b3. These findings provide basic information on the region‐ and neuronal‐subtype‐dependent expression of Na,K‐ATPase α and β subunit isoforms, as well as a rationale for the selective involvement of neurons expressing high levels of Atp1a3 in neurological disorders.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Differences in behavior between surface and cave Astyanax mexicanus may be mediated by changes in catecholamine signaling

The teleost fish Astyanax mexicanus is extant in an ancestral surface form (right) and derived cave forms (left). Adaptation to life in nutrient poor caves without predation increased exploratory foraging behaviors and decreased aversion to potential predatory cues in the cavefishes. Tyrosine hydroxylase immunohistochemistry revealed larger catecholaminergic neurons in regions of the cave Astyanax brain that may mediate these changes in behavior.

## Abstract

Astyanax mexicanus is a teleost fish that is in the process of allopatric speciation. Ancestral Astyanax are found in surface rivers and derived blind forms are found in cave systems. Adaptation to life in nutrient poor caves without predation includes the evolution of enhanced food seeking behaviors and loss of defensive responses. These behavioral adaptations may be mediated by changes in catecholaminergic control systems in the brain. We examined the distribution of tyrosine hydroxylase, a conserved precursor for the synthesis of the catecholamines dopamine and noradrenaline, in the brains of surface and cave Astyanax using immunohistochemistry. We found differences in tyrosine hydroxylase staining in regions that are associated with nonvisual sensory perception, motor control, endocrine release, and attention. These differences included significant increases in the diameters of tyrosine hydroxylase immunoreactive soma in cave Astyanax in the olfactory bulb, basal telencephalon, preoptic nuclei, ventral thalamus, posterior tuberculum, and locus coeruleus. These increases in modulation by dopamine and noradrenaline likely indicate changes in behavioral control that underlie adaptations to the cave environment.

in Journal of Comparative Neurology on September 14, 2020 08:04 AM.

• #### Image manipulation with natural language using Two-sided Attentive Conditional Generative Adversarial Network

Publication date: Available online 12 September 2020

Source: Neural Networks

in Neural Networks on September 14, 2020 07:00 AM.

• #### Circuit and molecular architecture of a ventral hippocampal network

Nature Neuroscience, Published online: 14 September 2020; doi:10.1038/s41593-020-0705-8

The ventral hippocampus is central in the processing of emotional information. Here, a combination of viral and sequencing approaches defines the organizational logic of the extended ventral CA1 circuit.

in Nature Neuroscience on September 14, 2020 12:00 AM.

• #### Dense neuronal reconstruction through X-ray holographic nano-tomography

Nature Neuroscience, Published online: 14 September 2020; doi:10.1038/s41593-020-0704-9

Kuan, Phelps, et al. used synchrotron X-ray imaging and deep learning to map dense neuronal wiring in fly and mouse tissue, enabling examination of individual cells and connectivity in circuits governing motor control and perceptual decision-making.

in Nature Neuroscience on September 14, 2020 12:00 AM.

• #### MassIVE.quant: a community resource of quantitative mass spectrometry–based proteomics datasets

Nature Methods, Published online: 14 September 2020; doi:10.1038/s41592-020-0955-0

MassIVE.quant is a data repository and data resource for reproducible quantitative mass spectrometry–based proteomics.

in Nature Methods on September 14, 2020 12:00 AM.

• #### In vivo detection of antigen-specific CD8+ T cells by immuno-positron emission tomography

Nature Methods, Published online: 14 September 2020; doi:10.1038/s41592-020-0934-5

Antigen-specific CD8+ T cells can be imaged by immunoPET with the help of synTacs, MHC-based tools that bind to relevant T-cell receptors.

in Nature Methods on September 14, 2020 12:00 AM.

• #### Live-cell super-resolved PAINT imaging of piconewton cellular traction forces

Nature Methods, Published online: 14 September 2020; doi:10.1038/s41592-020-0929-2

Tension-PAINT integrates molecular tension probes with DNA-PAINT to enable ~25-nm-resolution mapping of piconewton mechanical events. Tension-PAINT can be used to study dynamic forces, and an irreversible variant integrates force history over time.

in Nature Methods on September 14, 2020 12:00 AM.

• #### Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

Nature Reviews Neuroscience, Published online: 14 September 2020; doi:10.1038/s41583-020-0367-2

A resurgence in interest in the therapeutic potential of psychedelic drugs has boosted research into their neurobiological and cognitive effects. Vollenweider and Preller review recent advances in the field and consider the implications of recent discoveries for the therapeutic use of psychedelics.

in Nature Reviews on September 14, 2020 12:00 AM.

• #### Emergence of abstract rules in the primate brain

Nature Reviews Neuroscience, Published online: 14 September 2020; doi:10.1038/s41583-020-0364-5

Goal-directed primate behaviour is guided by abstract rules that group events and experiences into meaningful concepts. Here, Mansouri and colleagues discuss the distributed cortical and subcortical brain regions thought to underlie the formation, maintenance and implementation of abstract rules and propose a unified framework describing the neural architecture of rule-guided primate behaviour.

in Nature Reviews on September 14, 2020 12:00 AM.

• #### Symmetry breaking in twisted double bilayer graphene

Nature Physics, Published online: 14 September 2020; doi:10.1038/s41567-020-1030-6

Transport measurements show that spontaneous symmetry breaking plays a crucial role in the correlated insulating and metallic states in twisted double bilayer graphene.

in Nature Physics on September 14, 2020 12:00 AM.

• #### Chemotaxis under flow disorder shapes microbial dispersion in porous media

Nature Physics, Published online: 14 September 2020; doi:10.1038/s41567-020-1002-x

Bacteria live in heterogeneous environments, so it is important to investigate their behaviour in porous media. Here the authors show that flow disorder enhances the effect of chemical gradients in micropockets in a porous medium, which then aid the transport of bacteria.

in Nature Physics on September 14, 2020 12:00 AM.

Nature Physics, Published online: 14 September 2020; doi:10.1038/s41567-020-0995-5

A new form of superradiance is predicted that ‘in contrast to the standard effect’ arises even for vanishing numbers of particles per wavelength. This finding may enable coherent emission in plasma accelerators.

in Nature Physics on September 14, 2020 12:00 AM.

• #### Weak-to-strong transition of quantum measurement in a trapped-ion system

Nature Physics, Published online: 14 September 2020; doi:10.1038/s41567-020-0973-y

A weak-to-strong quantum measurement transition has been observed in a single-trapped-ion system, where the ion’s internal electronic state and its vibrational motion play the roles of the measured system and the measuring pointer.

in Nature Physics on September 14, 2020 12:00 AM.

• #### Diamond photonics is scaling up

Nature Photonics, Published online: 14 September 2020; doi:10.1038/s41566-020-0695-9

The integration of diamond waveguide arrays into an aluminium nitride photonic platform offers hope for the realization of scalable chips for quantum information processing.

in Nature Photomics on September 14, 2020 12:00 AM.

• #### Extreme ionization of gold atoms

Nature Photonics, Published online: 14 September 2020; doi:10.1038/s41566-020-0694-x

Gold atoms are stripped of 72 of their electrons to form nitrogen-like Au72+ ions inside extremely hot plasmas by irradiating gold foils and nanowires with highly relativistic femtosecond laser pulses.

in Nature Photomics on September 14, 2020 12:00 AM.

• #### Harmonic spin–orbit angular momentum cascade in nonlinear optical crystals

Nature Photonics, Published online: 14 September 2020; doi:10.1038/s41566-020-0691-0

An experimental study of the second-harmonic-generation process in a beta barium borate crystal shows that homogeneous optical crystals can exhibit the rich physics of the spin–orbit angular momentum cascade in the nonlinear optical regime.

in Nature Photomics on September 14, 2020 12:00 AM.

• #### Vectorized optoelectronic control and metrology in a semiconductor

Nature Photonics, Published online: 14 September 2020; doi:10.1038/s41566-020-0690-1

Engineering of the spatial distribution of currents in a semiconductor is demonstrated using vectorial arrangement of optical fields, enabling an ultrafast magnetic field source.

in Nature Photomics on September 14, 2020 12:00 AM.

• #### Tunable free-electron X-ray radiation from van der Waals materials

Nature Photonics, Published online: 14 September 2020; doi:10.1038/s41566-020-0689-7

Tunable X-ray generation, from ultrathin van der Waals materials impacted by relativistic electrons, is demonstrated.

in Nature Photomics on September 14, 2020 12:00 AM.

• #### Tunable pseudo-magnetic fields for polaritons in strained metasurfaces

Nature Photonics, Published online: 14 September 2020; doi:10.1038/s41566-020-0688-8

A method to tune pseudo-magnetic fields for polaritons on a strained metasurface is demonstrated.

in Nature Photomics on September 14, 2020 12:00 AM.

• #### Brain Vital Signs Detect Information Processing Differences When Neuromodulation Is Used During Cognitive Skills Training

Background: Neuromodulation through translingual neurostimulation (TLNS) has been shown to initiate long-lasting processes of neuronal reorganization with a variety of outcomes (i.e., neuroplasticity). Non-invasive TLNS is increasingly accessible through the Portable Neuromodulation Stimulator (PoNS®), a medical device that delivers electrical stimulation to the tongue to activate the trigeminal (V) and facial (VII) cranial nerves. Anecdotal reports from previous clinical studies have suggested incidental improvements in cognitive function. To objectively explore this observation, we examined TLNS-related effects on the semantic N400 brain vital sign cognitive response during cognitive skills training in healthy individuals.

Methods: Thirty-seven healthy volunteers were randomized to receive simultaneous TLNS (treatment) or no TLNS (control) while undergoing cognitive skills training. Cognitive training was conducted for two 20-min sessions (morning and afternoon/evening) over 3 consecutive days. Brain vital signs were evaluated at baseline, Day 1, and Day 3. Analyses focused on cognitive processing as measured by N400 changes in amplitude and latency.

Results: Over the 3-day course of cognitive training, the N400 amplitude decreased significantly in the control group due to habituation (p = 0.028). In contrast, there was no significant change in the TLNS treatment group.

Conclusion: TLNS led to a sustained N400 response during cognitive skills training, as measured by the brain’s vital signs framework. The study findings suggest differential learning effects due to neuromodulation, consistent with increased attention and cognitive vigilance.

in Frontiers in Human Neuroscience on September 14, 2020 12:00 AM.

• #### Dropout in Neural Networks Simulates the Paradoxical Effects of Deep Brain Stimulation on Memory

Neuromodulation techniques such as deep brain stimulation (DBS) are a promising treatment for memory-related disorders including anxiety, addiction, and dementia. However, the outcomes of such treatments appear to be somewhat paradoxical, in that these techniques can both disrupt and enhance memory even when applied to the same brain target. In this article, we hypothesize that disruption and enhancement of memory through neuromodulation can be explained by the dropout of engram nodes. We used a convolutional neural network (CNN) to classify handwritten digits and letters and applied dropout at different stages to simulate DBS effects on engrams. We showed that dropout applied during training improved the accuracy of prediction, whereas dropout applied during testing dramatically decreased the accuracy of prediction, which mimics enhancement and disruption of memory, respectively. We further showed that transfer learning of neural networks with dropout had increased the accuracy and rate of learning. Dropout during training provided a more robust “skeleton” network and, together with transfer learning, mimicked the effects of chronic DBS on memory. Overall, we showed that the dropout of engram nodes is a possible mechanism by which neuromodulation techniques such as DBS can both disrupt and enhance memory, providing a unique perspective on this paradox.

in Frontiers in Ageing Neuroscience on September 14, 2020 12:00 AM.

• #### ALS Genetics: Gains, Losses, and Implications for Future Therapies

In this review, Kim et al. discuss evidence for loss-of-function mutations and mechanisms in amyotrophic lateral sclerosis (ALS) and propose the need to consider both gain and loss of function for designing effective and safe therapeutic strategies.

in Neuron: In press on September 14, 2020 12:00 AM.

• #### A Systematic Nomenclature for the Drosophila Ventral Nerve Cord

The ventral nerve cord (VNC) of Drosophila is an important model system for understanding how nervous systems generate locomotion. In this issue of Neuron, Court et al. define the structures of the adult VNC to provide an anatomical framework for analyzing the functional organization of the VNC.

in Neuron: In press on September 14, 2020 12:00 AM.

• #### Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism

Sensory experience induces Fn14 expression in relay neurons and TWEAK expression in microglia to drive refinement of retinogeniculate connectivity. Microglial TWEAK signals through neuronal Fn14 to eliminate a subset of synapses proximal to TWEAK-expressing microglia, whereas Fn14 acts alone at other synapses to strengthen connectivity.

in Neuron: In press on September 14, 2020 12:00 AM.

• #### Impact of network‐targeted multichannel transcranial direct current stimulation on intrinsic and network‐to‐network functional connectivity

Based on physiological data, biophysical modeling allows the optimization of tDCS montages for stimulation of brain networks. The efficacy of network‐targeted electrical stimulation is shown by the increase of spontaneous activity in the targeted network, as well as the modulation of its interplay with negatively correlated brain networks.

## Abstract

Dynamics within and between functional resting‐state networks have a crucial role in determining both healthy and pathological brain functioning in humans. The possibility to noninvasively interact and selectively modulate the activity of networks would open to relevant applications in neuroscience. Here we tested a novel approach for multichannel, network‐targeted transcranial direct current stimulation (net‐tDCS), optimized to increase excitability of the sensorimotor network (SMN) while inducing cathodal inhibitory modulation over prefrontal and parietal brain regions negatively correlated with the SMN. Using an MRI‐compatible multichannel transcranial electrical stimulation (tES) device, 20 healthy participants underwent real and sham tDCS while at rest in the MRI scanner. Changes in functional connectivity (FC) during and after stimulation were evaluated, looking at the intrinsic FC of the SMN and the strength of the negative connectivity between SMN and the rest of the brain. Standard, bifocal tDCS targeting left motor cortex (electrode ~C3) and right frontopolar (~Fp2) regions was tested as a control condition in a separate sample of healthy subjects to investigate network specificity of multichannel stimulation effects. Net‐tDCS induced greater FC increase over the SMN compared to bifocal tDCS, during and after stimulation. Moreover, exploratory analysis of the impact of net‐tDCS on negatively correlated networks showed an increase in the negative connectivity between SMN and prefrontal/parietal areas targeted by cathodal stimulation both during and after real net‐tDCS. Results suggest preliminary evidence of the possibility of manipulating distributed network connectivity patterns through net‐tDCS, with potential relevance for the development of cognitive enhancement and therapeutic tES solutions.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Neuronal gamma oscillations and activity‐dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue

The role of surveying microglia (resident immune cells) during cortical information processing in the healthy brain is widely unknown. This study shows that neuronal gamma oscillations emerging from precise synaptic communication between pyramidal cells and interneurons during higher brain functions remain regular after pharmacological removal of microglia from cortex tissue.

## Abstract

Microglial cells (resident macrophages) feature rapid activation in CNS disease and can acquire multiple phenotypes exerting neuroprotection or neurotoxicity. The functional impact of surveying (“resting”) microglia on neural excitability and neurotransmission in physiology is widely unknown, however. We addressed this issue in male rat hippocampal slice cultures (in situ) by pharmacological microglial ablation within days and by characterizing neuronal gamma‐band oscillations (30–70 Hz) that are highly sensitive to neuromodulators and disturbances in ion and energy regulation. Gamma oscillations support action potential timing and synaptic plasticity, associate with higher brain functions like perception and memory, and require precise communication between excitatory pyramidal cells and inhibitory (GABAergic) interneurons. The slice cultures featured well‐preserved hippocampal cytoarchitecture and parvalbumin‐positive interneuron networks, microglia with ramified morphology, and low basal levels of IL‐6, TNF‐α, and nitric oxide (NO). Stimulation of slice cultures with the pro‐inflammatory cytokine IFN‐γ or bacterial LPS serving as positive controls for microglial reactivity induced MHC‐II expression and increased cytokine and NO release. Chronic exposure of slice cultures to liposome‐encapsulated clodronate reduced the microglial cell population by about 96%, whereas neuronal structures, astrocyte GFAP expression, and basal levels of cytokines and NO were unchanged. Notably, the properties of gamma oscillations reflecting frequency, number and synchronization of synapse activity were regular after microglial depletion. Also, electrical stimulus‐induced transients of the extracellular potassium concentration ([K+]o) reflecting cellular K+ efflux, clearance and buffering were unchanged. This suggests that nonreactive microglia are dispensable for neuronal homeostasis and neuromodulation underlying network signaling and rhythm generation in cortical tissue.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Lrrk2 modulation of Wnt signaling during zebrafish development

Mutations in leucine‐rich repeat kinase 2 (lrrk2) are the most common genetic cause of Parkinson's disease. Here, we generated a zebrafish lrrk2 allelic series to study the requirements for Lrrk2 during development and to dissect the importance of its various domains. The alleles are predicted to encode proteins that either lack all functional domains (lrrk2sbu304), the GTPase and kinase domains (lrrk2sbu71 ) or the kinase domain (lrrk2sbu96 ). We found that Wnt pathway activation is attenuated in lrrk2sbu304/sbu304 , which lacks both scaffolding and catalytic domains, but not in the other alleles during late embryogenesis. This supports a model in which Lrrk2 scaffolding functions are key to a context‐dependent role in promoting canonical Wnt signaling.

## Abstract

Mutations in leucine‐rich repeat kinase 2 (lrrk2) are the most common genetic cause of Parkinson's disease. Difficulty in elucidating the pathogenic mechanisms resulting from disease‐associated Lrrk2 variants stems from the complexity of Lrrk2 function and activities. Lrrk2 contains multiple protein–protein interacting domains, a GTPase domain, and a kinase domain. Lrrk2 is implicated in many cellular processes including vesicular trafficking, autophagy, cytoskeleton dynamics, and Wnt signaling. Here, we generated a zebrafish lrrk2 allelic series to study the requirements for Lrrk2 during development and to dissect the importance of its various domains. The alleles are predicted to encode proteins that either lack all functional domains (lrrk2sbu304), the GTPase, and kinase domains (lrrk2sbu71 ) or the kinase domain (lrrk2sbu96 ). All three lrrk2 mutants are viable, morphologically normal, and display wild‐type‐like locomotion. Because Lrrk2 modulates Wnt signaling in some contexts, we assessed Wnt signaling in all three mutant lines. Analysis of Wnt signaling by studying the expression of target genes using whole mount RNA in situ hybridization and a transgenic Wnt reporter revealed wild‐type domains of Wnt activity in each of the mutants. However, we found that Wnt pathway activation is attenuated in lrrk2sbu304/sbu304 , which lacks both scaffolding and catalytic domains, but not in the other alleles during late embryogenesis. This supports a model in which Lrrk2 scaffolding functions are key to a context‐dependent role in promoting canonical Wnt signaling.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

## Abstract

Iron is essential for normal cellular function, however, excessive accumulation of iron in neural tissue has been implicated in both cortical and retinal diseases. The exact role of iron in the pathogenesis of neurodegenerative disorders remains incompletely understood. However, iron‐induced damage to the brain and retina is often attributed to the redox ability of iron to generate dangerous free radicals, which exacerbates local oxidative stress and neuronal damage. Iron chelators are compounds designed to scavenge labile iron, aiding to regulate iron bioavailability. Recently there has been growing interest in the application of chelating agents for treatment of diseases including neurodegenerative conditions, characterized by increased oxidative stress. This article reviews both clinical and preclinical evidence relating to the effectiveness of iron chelation therapy in conditions of iron dyshomeostasis linked to neurodegeneration in the brain and retina. The limitations as well as future opportunities iron chelation therapy are discussed.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Degron capability of the hydrophobic C‐terminus of the polyglutamine disease protein, ataxin‐3

The C‐terminus of ataxin‐3 regulates its proteasomal degradation, with isoform 2 being more rapidly degraded. Fusion of the tail of ataxin‐3 isoform 2 to GFP also increases its proteasomal turnover.

## Abstract

Ataxin‐3 is a deubiquitinase and polyglutamine disease protein whose cellular properties and functions are not entirely understood. Mutations in ataxin‐3 cause spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder that is a member of the polyglutamine family of diseases. Two major isoforms arise from alternative splicing of ATXN3 and are differently toxic in vivo as a result of faster proteasomal degradation of one isoform compared to the other. The isoforms vary only at their C‐termini, suggesting that the hydrophobic C‐terminus of the more quickly degraded form of ataxin‐3 (here referred to as isoform 2) functions as a degron—that is, a peptide sequence that expedites the degradation of its host protein. We explored this notion in this study and present evidence that: (a) the C‐terminus of ataxin‐3 isoform 2 signals its degradation in a proteasome‐dependent manner, (b) this effect from the C‐terminus of isoform 2 does not require the ubiquitination of ataxin‐3, and (c) the isolated C‐terminus of isoform 2 can enhance the degradation of an unrelated protein. According to our data, the C‐terminus of ataxin‐3 isoform 2 is a degron, increasing overall understanding of the cellular properties of the SCA3 protein.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Olfactory neurons in Drosophila

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Baclofen, naltrexone and sorbitol synergistically contribute to PXT3003 effects on myelination in Pmp22 transgenic DRG co‐cultures (a) and motor phenotype in CMT1A rats (b). Recovery of neuromuscular junction innervation (c) plays a decisive role in the preservation of fast‐contracting motor fibers (d) which is uncoupled from dysmyelination in CMT1A rats.

## Abstract

Charcot–Marie–Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low‐dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co‐culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant (“translational”) study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003‐treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003‐treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003‐treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### In vivo microstimulation with cathodic and anodic asymmetric waveforms modulates spatiotemporal calcium dynamics in cortical neuropil and pyramidal neurons of male mice

Electrical microstimulation can treat neurological disorders; however, the mechanisms defining therapeutic efficacy are poorly characterized. In the mouse cortex, increasing the stimulation waveform asymmetry differentially modulates the spatial distribution and level of sustained neuronal activation, depending on leading polarity, under mesoscale (top) and two‐photon (bottom) imaging. Blood vessels in red.

## Abstract

Electrical stimulation has been critical in the development of an understanding of brain function and disease. Despite its widespread use and obvious clinical potential, the mechanisms governing stimulation in the cortex remain largely unexplored in the context of pulse parameters. Modeling studies have suggested that modulation of stimulation pulse waveform may be able to control the probability of neuronal activation to selectively stimulate either cell bodies or passing fibers depending on the leading polarity. Thus, asymmetric waveforms with equal charge per phase (i.e., increasing the leading phase duration and proportionately decreasing the amplitude) may be able to activate a more spatially localized or distributed population of neurons if the leading phase is cathodic or anodic, respectively. Here, we use two‐photon and mesoscale calcium imaging of GCaMP6s expressed in excitatory pyramidal neurons of male mice to investigate the role of pulse polarity and waveform asymmetry on the spatiotemporal properties of direct neuronal activation with 10‐Hz electrical stimulation. We demonstrate that increasing cathodic asymmetry effectively reduces neuronal activation and results in a more spatially localized subpopulation of activated neurons without sacrificing the density of activated neurons around the electrode. Conversely, increasing anodic asymmetry increases the spatial spread of activation and highly resembles spatiotemporal calcium activity induced by conventional symmetric cathodic stimulation. These results suggest that stimulation polarity and asymmetry can be used to modulate the spatiotemporal dynamics of neuronal activity thus increasing the effective parameter space of electrical stimulation to restore sensation and study circuit dynamics.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Resting‐state connectivity and network parameter analysis in alcohol‐dependent males. A simultaneous EEG‐MEG study

Alcohol‐dependent individuals present a differential pattern of resting‐state EEG‐MEG connectivity, as well as local communication alterations in brain network. Results point toward difficulties in information flow efficiency and cost, and a possible compensatory effort.

## Abstract

There is supporting evidence of alcohol negative effects on the brain: neuroimaging and psychophysiological studies finding anatomical and functional connectivity (FC) changes associated with the dependence process. Thus, the aim of this work was to evaluate brain FC and network characteristics of alcohol‐dependent individuals in resting state. For this study, we included males diagnosed with alcohol dependence (N = 25) and a group of healthy individuals (N = 23). Simultaneous EEG‐MEG (electroencephalographic and magnetoencephalographic) activity was recorded in 5 min of eyes‐closed resting state. EEG‐MEG activity was preprocessed and FC was computed through the leakage‐corrected version of phase locking value (ciPLV). Additionally, local (degree, efficiency, clustering) and global (efficiency, characteristic path length) network parameters were computed. Connectivity analysis showed an increase in phase‐lagged synchronization, mainly between frontal and frontotemporal regions, in high beta band, and a decrease in interhemispheric gamma, for alcohol‐dependent individuals. Network analysis revealed intergroup differences at the local level for high beta, indicating higher degree, clustering, and efficiency, mostly at frontal nodes, together with a decrease in these measures at more posterior sites for patients’ group. The hyper‐synchronization in beta, next to the hypo‐synchronization in gamma, could indicate an alteration in communication between hemispheres, but also a possible functional compensation mechanism in neural circuits. This could be also supported by network characteristic data, where local alterations in communication are observed.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Amyloidosis is associated with thicker myelin and increased oligodendrogenesis in the adult mouse brain

Myelin structure is altered in the hippocampus of mice overexpressing a pathological variant of the human amyloid precursor protein (PDGFB‐APPSw.Ind; APP mice). APP mice have longer paranodes, thicker myelin, and shorter nodes of Ranvier than wildtype mice by 3 months of age, however, total axon density and the proportion of axons that were myelinated was normal. Between 4 and 6 months of age, APP mice have more new oligodendrocytes added to the hippocampus, entorhinal cortex, and fimbria, while total oligodendrocyte and oligodendrocyte progenitor cell density remained stable, suggesting that new oligodendrocytes may be produced to replace oligodendrocytes lost due to amyloid pathology.

## Abstract

In Alzheimer's disease, amyloid plaque formation is associated with the focal death of oligodendrocytes and soluble amyloid β impairs the survival of oligodendrocytes in vitro. However, the response of oligodendrocyte progenitor cells (OPCs) to early amyloid pathology remains unclear. To explore this, we performed a histological, electrophysiological, and behavioral characterization of transgenic mice expressing a pathological form of human amyloid precursor protein (APP), containing three single point mutations associated with the development of familial Alzheimer's disease (PDGFB‐APPSw.Ind , also known as J20 mice). PDGFB‐APPSw.Ind transgenic mice had impaired survival from weaning, were hyperactive by 2 months of age, and developed amyloid plaques by 6 months of age, however, their spatial memory remained intact over this time course. Hippocampal OPC density was normal in P60‐P180 PDGFB‐APPSw.Ind transgenic mice and, by performing whole‐cell patch‐clamp electrophysiology, we found that their membrane properties, including their response to kainate (100 µM), were largely normal. However, by P100, the response of hippocampal OPCs to GABA was elevated in PDGFB‐APPSw.Ind transgenic mice. We also found that the nodes of Ranvier were shorter, the paranodes longer, and the myelin thicker for hippocampal axons in young adult PDGFB‐APPSw.Ind transgenic mice compared with wildtype littermates. Additionally, oligodendrogenesis was normal in young adulthood, but increased in the hippocampus, entorhinal cortex, and fimbria of PDGFB‐APPSw.Ind transgenic mice as pathology developed. As the new oligodendrocytes were not associated with a change in total oligodendrocyte number, these cells are likely required for cell replacement.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Direct arterial damage and neurovascular unit disruption by mechanical thrombectomy in a rat stroke model

Our findings suggest that MT causes mechanical damage of vessel intima, as well as neutrophil, VEGF, and MMP9 upregulation, which results in NVU disruption leading to the increase of infarct volume and hemorrhagic complications in acute ischemic stroke, when combined with tPA.

## Abstract

Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke that could cause hemorrhagic complications. We aimed to evaluate the pathology of MT‐induced arterial damage and neurovascular unit (NVU) disruption in relation to tissue‐type plasminogen activator (tPA) injection for acute ischemic stroke. We induced transient middle cerebral artery occlusion in male SHR/Izm rats for 2 hr. This was followed by reperfusion with/without tPA (3 mg/kg) and “rough suture” insertion that mimicked MT once or thrice (MT1 or MT3). Compared with the control group, the tPA + MT3 group presented with an increase in the cerebral infarct and hemorrhage with severer IgG leakage. Moreover, structural damage reaching the tunica media was detected in the MT3 and tPA + MT3 groups. The tPA + MT3 group presented with increased matrix metalloproteinase‐9 (MMP‐9) and vascular endothelial growth factor (VEGF) expression with some MMP9‐positive cells expressing a neutrophil marker myeloperoxidase. Furthermore, basal lamina detachment from astrocyte foot processes was observed in the tPA + MT1 and tPA + MT3 groups. These findings suggest that MT causes direct arterial damage, as well as VEGF and MMP9 upregulation, which results in NVU disruption and hemorrhagic complications in acute ischemic stroke, especially when combined with tPA.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Outcome measures from experimental traumatic brain injury in male rats vary with the complete temporal biomechanical profile of the injury event

Injury to the brain can vary greatly due to differences in the biomechanics of the traumatic event. This study demonstrates that the sequelae of neuronal loss and behavioral outcomes are related to the rate, peak, and impulse of the injury. Left: Neuronal degeneration for fast‐rate injury is lower than slow‐rate injuries. *p < 0.05. Right: Chronic neuronal loss is equivalent across injury rates *p < 0.05 compared to sham.

## Abstract

Millions suffer a traumatic brain injury (TBI) each year wherein the outcomes associated with injury can vary greatly between individuals. This study postulates that variations in each biomechanical parameter of a head trauma lead to differences in histological and behavioral outcome measures that should be considered collectively in assessing injury. While trauma severity typically scales with the magnitude of injury, much less is known about the effects of rate and duration of the mechanical insult. In this study, a newly developed voice‐coil fluid percussion injury system was used to investigate the effects of injury rate and fluid percussion impulse on a collection of post‐injury outcomes in male rats. Collectively the data suggest a potential shift in the specificity and progression of neuronal injury and function rather than a general scaling of injury severity. While a faster, shorter fluid percussion first presents as a mild TBI, neuronal loss and some behavioral tasks were similar among the slower and faster fluid percussion injuries. This study concludes that the sequelae of neuronal degeneration and behavioral outcomes are related to the complete temporal profile of the fluid percussion and do not scale only with peak pressure.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Caudate nuclei volume alterations and cognition and mood dysfunctions in adolescents with single ventricle heart disease

Single ventricle heart disease (SVHD) adolescents accompany smaller caudate nuclei volumes, localized in the rostral, mid‐dorsolateral, and caudal sites, regions that have projections to memory and mood regulatory areas. These data suggest that SVHD adolescents have brain structural basis for deficient functions in the condition.

## Abstract

Adolescents with single ventricle heart disease (SVHD) exhibit mood and cognitive deficits, which may result from injury to the basal ganglia structures, including the caudate nuclei. However, the integrity of the caudate in SVHD adolescents is unclear. Our aim was to examine the global and regional caudate volumes, and evaluate the relationships between caudate volumes and cognitive and mood scores in SVHD and healthy adolescents. We acquired two high‐resolution T1‐weighted images from 23 SVHD and 37 controls using a 3.0‐Tesla MRI scanner, as well as assessed mood (Patient Health Questionnaire‐9 [PHQ‐9]; Beck Anxiety Inventory [BAI]) and cognition (Montreal Cognitive Assessment [MoCA]; Wide Range Assessment of Memory and Learning–2; General Memory Index [GMI]) functions. Both left and right caudate nuclei were outlined, which were then used to calculate and compare volumes between groups using ANCOVA (covariates: age, gender, and head‐size), as well as perform 3D surface morphometry. Partial correlations (covariates: age, gender, and head‐size) were used to examine associations between caudate volumes, cognition, and mood scores in SVHD and controls. SVHD subjects showed significantly higher PHQ‐9 and BAI scores, indicating more depressive and anxiety symptoms, as well as reduced GMI scores, suggesting impaired cognition, compared to controls. SVHD patients showed significantly reduced caudate volumes (left, 3,198.8 ± 490.1 vs. 3,605.0 ± 480.4 mm3, p < 0.004; right, 3,162.1 ± 475.4 vs. 3,504.8 ± 465.9 mm3, p < 0.011) over controls, and changes were localized in the rostral, mid‐dorsolateral, and caudal areas. Significant negative correlations emerged between caudate volumes with PHQ‐9 and BAI scores and positive correlations with GMI and MoCA scores in SVHD and controls. SVHD adolescents show significantly reduced caudate volumes, especially in sites that have projections to regulate mood and cognition, which may result from developmental and/or hypoxia‐/ischemia‐induced processes.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Partial deletion of p75NTR in large‐diameter DRG neurons exerts no influence upon the survival of peripheral sensory neurons in vivo

The cellular mechanism underpinning the p75NTR receptor regulated peripheral neuron survival is unclear. We identify that neuronal p75NTR expression is not essential for maintaining peripheral sensory neuron survival in health and after demyelinating neuropathy, providing new insights into the mechanism of p75NTR mediated peripheral nervous system functions.

## Abstract

The p75 neurotrophin receptor (p75NTR) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75NTR by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal‐specific conditional knockout strategy, we demonstrate the partial depletion of p75NTR in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2‐month‐old mice is not affected following the deletion of p75NTR in large‐diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75NTR in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75NTR is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo. Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75NTR expressed by a subtype of neurons in vivo. Thus, our findings provide new insights into the mechanism underpinning p75NTR‐mediated neuronal survival in the PNS.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Ciliary melanin‐concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex‐independent manner

Here we report the distribution of a receptor found in primary cilia, describing an unprecedent wide distribution in the nervous system, differences between rodent species, and a lack of differences between males and females. Our results suggest melanin‐concentrating hormone may be used to target cilia in a large number of areas of the nervous system.

## Abstract

Melanin‐concentrating hormone (MCH) is a ubiquitous vertebrate neuropeptide predominantly synthesized by neurons of the diencephalon that can act through two G protein‐coupled receptors, called MCHR1 and MCHR2. The expression of Mchr1 has been investigated in both rats and mice, but its synthesis remains poorly described. After identifying an antibody that detects MCHR1 with high specificity, we employed immunohistochemistry to map the distribution of MCHR1 in the CNS of rats and mice. Multiple neurochemical markers were also employed to characterize some of the neuronal populations that synthesize MCHR1. Our results show that MCHR1 is abundantly found in a subcellular structure called the primary cilium, which has been associated, among other functions, with the detection of free neurochemical messengers present in the extracellular space. Ciliary MCHR1 was found in a wide range of areas, including the olfactory bulb, cortical mantle, striatum, hippocampal formation, amygdala, midline thalamic nuclei, periventricular hypothalamic nuclei, midbrain areas, and in the spinal cord. No differences were observed between male and female mice, and interspecies differences were found in the caudate‐putamen nucleus and the subgranular zone. Ciliary MCHR1 was found in close association with several neurochemical markers, including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and corticotropin‐releasing factor. Given the role of neuronal primary cilia in sensing free neurochemical messengers in the extracellular fluid, the widespread distribution of ciliary MCHR1, and the diverse neurochemical populations who synthesize MCHR1, our data indicate that nonsynaptic communication plays a prominent role in the normal function of the MCH system.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development, functional connectivity, and critical period plasticity

Depletion of microglia during cortical critical period profoundly alters glutamatergic synapse developmental trajectory Microglia is critical for visual cortex spine pruning, circuit refinement, intracortical connectivity, and critical period plasticity

## Abstract

Microglia populate the early developing brain and mediate pruning of the central synapses. Yet, little is known on their functional significance in shaping the developing cortical circuits. We hypothesize that the developing cortical circuits require microglia for proper circuit maturation and connectivity, and as such, ablation of microglia during the cortical critical period may result in a long‐lasting circuit abnormality. We administered PLX3397, a colony‐stimulating factor 1 receptor inhibitor, to mice starting at postnatal day 14 and through P28, which depletes >75% of microglia in the visual cortex (VC). This treatment largely covers the critical period (P19‐32) of VC maturation and plasticity. Patch clamp recording in VC layer 2/3 (L2/3) and L5 neurons revealed increased mEPSC frequency and reduced amplitude, and decreased AMPA/NMDA current ratio, indicative of altered synapse maturation. Increased spine density was observed in these neurons, potentially reflecting impaired synapse pruning. In addition, VC intracortical circuit functional connectivity, assessed by laser scanning photostimulation combined with glutamate uncaging, was dramatically altered. Using two photon longitudinal dendritic spine imaging, we confirmed that spine elimination/pruning was diminished during VC critical period when microglia were depleted. Reduced spine pruning thus may account for increased spine density and disrupted connectivity of VC circuits. Lastly, using single‐unit recording combined with monocular deprivation, we found that ocular dominance plasticity in the VC was obliterated during the critical period as a result of microglia depletion. These data establish a critical role of microglia in developmental cortical synapse pruning, maturation, functional connectivity, and critical period plasticity.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Role of 5‐HT1A and 5‐HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat

Serotonin (5‐hydroxytryptamine, 5‐HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. We focused on the identification of the signaling pathways involved in the activation of rat primary afferent neurons by 5‐HT and their involvement in itch and pain sensing. Transient responses evoked by 5‐HT are mediated by ionotropic 5‐HT3 receptors. Sustained responses to 5‐HT require activation of 5‐HT1A receptors coupled to Gi/o, leading to a decrease in membrane conductance, membrane depolarization, opening of voltage‐gated calcium channels and calcium entry. Both responses appear to be involved in triggering serotonergic itch in both male and female Wistar rats.

## Abstract

Serotonin (5‐hydroxytryptamine, 5‐HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5‐HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch‐clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5‐HT receptor subtypes, 5‐HT1A and 5‐HT3, in mediating the sustained and transient effects, respectively, of 5‐HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5‐HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage‐gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Issue Information

in Journal of Neuroscience Research on September 13, 2020 06:00 PM.

• #### Women in neuroscience special issue: Pandemic edition

in Journal of Neuroscience Research on September 13, 2020 05:19 PM.

• #### The brain of the African wild dog. II. The olfactory system

Immunohistochemical staining for vesicular glutamate transporter 2 reveals the glomeruli in the main olfactory bulb of the brain of the African wild dog. Stereological estimates of the numbers of glomeruli reveal that the African wild dog has up to 1700 glomeruli. Scale bar = 250 μm.

## Abstract

Employing a range of neuroanatomical stains, we detail the organization of the main and accessory olfactory systems of the African wild dog. The organization of both these systems follows that typically observed in mammals, but variations of interest were noted. Within the main olfactory bulb, the size of the glomeruli, at approximately 350 μm in diameter, are on the larger end of the range observed across mammals. In addition, we estimate that approximately 3,500 glomeruli are present in each main olfactory bulb. This larger main olfactory bulb glomerular size and number of glomeruli indicates that enhanced peripheral processing of a broad range of odorants is occurring in the main olfactory bulb of the African wild dog. Within the accessory olfactory bulb, the glomeruli did not appear distinct, rather forming a homogenous syncytia‐like arrangement as seen in the domestic dog. In addition, the laminar organization of the deeper layers of the accessory olfactory bulb was indistinct, perhaps as a consequence of the altered architecture of the glomeruli. This arrangement of glomeruli indicates that rather than parcellating the processing of semiochemicals peripherally, these odorants may be processed in a more nuanced and combinatorial manner in the periphery, allowing for more rapid and precise behavioral responses as required in the highly social group structure observed in the African wild dog. While having a similar organization to that of other mammals, the olfactory system of the African wild dog has certain features that appear to correlate to their environmental niche.

in Journal of Comparative Neurology on September 13, 2020 08:56 AM.

• #### A proteomic view on the differential phenotype of Schwann cells derived from mouse sensory and motor nerves

Schwann cells (SCs) were found to have sensory and motor phenotypes and associated with the modality specific promotion of sensory and motor nerve regeneration. To explore the differences between them, we established a workflow to obtain highly purified SCs derived from sensory nerve (SNdSCs) and motor nerve (MNdSCs) from B6; D2‐Tg(s100B‐EGFP)1Wjt/J mice. The SNdSCs and MNdSCs were isolated from dorsal and ventral roots by FACS sorting. The proteome of SNdSCs and MNdSCs was compared by a quantitative proteomic analysis based on iTRAQ labeling and the mouse Schwann proteome was obtained. Several differentially expressed proteins between SNdSCs and MNdSCs were verified.

## Abstract

Schwann cells (SCs) are myelin‐forming glial cells of the peripheral nervous system. Recent studies suggested that SCs comprise two phenotypes: sensory SCs and motor SCs, which are associated with the modality‐specific promotion of sensory and motor axon growth during peripheral neuronal regeneration. However, the molecular basis of the two phenotypic SCs is unclear. We established a workflow to obtain highly purified SCs derived from sensory nerve (SNdSCs) and motor nerve (MNdSCs) from B6; D2‐Tg(s100B‐EGFP)1Wjt/J mice. Subsequently, a quantitative proteomic analysis based on iTRAQ labeling was performed to compare the proteome of SNdSCs and MNdSCs. A total of 6,567 proteins were identified, of which 63 and 11 proteins were overexpressed in SNdSCs and MNdSCs, respectively. Three of the overexpressed proteins were further validated by western blot and immunocytochemistry: GMFB and CNPase, which were overexpressed in sensory SNdSCs, and histone H4, which was overexpressed in MNdSCs. The expression pattern of the three proteins was also validated in the dorsal roots and ventral roots. Bioinformatics analysis indicated that proteins highly expressed in SNdSCs are mainly involved in RNA processing and protein synthesis, while those overexpressed in MNdSCs are related to cell proliferation. Real‐time cell analysis confirmed that the proliferation activity of MNdSCs is higher than that of SNdSCs. This study is the first to provide a proteomic view of the differential phenotype of mouse SNdSCs and MNdSCs. The data may serve as a valuable source for the study of the biological characteristics of these two SC phenotypes and their roles in nerve‐specific regeneration.

in Journal of Comparative Neurology on September 13, 2020 08:34 AM.

## Objectives

To examine the association between cerebellar hemorrhage (CBH) size and location and preschool‐age neurodevelopment in very preterm neonates.

## Methods

Preterm MRIs of 221 very preterm neonates (median GA 27.9) were manually segmented for CBH quantification and location. Neurodevelopmental assessments at chronological age 4.5 years included motor (MABC‐2), visuomotor integration (Beery VMI‐6), cognitive (WPPSI‐III), and behavioral (CBCL) outcomes. Multivariable linear regression models examined the association between CBH size and 4.5‐year outcomes accounting for sex, gestational age, and supratentorial injury. Probabilistic maps assessed CBH location and likelihood of a lesion to predict adverse outcome.

## Results

Thirty‐six neonates had CBH: 14 (6%) with only punctate CBH and 22 (10%) with ≥1 larger CBH. CBH occurred mostly in the inferior aspect of the posterior lobes. CBH total volume was independently associated with MABC‐2 motor scores at 4.5 years (β=‐0.095, 95% CI [‐0.184, ‐0.005]) with a standardized β coefficient (‐0.16) that was similar to that of white matter injury volume (standardized β=‐0.22). CBH size was similarly associated with visuomotor integration and externalizing behavior but not cognition. Voxel‐wise odds ratio and lesion‐symptom maps demonstrated that CBH extending more deeply into the cerebellum predicted adverse motor, visuomotor, and behavioral outcomes.

## Interpretation

CBH size and location on preterm MRI were associated with reduced preschool motor and visuomotor function and more externalizing behavior independent of supratentorial brain injury in a dose‐dependent fashion. The volumetric quantification and localisation of CBH, even when punctate, may allow opportunity to improve motor and behavioral outcomes by providing targeted intervention.

in Annals of Neurology on September 12, 2020 06:20 PM.

• #### Ictal pulvinar hyperperfusion sign

in Annals of Neurology on September 12, 2020 06:14 PM.

## Objective

To examine associations between tau and amyloid β (Aβ) molecular positron emission tomography (PET) and both Alzheimer‐related pathology and 4‐repeat tau pathology in autopsy‐confirmed frontotemporal lobar degeneration (FTLD).

## Methods

Twenty‐four patients had [18F]‐flortaucipir–PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD‐TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)‐PET. Braak staging, Aβ plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta‐ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden.

## Results

Nine cases (37.5%) had Aβ plaques. Global PiB SUVR correlated with Aβ plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty‐one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta‐ROI SUVRs were not elevated in Braak IV or primary age‐related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions.

## Interpretation

Molecular PET shows expected correlations with Alzheimer‐related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020

in Annals of Neurology on September 12, 2020 03:25 PM.

## Abstract

Hippocampal circuit alterations that differentially affect hippocampal subfields are associated with age‐related memory decline. Additionally, functional organization along the longitudinal axis of the hippocampus has revealed distinctions between anterior and posterior (A‐P) connectivity. Here, we examined the functional connectivity (FC) differences between young and older adults at high‐resolution within the medial temporal lobe network (entorhinal, perirhinal, and parahippocampal cortices), allowing us to explore how hippocampal subfield connectivity across the longitudinal axis of the hippocampus changes with age. Overall, we found reliably greater connectivity for younger adults than older adults between the hippocampus and parahippocampal cortex (PHC) and perirhinal cortex (PRC). This drop in functional connectivity was more pronounced in the anterior regions of the hippocampus than the posterior ones, consistent for each of the hippocampal subfields. Further, intra‐hippocampal connectivity also reflected an age‐related decrease in functional connectivity within the anterior hippocampus in older adults that was offset by an increase in posterior hippocampal functional connectivity. Interestingly, the anterior–posterior dysfunction in older adults between hippocampus and PHC was predictive of lure discrimination performance on the Mnemonic similarity task (MST), suggesting a role in memory performance. While age‐related dysfunction within the hippocampal subfields has been well‐documented, these results suggest that the age‐related dysfunction in hippocampal connectivity across the longitudinal axis may also contribute significantly to memory decline in older adults.

in Hippocampus on September 12, 2020 02:54 PM.

• #### Novel circular RNA 2960 contributes to secondary damage of spinal cord injury by sponging miRNA‐124

Sequencing analysis for the lesion site of the rat SCI model revealed that the injury significantly stimulated the expression of circRNA‐2960, which acted as a miRNA‐124 sponge to regulate the downstream pathways. Increased circRNA‐2960 expression in SCI decreased the activity of miRNA‐124, which further promoted neuroinflammation and apoptosis

## Abstract

Recent studies have shown that circular RNAs (circRNAs) are involved in many human diseases, but their roles in secondary damage after spinal cord injury (SCI) remain unclear. In the current study circRNA sequencing was performed in the damaged tissues of SCI rats on the seventh day after injury, and related molecular mechanisms were investigated. Quantitative PCR validations of molecules that exhibited significantly altered expression in SCI mice were performed. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to assess differentially expressed circRNAs. A novel circRNA‐2960 was the most significantly upregulated in the SCI group. It could downregulate its target molecule miRNA‐124, then exacerbate the inflammatory response and induce apoptosis at the lesion site. Disrupting circRNA‐2960 expression promoted recovery of tissues affected by secondary SCI damage. The results of the present study may provide new insight into the mechanisms of secondary injury in SCI, and a new molecular marker for the diagnosis and treatment of SCI.

in Journal of Comparative Neurology on September 12, 2020 08:10 AM.

• #### Sex‐specific peripheral and central responses to stress‐induced depression and treatment in a mouse model

Social defeat stress induces sex‐specific inflammatory cytokine/chemokine responses in the periphery and sex‐specific transcriptional regulation in the prefrontal cortex (PFC). Treatment with dihydrocaffeic acid/malvidin‐glucoside modulates periphery inflammation and gene expression in the prefrontal cortex and alleviates depression‐like phenotype. CSDS, chronic social defeat stress; DHCA, dihydrocaffeic acid.

## Abstract

Major depressive disorder affects ~20% of the world population and is characterized by strong sexual dimorphism with females being two to three times more likely to develop this disorder. Previously, we demonstrated that a combination therapy with dihydrocaffeic acid and malvidin‐glucoside to synergistically target peripheral inflammation and stress‐induced synaptic maladaptation in the brain was effective in alleviating chronic social defeat stress (CSDS)‐induced depression‐like phenotype in male mice. Here, we test the combination therapy in a female CSDS model for depression and compared sex‐specific responses to stress in the periphery and the central nervous system. Similar to male mice, the combination treatment is also effective in promoting resilience against the CSDS‐induced depression‐like behavior in female mice. However, there are sex‐specific differences in peripheral immune responses and differential gene regulation in the prefrontal cortex to chronic stress and to the treatment. These data indicate that while therapeutic approaches to combat stress‐related disorders may be effective in both sexes, the mechanisms underlying these effects differ, emphasizing the need for inclusion of both sexes in preclinical studies using animal models.

in Journal of Neuroscience Research on September 11, 2020 06:41 PM.

• #### The New Normal in Clinical Trials: Decentralized Studies

in Annals of Neurology on September 11, 2020 04:23 PM.

## Objective

Deep brain stimulation (DBS) is a treatment option for refractory chronic cluster headache (CCH). Despite several recent prospective case series reporting a good outcome, the effectiveness and the optimal stimulation target of DBS for CCH remain unclear. We aimed to obtain precise estimates and predictors of long‐term pain relief in an individual patient data meta‐analysis. Furthermore, we aimed to construct a probabilistic stimulation map of effective DBS.

## Methods

We invited investigators of published cohorts of patients undergoing DBS for CCH, identified by a systematic review of MEDLINE from inception to Febuary 15, 2019, to provide individual patient data on baseline covariates, pre‐ and postoperative headache scores at median (12‐month) and long‐term follow‐up, in addition to individual imaging data to obtain individual electrode positions. We calculated a stimulation map using voxel‐wise statistical analysis. We used multiple regression analysis to estimate predictors of pain relief.

## Results

Among 40 patients from four different cohorts representing ~50% of all previously published cases, we found a significant 77% mean reduction in headache attack frequency over a mean follow‐up of 44 months, with an overall response rate of 75%. Positive outcome was not associated with baseline covariates. We identified 2 hotspots of stimulation covering the midbrain ventral and retrorubral tegmentum.

## Interpretation

This study supports the hypothesis that DBS provides long‐term pain relief for the majority of CCH patients. Our stimulation map of the region of influence of therapeutic DBS identified an optimal anatomical target site that can help surgeons to guide their surgical planning in the future. ANN NEUROL 2020

in Annals of Neurology on September 11, 2020 04:20 PM.

in Annals of Neurology on September 11, 2020 04:03 PM.

• #### Development and migration of the zebrafish rhombencephalic octavolateral efferent neurons

In this study, we provide an overview of rhombencephalic octavolateral efferent neuron (OEN) development in the zebrafish. OENs are born in two groups: the rostral (REN) group is born in r4 with the facial branchiomotor neurons (FBMNs), while the caudal (CEN) group is born in r5. From there, the OENs migrate alongside the FBMNs to r6 and r7, where they cluster into bilateral nuclei. However, we identify several key differences between the mechanisms OENs and FBMNs use to migrate.

## Abstract

In vertebrate animals, motor and sensory efferent neurons carry information from the central nervous system (CNS) to peripheral targets. These two types of efferent systems sometimes bear a close resemblance, sharing common segmental organization, axon pathways, and chemical messengers. Here, we focus on the development of the octavolateral efferent neurons (OENs) and their interactions with the closely‐related facial branchiomotor neurons (FBMNs) in zebrafish. Using live‐imaging approaches, we investigate the birth, migration, and projection patterns of OENs. We find that OENs are born in two distinct groups: a group of rostral efferent neurons (RENs) that arises in the fourth segment, or rhombomere (r4), of the hindbrain and a group of caudal efferent neurons (CENs) that arises in r5. Both RENs and CENs then migrate posteriorly through the hindbrain between 18 and 48 hrs postfertilization, alongside the r4‐derived FBMNs. Like the FBMNs, migration of the r4‐derived RENs depends on function of the segmental identity gene hoxb1a; unlike the FBMNs, however, both OEN populations move independently of prickle1b. Further, we investigate whether the previously described “pioneer” neuron that leads FBMN migration through the hindbrain is an r4‐derived FBMN/REN or an r5‐derived CEN. Our experiments verify that the pioneer is an r4‐derived neuron and reaffirm its role in leading FBMN migration across the r4/5 border. In contrast, the r5‐derived CENs migrate independently of the pioneer. Together, these results indicate that the mechanisms OENs use to navigate the hindbrain differ significantly from those employed by FBMNs.

in Journal of Comparative Neurology on September 11, 2020 03:26 PM.

• #### Photoreceptors in skate are arranged to allow for a broad horizontal field of view

Photoreceptor morphology and anatomy, including their density distribution and orientation were studied in the skate Leucoraja erinacea. In addition to a dorsal visual streak, which is typical in elasmobranchs, photoreceptors were noticeably tilted, a finding that has to date not received much attention. Skate L. erinacea (left), and image of a whole‐mounted retina showing retinal photoreceptors (right).

## Abstract

Studying retinal specializations offers insights into eye functionality and visual ecology. Using light microscopic techniques, including retinal whole‐mounts, we investigated photoreceptor densities in the retina of the skate Leucoraja erinacea. We show that photoreceptors are not sized or oriented in the same way, and that they are not evenly distributed across the retina. There was a dorsally located horizontal visual streak with increased photoreceptor density, with additional local maxima in which densities were highest. Photoreceptors were longest and thinnest inside this visual streak, becoming shorter and thicker toward the periphery and toward the ventral retina. Furthermore, in the peripheral retinal parts, photoreceptors (particularly the outer segments) were noticeably tilted with respect to the retinal long axis. In order to understand how photoreceptors are tilted inside the eye, we used computerized tomography (CT) and micro‐CT, to obtain geometrical dimensions of the whole skate eye. These CT/micro‐CT data provided us with the outlines of the skate eye and the location of the retina and this enabled us to reconstruct how photoreceptors tilt in an intact eye. Findings were analyzed relative to previously published ganglion cell distributions in this species, showing a posteriorly located retinal area with photoreceptor: ganglion cell convergence as low as 39:1. Some peripheral areas showed ratios as high as 391:1. We frame our findings in terms of the animal's anatomy: body and eye shape, specifically the location of the tapetum, as well as the visual demands associated with lifestyle and habitat type. A speculative function in polarization sensitivity is discussed.

in Journal of Comparative Neurology on September 11, 2020 03:00 PM.

• #### Attractor-state itinerancy in neural circuits with synaptic depression

Neural populations with strong excitatory recurrent connections can support bistable states in their mean firing rates. Multiple fixed points in a network of such bistable units can be used to model memory ret...

in The Journal of Mathematical Neuroscience on September 11, 2020 12:00 AM.

• #### Histone Deacetylase 6 and the Disease Mechanisms of α-Synucleinopathies

The abnormal accumulation of α-Synuclein (α-Syn) is a prominent pathological feature in a group of diseases called α-Synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The formation of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) in neurons and oligodendrocytes, respectively, is highly investigated. However, the molecular mechanisms behind α-Syn improper folding and aggregation remain unclear. Histone deacetylase 6 (HDAC6) is a Class II deacetylase, containing two active catalytic domains and a ubiquitin-binding domain. The properties of HDAC6 and its exclusive cytoplasmic localization allow HDAC6 to modulate the microtubule dynamics, acting as a specific α-tubulin deacetylase. Also, HDAC6 can bind ubiquitinated proteins, facilitating the formation of the aggresome, a cellular defense mechanism to cope with higher levels of misfolded proteins. Several studies report that the aggresome shares similarities in size and composition with LBs and GCIs. HDAC6 is found to co-localize with α-Syn in neurons and in oligodendrocytes, together with other aggresome-related proteins. The involvement of HDAC6 in several neurodegenerative diseases is already under discussion, however, the results obtained by modulating HDAC6 activity are not entirely conclusive. The main goal of this review is to summarize and critically discuss previous in vitro and in vivo data regarding the specific role of HDAC6 in the context of α-Syn accumulation and protein aggregation in α-Synucleinopathies.

in Frontiers in Synaptic Neuroscience on September 11, 2020 12:00 AM.

• #### Food Anticipatory Activity on Circadian Time Scales Is Not Dependent on Central Serotonin: Evidence From Tryptophan Hydroxylase-2 and Serotonin Transporter Knockout Mice

A number of studies implicate biogenic amines in regulating circadian rhythms. In particular, dopamine and serotonin influence the entrainment of circadian rhythms to daily food availability. To study circadian entrainment to feeding, food availability is typically restricted to a short period within the light cycle daily. This results in a notable increase in pre-meal activity, termed “food anticipatory activity” (FAA), which typically develops within about 1 week of scheduled feeding. Several studies have implicated serotonin as a negative regulator of FAA: (1) aged rats treated with serotonin 5-HT2 and 3 receptor antagonists showed enhanced FAA, (2) mice lacking for the 2C serotonin receptor demonstrate enhanced FAA, and (3) pharmacologically increased serotonin levels suppressed FAA while decreased serotonin levels enhanced FAA in mice. We sought to confirm and extend these findings using genetic models with impairments in central serotonin production or re-uptake, but were surprised to find that both serotonin transporter (Slc6a4) and tryptophan hydroxylase-2 knockout mice demonstrated a normal behavioral response to timed, calorie restricted feeding. Our data suggest that FAA is largely independent of central serotonin and/or serotonin reuptake and that serotonin may not be a robust negative regulator of FAA.

in Frontiers in Molecular Neuroscience on September 11, 2020 12:00 AM.

• #### Commentary: Effects of ALS-associated TANK binding kinase 1 mutations on protein-protein interactions and kinase activity

in Frontiers in Neuroscience: Neurodegeneration on September 11, 2020 12:00 AM.

• #### NWB Query Engines: Tools to Search Data Stored in Neurodata Without Borders Format

The Neurodata Without Borders (abbreviation NWB) format is a current technology for storing neurophysiology data along with the associated metadata. Data stored in the format is organized into separate HDF5 files, each file usually storing the data associated with a single recording session. While the NWB format provides a structured method for storing data, so far there have not been tools which enable searching a collection of NWB files in order to find data of interest for a particular purpose. We describe here three tools to enable searching NWB files. The tools have different features making each of them most useful for a particular task. The first tool, called the NWB Query Engine, is written in Java. It allows searching the complete content of NWB files. It was designed for the first version of NWB (NWB 1) and supports most (but not all) features of the most recent version (NWB 2). For some searches, it is the fastest tool. The second tool, called “search_nwb” is written in Python and also allow searching the complete contents of NWB files. It works with both NWB 1 and NWB 2, as does the third tool. The third tool, called “nwbindexer” enables searching a collection of NWB files using a two-step process. In the first step, a utility is run which creates an SQLite database containing the metadata in a collection of NWB files. This database is then searched in the second step, using another utility. Once the index is built, this two-step processes allows faster searches than are done by the other tools, but does not enable as complete of searches. All three tools use a simple query language which was developed for this project. Software integrating the three tools into a web-interface is provided which enables searching NWB files by submitting a web form.

in Frontiers in Neuroinformatics on September 11, 2020 12:00 AM.

• #### Motor and Predictive Processes in Auditory Beat and Rhythm Perception

In this article, we review recent advances in research on rhythm and musical beat perception, focusing on the role of predictive processes in auditory motor interactions. We suggest that experimental evidence of the motor system’s role in beat perception, including in passive listening, may be explained by the generation and maintenance of internal predictive models, concordant with the Active Inference framework of sensory processing. We highlight two complementary hypotheses for the neural underpinnings of rhythm perception: The Action Simulation for Auditory Prediction hypothesis (Patel and Iversen, 2014) and the Gradual Audiomotor Evolution hypothesis (Merchant and Honing, 2014) and review recent experimental progress supporting each of these hypotheses. While initial formulations of ASAP and GAE explain different aspects of beat-based timing–the involvement of motor structures in the absence of movement, and physical entrainment to an auditory beat respectively–we suggest that work under both hypotheses provide converging evidence toward understanding the predictive role of the motor system in the perception of rhythm, and the specific neural mechanisms involved. We discuss future experimental work necessary to further evaluate the causal neural mechanisms underlying beat and rhythm perception.

in Frontiers in Human Neuroscience on September 11, 2020 12:00 AM.

• #### Enhancement of Facilitation Training for Aphasia by Transcranial Direct Current Stimulation

We aimed to enhance the performance of naming and sentence production in chronic post-stroke aphasia by tablet-based language training combined with transcranial direct current stimulation (tDCS) conducted on non-consecutive days. We applied a deblocking method involved in stimulation–facilitation therapy to six participants with chronic aphasia who performed naming and sentence production tasks for impaired modalities, immediately after a spoken-word picture-matching task for an intact modality. The participants took part in two conditional sessions: a tDCS condition in which they performed a spoken word-picture matching task while we delivered an anodal tDCS over the left inferior frontal cortex; and a sham condition in which sham stimulation was delivered. We hypothesized that, compared with the sham stimulation, the application of anodal tDCS over the left inferior frontal cortex during the performance of tasks requiring access to semantic representations would enhance the deblocking effect, thereby improving the performances for subsequent naming and sentence production. Our results showed greater improvements 2 weeks after training with tDCS than those after training with sham stimulation. The accuracy rate of naming was significantly higher in the tDCS condition than in the sham condition, regardless of whether the words were trained or not. Also, we found a significant improvement in the production of related words and sentences for the untrained words in the tDCS condition, compared with that found pre-training, while in the sham condition we found no significant improvement compared with that found pre-training. These results support our hypothesis and suggest the effectiveness of the use of tDCS during language training on non-consecutive days.

in Frontiers in Human Neuroscience on September 11, 2020 12:00 AM.

• #### Sex Differences in Neural Responses to the Perception of Social Interactions

Social interaction is critical to emotional well-being. Previous studies have suggested sex differences in the perception of social interaction. However, the findings depend on the nature of interactions and whether it involves facial emotions. Here, we explored sex differences in neural responses to the perception of social interaction using the Human Connectome Project data. Participants (n = 969, 505 women) were engaged in a social cognition task with geometric objects moving and colliding to simulate social interaction. Behaviorally, men relative to women demonstrated higher accuracy in perceiving social vs. random interactions. Men vs. women showed higher activation in the right superior temporal gyrus, bilateral occipital and posterior cingulate cortex and precuneus, and women vs. men showed higher activation in the right inferior frontal cortex, during exposure to social vs. random interactions. In whole-brain regressions, the differences in accuracy rate in identifying social vs. random interactions (ARSOC – ARRAN) were associated with higher activation in the paracentral lobule (PCL) and lower activation in bilateral anterior insula (AI), pre-supplementary motor area (preSMA), and left middle frontal gyrus (MFG) in men and women combined, lower activation in bilateral AI, preSMA and left MFG in men alone, and higher activation in the PCL and the medial orbitofrontal cortex in women alone. The latter sex differences were confirmed by slope tests. Further, the PCL activity mediated the correlation between an internalizing syndromal score, as assessed by the Achenbach Self-Report, and (ARSOC – ARRAN) across all subjects. These findings highlighted sex differences in the behavioral and neural processes underlying the perception of social interaction, as well as the influence of internalizing traits on these processes.

in Frontiers in Human Neuroscience on September 11, 2020 12:00 AM.

• #### A Theoretical Framework for How We Learn Aesthetic Values

How do we come to like the things that we do? Each one of us starts from a relatively similar state at birth, yet we end up with vastly different sets of aesthetic preferences. These preferences go on to define us both as individuals and as members of our cultures. Therefore, it is important to understand how aesthetic preferences form over our lifetimes. This poses a challenging problem: to understand this process, one must account for the many factors at play in the formation of aesthetic values and how these factors influence each other over time. A general framework based on basic neuroscientific principles that can also account for this process is needed. Here, we present such a framework and illustrate it through a model that accounts for the trajectories of aesthetic values over time. Our framework is inspired by meta-analytic data of neuroimaging studies of aesthetic appraisal. This framework incorporates effects of sensory inputs, rewards, and motivational states. Crucially, each one of these effects is probabilistic. We model their interactions under a reinforcement-learning circuitry. Simulations of this model and mathematical analysis of the framework lead to three main findings. First, different people may develop distinct weighing of aesthetic variables because of individual variability in motivation. Second, individuals from different cultures and environments may develop different aesthetic values because of unique sensory inputs and social rewards. Third, because learning is stochastic, stemming from probabilistic sensory inputs, motivations, and rewards, aesthetic values vary in time. These three theoretical findings account for different lines of empirical research. Through our study, we hope to provide a general and unifying framework for understanding the various aspects involved in the formation of aesthetic values over time.

in Frontiers in Human Neuroscience on September 11, 2020 12:00 AM.

• #### Editorial: Brain-Behaviour Interfaces in Linguistic Communication

in Frontiers in Human Neuroscience on September 11, 2020 12:00 AM.

• #### Retrospective Evaluation of Sequential Events and the Influence of Preference-Dependent Working Memory: A Computational Examination

Humans organize sequences of events into a single overall experience, and evaluate the aggregated experience as a whole, such as a generally pleasant dinner, movie, or trip. However, such evaluations are potentially computationally taxing, and so our brains must employ heuristics (i.e., approximations). For example, the peak-end rule hypothesis suggests that we average the peaks and end of a sequential event vs. integrating every moment. However, there is no general model to test viable hypotheses quantitatively. Here, we propose a general model and test among multiple specific ones, while also examining the role of working memory. The models were tested with a novel picture-rating task. We first compared averaging across entire sequences vs. the peak-end heuristic. Correlation tests indicated that averaging prevailed, with peak and end both still having significant prediction power. Given this, we developed generalized order-dependent and relative-preference-dependent models to subsume averaging, peak and end. The combined model improved the prediction power. However, based on limitations of relative-preference—including imposing a potentially arbitrary ranking among preferences—we introduced an absolute-preference-dependent model, which successfully explained the remembered utilities. Yet, because using all experiences in a sequence requires too much memory as real-world settings scale, we then tested “windowed” models, i.e., evaluation within a specified window. The windowed (absolute) preference-dependent (WP) model explained the empirical data with long sequences better than without windowing. However, because fixed-windowed models harbor their own limitations—including an inability to capture peak-event influences beyond a fixed window—we then developed discounting models. With (absolute) preference-dependence added to the discounting rate, the results showed that the discounting model reflected the actual working memory of the participants, and that the preference-dependent discounting (PD) model described different features from the WP model. Taken together, we propose a combined WP-PD model as a means by which people evaluate experiences, suggesting preference-dependent working-memory as a significant factor underlying our evaluations.

in Frontiers in Computational Neuroscience on September 11, 2020 12:00 AM.

• #### The Mitochondrial Unfolded Protein Response: A Hinge Between Healthy and Pathological Aging

Aging is the time-dependent functional decline that increases the vulnerability to different forms of stress, constituting the major risk factor for the development of neurodegenerative diseases. Dysfunctional mitochondria significantly contribute to aging phenotypes, accumulating particularly in post-mitotic cells, including neurons. To cope with deleterious effects, mitochondria feature different mechanisms for quality control. One such mechanism is the mitochondrial unfolded protein response (UPRMT), which corresponds to the transcriptional activation of mitochondrial chaperones, proteases, and antioxidant enzymes to repair defective mitochondria. Transcription of target UPRMT genes is epigenetically regulated by Histone 3-specific methylation. Age-dependency of this regulation could explain a differential UPRMT activity in early developmental stages or aged organisms. At the same time, precise tuning of mitochondrial stress responses is crucial for maintaining neuronal homeostasis. However, compared to other mitochondrial and stress response programs, the role of UPRMT in neurodegenerative disease is barely understood and studies in this topic are just emerging. In this review, we document the reported evidence characterizing the evolutionarily conserved regulation of the UPRMT and summarize the recent advances in understanding the role of the pathway in neurodegenerative diseases and aging.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice

Accumulating evidence has indicated that embryonic inflammation could accelerate age-associated cognitive impairment, which can be attributed to dysregulation of synaptic plasticity-associated proteins, such as RNA-binding proteins (RBPs). Staufen is a double-stranded RBP that plays a critical role in the modulation of synaptic plasticity and memory. However, relatively few studies have investigated how embryonic inflammation affects cognition and neurobiology during aging, or how the adolescent psychosocial environment affects inflammation-induced remote cognitive impairment. Consequently, the aim of this study was to investigate whether these adverse factors can induce changes in Staufen expression, and whether these changes are correlated with cognitive impairment. In our study, CD-1 mice were administered lipopolysaccharides (LPS, 50 μg/kg) or an equal amount of saline (control) intraperitoneally during days 15–17 of gestation. At 2 months of age, male offspring were randomly exposed to stress (S), an enriched environment (E), or not treated (CON) and then assigned to five groups: LPS, LPS+S, LPS+E, CON, and CON+S. Mice were evaluated at 3-month-old (young) and 15-month-old (middle-aged). Cognitive function was assessed using the Morris water maze test, while Staufen expression was examined at both the protein and mRNA level using immunohistochemistry/western blotting and RNAscope technology, respectively. The results showed that the middle-aged mice had worse cognitive performance and higher Staufen expression than young mice. Embryonic inflammation induced cognitive impairment and increased Staufen expression in the middle-aged mice, whereas adolescent stress/an enriched environment would accelerated/mitigated these effects. Meanwhile, Staufen expression was closely correlated with cognitive performance. Our findings suggested embryonic inflammation can accelerate age-associated learning and memory impairments, and these effects may be related to the Staufen expression.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Afferent and Efferent Visual Markers of Alzheimer’s Disease: A Review and Update in Early Stage Disease

Vision, which requires extensive neural involvement, is often impaired in Alzheimer’s disease (AD). Over the last few decades, accumulating evidence has shown that various visual functions and structures are compromised in Alzheimer’s dementia and when measured can detect those with dementia from those with normal aging. These visual changes involve both the afferent and efferent parts of the visual system, which correspond to the sensory and eye movement aspects of vision, respectively. There are fewer, but a growing number of studies, that focus on the detection of predementia stages. Visual biomarkers that detect these stages are paramount in the development of successful disease-modifying therapies by identifying appropriate research participants and in identifying those who would receive future therapies. This review provides a summary and update on common afferent and efferent visual markers of AD with a focus on mild cognitive impairment (MCI) and preclinical disease detection. We further propose future directions in this area. Given the ease of performing visual tests, the accessibility of the eye, and advances in ocular technology, visual measures have the potential to be effective, practical, and non-invasive biomarkers of AD.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease

The loss of cognitive function in Alzheimer’s disease is pathologically linked with neurofibrillary tangles, amyloid deposition, and loss of neuronal communication. Cerebral insulin resistance and mitochondrial dysfunction have emerged as important contributors to pathogenesis supporting our hypothesis that cerebral fructose metabolism is a key initiating pathway for Alzheimer’s disease. Fructose is unique among nutrients because it activates a survival pathway to protect animals from starvation by lowering energy in cells in association with adenosine monophosphate degradation to uric acid. The fall in energy from fructose metabolism stimulates foraging and food intake while reducing energy and oxygen needs by decreasing mitochondrial function, stimulating glycolysis, and inducing insulin resistance. When fructose metabolism is overactivated systemically, such as from excessive fructose intake, this can lead to obesity and diabetes. Herein, we present evidence that Alzheimer’s disease may be driven by overactivation of cerebral fructose metabolism, in which the source of fructose is largely from endogenous production in the brain. Thus, the reduction in mitochondrial energy production is hampered by neuronal glycolysis that is inadequate, resulting in progressive loss of cerebral energy levels required for neurons to remain functional and viable. In essence, we propose that Alzheimer’s disease is a modern disease driven by changes in dietary lifestyle in which fructose can disrupt cerebral metabolism and neuronal function. Inhibition of intracerebral fructose metabolism could provide a novel way to prevent and treat this disease.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Non-linear Relationship Between Plasma Amyloid-β 40 Level and Cognitive Decline in a Cognitively Normal Population

Objectives

Recent studies regarding the relationships between plasma amyloid-β (Aβ) levels and cognitive performance had inconsistent results. In this study, we aimed to characterize the relationship between cognitive decline and plasma Aβ levels in a large-sample cognitively normal population.

Methods

This population-based, prospective cohort study included 1,240 participants with normal cognition. The Mini-Mental State Examination (MMSE) was used to assess cognitive function at baseline and 2 years later. Restricted cubic splines, multivariate logistic regression, and multivariate linear regression models were used to evaluate the type of relationship between cognitive decline during the 2-year follow-up period and plasma Aβ levels (Aβ40, Aβ42, and Aβ42/40).

Results

Participants with moderate Aβ40 levels had the highest risk of cognitive decline during a 2-year follow-up relative to individuals with low Aβ40 [odds ratio (OR): 0.60, 95% confidence interval (CI): 0.45–0.81, p < 0.001] or high Aβ40 (OR: 0.65, 95% CI: 0.49–0.87, p = 0.004) levels. The association between Aβ40 and cognitive decline did not depend on sex, education level, or APOE ε4 status. There was an interaction found between age (≤ 65 and > 65 years) and Aβ40 (p for interaction = 0.021). In individuals older than 65 years, there was a positive linear relationship between plasma Aβ40 and cognitive decline (OR: 1.02, 95% CI: 1.00–1.04, p = 0.027). For participants ≤ 65 years old, the lower Aβ40 and higher Aβ40 groups had a lower risk of cognitive decline than the medium Aβ40 group (OR: 0.69, 95% CI: 0.50–0.94, p = 0.02; OR: 0.63, 95% CI: 0.45–0.86, p = 0.004). None of relationship between plasma Aβ42, Aβ42/40 and cognitive decline was found during a 2-year follow-up.

Conclusion

The relationship between plasma Aβ40 and cognitive decline was not linear, but an inverted-U shape in a cognitively normal population. The underlying mechanism requires further investigation.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Weaker Braking Force, A New Marker of Worse Gait Stability in Alzheimer Disease

Background: Braking force is a gait marker associated with gait stability. This study aimed to determine the alteration of braking force and its correlation with gait stability in Alzheimer disease (AD).

Methods: A total of 32 AD patients and 32 healthy controls (HCs) were enrolled in this study. Gait parameters (braking force, gait variability, and fall risk) in the walking tests of Free walk, Barrier, and Count backward were measured by JiBuEn® gait analysis system. Gait variability was calculated by the coefficient of variation (COV) of stride time, stance time, and swing time.

Results: The braking force of AD was significantly weaker than HCs in three walking tests (P < 0.001, P < 0.001, P = 0.007). Gait variability of AD showed significant elevation than HCs in the walking of Count backward (COVstride: P = 0.013; COVswing: P = 0.006). Fall risk of AD was significantly higher than HCs in three walking tests (P = 0.001, P = 0.001, P = 0.001). Braking force was negatively associated with fall risks in three walking tests (P < 0.001, P < 0.001, P < 0.001). There were significant negative correlations between braking force and gait variability in the walking of Free walk (COVstride: P = 0.018; COVswing: P = 0.013) and Barrier (COVstride: P = 0.002; COVswing: P = 0.001), but not Count backward (COVstride: P = 0.888; COVswing: P = 0.555).

Conclusion: Braking force was weaker in AD compared to HCs, reflecting the worse gait stability of AD. Our study suggests that weakening of braking force may be a new gait marker to indicate cognitive and motor impairment and predict fall risk in AD.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Association Between Peripheral Adiponectin and Lipids Levels and the Therapeutic Response to Donepezil Treatment in Han Chinese Patients With Alzheimer’s Disease

Acetylcholinesterase inhibitors (AChEIs) including donepezil (DNP) are considered to be the most promising therapeutic possibilities of Alzheimer’s disease (AD). The response to DNP in AD patients varies and it is valuable to identify the potential markers that can predict the efficacy. Moreover, DNP has been found to affect bone function, but the exact mechanism is still unclear. Lipids and adipokine may link to AD and DNP directly or indirectly and might be potential biomarkers or therapeutic drug targets. The goal of this study was to investigate the relationships among adiponectin (APN), lipids levels, and the response to DNP, and to identify whether the effect of DNP in AD treatment is related to its effect on the level of APN in systemic circulation. The study recruited 85 AD patients with DNP treatment, of whom 47 were DNP responders and 38 were DNP nonresponders. The Mini-Mental State Examination was performed to evaluate the memory impairment. Plasma APN was measured with ELISA. The genotypes of single nucleotide polymorphisms rs1501299 and rs22417661 in APN for each patient were identified. Plasma lipids were quantified with gas chromatography coupled with mass spectrometry. Correlations among APN, lipid metabolomics, and DNP responded were evaluated. APN was significantly decreased in DNP responders. Methyl stearate and glycerol-3-phosphate, used for characterizing adipogenic differentiation, were significantly decreased in DNP responders compared to DNP nonresponders. APN and small-molecule lipids can be used as potential biomarkers to evaluate the efficacy of DNP. The results of metabolomics indicated that there was no change in the metabolic pathway of fatty acid metabolism and glucose metabolism in DNP responders, suggesting that APN-related biological function did not decrease in DNP responders. Our result suggests that more attention should be pay to the sources and biological functions of APN in AD with DNP treatment.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### The Effects of Transcranial Direct Current Stimulation (tDCS) on Balance Control in Older Adults: A Systematic Review and Meta-Analysis

Background: Recently, considerable research has been conducted to study the effects of transcranial direct current stimulation (tDCS) on balance control in older adults. We completed a comprehensive systematic review and meta-analysis to assess the efficacy of tDCS on balance control in this population.

Methods: A search strategy based on the PICOS principle was used to find the literatures in the databases of PubMed, EMBASE, EBSCO, Web of Science. The quality and risk of bias in the studies were independently assessed by two researchers.

Results: Ten studies were included in the systematic review. A meta-analysis was completed on six of these ten, with a total of 280 participants. As compared to sham (i.e., control), tDCS induced significant improvement with low heterogeneity in balance control in older adults. Specifically, tDCS induced large effects on the performance of the timed-up-and-go test, the Berg balance scale, and standing postural sway (e.g., sway area) and gait (e.g., walking speed) in dual task conditions (standardized mean differences (SMDs) = −0.99~3.41 95% confidence limits (CL): −1.52~4.50, p < 0.006, I2 < 52%). Moderate-to-large effects of tDCS were also observed in the standing posture on a static or movable platform (SMDs = 0.37~1.12 95%CL: −0.09~1.62, p < 0.03, I2 < 62%).

Conclusion: Our analysis indicates that tDCS holds promise to promote balance in older adults. These results warrant future studies of larger sample size and rigorous study design and results report, as well as specific research to establish the relationship between the parameter of tDCS and the extent of tDCS-induced improvement in balance control in older adults.

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Editorial: Interventional Strategies for Enhancing Quality of Life and Health Span in Older Adults

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Catecholamines in Alzheimer's Disease: A Systematic Review and Meta-Analysis

Background and Purpose: Previous studies found inconsistent results regarding the relationship between Alzheimer's disease (AD) and catecholamines, such as dopamine (DA), norepinephrine (NE), and epinephrine (EPI). Therefore, the purpose of this study was to perform a systematic review and meta-analysis to evaluate the results of previous studies on this relationship.

Method: Literature retrieval of eligible studies was performed in four databases (Web of Science, PubMed, Embase, and PsycARTICLES). Standardized mean differences (SMDs) were calculated to assess differences in catecholamine concentrations between the AD groups and controls.

Results: Thirteen studies met the eligibility criteria. Compared with the controls, significant lower concentrations of NE (SMD = −1.10, 95% CI: −2.01 to −0.18, p = 0.019) and DA (SMD = −1.12, 95% CI: −1.88 to −0.37, p = 0.003) were observed in patients with AD. No difference was found in the concentrations of EPI between the two groups (SMD = −0.74, 95% CI: −1.85 to 0.37, p = 0.189).

Conclusion: Overall, these findings are in line with the hypothesis that reduced NE and DA may be an important indicator for AD (Registration number CRD42018112816).

in Frontiers in Ageing Neuroscience on September 11, 2020 12:00 AM.

• #### Integrative Benchmarking to Advance Neurally Mechanistic Models of Human Intelligence

Schrimpf et al. advocate for integrating brain data in the form of benchmarks across labs via a platform called Brain-Score to advance the development of unified, neurally mechanistic models that explain entire domains of human intelligence such as vision.

in Neuron: In press on September 11, 2020 12:00 AM.

• #### Ten quick tips for teaching with participatory live coding

by Alexander Nederbragt, Rayna Michelle Harris, Alison Presmanes Hill, Greg Wilson

in PLoS Computational Biology on September 10, 2020 09:00 PM.

• #### Controlling control—A primer in open-source experimental control systems

by Christopher James Forman

Biological systems are composed of countless interlocking feedback loops. Reactor control systems—such as Chi-Bio (https://chi.bio/), recently published in PLOS Biology—enable biologists to drive multiple processes within living biological samples, using a single experimental framework. Consequently, the dynamic relationships between many biological variables can be explored simultaneously in situ. Similar multivariable experimental reactors are employed beyond biology in the study of active matter and non-equilibrium chemical reactions, in which physical systems are maintained far from equilibrium through the continuous introduction of energy or matter. Inexpensive state-of-the-art components enable open-source implementation of such multiparameter architectures, which represent a move away from expensive systems optimised for single measurements, towards affordable and reconfigurable multi-measurement systems. The transfer of well-understood engineering knowledge into the hands of biological and chemical specialists via open-source channels allows rapid cycles of experimental development and heralds a change in experimental capability that is driving increased theoretical and practical understanding of out-of-equilibrium systems across a wide range of scientific fields.

in PLoS Biology on September 10, 2020 09:00 PM.

• #### Autoantibodies Blocking M3 Muscarinic Receptors Cause Postganglionic Cholinergic Dysautonomia

A 10‐year‐old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7 days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme‐linked immunosorbent assay for all 5 muscarinic receptors (M1–M5), we identified in the patient's serum antibodies that selectively bound to M3 receptors. In vitro functional studies confirmed that these autoantibodies selectively blocked M3 receptor activation. Thus, autoantibodies against M3 acetylcholine receptors cause acute postganglionic cholinergic dysautonomia. ANN NEUROL 2020

in Annals of Neurology on September 10, 2020 04:20 PM.

## Objective

Medial temporal lobe epilepsy (TLE) is the most common form of medication‐resistant focal epilepsy in adults. Despite removal of medial temporal structures, more than one‐third of patients continue to have disabling seizures postoperatively. Seizure refractoriness implies that extramedial regions are capable of influencing the brain network and generating seizures. We tested whether abnormalities of structural network integration could be associated with surgical outcomes.

## Methods

Presurgical magnetic resonance images from 121 patients with drug‐resistant TLE across 3 independent epilepsy centers were used to train feed‐forward neural network models based on tissue volume or graph‐theory measures from whole‐brain diffusion tensor imaging structural connectomes. An independent dataset of 47 patients with TLE from 3 other epilepsy centers was used to assess the predictive values of each model and regional anatomical contributions toward surgical treatment results.

## Results

The receiver operating characteristic area under the curve based on regional betweenness centrality was 0.88, significantly higher than a random model or models based on gray matter volumes, degree, strength, and clustering coefficient. Nodes most strongly contributing to the predictive models involved the bilateral parahippocampal gyri, as well as the superior temporal gyri.

## Interpretation

Network integration in the medial and lateral temporal regions was related to surgical outcomes. Patients with abnormally integrated structural network nodes were less likely to achieve seizure freedom. These findings are in line with previous observations related to network abnormalities in TLE and expand on the notion of underlying aberrant plasticity. Our findings provide additional information on the mechanisms of surgical refractoriness. ANN NEUROL 2020

in Annals of Neurology on September 10, 2020 04:14 PM.

• #### Generalized half-center oscillators with short-term synaptic plasticity

Author(s): V. Baruzzi, M. Lodi, M. Storace, and A. Shilnikov

How can we develop simple yet realistic models of the small neural circuits known as central pattern generators (CPGs), which contribute to generate complex multiphase locomotion in living animals? In this paper we introduce a new model (with design criteria) of a generalized half-center oscillator,...

[Phys. Rev. E 102, 032406] Published Thu Sep 10, 2020

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

## Graphical Abstract

Using the capacity of a systemic growth hormone (GH) injection to induce STAT5 phosphorylation in the mouse brain, we identified several neurochemically distinct neuronal populations in the hypothalamic paraventricular nucleus that are directly responsive to GH, including tyrosine hydroxylase (TH)‐, somatostatin (SST)‐, thyrotropin‐releasing hormone (TRH)‐ and corticotropin‐releasing hormone (CRH)‐producing neurons.

## Abstract

Multiple neuroendocrine, autonomic and behavioral responses are regulated by the paraventricular nucleus of the hypothalamus (PVH). Previous studies have shown that PVH neurons express the growth hormone (GH) receptor (GHR), although the role of GH signaling on PVH neurons is still unknown. Given the great heterogeneity of cell types located in the PVH, we performed a detailed analysis of the neurochemical identity of GH‐responsive cells to understand the possible physiological importance of GH action on PVH neurons. GH‐responsive cells were detected via the phosphorylated form of the signal transducer and activator of transcription‐5 (pSTAT5) in adult male mice that received an intraperitoneal GH injection. Approximately 51% of GH‐responsive cells in the PVH co‐localized with the vesicular glutamate transporter 2. Rare co‐localizations between pSTAT5 and vesicular GABA transporter or vasopressin were observed, whereas approximately 20% and 38% of oxytocin and tyrosine hydroxylase (TH) cells, respectively, were responsive to GH in the PVH. Approximately 55%, 35% and 63% of somatostatin, thyrotropin‐releasing hormone (TRH) and corticotropin‐releasing hormone (CRH) neurons expressed GH‐induced pSTAT5, respectively. Additionally, 8%, 49% and 75% of neuroendocrine TH, TRH and CRH neurons, and 67%, 32% and 74% of nonneuroendocrine TH, TRH and CRH neurons were responsive to GH in the PVH of Fluoro‐Gold‐injected mice. Our findings suggest that GH action on PVH neurons is involved in the regulation of the thyroid, somatotropic and adrenal endocrine axes, possibly influencing homeostatic and stress responses.

in Journal of Comparative Neurology on September 10, 2020 09:46 AM.

• #### Whole‐brain efferent and afferent connectivity of mouse ventral tegmental area melanocortin‐3 receptor neurons

VTA MC3R neurons are a likely site of interaction between homeostatic and hedonic feeding circuits. VTA MC3R neurons send efferent projections to, and receive afferent input from, multiple brain regions involved in feeding, reward, and aversion. Very few POMC and AgRP neurons were labeled by monosynaptic rabies from multiple VTA neuron subtypes.

## Abstract

The mesolimbic dopamine (DA) system is involved in the regulation of multiple behaviors, including feeding, and evidence demonstrates that the melanocortin system can act on the mesolimbic DA system to control feeding and other behaviors. The melanocortin‐3 receptor (MC3R) is an important component of the melanocortin system, but its overall role is poorly understood. Because MC3Rs are highly expressed in the ventral tegmental area (VTA) and are likely to be the key interaction point between the melanocortin and mesolimbic DA systems, we set out to identify both the efferent projection patterns of VTA MC3R neurons and the location of the neurons providing afferent input to them. VTA MC3R neurons were broadly connected to neurons across the brain but were strongly connected to a discrete set of brain regions involved in the regulation of feeding, reward, and aversion. Surprisingly, experiments using monosynaptic rabies virus showed that proopiomelanocortin (POMC) and agouti‐related protein (AgRP) neurons in the arcuate nucleus made few direct synapses onto VTA MC3R neurons or any of the other major neuronal subtypes in the VTA, despite being extensively labeled by general retrograde tracers injected into the VTA. These results greatly contribute to our understanding of the anatomical interactions between the melanocortin and mesolimbic systems and provide a foundation for future studies of VTA MC3R neurons and the circuits containing them in the control of feeding and other behaviors.

in Journal of Comparative Neurology on September 10, 2020 09:41 AM.

• #### Retina‐specific targeting of pericytes reveals structural diversity and enables control of capillary blood flow

Ivanova et al., use sparse labeling of mural cells in the retina to identify pericyte diversity and to selectively manipulate capillary blood flow.

## Abstract

Pericytes are a unique class of mural cells essential for angiogenesis, maintenance of the vasculature and are key players in microvascular pathology. However, their diversity and specific roles are poorly understood, limiting our insight into vascular physiology and the ability to develop effective therapies. Here, in the mouse retina, a tractable model of the CNS, we evaluated distinct classes of mural cells along the vascular tree for both structural characterization and physiological manipulation of blood flow. To accomplish this, we first tested three inducible mural cell‐specific mouse lines using a sensitive Ai14 reporter and tamoxifen application either by a systemic injection, or by local administration in the form of eye drops. The specificity and pattern of cre activation varied significantly across the three lines, under either the PDGFRβ or NG2 promoter (Pdgfrβ‐CreRha, Pdgfrβ‐CreCsln, and Cspg4‐Cre). In particular, a mouse line with Cre under the NG2 promoter resulted in sparse TdTomato labeling of mural cells, allowing for an unambiguous characterization of anatomical features of individual sphincter cells and capillary pericytes. Furthermore, in one PDGFRβ line, we found that focal eye drop application of tamoxifen led to an exclusive Cre‐activation in pericytes, without affecting arterial mural cells. We then used this approach to boost capillary blood flow by selective expression of Halorhodopsin, a highly precise hyperpolarizing optogenetic actuator. The ability to exclusively target capillary pericytes may prove a precise and potentially powerful tool to treat microcirculation deficits, a common pathology in numerous diseases.

in Journal of Comparative Neurology on September 10, 2020 09:24 AM.

• #### Manu Prakash

Nature Methods, Published online: 10 September 2020; doi:10.1038/s41592-020-0968-8

Frugally built technology to study the ocean’s microbes, and engineering for societal good.

in Nature Methods on September 10, 2020 12:00 AM.

• #### A taste for hunger and thirst

Nature Reviews Neuroscience, Published online: 10 September 2020; doi:10.1038/s41583-020-00380-1

Glutamatergic neurons in the peri-locus coeruleus respond during ingestion of palatable food or drink and promote hedonic ingestion.

in Nature Reviews on September 10, 2020 12:00 AM.

• #### Episodic Memories: How do the Hippocampus and the Entorhinal Ring Attractors Cooperate to Create Them?

The brain is capable of registering a constellation of events, encountered only once, as an episodic memory that can last for a lifetime. As evidenced by the clinical case of the patient HM, memories preserving their episodic nature still depend on the hippocampal formation, several years after being created, while semantic memories are thought to reside in neocortical areas. The neurobiological substrate of one-time learning and life-long storing in the brain, that must exist at the cellular and circuit level, is still undiscovered. The breakthrough is delayed by the fact that studies jointly investigating the rodent hippocampus and entorhinal cortex are mostly targeted at understanding the spatial aspect of learning. Here, we present the concept of an entorhinal cortical module, termed EPISODE module, that could explain how the representations of different elements constituting episodic memories can be linked together at the stage of encoding. The new model that we propose here reconciles the structural and functional observations made in the entorhinal cortex and explains how the downstream hippocampal processing organizes the representations into meaningful sequences.

in Frontiers in Systems Neuroscience on September 10, 2020 12:00 AM.

• #### Early-Occurring Dendritic Spines Alterations in Mouse Models of Alzheimer’s Disease Inform on Primary Causes of Neurodegeneration

The consensus that synaptic failure is the earliest cause of cognitive deterioration in Alzheimer’s disease (AD) has initially led to investigate structural (dendritic spines) and physiological (LTP) synaptic dysfunctions in mouse models of AD with established cognitive alterations. The challenge is now to track down ultra-early alterations in spines to uncover causes rather than disease’s symptoms. This review article pinpoints dysregulations of the postsynaptic density (PSD) protein network which alter the morphology and function of spines in pre- and early- symptomatic hAPP mouse models of AD, and, hence, inform on primary causes of neurodegeneration.

in Frontiers in Synaptic Neuroscience on September 10, 2020 12:00 AM.

• #### The Role of Copper in Tau-Related Pathology in Alzheimer’s Disease

All tauopathies, including Alzheimer’s disease (AD), are characterized by the intracellular accumulation of abnormal forms of tau protein in neurons and glial cells, which negatively affect microtubule stability. Under physiological conditions, tubulin-associated unit (Tau) protein is intrinsically disordered, almost without secondary structure, and is not prone to aggregation. In AD, it assembles, and forms paired helical filaments (PHFs) that further build-up neurofibrillary tangles (NFTs). Aggregates are composed of hyperphosphorylated tau protein that is more prone to aggregation. The pathology of AD is also linked to disturbed copper homeostasis, which promotes oxidative stress (OS). Copper imbalance is widely observed in AD patients. Deregulated copper ions may initiate and exacerbate tau hyperphosphorylation and formation of β-sheet-rich tau fibrils that ultimately contribute to synaptic failure, neuronal death, and cognitive decline observed in AD patients. The present review summarizes factors affecting the process of tau aggregation, conformational changes of small peptide sequences in the microtubule-binding domain required for these motifs to act as seeding sites in aggregation, and the role of copper in OS induction, tau hyperphosphorylation and tau assembly. A better understanding of the various factors that affect tau aggregation under OS conditions may reveal new targets and novel pharmacological approaches for the therapy of AD.

in Frontiers in Molecular Neuroscience on September 10, 2020 12:00 AM.

• #### Overexpression of GSK-3β in Adult Tet-OFF GSK-3β Transgenic Mice, and Not During Embryonic or Postnatal Development, Induces Tau Phosphorylation, Neurodegeneration and Learning Deficits

GSK-3β or tau-kinase I is particularly abundant in the central nervous system (CNS), playing a key role in the pathogenesis of Alzheimer’s disease (AD). Accordingly, transgenic mouse models overexpressing this kinase recapitulate some aspects of this disease, such as tau hyperphosphorylation, neuronal death, and microgliosis. These alterations have been studied in mouse models showing GSK-3β overexpression from birth. In this case, some of these alterations may be due to adaptations that occur during development. Here we explored the potential of the Tet-OFF conditional system in the murine CamKIIα-tTA/GSK-3β model to increase the activity of GSK-3β only during adulthood. To this end, the overexpression of GSK-3β remained OFF during embryonic and postnatal development by administration of doxycycline in drinking water for 6 months, while it was turned ON in adult animals by removal of the treatment for 6 months. In these conditions, the CamKIIα-tTA/GSK-3β mouse is characterized by an increase in phosphorylated tau, cell death, and microgliosis. Furthermore, the increase in GSK-3β expression in the adult animals triggered a cognitive deficit, as determined through the hippocampus-dependent object recognition test (OR). These results demonstrate that the GSK-3β plays a key role in AD and that previously published data with other transgenic models are neither caused by or a consequence of adaptations to high levels of the enzyme during development.

in Frontiers in Molecular Neuroscience on September 10, 2020 12:00 AM.

• #### The Fragile X Mental Retardation Protein Regulates Striatal Medium Spiny Neuron Synapse Density and Dendritic Spine Morphology

The fragile X mental retardation protein (FMRP), an RNA-binding protein that mediates the transport, stability, and translation of hundreds of brain RNAs, is critically involved in regulating synaptic function. Loss of FMRP, as in fragile X syndrome (FXS), is a leading monogenic cause of autism and results in altered structural and functional synaptic plasticity, widely described in the hippocampus and cortex. Though FXS is associated with hyperactivity, impaired social interaction, and the development of repetitive or stereotyped behaviors, all of which are influenced by striatal activity, few studies have investigated the function of FMRP here. Utilizing a cortical-striatal co-culture model, we find that striatal medium spiny neurons (MSNs) lacking FMRP fail to make normal increases in PSD95 expression over a short time period and have significant deficits in dendritic spine density and colocalized synaptic puncta at the later measured time point compared to wildtype (WT) MSNs. Acute expression of wtFMRP plasmid in Fmr1 KO co-cultures results in contrasting outcomes for these measures on MSNs at the more mature time point, reducing spine density across multiple spine types but making no significant changes in colocalized puncta. FMRP’s KH2 and RGG RNA-binding domains are required for normal elimination of PSD95, and interruption of these domains slightly favors elimination of immature spine types. Further, KH2 is required for normal levels of colocalized puncta. Our data are largely consistent with a basal role for FMRP and its RNA-binding domains in striatal synapse stabilization on developing MSNs, and in light of previous findings, suggest distinct regional and/or cell type-specific roles for FMRP in regulating synapse structure.

in Frontiers in Molecular Neuroscience on September 10, 2020 12:00 AM.

• #### miRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice

The transcriptome of non-coding RNA (ncRNA) species is increasingly focused in Alzheimer’s disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRs), each with their own specific biological function. We used smallRNASeq to assess miR expression in the hippocampus of young (3 month old) and aged (8 month old) Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aβ4–42, develop age-related neuron loss, reduced neurogenesis and behavioral deficits. Our results do not only confirm known miR-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRs associated to the disease. Twenty-five miRs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRs were differentially expressed only in aged wildtype mice, and 33 only in aged Tg4-42 mice. No significant alteration in the miRNome was detected in young mice, which indicates that the changes observed in aged mice are down-stream effects of Aβ-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRs were predicted using miRWalk. For miRs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRs only differentially expressed in wildtype mice and 85 genes were targeted by miRs differentially expressed in both mouse models. Genes targeted by differentially expressed miRs in the Tg4-42 model were enriched for negative regulation of long-term synaptic potentiation, learning or memory, regulation of trans-synaptic signaling and modulation of chemical synaptic transmission obtained. This untargeted miR sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed miRs involved in AD, which can serve as biomarkers or therapeutic targets.

in Frontiers in Neuroscience: Neurodegeneration on September 10, 2020 12:00 AM.

• #### From Coarse to Fine-Grained Parcellation of the Cortical Surface Using a Fiber-Bundle Atlas

In this article, we present a hybrid method to create fine-grained parcellations of the cortical surface, from a coarse-grained parcellation according to an anatomical atlas, based on cortico-cortical connectivity. The connectivity information is obtained from segmented superficial and deep white matter bundles, according to bundle atlases, instead of the whole tractography. Thus, a direct matching between the fiber bundles and the cortical regions is obtained, avoiding the problem of finding the correspondence of the cortical parcels among subjects. Generating parcels from segmented fiber bundles can provide a good representation of the human brain connectome since they are based on bundle atlases that contain the most reproducible short and long connections found on a population of subjects. The method first processes the tractography of each subject and extracts the bundles of the atlas, based on a segmentation algorithm. Next, the intersection between the fiber bundles and the cortical mesh is calculated, to define the initial and final intersection points of each fiber. A fiber filtering is then applied to eliminate misclassified fibers, based on the anatomical definition of each bundle and the labels of Desikan-Killiany anatomical parcellation. A parcellation algorithm is then performed to create a subdivision of the anatomical regions of the cortex, which is reproducible across subjects. This step resolves the overlapping of the fiber bundle extremities over the cortical mesh within each anatomical region. For the analysis, the density of the connections and the degree of overlapping, is considered and represented with a graph. One of our parcellations, an atlas composed of 160 parcels, achieves a reproducibility across subjects of ≈0.74, based on the average Dice's coefficient between subject's connectivity matrices, rather than ≈0.73 obtained for a macro anatomical parcellation of 150 parcels. Moreover, we compared two of our parcellations with state-of-the-art atlases, finding a degree of similarity with dMRI, functional, anatomical, and multi-modal atlases. The higher similarity was found for our parcellation composed of 185 sub-parcels with another parcellation based on dMRI data from the same database, but created with a different approach, leading to 130 parcels in common based on a Dice's coefficient ≥0.5.

in Frontiers in Neuroinformatics on September 10, 2020 12:00 AM.

• #### Tracking Changes in Frontal Lobe Hemodynamic Response in Individual Adults With Developmental Language Disorder Following HD tDCS Enhanced Phonological Working Memory Training: An fNIRS Feasibility Study

Background: Current research suggests a neurobiological marker of developmental language disorder (DLD) in adolescents and young adults may be an atypical neural profile coupled with behavioral performance that overlaps with that of normal controls. Although many imaging techniques are not suitable for the study of speech and language processing in DLD populations, fNIRS may be a viable option. In this study we asked if fNIRS can be used to identify atypical cortical activation patterns in individual adults with DLD and track potential changes in cortical activation patterns following a phonological working memory training protocol enhanced with anodal HD tDCS stimulation to the presupplementary motor area (preSMA).

Objective/Hypothesis: The purpose of this study was two-fold: (1) to determine if fNIRS can be used to identify atypical hemodynamic responses in individual young adults with DLD during active spoken word processing and, (2) to determine if fNIRS can detect changes in hemodynamic response in these same adults with DLD following anodal HD tDCS enhanced phonological working memory training.

Methods: Two adult subjects with DLD (female, age 25) completed a total of two sessions of fNIRs working memory task prior to and following one session of a non-word repetition task paired with anodal HD tDCS (1.0 mA tDCS; 20 min) to the preSMA. Standardized z-scores of behavioral measures (accuracy and reaction time) and changes in hemodynamic response during an n-back working memory task for the two participants with DLD was compared to that of a normative sample of 21 age- and gender- matched normal controls (ages 18 to 25) prior to and following phonological working memory training.

Results: Individual standardized z-scores for each participant with DLD indicated that prior to training, hemoglobin response in the prefrontal lobe for both participants was markedly different from each other and normal controls. Following training, standard scores showed that the hemodynamic response for both participants moved within normal limits for ROIs.

Conclusion: These findings highlight the feasibility of fNIRS to establish individual differences in the link between behavior and neural patterns in single subjects with DLD, as well as track individual differences in changes in brain activity following working memory training.

in Frontiers in Human Neuroscience on September 10, 2020 12:00 AM.

• #### Brain Vital Signs Detect Cognitive Improvements During Combined Physical Therapy and Neuromodulation in Rehabilitation From Severe Traumatic Brain Injury: A Case Report

Using a longitudinal case study design, we have tracked the recovery of motor function following severe traumatic brain injury (TBI) through a multimodal neuroimaging approach. In 2006, Canadian Soldier Captain (retired) Trevor Greene (TG) was attacked with an axe to the head while on tour in Afghanistan. TG continues intensive daily rehabilitation, which recently included the integration of physical therapy (PT) with neuromodulation using translingual neurostimulation (TLNS) to facilitate neuroplasticity. Recent findings with PT + TLNS demonstrated that recovery of motor function occurred beyond conventional time limits, currently extending past 14-years post-injury. To investigate whether PT + TLNS similarly resulted in associated cognitive function improvements, we examined event-related potentials (ERPs) with the brain vital signs framework. In parallel with motor function improvements, brain vital signs detected significant increases in basic attention (as measured by P300 response amplitude) and cognitive processing (as measured by contextual N400 response amplitude). These objective cognitive improvements corresponded with TG’s self-reported improvements, including a noteworthy and consistent reduction in ongoing symptoms of post-traumatic stress disorder (PTSD). The findings provide valuable insight into the potential importance of non-invasive neuromodulation in cognitive rehabilitation, in addition to initial indications for physical rehabilitation.

in Frontiers in Human Neuroscience on September 10, 2020 12:00 AM.

• #### (New) Realist Social Cognition

in Frontiers in Human Neuroscience on September 10, 2020 12:00 AM.

• #### Degeneracy and Complexity in Neuro-Behavioral Correlates of Team Coordination

Team coordination—members of a group acting together rather than performing specific actions individually—is essential for success in many real-world tasks such as military missions, sports, workplace, or school interactions. However, team coordination is highly variable, which is one reason why its underlying neural processes are largely unknown. Here we used dual electroencephalography (EEG) in dyads to study the neurobehavioral dynamics of team coordination in an ecologically valid task that places intensive demands on joint performance. We present a novel conceptual framework to interpret neurobehavioral variability in terms of degeneracy, a fundamental property of complex biological systems said to enhance flexibility and robustness. We characterize degeneracy conceptually in terms of a manifold representing the geometric locus of the dynamics in the high dimensional state-space of neurobehavioral signals. The geometry and dimensionality of the manifold are determined by task constraints and team coordination requirements which restrict the manifold to trajectories that are conducive to successful task performance. Our results indicate that team coordination is associated with dimensionality reduction of the manifold as evident in increased inter-brain phase coherence of beta and gamma rhythms during critical phases of task performance where subjects exchange information. Team coordination was also found to affect the shape of the manifold manifested as a symmetry breaking of centro-parietal wavelet power patterns across subjects in trials with high team coordination. These results open a conceptual and empirical path to identifying the mechanisms underlying team performance in complex tasks.

in Frontiers in Human Neuroscience on September 10, 2020 12:00 AM.

• #### Assessing the Impact of Ih Conductance on Cross-Frequency Coupling in Model Pyramidal Neurons

Large cortical and hippocampal pyramidal neurons are elements of neuronal circuitry that have been implicated in cross-frequency coupling (CFC) during cognitive tasks. We investigate potential mechanisms for CFC within these neurons by examining the role that the hyperpolarization-activated mixed cation current (Ih) plays in modulating CFC characteristics in multicompartment neuronal models. We quantify CFC along the soma-apical dendrite axis and tuft of three models configured to have different spatial distributions of Ih conductance density: (1) exponential gradient along the soma-apical dendrite axis, (2) uniform distribution, and (3) no Ih conductance. We simulated two current injection scenarios: distal apical 4 Hz modulation and perisomatic 4 Hz modulation, each with perisomatic, mid-apical, and distal apical 40 Hz injections. We used two metrics to quantify CFC strength—modulation index and height ratio—and we analyzed CFC phase properties. For all models, CFC was strongest in distal apical regions when the 40 Hz injection occurred near the soma and the 4 Hz modulation occurred in distal apical dendrite. The strongest CFC values were observed in the model with uniformly distributed Ih conductance density, but when the exponential gradient in Ih conductance density was added, CFC strength decreased by almost 50%. When Ih was in the model, regions with much larger membrane potential fluctuations at 4 Hz than at 40 Hz had stronger CFC. Excluding the Ih conductance from the model resulted in CFC either reduced or comparable in strength relative to the model with the exponential gradient in Ih conductance. The Ih conductance also imposed order on the phase characteristics of CFC such that minimum (maximum) amplitude 40 Hz membrane potential oscillations occurred during Ih conductance deactivation (activation). On the other hand, when there was no Ih conductance, phase relationships between minimum and maximum 40 Hz oscillation often inverted and occurred much closer together. This analysis can help experimentalists discriminate between CFC that originates from different underlying physiological mechanisms and can help illuminate the reasons why there are differences between CFC strength observed in different regions of the brain and between different populations of neurons based on the configuration of the Ih conductance.

in Frontiers in Computational Neuroscience on September 10, 2020 12:00 AM.

• #### Kinematic Changes in a Mouse Model of Penetrating Hippocampal Injury and Their Recovery After Intranasal Administration of Endometrial Mesenchymal Stem Cell-Derived Extracellular Vesicles

Locomotion speed changes appear following hippocampal injury. We used a hippocampal penetrating brain injury mouse model to analyze other kinematic changes. We found a significant decrease in locomotion speed in both open-field and tunnel walk tests. We described a new quantitative method that allows us to analyze and compare the displacement curves between mice steps. In the tunnel walk, we marked mice with indelible ink on the knee, ankle, and metatarsus of the left and right hindlimbs to evaluate both in every step. Animals with hippocampal damage exhibit slower locomotion speed in both hindlimbs. In contrast, in the cortical injured group, we observed significant speed decrease only in the right hindlimb. We found changes in the displacement patterns after hippocampal injury. Mesenchymal stem cell-derived extracellular vesicles had been used for the treatment of several diseases in animal models. Here, we evaluated the effects of intranasal administration of endometrial mesenchymal stem cell-derived extracellular vesicles on the outcome after the hippocampal injury. We report the presence of vascular endothelial growth factor, granulocyte–macrophage colony-stimulating factor, and interleukin 6 in these vesicles. We observed locomotion speed and displacement pattern preservation in mice after vesicle treatment. These mice had lower pyknotic cells percentage and a smaller damaged area in comparison with the nontreated group, probably due to angiogenesis, wound repair, and inflammation decrease. Our results build up on the evidence of the hippocampal role in walk control and suggest that the extracellular vesicles could confer neuroprotection to the damaged hippocampus.

in Frontiers in Cellular Neuroscience on September 10, 2020 12:00 AM.

• #### Comparison of CRISPR/Cas Endonucleases for in vivo Retinal Gene Editing

CRISPR/Cas has opened the prospect of direct gene correction therapy for some inherited retinal diseases. Previous work has demonstrated the utility of adeno-associated virus (AAV) mediated delivery to retinal cells in vivo; however, with the expanding repertoire of CRISPR/Cas endonucleases, it is not clear which of these are most efficacious for retinal editing in vivo. We sought to compare CRISPR/Cas endonuclease activity using both single and dual AAV delivery strategies for gene editing in retinal cells. Plasmids of a dual vector system with SpCas9, SaCas9, Cas12a, CjCas9 and a sgRNA targeting YFP, as well as a single vector system with SaCas9/YFP sgRNA were generated and validated in YFP-expressing HEK293A cell by flow cytometry and the T7E1 assay. Paired CRISPR/Cas endonuclease and its best performing sgRNA was then packaged into an AAV2 capsid derivative, AAV7m8, and injected intravitreally into CMV-Cre:Rosa26-YFP mice. SpCas9 and Cas12a achieved better knockout efficiency than SaCas9 and CjCas9. Moreover, no significant difference in YFP gene editing was found between single and dual CRISPR/SaCas9 vector systems. With a marked reduction of YFP-positive retinal cells, AAV7m8 delivered SpCas9 was found to have the highest knockout efficacy among all investigated endonucleases. We demonstrate that the AAV7m8-mediated delivery of CRISPR/SpCas9 construct achieves the most efficient gene modification in neurosensory retinal cells in vivo.

in Frontiers in Cellular Neuroscience on September 10, 2020 12:00 AM.

• #### Shifting Developmental Trajectories During Critical Periods of Brain Formation

Critical periods of brain development are epochs of heightened plasticity driven by environmental influence necessary for normal brain function. Recent studies are beginning to shed light on the possibility that timely interventions during critical periods hold potential to reorient abnormal developmental trajectories in animal models of neurological and neuropsychiatric disorders. In this review, we re-examine the criteria defining critical periods, highlighting the recently discovered mechanisms of developmental plasticity in health and disease. In addition, we touch upon technological improvements for modeling critical periods in human-derived neural networks in vitro. These scientific advances associated with the use of developmental manipulations in the immature brain of animal models are the basic preclinical systems that will allow the future translatability of timely interventions into clinical applications for neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD) and schizophrenia.

in Frontiers in Cellular Neuroscience on September 10, 2020 12:00 AM.

• #### PHF-Core Tau as the Potential Initiating Event for Tau Pathology in Alzheimer’s Disease

Worldwide, around 50 million people have dementia. Alzheimer’s disease (AD) is the most common type of dementia and one of the major causes of disability and dependency among the elderly worldwide. Clinically, AD is characterized by impaired memory accompanied by other deficiencies in the cognitive domain. Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) are histopathological lesions that define brains with AD. NFTs consist of abundant intracellular paired helical filaments (PHFs) whose main constituent is tau protein. Tau undergoes posttranslational changes including hyperphosphorylation and truncation, both of which favor conformational changes in the protein. The sequential pathological processing of tau is illustrated with the following specific markers: pT231, TG3, AT8, AT100, and Alz50. Two proteolysis sites for tau have been described—truncation at glutamate 391 and at aspartate 421—and which can be demonstrated by reactivity with the antibodies 423 and TauC-3, respectively. In this review, we describe the molecular changes in tau protein as pre-NFTs progress to extracellular NFTs and during which the formation of a minimal nucleus of the filament, as the PHF core, occurs. We also analyzed the PHF core as the initiator of PHFs and tau phosphorylation as a protective neuronal mechanism against the assembly of the PHF core.

in Frontiers in Cellular Neuroscience on September 10, 2020 12:00 AM.

• #### Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness

The self-formation of retinal tissue from pluripotent stem cells generated a tremendous promise for developing new therapies of retinal degenerative diseases, which previously seemed unattainable. Together with use of induced pluripotent stem cells or/and CRISPR-based recombineering the retinal organoid technology provided an avenue for developing models of human retinal degenerative diseases “in a dish” for studying the pathology, delineating the mechanisms and also establishing a platform for large-scale drug screening. At the same time, retinal organoids, highly resembling developing human fetal retinal tissue, are viewed as source of multipotential retinal progenitors, young photoreceptors and just the whole retinal tissue, which may be transplanted into the subretinal space with a goal of replacing patient’s degenerated retina with a new retinal “patch.” Both approaches (transplantation and modeling/drug screening) were projected when Yoshiki Sasai demonstrated the feasibility of deriving mammalian retinal tissue from pluripotent stem cells, and generated a lot of excitement. With further work and testing of both approaches in vitro and in vivo, a major implicit limitation has become apparent pretty quickly: the absence of the uniform layer of Retinal Pigment Epithelium (RPE) cells, which is normally present in mammalian retina, surrounds photoreceptor layer and develops and matures first. The RPE layer polarize into apical and basal sides during development and establish microvilli on the apical side, interacting with photoreceptors, nurturing photoreceptor outer segments and participating in the visual cycle by recycling 11-trans retinal (bleached pigment) back to 11-cis retinal. Retinal organoids, however, either do not have RPE layer or carry patches of RPE mostly on one side, thus directly exposing most photoreceptors in the developing organoids to neural medium. Recreation of the critical retinal niche between the apical RPE and photoreceptors, where many retinal disease mechanisms originate, is so far unattainable, imposes clear limitations on both modeling/drug screening and transplantation approaches and is a focus of investigation in many labs. Here we dissect different retinal degenerative diseases and analyze how and where retinal organoid technology can contribute the most to developing therapies even with a current limitation and absence of long and functional outer segments, supported by RPE.

in Frontiers in Cellular Neuroscience on September 10, 2020 12:00 AM.

• #### Downregulation of TrkC Receptors Increases Dendritic Arborization of Purkinje Cells in the Developing Cerebellum of the Opossum, Monodelphis domestica

In therian mammals, the cerebellum is one of the late developing structures in the brain. Specifically, the proliferation of cerebellar granule cells occurs after birth, and even in humans, the generation of these cells continues during the first year of life. The main difference between marsupials and eutherians is that the majority of the brain structures in marsupials develop after birth. Herein, we report that in the newborn laboratory opossum (Monodelphis domestica), the cerebellar primordium is distinguishable in Nissl-stained sections. Additionally, bromodeoxyuridine birthdating experiments revealed that the first neurons form the deep cerebellar nuclei (DCN) and Purkinje cells, and are generated within postnatal days (P) 1 and 5. Three weeks after birth, progenitors of granule cells in the external germinal layer (EGL) proliferate, producing granule cells. These progenitor cells persist for a long time, approximately 5 months. Furthermore, to study the effects of neurotrophic tropomyosin receptor kinase C (TrkC) during cerebellar development, cells were obtained from P3 opossums and cultured for 8 days. We found that TrkC downregulation stimulates dendritic branching of Purkinje neurons, which was surprising. The number of dendritic branches was higher in Purkinje cells transfected with the shRNA TrkC plasmid. However, there was no morphological change in the number of dendritic branches of granule cells transfected with either control or shRNA TrkC plasmids. We suggest that inhibition of TrkC activity enables NT3 binding to the neurotrophic receptor p75NTR that promotes dendritic arborization of Purkinje cells. This effect of TrkC receptors on dendritic branching is cell type specific, which could be explained by the strong expression of TrkC in Purkinje cells but not in granule cells. The data indicate a new role for TrkC receptors in Monodelphis opossum.

in Frontiers in Neuroanatomy on September 10, 2020 12:00 AM.

• #### Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer’s Disease

in Frontiers in Ageing Neuroscience on September 10, 2020 12:00 AM.

• #### The Neuroanatomical Ultrastructure and Function of a Biological Ring Attractor

Many animals use a neural compass to navigate. Turner-Evans et al. reconstructed key parts of the Drosophila compass circuit, revealing both novel structural motifs and motifs proposed by theories of compass network function. Functional experiments support the proposed role of these motifs in storing and updating the compass.

in Neuron: In press on September 10, 2020 12:00 AM.

• #### Circadian VIPergic Neurons of the Suprachiasmatic Nuclei Sculpt the Sleep-Wake Cycle

The “master” circadian clock generally indicates day and night by tonic daytime firing. A specific population of neurons, active when the rest of the SCN is silent, directs nighttime “siesta” sleep but not daytime sleep, thereby timing end-of-day alertness.

in Neuron: In press on September 10, 2020 12:00 AM.

• #### Tempora: Cell trajectory inference using time-series single-cell RNA sequencing data

by Thinh N. Tran, Gary D. Bader

Single-cell RNA sequencing (scRNA-seq) can map cell types, states and transitions during dynamic biological processes such as tissue development and regeneration. Many trajectory inference methods have been developed to order cells by their progression through a dynamic process. However, when time series data is available, most of these methods do not consider the available time information when ordering cells and are instead designed to work only on a single scRNA-seq data snapshot. We present Tempora, a novel cell trajectory inference method that orders cells using time information from time-series scRNA-seq data. In performance comparison tests, Tempora inferred known developmental lineages from three diverse tissue development time series data sets, beating state of the art methods in accuracy and speed. Tempora works at the level of cell clusters (types) and uses biological pathway information to help identify cell type relationships. This approach increases gene expression signal from single cells, processing speed, and interpretability of the inferred trajectory. Our results demonstrate the utility of a combination of time and pathway information to supervise trajectory inference for scRNA-seq based analysis.

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

• #### Similarities and differences in spatial and non-spatial cognitive maps

by Charley M. Wu, Eric Schulz, Mona M. Garvert, Björn Meder, Nicolas W. Schuck

Learning and generalization in spatial domains is often thought to rely on a “cognitive map”, representing relationships between spatial locations. Recent research suggests that this same neural machinery is also recruited for reasoning about more abstract, conceptual forms of knowledge. Yet, to what extent do spatial and conceptual reasoning share common computational principles, and what are the implications for behavior? Using a within-subject design we studied how participants used spatial or conceptual distances to generalize and search for correlated rewards in successive multi-armed bandit tasks. Participant behavior indicated sensitivity to both spatial and conceptual distance, and was best captured using a Bayesian model of gener