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    Journal of Neurology

    in Journal of Neurology on December 01, 2020 12:00 AM.

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    Experimental Brain Research

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

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    The Cerebellum

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

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    Journal of Molecular Neuroscience

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

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    A First Case of Acute Cerebellitis Associated with Coronavirus Disease (COVID-19): a Case Report and Literature Review

    Abstract

    Novel coronavirus (severe acute respiratory syndrome-coronavirus-2: SARS-CoV-2), which originated from Wuhan, China, has spread to the other countries in a short period of time. We report a 47-year-old male who was admitted to our hospital due to suffering from progressive vertigo and ataxia for 7 days prior to the admission. Neurological examination revealed cerebellar dysfunction, and brain magnetic resonance imaging (MRI) depicted edema of the cerebellar hemisphere associated with leptomeningeal enhancement. Cerebrospinal fluid (CSF) analysis showed mild lymphocytic pleocytosis, elevated protein, and lactate dehydrogenase. SARS-CoV-2 RNA was detected in the oropharyngeal/nasopharyngeal and CSF specimens. As a result, treatment with lopinavir/ritonavir was initiated, and patient symptoms and signs improved significantly during the course of hospitalization. To the best of our knowledge, this is the first case of acute cerebellitis associated with COVID-19 disease which is reported in the literature so far.

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

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    Crossed Cerebellar Diaschisis in Patients with Diffuse Glioma Is Associated with Impaired Supratentorial Cerebrovascular Reactivity and Worse Clinical Outcome

    Abstract

    Crossed cerebellar diaschisis (CCD) can be associated with impaired cerebrovascular reactivity (CVR) and poor clinical outcome, but whether this holds true for patients with diffuse glioma is unknown. With blood oxygenation level–dependent (BOLD)-CVR imaging, we determined the presence of CCD in patients with diffuse glioma and investigated its relationship with cerebrovascular reactivity and clinical outcome. For eighteen enrolled subjects (nineteen datasets) with diffuse glioma, CCD was deferred from BOLD-CVR using a predetermined cerebellar asymmetry index (CAI) cutoff value of 6.0%. A FET-PET study was done as a verification of the CCD diagnosis. BOLD-CVR values as well as clinical performance scores (i.e., Karnofsky performance score (KPS), disability rating scale (DRS), and modified Rankin scale (mRS)) by BOLD-CVR scan at 3-month clinical follow-up were assessed and compared for the CCD-positive and CCD-negative group. CCD was present in 26.3% of subjects and strongly associated with impaired BOLD-CVR of the affected (i.e., the hemisphere harboring the glioma) and unaffected supratentorial hemisphere (CCD(+) vs. CCD(−): 0.08 ± 0.11 vs. 0.18 ± 0.04; p = 0.007 and 0.08 ± 0.12 vs. 0.19 ± 0.04; p = 0.007, respectively). This finding was independent of tumor volume (p = 0.48). Furthermore, poorer initial (by scan) clinical performance scores at follow-up were found for the CCD(+) group. The presence of crossed cerebellar diaschisis in patients with diffuse glioma is associated with impaired supratentorial cerebrovascular reactivity and worse clinical outcome.

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

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    Ataxia Associated with CADASIL: a Pathology-Confirmed Case Report and Literature Review

    Abstract

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is primarily characterized by migraine, stroke, mood disturbances, and cognitive decline. Ataxia has seldom been reported as a presenting symptom. Here, we review reports of CADASIL presenting as ataxia and compare these to the first pathologically confirmed case of CADASIL presenting with progressive ataxia. A 50-year-old woman presented with progressive truncal ataxia. Brain magnetic resonance imaging (MRI) revealed white matter hyperintensities in the bilateral anterior temporal lobes, external capsules, and periventricular areas, but not the cerebellum. Electron microscopy of skin biopsy material revealed multiple granular osmiophilic materials. Genetic testing confirmed a c.4552C > A mutation in exon 25 of the NOTCH3 gene. CADASIL is a rare cause of progressive ataxia, and only four cases of CADASIL presenting with ataxia have been reported in the literature. We also discuss the possible pathophysiology of cerebellar ataxia associated with CADASIL.

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

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    Cathodal Cerebellar tDCS Combined with Visual Feedback Improves Balance Control

    Abstract

    Balance control is essential to maintain a stable body position and to prevent falls. The aim of this study was to determine whether balance control could be improved by using cerebellar transcranial direct current stimulation (tDCS) and visual feedback in a combined approach. A total of 90 healthy volunteers were randomly assigned to six groups defined by the delivery of tDCS (cathodal or anodal or sham) and the provision or not of visual feedback on balance during the acquisition phase. tDCS was delivered over the cerebellar hemisphere ipsilateral to the dominant leg for 20 min at 2 mA during a unipedal stance task. Body sway (i.e., ankle angle and hip position) was measured as an overall maximal unit in anteroposterior and mediolateral direction, together with participant rating of perception of stability, before (baseline), during (acquisition), and after (final) the intervention. We found a reduction in body sway during the acquisition session when visual feedback alone was provided. When the visual feedback was removed (final session), however, body sway increased above baseline. Differently, the reduction in overall maximal body sway was maintained during the final session when the delivery of cathodal tDCS and visual feedback was combined. These findings suggest that cathodal tDCS may support the short-term maintenance of the positive effects of visual feedback on balance and provide the basis for a new approach to optimize balance control, with potential translational implications for the elderly and patients with impaired posture control.

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

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    Cerebellar Damage Affects Contextual Priors for Action Prediction in Patients with Childhood Brain Tumor

    Abstract

    Predictive coding accounts of action perception sustain that kinematics information is compared with contextual top-down predictions (i.e., priors) to understand actions in conditions of perceptual ambiguity. It has been previously shown that the cerebellum contributes to motor simulation of observed actions. Here, we tested the hypothesis that a specific contribution of the cerebellum to action perception is to provide contextual priors that guide the sampling of perceptual kinematic information. To this aim, we compared the performance of 42 patients with childhood brain tumor affecting infratentorial (ITT) or supratentorial (STT) areas with that of peers with typical development in an action prediction task. First, participants were exposed to videos depicting a child performing different reaching-to-grasp actions, which were associated with contextual cues in a probabilistic fashion. Then, they were presented with shortened versions of the same videos and asked to infer the action outcome; since kinematics was ambiguous, we expected their responses would be biased toward the previously learned contextual priors. We found that patients with brain tumor were impaired in predicting actions when compared to healthy controls. However, STT patients presented a reliable probabilistic effect, while ITT patients, who had cerebellar damage, did not rely on contextual priors in predicting actions. Furthermore, we found an association between the use of contextual priors and the ability to infer others’ mental states as assessed by a standardized test. These results suggest that the cerebellum provides contextual priors to understand others’ actions and this predictive function might underlie complex social cognition abilities.

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

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    Factors Associated with Intergenerational Instability of ATXN3 CAG Repeat and Genetic Anticipation in Chinese Patients with Spinocerebellar Ataxia Type 3

    Abstract

    Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher’s exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.

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

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    Cerebellar Intermittent Theta-Burst Stimulation Combined with Vestibular Rehabilitation Improves Gait and Balance in Patients with Multiple Sclerosis: a Preliminary Double-Blind Randomized Controlled Trial

    Abstract

    Difficulties in gait and balance disorders are among the most common mobility limitations in multiple sclerosis (MS), mainly due to a damage of cerebellar circuits. Moreover, the cerebellum plays a critical role in promoting new motor tasks, which is an essential function for neurorehabilitation. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol able to increase cerebellar activity, on gait and balance in a sample of 20 hospitalized participants with MS, undergoing vestibular rehabilitation (VR), an exercise-based program primarily designed to reduce vertigo and dizziness, gaze instability, and/or imbalance and falls in MS. Patients were assigned to receive either c-iTBS or sham iTBS before being treated with VR during 2 weeks. VR consisted of two types of training: gaze stability and postural stability exercises. The primary outcome measure was the change from baseline in the Tinetti Balance and Gait scale (TBG). The secondary outcome measures were changes from baseline in Berg Balance Scale (BBS), Fatigue Severity Scale (FSS), Two Minute Walking Test (2MWT), and Timed 25-ft walk test (T25FW) scales. MS patients treated with c-iTBS-VR showed a significant improvement in the TBG as compared to patients treated with sham iTBS-VR. Moreover, MS patients in the c-iTBS groups showed better performances in the vestibular-ocular reflex exercises. Combined c-iTBS and VR improves gait and balance abilities more than standard VR treatment in MS patients with a high level of disability.

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

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    Effects of Cerebellar tDCS on Inhibitory Control: Evidence from a Go/NoGo Task

    Abstract

    Response inhibition as an executive function refers to the ability to suppress inappropriate but prepotent responses. Several brain regions have been implicated in the process underlying inhibitory control, including the cerebellum. The aim of the present study was to explore the role of the cerebellum in executive functioning, particularly in response inhibition. For this purpose, we transitorily inhibited cerebellar activity by means of cathodal tDCS and studied the effects of this inhibition on ERP components elicited during a Go/NoGo task in healthy subjects. Sixteen healthy subjects underwent a Go/NoGo task prior to and after cathodal and sham cerebellar tDCS in separate sessions. A reduction in N2-NoGo amplitude and a prolongation in N2-NoGo latency emerged after cathodal tDCS whereas no differences were detected after sham stimulation. Moreover, commission errors in NoGo trials were significantly higher after cathodal tDCS than at the basal evaluation. No differences emerged between performances in Go trials and those after sham stimulation. These data indicate that cerebellar inhibition following cathodal stimulation alters the ability to allocate attentional resources to stimuli containing conflict information and the inhibitory control. The cerebellum may regulate the attentional mechanisms of stimulus orientation and inhibitory control both directly, by making predictions of errors or behaviors related to errors, and indirectly, by controlling the functioning of the cerebral cortical areas involved in the perception of conflict signals and of the basal ganglia involved in the inhibitory control of movement.

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

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    Is Purkinje Neuron Hyperpolarisation Important for Cerebellar Synaptic Plasticity? A Retrospective and Prospective Analysis

    Abstract

    Two recent studies have demonstrated that the dendritic Ca2+ signal associated with a climbing fibre (CF) input to the cerebellar Purkinje neuron (PN) depends on the membrane potential (Vm). Specifically, when the cell is hyperpolarised, this signal is mediated by T-type voltage-gated Ca2+ channels; in contrast, when the cell is firing, the CF-PN signal is mediated by P/Q-type voltage-gated Ca2+ channels. When the CF input is paired with parallel fibre (PF) activity, the signal is locally amplified at the sites of PF-activated synapses according to the Vm at the time of the CF input, suggesting that the standing Vm is a critical parameter for the induction of PF synaptic plasticity. In this review, I analyse how the Vm can potentially play a role in cerebellar learning focussing, in particular, on the hyperpolarised state that appears to occur episodically, since PNs are mostly firing under physiological conditions. By revisiting the recent literature reporting in vivo recordings and synaptic plasticity studies, I speculate on how a putative role of the PN Vm can provide an interpretation for the results of these studies.

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

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    Cerebellar Volumes Associate with Behavioral Phenotypes in Prader-Willi Syndrome

    Abstract

    The objective of this study was to investigate lobule-specific cerebellar structural alterations relevant to clinical behavioral characteristics of Prader-Willi syndrome (PWS). We performed a case-control study of 21 Japanese individuals with PWS (age; median 21.0, range 13–50 years, 14 males, 7 females) and 40 age- and sex-matched healthy controls with typical development. Participants underwent 3-Tesla magnetic resonance imaging. Three-dimensional T1-weighted images were assessed for cerebellar lobular volume and adjusted for total intracerebellar volume (TIV) using a spatially unbiased atlas template to give a relative volume ratio. A region of interest analysis included the deep cerebellar nuclei. A correlation analysis was performed between the volumetric data and the clinical behavioral scores derived from the standard questionnaires (hyperphagia, autism, obsession, and maladaptive index) for global intelligence assessment in paired subgroups. In individuals with PWS, TIV was significantly reduced compared with that of controls (p < 0.05, family-wise error corrected; mean [standard deviation], 1014.1 [93.0] mm3). Decreased relative lobular volume ratios were observed in posterior inferior lobules with age, sex, and TIV as covariates (Crus I, Crus II, lobules VIIb, VIIIa, VIIIb, and IX). However, increased ratios were found in the dentate nuclei bilaterally in individuals with PWS (p < 0.01); the mean (standard deviation) × 10−3 was as follows: left, 1.58 (0.26); right, 1.67 (0.30). The altered lobular volume ratios showed negative correlations with hyperphagic and autistic characteristics and positive correlations with obsessive and intellectual characteristics. This study provides the first objective evidence of topographic patterns of volume differences in cerebellar structures consistent with clinical behavioral characteristics in individuals with PWS and strongly suggests a cerebellar contribution to altered functional brain connectivity in PWS.

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

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    Associations of Reading Efficiency with White Matter Properties of the Cerebellar Peduncles in Children

    Abstract

    Reading in children has been associated with microstructural properties of the cerebellar peduncles, the white matter pathways connecting the cerebellum to the cerebrum. In this study, we used two independent neuroimaging modalities to assess which features of the cerebellar peduncles would be associated with reading. Twenty-three 8-year-old children were evaluated on word reading efficiency and imaged using diffusion MRI (dMRI) and quantitative T1 relaxometry (qT1). We segmented the superior (SCP), middle, and inferior cerebellar peduncles and extracted two metrics: fractional anisotropy (FA) from dMRI and R1 from qT1. Tract-FA was significantly correlated with tract-R1 in left and right SCPs (left: rP(21) = .63, right: rP(21) = .76, p ≤ .001) suggesting that FA of these peduncles, at least in part, indexed myelin content. Tract-FA and tract R1 were not correlated in the other cerebellar peduncles. Reading efficiency negatively correlated with tract-FA of the left (rP(21) = − .43, p = .040) and right SCP (rP(21) = − .37, p = .079). Reading efficiency did not correlate with tract-R1 in the SCPs. The negative association of reading efficiency with tract-FA and the lack of association of reading efficiency with tract-R1 implicate properties other than myelin content as relevant to the information flow between the cerebellum and the cerebrum for individual differences in reading skills in children.

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

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    Essential Tremor Within the Broader Context of Other Forms of Cerebellar Degeneration

    Abstract

    Essential tremor (ET) has recently been reconceptualized by many as a degenerative disease of the cerebellum. Until now, though, there has been no attempt to frame it within the context of these diseases. Here, we compare the clinical and postmortem features of ET with other cerebellar degenerations, thereby placing it within the broader context of these diseases. Action tremor is the hallmark feature of ET. Although often underreported in the spinocerebellar ataxias (SCAs), action tremors occur, and it is noteworthy that in SCA12 and 15, they are highly prevalent, often severe, and can be the earliest disease manifestation, resulting in an initial diagnosis of ET in many cases. Intention tremor, sometimes referred to as “cerebellar tremor,” is a common feature of ET and many SCAs. Other features of cerebellar dysfunction, gait ataxia and eye motion abnormalities, are seen to a mild degree in ET and more markedly in SCAs. Several SCAs (e.g., SCA5, 6, 14, and 15), like ET, follow a milder and more protracted disease course. In ET, numerous postmortem changes have been localized to the cerebellum and are largely confined to the cerebellar cortex, preserving the cerebellar nuclei. Purkinje cell loss is modest. Similarly, in SCA3, 12, and 15, Purkinje cell loss is limited, and in SCA12 and 15, there is preservation of cerebellar nuclei and relative sparing of other central nervous system regions. Both clinically and pathologically, there are numerous similarities and intersection points between ET and other disorders of cerebellar degeneration.

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

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    GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plasticity, and Neuromodulation

    Abstract

    G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons and play an important role in controlling neuronal excitability. Although previous studies have revealed a high expression of GIRK subunits in the cerebellum, their functional role has never been clearly described. Using patch-clamp recordings in mice cerebellar slices, we examined the properties of the GIRK currents in Purkinje cells (PCs) and investigated the effects of a selective agonist of GIRK1-containing channels, ML297 (ML), on PC firing and synaptic plasticity. We demonstrated that GIRK channel activation decreases the PC excitability by inhibiting both sodium and calcium spikes and, in addition, modulates the complex spike response evoked by climbing fiber stimulation. Our results indicate that GIRK channels have also a marked effect on synaptic plasticity of the parallel fiber-PC synapse, as the application of ML297 increased the expression of LTP while preventing LTD. We, therefore, propose that the recruitment of GIRK channels represents a crucial mechanism by which neuromodulators can control synaptic strength and membrane conductance for proper refinement of the neural network involved in memory storage and higher cognitive functions.

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

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    Abnormal Cerebellar Volume in Patients with Remitted Major Depression with Persistent Cognitive Deficits

    Abstract

    Cerebellar involvement in major depressive disorder (MDD) has been demonstrated by a growing number of studies, but it is unknown whether cognitive functioning in depressed individuals is related to cerebellar gray matter volume (GMV) abnormalities. Impaired attention and executive dysfunction are characteristic cognitive deficits in MDD, and critically, they often persist despite remission of mood symptoms. In this study, we investigated cerebellar GMV in patients with remitted MDD (rMDD) that showed persistent cognitive impairment. We applied cerebellum-optimized voxel-based morphometry in 37 patients with rMDD and with cognitive deficits, in 12 patients with rMDD and without cognitive deficits, and in 36 healthy controls (HC). Compared with HC, rMDD patients with cognitive deficits had lower GMV in left area VIIA, crus II, and in vermal area VIIB. In patients with rMDD, regression analyses demonstrated significant associations between GMV reductions in both regions and impaired attention and executive dysfunction. Compared with HC, patients without cognitive deficits showed increased GMV in bilateral area VIIIB. This study supports cerebellar contributions to the cognitive dimension of MDD. The data also point towards cerebellar area VII as a potential target for non-invasive brain stimulation to treat cognitive deficits related to MDD.

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

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    Consensus Paper: Cerebellum and Social Cognition

    Abstract

    The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social “mirroring”) which is very close to its original role in motor learning, as well as in social understanding of other individuals’ mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social “mentalizing”). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions.

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

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    Correction to: Silencing RNF13 Alleviates Parkinson’s Disease – Like Problems in Mouse Models by Regulating the Endoplasmic Reticulum Stress–Mediated IRE1α-TRAF2-ASK1-JNK Pathway

    A Correction to this paper has been published: https://doi.org/10.1007/s12031-020-01746-x

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

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    Molecular Mechanisms of Cognitive Impairment and Intellectual Disability—Virtual ESN Mini-Conference in Conjunction with the FENS Forum, July 11–15, 2020

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

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    Correction to: Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

    The article “Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures”.

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

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    The Master of Puppets: Pleiotropy of PDGFRB and its Relationship to Multiple Diseases

    Abstract

    The platelet-derived growth factor receptor beta (PDGFRB) gene is involved in proliferative and developmental processes in mammals. Variations in this gene lead to several different syndromic conditions, such as infantile myofibromatosis I, sporadic port-wine stain, primary familial brain calcification, and the Penttinen and overgrowth syndromes. Our objective was to investigate PDGFRB’s genetic relationship to clinical conditions and evaluate the protein interactions using GeneNetwork, GeneMANIA, and STRING network databases. We have evidenced the gene’s pleiotropy through its many connections and its link to syndromic conditions. Therefore, PDGFRB may be an important therapeutic target for treating such conditions.

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

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    Polymorphism in the 3′-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses

    Abstract

    Schizophrenia (SCZ) is a multifactorial disorder caused by environmental and genetic factors. Studies have shown that various single-nucleotide polymorphisms (SNPs) in the binding sites of microRNAs contribute to the risk of developing SCZ. We aimed to investigate whether the variants located in the 3′-UTR region of LIF (rs929271T>G) and ATF6B (rs8283G>A) were associated with increased susceptibility to SCZ in a population from the south-east of Iran. In this case-control study, a total of 396 subjects were recruited. SNPs were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotyping results showed that the G allele of rs929271 significantly increased the risk of SCZ (OR = 1.58 95%CI = 1.19–2.10, p = 0.001). As for rs929271, the GG genotype of co-dominant (OR = 2.54 95%CI = 1.39–4.64, p = 0.002) and recessive (OR = 2.91 95%CI = 1.77–4.80, p < 0.001) models were strongly linked to SCZ. No significant differences were observed between rs8283 polymorphism and predisposition to SCZ. In silico analyses predicted that rs929271 might alter the binding sites of microRNAs, which was believed to have an unclear role in the development of SCZ. Moreover, rs929271 polymorphism changed the LIF-mRNA folding structure. These findings provide fine pieces of evidence regarding the possible effects of LIF polymorphism in the development of SCZ and regulation of the LIF gene targeted by microRNAs.

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

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    Genotype and Phenotype Correlations for TBL1XR1 in Neurodevelopmental Disorders

    Abstract

    TBL1XR1 is a member of the WD40 repeat-containing gene family. Mutations of TBL1XR1 have been reported in neurodevelopmental disorders (NDDs). Although the phenotypes of some patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with TBL1XR1 mutations. Herein, we report a new de novo frameshift mutation in TBL1XR1 (NM_024665.4, c.388_389delAC, p.T130Sfs*14) in a patient with autism spectrum disorder (ASD). To explore the correlations between genotypes and phenotypes for TBL1XR1 in NDDs, we manually curated and analyzed 38 variants and the associated phenotypes from 50 individuals with NDDs. TBL1XR1 mutations lead to a wide range of phenotypic defects. We conclude that the most common phenotypes associated with TBL1XR1 mutations were language and motor developmental delay, intellectual disabilities, facial deformity, hypotonia, and microcephaly. Our study provides a comprehensive spectrum of neurodevelopmental phenotypes caused by TBL1XR1 mutations, which is important for genetic diagnosis and precision clinical management.

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

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    The New CIC Mutation Associates with Mental Retardation and Severity of Seizure in Turkish Child with a Rare Class I Glucose-6-Phosphate Dehydrogenase Deficiency

    Abstract

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disease that causes acute or chronic hemolytic anemia and potentially leads to severe jaundice in response to oxidative agents. Capicua transcriptional repressor (CIC) is an important gene associated with mental retardation, autosomal dominant 45. Affiliated tissues including skin, brain, bone, and related phenotypes are intellectual disability and seizures. Clinical, biochemical, and whole exome analysis are carried out in a Turkish family. Mutation analysis of G6PD and CIC genes by Sanger sequencing in the whole family was carried out to reveal the effect of these mutations on the patient’s clinical outcome. Here, we present the case of epilepsy in an 8-year-old child with a hemizygous variation in G6PD gene and heterozygous mutation in CIC gene, resulting in focal epileptiform activity and hypsarrhythmia in electroencephalography (EEG), seizures, psychomotor retardation, speech impairment, intellectual disability, developmental regression, and learning difficulties. Whole exome sequencing confirmed the diagnosis of X-linked increased susceptibility for hemolytic anemia due to G6PD deficiency and mental retardation type 45 due to CIC variant, which explained the development of epileptic seizures. Considering CIC variant and relevant relation with the severity and course of the disease, G6PD mutations sustained through the family are defined as hereditary. Our findings could represent the importance of variants found in G6PD as well as CIC genes linked to the severity of epilepsy, which was presumed based on the significant changes in protein configuration.

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

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    Effects of Single-Dose and Long-Term Ketamine Administration on Tau Phosphorylation–Related Enzymes GSK-3β, CDK5, PP2A, and PP2B in the Mouse Hippocampus

    Abstract

    Ketamine is a recreational drug that causes emotional and cognitive impairments, but its specific mechanisms of action are still unclear. Recent evidence suggests that Tau protein phosphorylation and targeted delivery to the postsynaptic area are closely related to its neurotoxicity, and our recent studies have shown that long-term ketamine administration causes excessive Tau protein phosphorylation. However, the regulatory mechanism of Tau protein phosphorylation induced by ketamine has not been clarified. In the present study, we administered a single ketamine injection and long-term (6 months) ketamine injections in C57BL/6 mice, to investigate the effects of different doses of ketamine on the expression levels of Tau protein and its phosphorylation, the expression levels and activities of the related protein phosphokinases GSK-3β and CDK5, and the expression levels and activities of the related protein phosphatases PP2A and PP2B in the mouse hippocampus. Our results showed that both single-dose and long-term ketamine administration induced excessive phosphorylation of the Tau protein at ser202/thr205 and ser396. A single ketamine administration caused an increase in the activity of GSK-3β (at high doses) and a decrease in the activity of PP2A. On the other hand, long-term ketamine administration resulted in an increase in the activities of GSK-3β (at high doses) and CDK5, and a decrease in the activity of PP2A. Our results indicate that GSK-3β, CDK5, and PP2A may be involved in ketamine-induced Tau protein phosphorylation.

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

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    AMPK-SIRT1-PGC1α Signal Pathway Influences the Cognitive Function of Aged Rats in Sevoflurane-Induced Anesthesia

    Abstract

    To understand the effect of AMP-activated protein kinase (AMPK)-SIRT1 (silent information regulator 1)-PPARγ coactivator-1α (PGC1α) signaling pathway on the cognitive function of sevoflurane-anesthetized aged rats. Aged rats were divided into Normal group, Sevo group (Sevoflurane anesthesia), Sevo + AICAR (the AMPK activator) group, Sevo + EX527 group (the AMPK inhibitor), and Sevo + AICAR + EX527 group. The cognitive function of rats was determined by the Morris water maze. Hippocampal neuronal apoptosis was evaluated by TUNEL and Fluoro-Jade C (FJC) staining, and the expression of cleaved caspase-3 was detected by immunohistochemistry. ROS, SOD, and MDA levels and the fluorescence intensity of GFAP in the hippocampus were assayed. The mitochondrial membrane potential (MMP), mitochondrial mass, ATP level, and the expression of AMPK-SIRT1-PGC1α were determined by the corresponding methods. Rats in the Sevo group manifested significant extension in the escape latency, with fewer platform crossings; and meanwhile, the apoptotic rate, the number of FJC-positive cells, and the fluorescence intensity of GFAP of neurons were elevated, with up-regulation of cleaved caspase-3. Moreover, the level of MDA and ROS was increased evidently, with significant down-regulation of SOD activity, ATP, mitochondrial mass and MMP levels, and AMPK, SIRT1 and PGC-1α protein expressions. However, sevoflurane-induced changes above were improved after the administration of AICAR, and EX527 could reverse AICAR-induced improvements in Sevo-anesthetized aged rats. Activating AMPK-SIRT1-PGC1α pathway can improve the cognitive function and mitigate the neuronal injury in Sevo-anesthetized aged rats by antagonizing the oxidative stress and maintaining the mitochondrial function.

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

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    Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway

    Abstract

    Sepsis can induce acute and chronic changes in the central nervous system termed sepsis-associated encephalopathy (SAE). Not only cognitive deficits but also anxiety, depression, and post-traumatic stress disorder are common in severe sepsis survivors. In this study, we demonstrated that amitriptyline, a classic tricyclic antidepressant, reduced sepsis-induced brain damage through the tropomyosin receptor kinase A (TrkA) signaling pathway. Amitriptyline ameliorated neuronal loss assessed by Nissl staining in a mouse cecal ligation and puncture (CLP)–induced sepsis model. Furthermore, amitriptyline reduced early gliosis assessed by immunofluorescence and late cognitive deficits assessed by the Morris water maze (MWM) test. Moreover, amitriptyline treatment attenuated oxidative stress indicated by less superoxide dismutase (SOD) and catalase (CAT) activity consumption and malondialdehyde (MDA) accumulation. Interestingly, those protective effects of amitriptyline could be abolished by GW441756, a TrkA signaling pathway inhibitor. Immunoblot directly showed that TrkA signaling pathway–associated proteins, such as Akt and GSK3β, were involved in the neuroprotective effects of amitriptyline. Thus, amitriptyline appears to be an encouraging candidate to treat cognitive deficits and depression after severe sepsis.

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

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    Prostaglandin E1 Improves Cerebral Microcirculation Through Activation of Endothelial NOS and GRPCH1

    Abstract

    Endothelial dysfunction greatly contributes to microcirculation disorder. The role of prostaglandin E1 (PGE1) in cerebral microcirculation was explored in vitro. LPS (0.5 or 1 μg/ml) was added to induce injury in human brain microvascular endothelial cells (HCMEC/D3). CCK-8 was applied to check viabilities of HCMEC/D3 before and after LPS treatment. Western blot witnessed the changes in protein expressions of inflammatory cytokines, IL-6 and TNF-α. Caspase-3/7 activity was analyzed and so were the protein expressions of pro-apoptotic gene BAX and anti-apoptotic gene Bcl-2. mRNA expressions of eNOS and GTPCH1 were evaluated by RT-qPCR. After overexpressing eNOS or GTPCH1 in LPS-induced HCMEC/D3 cells, viabilities, inflammatory cytokines, caspase-3/7 activity, and apoptosis-related genes were detected. The modulation of PGE1 in eNOS and GTPCH1 production, viability, inflammation, and apoptosis was investigated. The inhibitor of eNOS or GTPCH1 was introduced to examine impacts of eNOS or GTPCH1 could have on the PGE1 function. LPS decreased cell viabilities, eNOS and GTPCH1 expression, and promoted inflammation and apoptosis in HCMEC/D3 cells. Overexpressed eNOS or GTPCH1 promoted cell viabilities and suppressed inflammation and apoptosis. PGE1 enhanced viability and decreased inflammation and apoptosis in cells treated by LPS. PGE1 activated eNOS and GTPCH1 and inhibition of eNOS or GTPCH1 led to the attenuation of the protective functions of PGE1 in LPS-induced cells. PGE1 protected HCMEC/D3 cells from injuries induced by LPS by activation of eNOS and GTPCH1, suggesting that PGE1 might be used to help maintain cerebral microcirculation in future.

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

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    Iron heterogeneity in early active multiple sclerosis lesions

    Objective

    Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients’ brains suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.

    Methods

    We used synchrotron X‐ray fluorescence imaging, histology and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.

    Results

    Immunopattern II early active lesions contain 64% more iron (95%CI: 17%, 127%; p=0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95%CI: 3%, 64%; p=0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95%CI: ‐40%, ‐14%; p<0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p<0.001). Micro‐focused X‐ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, while macrophages in immunopattern III lesions contain little iron.

    Interpretation

    Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin or different demyelination mechanisms, and paves the way for developing new or using existing iron‐sensitive MRI techniques to differentiate among immunopatterns in the general non‐biopsied MS patient population.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 27, 2020 08:37 PM.

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    Necessary conditions for STDP-based pattern recognition learning in a memristive spiking neural network

    Publication date: Available online 27 November 2020

    Source: Neural Networks

    Author(s): V.A. Demin, D.V. Nekhaev, I.A. Surazhevsky, K.E. Nikiruy, A.V. Emelyanov, S.N. Nikolaev, V.V. Rylkov, M.V. Kovalchuk

    in Neural Networks on November 27, 2020 02:00 PM.

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    Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

    Objective

    Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.

    Methods

    In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open‐label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.

    Results

    In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty‐seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223–535) vs 124 days (95% CI = 33–149); OLT: 426 days (95% CI = 258–628) vs 106 days (95% CI = 11–149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug‐resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.

    Interpretation

    Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2020

    in Annals of Neurology on November 27, 2020 11:13 AM.

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    Simplicity lacks robustness when projecting heat-health outcomes in a changing climate

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19994-1

    Extreme heat adversely affects human health, productivity, and well-being, with more frequent and intense heatwaves projected to increase exposures. However, current risk projections oversimplify critical inter-individual factors of human thermoregulation, resulting in unreliable and unrealistic estimates of future adverse health outcomes.

    in Nature Communications on November 27, 2020 12:00 AM.

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    Nanorods with multidimensional optical information beyond the diffraction limit

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19952-x

    Development of functional nanostructures can enable a range of applications in imaging and nanoscale science. Here, the authors fabricate and characterize complex heterogeneous nanorods with diverse, tunable sub-wavelength structures.

    in Nature Communications on November 27, 2020 12:00 AM.

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    High-frequency gas effusion through nanopores in suspended graphene

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19893-5

    Atomically thin porous graphene is promising for filtration and sieving applications. Here the authors, using a laser-actuated micro-drum device of bilayer graphene with controlled number of nanopores, and measuring the permeation rate of different gases, show that it can also be used for permeation-based sensing.

    in Nature Communications on November 27, 2020 12:00 AM.

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    RNA-mediated control of cell shape modulates antibiotic resistance in Vibrio cholerae

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19890-8

    Small regulatory RNAs (sRNAs) in Vibrio cholerae have been shown to modulate several biological processess including virulence, biofilm formation, quorum sensing, colony morphology and stress resistance. Here, the authors show that VadR sRNA acts as a posttranscriptional inhibitor of the crvA mRNA and that mutation of vadR increases cell curvature, whereas overexpression has the inverse effect.

    in Nature Communications on November 27, 2020 12:00 AM.

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    Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19879-3

    Firre encodes a lncRNA involved in nuclear organization in mammals. Here, the authors find that allelic deletion of Firre on the active X chromosome (Xa) results in dose-dependent loss of histone H3K27me3 on the inactive X chromosome (Xi), along with other trans-acting effects, including disruption of the perinuclear location and minor dysregulation of gene expression.

    in Nature Communications on November 27, 2020 12:00 AM.

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    Tumor evolutionary trajectories during the acquisition of invasiveness in early stage lung adenocarcinoma

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19855-x

    Invasive early stage lung adenocarcinoma has a heterogeneous prognosis. Here, the authors microdissect malignant pulmonary nodules to invasive and preinvasive components and study the mutations that are common or private between the lesions, allowing them to understand the evolutionary path of the tumours.

    in Nature Communications on November 27, 2020 12:00 AM.

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    Designer spin order in diradical nanographenes

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19834-2

    The ability to control magnetic coupling in graphene nanomaterials remains elusive. Here, the authors report an approach of engineering magnetic ground states in open-shell bipartite/nonbipartite nanographenes where the magnetic coupling sign between two spins are controlled via breaking bipartite lattice symmetry.

    in Nature Communications on November 27, 2020 12:00 AM.

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    A Cas-embedding strategy for minimizing off-target effects of DNA base editors

    Nature Communications, Published online: 27 November 2020; doi:10.1038/s41467-020-19690-0

    DNA base editors can display off-target effects on DNA and RNA. Here the authors embed the base editing enzymes in the middle of nCas9 to reduce these without impacting on-target editing.

    in Nature Communications on November 27, 2020 12:00 AM.

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    Daily briefing: The ‘hidden flower’ pollinated by lizards

    Nature, Published online: 27 November 2020; doi:10.1038/d41586-020-03374-2

    The first known African plant to use reptiles as its primary pollinator, how to adapt when your fieldwork is cancelled and neutrinos reveal the Sun’s inner workings.

    in Nature on November 27, 2020 12:00 AM.

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    Coronavirus diaries: Reasons to be cheerful, 1, 2, 3

    Nature, Published online: 27 November 2020; doi:10.1038/d41586-020-03369-z

    A second lockdown saps scientific creativity, says John Tregoning, but vaccine news and US election result offer hope at the end of a challenging year.

    in Nature on November 27, 2020 12:00 AM.

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    How to manage when your fieldwork is cancelled

    Nature, Published online: 27 November 2020; doi:10.1038/d41586-020-03368-0

    As COVID-19 restrictions continue to upend plans for data collection, scientists stuck at home are finding innovative ways to adapt their research questions. Here’s what they’re doing.

    in Nature on November 27, 2020 12:00 AM.

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    MIRRAGGE – Minimum Information Required for Reproducible AGGregation Experiments

    Reports on phase separation and amyloid formation for multiple proteins and aggregation-prone peptides are recurrently used to explore the molecular mechanisms associated with several human diseases. The information conveyed by these reports can be used directly in translational investigation, e.g., for the design of better drug screening strategies, or be compiled in databases for benchmarking novel aggregation-predicting algorithms. Given that minute protocol variations determine different outcomes of protein aggregation assays, there is a strong urge for standardized descriptions of the different types of aggregates and the detailed methods used in their production. In an attempt to address this need, we assembled the Minimum Information Required for Reproducible Aggregation Experiments (MIRRAGGE) guidelines, considering first-principles and the established literature on protein self-assembly and aggregation. This consensus information aims to cover the major and subtle determinants of experimental reproducibility while avoiding excessive technical details that are of limited practical interest for non-specialized users. The MIRRAGGE table (template available in Supplementary Information) is useful as a guide for the design of new studies and as a checklist during submission of experimental reports for publication. Full disclosure of relevant information also enables other researchers to reproduce results correctly and facilitates systematic data deposition into curated databases.

    in Frontiers in Molecular Neuroscience on November 27, 2020 12:00 AM.

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    Dynamic Causal Modeling for fMRI With Wilson-Cowan-Based Neuronal Equations

    Dynamic causal modeling (DCM) is an analysis technique that has been successfully used to infer about directed connectivity between brain regions based on imaging data such as functional magnetic resonance imaging (fMRI). Most variants of DCM for fMRI rely on a simple bilinear differential equation for neural activation, making it difficult to interpret the results in terms of local neural dynamics. In this work, we introduce a modification to DCM for fMRI by replacing the bilinear equation with a non-linear Wilson-Cowan based equation and use Bayesian Model Comparison (BMC) to show that this modification improves the model evidences. Improved model evidence of the non-linear model is shown for our empirical data (imitation of facial expressions) and validated by synthetic data as well as an empirical test dataset (attention to visual motion) used in previous foundational papers. For our empirical data, we conduct the analysis for a group of 42 healthy participants who performed an imitation task, activating regions putatively containing the human mirror neuron system (MNS). In this regard, we build 540 models as one family for comparing the standard bilinear with the modified Wilson-Cowan models on the family-level. Using this modification, we can interpret the sigmoid transfer function as an averaged f-I curve of many neurons in a single region with a sigmoidal format. In this way, we can make a direct inference from the macroscopic model to detailed microscopic models. The new DCM variant shows superior model evidence on all tested data sets.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 27, 2020 12:00 AM.

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    Evaluation of a P300-Based Brain-Machine Interface for a Robotic Hand-Orthosis Control

    This work presents the design, implementation, and evaluation of a P300-based brain-machine interface (BMI) developed to control a robotic hand-orthosis. The purpose of this system is to assist patients with amyotrophic lateral sclerosis (ALS) who cannot open and close their hands by themselves. The user of this interface can select one of six targets, which represent the flexion-extension of one finger independently or the movement of the five fingers simultaneously. We tested offline and online our BMI on eighteen healthy subjects (HS) and eight ALS patients. In the offline test, we used the calibration data of each participant recorded in the experimental sessions to estimate the accuracy of the BMI to classify correctly single epochs as target or non-target trials. On average, the system accuracy was 78.7% for target epochs and 85.7% for non-target trials. Additionally, we observed significant P300 responses in the calibration recordings of all the participants, including the ALS patients. For the BMI online test, each subject performed from 6 to 36 attempts of target selections using the interface. In this case, around 46% of the participants obtained 100% of accuracy, and the average online accuracy was 89.83%. The maximum information transfer rate (ITR) observed in the experiments was 52.83 bit/min, whereas that the average ITR was 18.13 bit/min. The contributions of this work are the following. First, we report the development and evaluation of a mind-controlled robotic hand-orthosis for patients with ALS. To our knowledge, this BMI is one of the first P300-based assistive robotic devices with multiple targets evaluated on people with ALS. Second, we provide a database with calibration data and online EEG recordings obtained in the evaluation of our BMI. This data is useful to develop and compare other BMI systems and test the processing pipelines of similar applications.

    in Frontiers in Neuroscience: Neural Technology on November 27, 2020 12:00 AM.

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    Repeatability of Neural and Autonomic Responses to Acute Psychosocial Stress

    FMRI Montreal Imaging Stress Tasks (MIST) have been shown to activate endocrine and autonomic stress responses that are mediated by a prefrontal cortex (PFC)-hippocampus-amygdala circuit. However, the stability of the neurobehavioral responses over time and the ability to monitor response to clinical interventions has yet to be validated. The objective of this study was to compare the fMRI and physiologic responses to acute psychosocial stress in healthy volunteers during initial and follow-up visits approximately 13 weeks later, simulating a typical duration of clinical intervention. We hypothesized that responses to stress would remain highly conserved across the 2 visits in the absence of an intervention. 15 healthy volunteers completed a variant of control math task (CMT) and stress math task (SMT) conditions based on MIST. Neural responses were modeled using an event-related design with estimates for math performance and auditory feedback for each task condition. For each visit, measures of stress reactivity included differential fMRI and heart rate (SMT-CMT), as well as salivary alpha-amylase before and after scanning sessions. The results revealed that differential fMRI, as well as increased heart rate and salivary alpha-amylase from before and after scanning remained similar between visits. Intraclass correlation coefficient (ICC) values revealed areas of reliable task-dependent BOLD fMRI signal response across visits for peaks of clusters for the main effect of condition (SMT vs CMT) within dorsal anterior cingulate cortex (ACC), insula, and hippocampus regions during math performance and within subgenual ACC, posterior cingulate cortex, dorsolateral PFC regions during auditory feedback. Given that the neurobehavioral response to acute stress remained highly conserved across visits in the absence of an intervention, this study confirms the utility for MIST for assessing longitudinal changes in controlled trials that can identify underlying neurobiological mechanisms involved in mediating the efficacy of stress-reduction interventions.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 27, 2020 12:00 AM.

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    tVNS Increases Liking of Orally Sampled Low-Fat Foods: A Pilot Study

    Recently a role for the vagus nerve in conditioning food preferences was established in rodents. In a prospective controlled clinical trial in humans, invasive vagus nerve stimulation shifted food choice toward lower fat content. Here we explored whether hedonic aspects of an orally sampled food stimulus can be modulated by non-invasive transcutaneous vagus nerve stimulation (tVNS) in humans. In healthy participants (n = 10, five women, 20–32 years old, no obesity) we tested liking and wanting ratings of food samples with varying fat or sugar content with or without tVNS in a sham-controlled within-participants design. To determine effects of tVNS on food intake, we also measured voluntary consumption of milkshake. Spontaneous eye blink rate was measured as a proxy for dopamine tone. Liking of low-fat, but not high-fat puddings, was higher for tVNS relative to sham stimulation. Other outcomes showed no differences. These findings support a role for the vagus nerve promoting post-ingestive reward signals. Our results suggest that tVNS may be used to increase liking of low-calorie foods, which may support healthier food choices.

    in Frontiers in Human Neuroscience on November 27, 2020 12:00 AM.

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    Motor Point Stimulation in Spinal Paired Associative Stimulation can Facilitate Spinal Cord Excitability

    Paired associative stimulation at the spinal cord (spinal PAS) has been shown to increase muscle force and dexterity by strengthening the corticomuscular connection, through spike timing dependent plasticity. Typically, transcranial magnetic stimulation (TMS) and transcutaneous peripheral nerve electrical stimulation (PNS) are often used in spinal PAS. PNS targets superficial nerve branches, by which the number of applicable muscles is limited. Alternatively, a muscle can be activated by positioning the stimulation electrode on the “motor point” (MPS), which is the most sensitive location of a muscle to electrical stimulation. Although this can increase the number of applicable muscles for spinal PAS, nobody has tested whether MPS can be used for the spinal PAS to date. Here we investigated the feasibility of using MPS instead of PNS for spinal PAS. Ten healthy male individuals (26.0 ± 3.5 yrs) received spinal PAS on two separate days with different stimulation timings expected to induce (1) facilitation of corticospinal excitability (REAL) or (2) no effect (CONTROL) on the soleus. The motor evoked potentials (MEP) response curve in the soleus was measured prior to the spinal PAS, immediately after (0 min) and at 10, 20, 30 min post-intervention as a measure of corticospinal excitability. The post-intervention MEP response curve areas were larger in the REAL condition than the CONTROL conditions. Further, the post-intervention MEP response curve areas were significantly larger than pre-intervention in the REAL condition but not in the CONTROL condition. We conclude that MPS can facilitate corticospinal excitability through spinal PAS.

    in Frontiers in Human Neuroscience on November 27, 2020 12:00 AM.

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    Children With Developmental Coordination Disorder Show Altered Visuomotor Control During Stair Negotiation Associated With Heightened State Anxiety

    Safe stair negotiation is an everyday task that children with developmental coordination disorder (DCD) are commonly thought to struggle with. Yet, there is currently a paucity of research supporting these claims. We investigated the visuomotor control strategies underpinning stair negotiation in children with (N = 18, age = 10.50 ± 2.04 years) and without (N = 16, age = 10.94 ± 2.08 years) DCD by measuring kinematics, gaze behavior and state anxiety as they ascended and descended a staircase. A questionnaire was administered to determine parents' confidence in their child's ability to safely navigate stairs and their child's fall history (within the last year). Kinematics were measured using three-dimensional motion capture (Vicon), whilst gaze was measured using mobile eye-tracking equipment (Pupil labs). The parents of DCD children reported significantly lower confidence in their child's ability to maintain balance on the stairs and significantly more stair-related falls in the previous year compared to the parents of typically developing (TD) children. During both stair ascent and stair descent, the children with DCD took longer to ascend/descend the staircase and displayed greater handrail use, reflecting a more cautious stair negotiation strategy. No differences were observed between groups in their margin of stability, but the DCD children exhibited significantly greater variability in their foot-clearances over the step edge, which may increase the risk of a fall. For stair descent only, the DCD children reported significantly higher levels of state anxiety than the TD children and looked significantly further along the staircase during the initial entry phase, suggesting an anxiety-related response that may bias gaze toward the planning of future stepping actions over the accurate execution of an ongoing step. Taken together, our findings provide the first quantifiable evidence that (a) safe stair negotiation is a significant challenge for children with DCD, and that (b) this challenge is reflected by marked differences in their visuomotor control strategies and state anxiety levels. Whilst it is currently unclear whether these differences are contributing to the frequency of stair-related falls in children with DCD, our findings pave the way for future research to answer these important questions.

    in Frontiers in Human Neuroscience on November 27, 2020 12:00 AM.

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    Reduced Olfactory Bulb Volume in Obesity and Its Relation to Metabolic Health Status

    Smell perception plays an important role in eating behavior and might be involved in body weight gain. Since a body of literature implies that olfactory perception and function is hampered in obesity, we here investigate neuroanatomical correlates of this phenomenon. We assessed olfactory bulb (OB) volume with magnetic resonance imaging in 67 healthy participants with a body mass index (BMI) from 18.9 to 45.4 kg/m2 (mean = 28.58 ± 6.64). Moreover, we obtained psychophysiological data on olfactory ability (Sniffin’ Sticks, Food associated odor test) and self-report measurements on eating behavior. Additionally, we collected parameters associated with metabolic health in obesity (waist-hip ratio, waist-height ratio, leptin levels, body fat percentage, fat mass index, insulin resistance) to investigate recently proposed mechanistic explanatory models of why olfaction may be altered in obesity. We showed that OB volume was significantly lower in participants with obesity when compared to those of normal weight. Moreover, we found weak to moderate negative correlations between OB volume and BMI and related measures of metabolic health, especially leptin, body fat percentage, waist-height ratio and insulin resistance. However, neither OB volume nor BMI were related to olfactory function in our young and healthy sample. Nevertheless, our results provide first indications that obesity is associated with brain anatomical changes in the OBs.

    in Frontiers in Human Neuroscience on November 27, 2020 12:00 AM.

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    Egocentric Navigation Abilities Predict Episodic Memory Performance

    The medial temporal lobe supports both navigation and declarative memory. On this basis, a theory of phylogenetic continuity has been proposed according to which episodic and semantic memories have evolved from egocentric (e.g., path integration) and allocentric (e.g., map-based) navigation in the physical world, respectively. Here, we explored the behavioral significance of this neurophysiological model by investigating the relationship between the performance of healthy individuals on a path integration and an episodic memory task. We investigated the path integration performance through a proprioceptive Triangle Completion Task and assessed episodic memory through a picture recognition task. We evaluated the specificity of the association between performance in these two tasks by including in the study design a verbal semantic memory task. We also controlled for the effect of attention and working memory and tested the robustness of the results by including alternative versions of the path integration and semantic memory tasks. We found a significant positive correlation between the performance on the path integration the episodic, but not semantic, memory tasks. This pattern of correlation was not explained by general cognitive abilities and persisted also when considering a visual path integration task and a non-verbal semantic memory task. Importantly, a cross-validation analysis showed that participants' egocentric navigation abilities reliably predicted episodic memory performance. Altogether, our findings support the hypothesis of a phylogenetic continuity between egocentric navigation and episodic memory and pave the way for future research on the potential causal role of egocentric navigation on multiple forms of episodic memory.

    in Frontiers in Human Neuroscience on November 27, 2020 12:00 AM.

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    Psychopathological Comorbidities and Clinical Variables in Patients With Medication Overuse Headache

    The psychopathological profile of patients with medication overuse headache (MOH) appears to be particularly complex. To better define it, we evaluated their performance on a targeted psychological profile assessment. We designed a case-control study comparing MOH patients and matched healthy controls (HC). Headache frequency, drug consumption, HIT-6, and MIDAS scores were recorded. All participants filled in the following questionnaires: Beck Depression Inventory-II Edition (BDI-2), trait subtest of State-Trait Anxiety Inventory (STAI-Y), Difficulties in Emotion Regulation Scale (DERS), Barratt Impulsiveness Scale (BIS-11), Toronto Alexithymia Scale (TAS-20). The primary endpoint was to establish if MOH patients have an altered psychopathological profile. The secondary endpoint was to establish whether the worst profile correlates with the worsening of headache and disability measures. We enrolled 48 consecutive MOH patients and 48 HC. MOH patients showed greater difficulty in recognition/regulation of emotions (DERS, TAS-20), depression (BDI-2), anxiety (STAI-Y), and impulsiveness (BIS-11). We found a positive correlation among DERS, BDI-2, STAI-Y, and BIS scores and MIDAS and HIT-6 scores and among DERS and headache frequency and drug consumption. MOH patients showed a high rate of emotion regulation difficulties, depression, and anxiety, which may negatively affect their headaches. The ability to regulate/recognize emotions may play a central role in sustaining medication overuse.

    in Frontiers in Human Neuroscience on November 27, 2020 12:00 AM.

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    Afferent Projections to Area Prostriata of the Mouse

    Area prostriata plays important roles in fast detection and analysis of peripheral visual information. It remains unclear whether the prostriata directly receives and integrates information from other modalities. To gain insight into this issue, we investigated brain-wide afferent projections to mouse prostriata. We find convergent projections to layer 1 of the prostriata from primary and association visual and auditory cortices; retrosplenial, lateral entorhinal, and anterior cingulate cortices; subiculum; presubiculum; and anterior thalamic nuclei. Innervation of layers 2–3 of the prostriata mainly originates from the presubiculum (including postsubiculum) and anterior midline thalamic region. Layer 5 of the prostriata mainly receives its inputs from medial entorhinal, granular retrosplenial, and medial orbitofrontal cortices and anteromedial thalamic nucleus while layer 6 gets its major inputs from ectorhinal, postrhinal, and agranular retrosplenial cortices. The claustrum, locus coeruleus, and basal forebrain provide relatively diffuse innervation to the prostriata. Moreover, Cre-dependent tracing in cortical areas reveals that the cells of origin of the prostriata inputs are located in layers 2–4 and 5 of the neocortical areas, layers 2 and 5 of the medial entorhinal cortex, and layer 5 of the retrosplenial cortex. These results indicate that the prostriata is a unique region where primary and association visual and auditory inputs directly integrate with many limbic inputs.

    in Frontiers in Neuroanatomy on November 27, 2020 12:00 AM.

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    Hypertrophy of the Anterior External Arcuate Fasciculus: A Rare Variant With Implications for the Development of the Arcuate Nucleus

    A rare anatomic variant of a markedly enlarged anterior external arcuate fasciculus (AEAF) on the ventral medullary surface is reported and compared to two controls. The hypertrophic AEAF was nine times larger in diameter than normal, whereas the arcuate nucleus (AN) and inferior olivary nucleus (ION) appeared histologically normal in size and neuronal distribution, and morphometric analysis of the AN confirmed that it was within the normal range. Calbindin-2 (calretinin, CALB2) expression was identified in the AN and in the fibers of the normal AEAF. The hypertrophic AEAF did not contain calbindin-2–expressing fibers. CALB2 expression was also present in the ventrolateral portion of the ION, both in the index case and in one of the control cases. The origin of the additional fibers was not identified; however, the potential origin of these fibers and its implications for the development of the AEAF are discussed.

    in Frontiers in Neuroanatomy on November 27, 2020 12:00 AM.

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    HPG-Dependent Peri-Pubertal Regulation of Adult Neurogenesis in Mice

    Adult neurogenesis, a striking form of neural plasticity, is involved in the modulation of social stimuli driving reproduction. Previous studies on adult neurogenesis have shown that this process is significantly modulated around puberty in female mice. Puberty is a critical developmental period triggered by increased secretion of the gonadotropin releasing hormone (GnRH), which controls the activity of the hypothalamic-pituitary-gonadal axis (HPG). Secretion of HPG-axis factors at puberty participates to the refinement of neural circuits that govern reproduction. Here, by exploiting a transgenic GnRH deficient mouse model, that progressively loses GnRH expression during postnatal development (GnRH::Cre;DicerloxP/loxPmice), we found that a postnatally-acquired dysfunction in the GnRH system affects adult neurogenesis selectively in the subventricular-zone neurogenic niche in a sexually dimorphic way. Moreover, by examining adult females ovariectomized before the onset of puberty, we provide important evidence that, among the HPG-axis secreting factors, the circulating levels of gonadal hormones during pre-/peri-pubertal life contribute to set-up the proper adult subventricular zone-olfactory bulb neurogenic system.

    in Frontiers in Neuroanatomy on November 27, 2020 12:00 AM.

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    Propofol Requirement and EEG Alpha Band Power During General Anesthesia Provide Complementary Views on Preoperative Cognitive Decline

    Background: Although cognitive decline (CD) is associated with increased post-operative morbidity and mortality, routinely screening patients remains difficult. The main objective of this prospective study is to use the EEG response to a Propofol-based general anesthesia (GA) to reveal CD.

    Methods: 42 patients with collected EEG and Propofol target concentration infusion (TCI) during GA had a preoperative cognitive assessment using MoCA. We evaluated the performance of three variables to detect CD (MoCA < 25 points): age, Propofol requirement to induce unconsciousness (TCI at SEF95: 8–13 Hz) and the frontal alpha band power (AP at SEF95: 8–13 Hz).

    Results: The 17 patients (40%) with CD were significantly older (p < 0.001), had lower TCI (p < 0.001), and AP (p < 0.001). We found using logistic models that TCI and AP were the best set of variables associated with CD (AUC: 0.89) and performed better than age (p < 0.05). Propofol TCI had a greater impact on CD probability compared to AP, although both were complementary in detecting CD.

    Conclusion: TCI and AP contribute additively to reveal patient with preoperative cognitive decline. Further research on post-operative cognitive trajectory are necessary to confirm the interest of intra operative variables in addition or as a substitute to cognitive evaluation.

    in Frontiers in Ageing Neuroscience on November 27, 2020 12:00 AM.

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    Voxel-Based Meta-Analysis of Gray Matter Abnormalities in Multiple System Atrophy

    Purpose: This study aimed to identify consistent gray matter volume (GMV) changes in the two subtypes of multiple system atrophy (MSA), including parkinsonism subtype (MSA-P), and cerebellar subtype (MSA-C), by conducting a voxel-wise meta-analysis of whole brain voxel-based morphometry (VBM) studies.

    Method: VBM studies comparing MSA-P or MSA-C and healthy controls (HCs) were systematically searched in the PubMed, Embase, and Web of Science published from 1974 to 20 October 2020. A quantitative meta-analysis of VBM studies on MSA-P or MSA-C was performed using the effect size-based signed differential mapping (ES-SDM) method separately. A complementary analysis was conducted using the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) method, which allows a familywise error rate (FWE) correction for multiple comparisons of the results, for further validation of the results.

    Results: Ten studies were included in the meta-analysis of MSA-P subtype, comprising 136 MSA-P patients and 211 HCs. Five studies were included in the meta-analysis of MSA-C subtype, comprising 89 MSA-C patients and 134 HCs. Cerebellum atrophy was detected in both MSA-P and MSA-C, whereas basal ganglia atrophy was only detected in MSA-P. Cerebral cortex atrophy was detected in both subtypes, with predominant impairment of the superior temporal gyrus, inferior frontal gyrus, temporal pole, insula, and amygdala in MSA-P and predominant impairment of the superior temporal gyrus, middle temporal gyrus, fusiform gyrus, and lingual gyrus in MSA-C. Most of these results survived the FWE correction in the complementary analysis, except for the bilateral amygdala and the left caudate nucleus in MSA-P, and the right superior temporal gyrus and the right middle temporal gyrus in MSA-C. These findings remained robust in the jackknife sensitivity analysis, and no significant heterogeneity was detected.

    Conclusion: A different pattern of brain atrophy between MSA-P and MSA-C detected in the current study was in line with clinical manifestations and provided the evidence of the pathophysiology of the two subtypes of MSA.

    in Frontiers in Ageing Neuroscience on November 27, 2020 12:00 AM.

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    Acupuncture for the Treatment of Alzheimer's Disease: An Overview of Systematic Reviews

    Background: Acupuncture may be an effective complementary treatment for Alzheimer's disease (AD). The aim of this study was to summarize the evidence provided by systematic reviews (SRs)/meta-analyses (MAs) on the effect of acupuncture on AD.

    Methods: Eight electronic databases were searched from their inception until October 19, 2020. The methodological quality, reporting quality, and risk of bias of the included SRs were assessed by the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), the Risk of Bias in Systematic Reviews (ROBIS) tool, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Moreover, the evidence quality of the outcome measures was assessed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE).

    Results: Eleven SRs/MAs met all inclusion criteria. According to the results of the AMSTAR-2, all included reviews were rated critically as being of low quality. With PRISMA, the reporting checklist was relatively complete, but some reporting weaknesses remained in the topics of the protocol and registration, search strategy, risk of bias, additional analyses, and funding. Based on the ROBIS tool, only two SRs/MAs had a low risk of bias. With the GRADE system, no high-quality evidence was found, and only seven outcomes provided moderate-quality evidence. Among the downgraded factors, the risk of bias within the original trials was ranked first, followed by inconsistency, imprecision, and publication bias.

    Conclusions: Acupuncture is a promising complementary treatment for AD. However, due to the low quality of the SRs/MAs supporting these results, high-quality studies with rigorous study designs and larger samples are needed before widespread recommendations can be made.

    in Frontiers in Ageing Neuroscience on November 27, 2020 12:00 AM.

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    Precisely-timed dopamine signals establish distinct kinematic representations of skilled movements

    Brain dopamine is critical for normal motor control, as evidenced by its importance in Parkinson Disease and related disorders. Current hypotheses are that dopamine influences motor control by 'invigorating' movements and regulating motor learning. Most evidence for these aspects of dopamine function comes from simple tasks (e.g., lever pressing). Therefore, the influence of dopamine on motor skills requiring multi-joint coordination is unknown. To determine the effects of precisely-timed dopamine manipulations on the performance of a complex, finely coordinated dexterous skill, we optogenetically stimulated or inhibited midbrain dopamine neurons as rats performed a skilled reaching task. We found that reach kinematics and coordination between gross and fine movements progressively changed with repeated manipulations. However, once established, rats transitioned abruptly between aberrant and baseline reach kinematics in a dopamine-dependent manner. These results suggest that precisely-timed dopamine signals have immediate and long-term influences on motor skill performance, distinct from simply 'invigorating' movement.

    in eLife on November 27, 2020 12:00 AM.

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    Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+ epicardial cells

    Brain natriuretic peptide (BNP) treatment increases heart function and decreases heart dilation after myocardial infarction (MI). Here, we investigated whether part of the cardioprotective effect of BNP in infarcted hearts related to improved neovascularisation. Infarcted mice were treated with saline or BNP for 10 days. BNP treatment increased vascularisation and the number of endothelial cells in all areas of infarcted hearts. Endothelial cell lineage tracing showed that BNP directly stimulated the proliferation of resident endothelial cells via NPR-A binding and p38 MAP kinase activation. BNP also stimulated the proliferation of WT1+ epicardium-derived cells but only in the hypoxic area of infarcted hearts. Our results demonstrated that these immature cells have a natural capacity to differentiate into endothelial cells in infarcted hearts. BNP treatment increased their proliferation but not their differentiation capacity. We identified new roles for BNP that hold potential for new therapeutic strategies to improve recovery and clinical outcome after MI.

    in eLife on November 27, 2020 12:00 AM.

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    Frontal eye field and caudate neurons make different contributions to reward-biased perceptual decisions

    Many decisions require trade-offs between sensory evidence and internal preferences. Potential neural substrates include the frontal eye field (FEF) and caudate nucleus, but their distinct roles are not understood. Previously we showed that monkeys’ decisions on a direction-discrimination task with asymmetric rewards reflected a biased accumulate-to-bound decision process (Fan et al., 2018) that was affected by caudate microstimulation (Doi et al., 2020). Here we compared single-neuron activity in FEF and caudate to each other and to accumulate-to-bound model predictions derived from behavior. Task-dependent neural modulations were similar in both regions. However, choice-selective neurons in FEF, but not caudate, encoded behaviorally derived biases in the accumulation process. Baseline activity in both regions was sensitive to reward context, but this sensitivity was not reliably associated with behavioral biases. These results imply distinct contributions of FEF and caudate neurons to reward-biased decision-making and put experimental constraints on the neural implementation of accumulation-to-bound-like computations.

    in eLife on November 27, 2020 12:00 AM.

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    Functional localization and categorization of intentional decisions in humans: a meta-analysis of brain imaging studies

    Brain-imaging research on intentional decision-making often employs a free-choice paradigm, in which participants choose among options with identical values or outcomes. Although the medial prefrontal cortex has commonly been associated with choices, there is no consensus on the wider network that underlies diverse intentional decisions and behaviours. Our systematic literature search identified 39 fMRI/PET experiments using various free-choice paradigms, with appropriate control conditions using external instructions. An Activation-Likelihood-Estimate (ALE) meta-analysis showed that, compared with external instructions, intentional decisions consistently activate the medial and dorsolateral prefrontal cortex, the right insula and the inferior parietal lobule. We then categorized the studies into four different types according to their experimental designs: reactive motor intention, perceptual intention, inhibitory intention and cognitive intention. We conducted conjunction and contrast meta-analyses to identify consistent and selective brain activations within each specific category of intentional decision. Finally, we used meta-analytic decoding to probe cognitive processes underlying free choices. Our findings suggest that the neurocognitive process underlying intentional decision incorporates anatomically separated components subserving distinct cognitive and computational roles.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Microstructural underpinnings and macroscale functional implications of temporal lobe connectivity gradients

    The temporal lobe is implicated in higher cognitive processes and is one of the regions that underwent substantial reorganization during primate evolution. Its functions are instantiated, in part, by its complex layout of structural connections. This study identified low-dimensional representations of structural connectivity variations in human temporal cortex and explored their microstructural underpinnings and associations to macroscale function. We identified three eigenmodes which described gradients in structural connectivity. These gradients reflected inter-regional variations in cortical microstructure derived from quantitative MRI and post-mortem histology. Gradient-informed models accurately predicted macroscale measures of temporal lobe function. Gradients aligned closely with established measures of functional reconfiguration and areal expansion between macaques and humans, highlighting the important role evolution has played in shaping temporal lobe function. Our results provide robust evidence for three axes of structural connectivity in human temporal cortex with consistent microstructural underpinnings and contributions to large-scale brain network function.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Dependence of perceptual saccadic suppression on peri-saccadic image flow properties and luminance contrast polarity

    Across saccades, perceptual detectability of brief visual stimuli is strongly diminished. We recently observed that this perceptual suppression phenomenon is jumpstarted in the retina, suggesting that the phenomenon might be significantly more visual in nature than normally acknowledged. Here, we explicitly compared saccadic suppression strength when saccades were made across a uniform image of constant luminance versus when saccades were made across image patches of different luminance, width, and trans-saccadic luminance polarity. We measured perceptual contrast thresholds of human subjects for brief peri-saccadic flashes of positive (luminance increments) or negative (luminance decrements) polarity. Perceptual thresholds were >6-7 times higher when saccades translated a luminance stripe or edge across the retina than when saccades were made over a completely uniform image patch. Critically, both background luminance and flash luminance polarity relative to the background strongly modulated peri-saccadic contrast thresholds. In addition, all of these very same visual dependencies also occurred in the absence of any saccades, but with qualitatively similar rapid translations of image patches across the retina. Our results support the notion that perceptual saccadic suppression may be fundamentally a visual phenomenon, and they motivate neurophysiological and theoretical investigations on the role of saccadic eye movement commands in modulating its properties.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Muscle Van Gogh-like 2 shapes the neuromuscular synapse by regulating MuSK signaling activity

    The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including the morphogens of the Wnt family. Yet, how the signal of these synaptic cues is transduced, and particularly during the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane remains unclear. We explored the function of Van Gogh-Like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We showed that the conditional genetic ablation of Vangl2 in muscle reproduces the NMJ differentiation defects in mice with constitutive Vangl2 deletion. These alterations persisted into adulthood with NMJs disassembly leading to an impairment of neurotransmission and motor function deficits. Mechanistically, we found that Vangl2 and the muscle-specific kinase MuSK acted in the same genetic pathway and that Vangl2 binds MuSK, thus controlling its signaling activity. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and shed light on the molecular mechanisms underlying NMJ assembly.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Task-specific roles of local interneurons for inter -and intraglomerular signaling in the insect antennal lobe

    Local interneurons (LNs) mediate complex interactions within the antennal lobe, the primary olfactory system of insects, and the functional analog of the vertebrate olfactory bulb. In the cockroach Periplaneta Americana, as in other insects, several types of LNs with distinctive physiological and morphological properties can be defined. Here, we combined whole-cell patch clamp recordings and Ca2+ imaging of individual LNs to analyze the role of spiking and nonspiking LNs in inter- and intraglomerular signaling during olfactory information processing. Spiking GABAergic LNs reacted to odorant stimulation with a uniform rise in [Ca2+]i in the ramifications of all innervated glomeruli. In contrast, in nonspiking LNs, glomerular Ca2+ signals were odorant specific and varied between glomeruli, resulting in distinct, glomerulus-specific tuning curves. The cell type-specific differences in Ca2+ dynamics support the idea that spiking LNs play a primary role in interglomerular signaling, while they assign nonspiking LNs an essential role in intraglomerular signaling.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Enhanced virus detection and metagenomic sequencing in patients with meningitis and encephalitis

    Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional diagnostic workflows largely rely on pathogen-specific diagnostic tests, sometimes over days to weeks. Metagenomic next-generation sequencing (mNGS) is a high-throughput platform that profiles all nucleic acid in a sample. We prospectively enrolled 68 patients from New England with known or suspected CNS infection and performed mNGS from both RNA and DNA to identify potential pathogens. Using a computational metagenomic classification pipeline based on KrakenUniq and BLAST, we detected pathogen nucleic acid in cerebrospinal fluid (CSF) from 22 subjects. This included some pathogens traditionally diagnosed by serology or not typically identified in CSF, including three transmitted by Ixodes scapularis ticks (Powassan virus, Borrelia burgdorferi, Anaplasma phagocytophilum). Among 24 subjects with no clinical diagnosis, we detected enterovirus in two subjects and Epstein Barr virus in one subject. We also evaluated two methods to enhance detection of viral nucleic acid, hybrid capture and methylated DNA depletion. Hybrid capture nearly universally increased viral read recovery. Although results for methylated DNA depletion were mixed, it allowed detection of varicella zoster virus DNA in two samples that were negative by standard mNGS. Overall, mNGS is a promising approach that can test for multiple pathogens simultaneously, with similar efficacy to pathogen-specific tests, and can uncover geographically relevant infectious CNS disease, such as tick-borne infections in New England. With further laboratory and computational enhancements, mNGS may become a mainstay of workup for encephalitis and meningitis.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Hybrid Hyperalignment: A single high-dimensional model of shared information embedded in cortical patterns of response and functional connectivity

    Shared information content is represented across brains in idiosyncratic functional topographies. Hyperalignment addresses these idiosyncrasies by using neural responses to project individuals' brain data into a common model space while maintaining the geometric relationships between distinct activity patterns. The dimensions of this common model can encode any kind of functional profiles shared across individuals, such as cortical response profiles collected during a common time-locked stimulus presentation (e.g. movie viewing) or functional connectivity profiles. Performing hyperalignment with either response-based or connectivity-based input data derives transformations to project individuals' neural data from anatomical space into the common model such that functional information is optimally aligned across brains. Previously, only response or connectivity profiles were used in the derivation of these transformations. In this study, we used three separate data sets collected while participants watched feature films to derive transformations representing both response-based and connectivity-based information with a single algorithm. Our new method, hybrid hyperalignment, aligns response-based information as well as or better than response hyperalignment while simultaneously aligning connectivity-based information better than connectivity hyperalignment, all in one information space. These results suggest that a single common information space could encode both shared cortical response and functional connectivity profiles across individuals.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Pharmacologic manipulation of complement receptor 3 prevents dendritic spine loss and cognitive impairment after acute cranial radiation

    Cranial irradiation induces healthy tissue damage that can lead to neurocognitive complications and negatively impact patient quality of life. One type of damage associated with cognitive impairment is loss of neuronal spine density. Based on developmental and disease studies implicating microglia and complement in dendritic spine loss, we hypothesized that irradiation-mediated spine loss is microglial complement receptor 3 (CR3)-dependent, and associated with late-delayed cognitive deficits. Utilizing a model of cranial irradiation (acute, 10 Gy gamma) in C57BL/6 mice we found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits whereas female mice and CR3 knockout mice do not. Moreover, pharmacological blockade of CR3 with leukadherin-1 (LA1) prevented these changes in irradiated male mice. Interestingly, CR3 KO mice showed reduced behavioral task performance suggesting that CR3 is important for normal learning and memory. Improving our understanding of irradiation-mediated mechanisms and sexual dimorphic responses is essential for the identification of novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Non-linear manifold learning in fMRI uncovers a low-dimensional space of brain dynamics

    Large-scale brain dynamics are believed to lie in a latent, low-dimensional space. Typically, the embeddings of brain scans are derived independently from different cognitive tasks or resting-state data, ignoring a potentially large-and shared-portion of this space. Here, we establish that a shared, robust, and interpretable low-dimensional space of brain dynamics can be recovered from a rich repertoire of task-based fMRI data. This occurs when relying on non-linear approaches as opposed to traditional linear methods. The embedding maintains proper temporal progression of the tasks, revealing brain states and the dynamics of network integration. We demonstrate that resting-state data embeds fully onto the same task embedding, indicating similar brain states are present in both task and resting-state data. Our findings suggest analysis of fMRI data from multiple cognitive tasks in a low-dimensional space is possible and desirable, and our proposed framework can thus provide an interpretable framework to investigate brain dynamics in the low-dimensional space.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Detection of cross-frequency coupling between brain areas: an extension of phase-linearity measurement.

    The current paper proposes a method to estimate phase to phase cross-frequency coupling between brain areas, applied to broadband signals, without any a priori hypothesis about the frequency of the synchronized components. N:m synchronization is the only form of cross-frequency synchronization that allows the exchange of information at the time resolution of the faster signal, hence likely to play a fundamental role in large-scale coordination of brain activity. The proposed method, named cross-frequency phase linearity measurement (CF-PLM), builds and expands upon the phase linearity measurement, an iso-frequency connectivity metrics previously published by our group. The main idea lies in using the shape of the interferometric spectrum of the two analyzed signals in order to estimate the strength of cross-frequency coupling. Here, we demonstrate that the CF-PLM successfully retrieves the (different) frequencies of the original broadband signals involved in the connectivity process. Furthermore, if the broadband signal has some frequency components that are synchronized in iso-frequency and some others that are synchronized in cross-frequency, our methodology can successfully disentangle them and describe the behaviour of each frequency component separately. We first provide a theoretical explanation of the metrics. Then, we test the proposed metric on simulated data from coupled oscillators synchronized in iso- and cross-frequency (using both Rossler and Kuramoto oscillator models), and subsequently apply it on real data from brain activity, using source-reconstructed Magnetoencephalography (MEG) data. In the synthetic data, our results show reliable estimates even in the presence of noise and limited sample sizes. In the real signals, components synchronized in cross-frequency are retrieved, together with their oscillation frequencies. All in all, our method is useful to estimate n:m synchronization, based solely on the phase of the signals (independently of the amplitude), and no a priori hypothesis is available about the expected frequencies. Our method can be exploited to more accurately describe patterns of cross-frequency synchronization and determine the central frequencies involved in the coupling.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for axon regeneration

    Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. This results in part from a failure of central injury to elicit a pro-regenerative response in sensory neurons. However, regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the different regenerative capacities after peripheral or central injury result in part from a lack of response of macrophages, satellite glial cells (SGC) or other non-neuronal cells in the DRG microenvironment remains largely unknown. To answer this question, we performed a single cell transcriptional profiling of DRG in response to peripheral (sciatic nerve crush) and central injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to peripheral and central injuries. Activation of the PPAR signaling pathway in SGC, which promotes axon regeneration after nerve injury, did not occur after central injuries. Treatment with the FDA-approved PPARa agonist fenofibrate, increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Using distance on the Riemannian manifold to compare representations in brain and models

    Representational similarity analysis (RSA) summarizes activity patterns for a set of experimental conditions into a matrix composed of pairwise comparisons between activity patterns. Two examples of such matrices are the condition-by-condition inner product matrix or the correlation matrix. These representational matrices reside on the manifold of positive semidefinite matrices, called the Riemannian manifold. We hypothesize that representational similarities would be more accurately quantified by considering the underlying manifold of the representational matrices. Thus, we introduce the distance on the Riemannian manifold as a metric for comparing representations. Analyzing simulated and real fMRI data and considering a wide range of metrics, we show that the Riemannian distance is least susceptible to sampling bias, results in larger intra-subject reliability, and affords searchlight mapping with high sensitivity and specificity. Furthermore, we show that the Riemannian distance can be used for measuring multi-dimensional connectivity. This measure captures both univariate and multivariate connectivity and is also more sensitive to nonlinear regional interactions compared to the state-of-the-art measures. Applying our proposed metric to neural network representations of natural images, we demonstrate that it also possesses outstanding performance in quantifying similarity in models. Taken together, our results lend credence to the proposition that RSA should consider the manifold of the representational matrices to summarize response patterns in the brain and models.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Establishment of Multi-stage Models of Drug Taking and Seeking in Mice

    A major impediment to identifying the molecular substrates of addiction and developing effective therapeutics has been the lack of animal models that both recapitulate clinical disease presentation and are amenable to genetic manipulation. Intravenous self-administration is the gold standard for modeling cocaine and opioid addiction-associated behaviors in animals, but technical limitations have precluded its widespread use in mice, the mammalian species for which the most genetic tools are available. Here, we describe the establishment and demonstrate the utility of multi-stage cocaine and remifentanil paradigms that overcome classic challenges in murine intravenous self-administration. We evaluated self-administration acquisition, maintenance, extinction, and cue-induced reinstatement of drug seeking longitudinally in large cohorts of mice with indwelling catheters. In short daily sessions, mice without prior operant conditioning engaged in drug-associated lever responding that was fixed ratio- and dose-dependent, extinguished by the withholding of drugs, and reinstated by the reintroduction of paired cues. Multivariate statistics, to which this type of longitudinal data is well-suited, revealed that patterns of cocaine and remifentanil taking were similar while those of cocaine and remifentanil seeking were distinct. Individual performance in both drug paradigms was a function of two latent variables we termed incentive motivation and discriminative control. These latent variables identified drug class-specific self-administration phenotypes and were differentially predicted by a priori novelty- and drug-induced locomotor activity in the open field. Application of this behavioral and statistical analysis approach to genetically engineered mice will facilitate the identification of the cell types and neural circuits driving addictive behaviors and their underlying constructs.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Electrophysiological signatures of acute systemic lipopolysaccharide: potential implications for delirium science

    Background: Novel preventive therapies are needed for postoperative delirium, which especially affects aged patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity (SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signaling. Methods: EEG and cortical cytokine measurements (interleukin 6 [IL-6], monocyte chemoattractant protein-1 [MCP-1]) were obtained from adult and aged mice. Behavior, SWA, and functional connectivity (alpha-band weighted phase lag index) were assayed before and after systemic administration of lipopolysaccharide (LPS) +/- piroxicam (cyclooxygenase inhibitor) or caffeine (adenosine receptor antagonist). To avoid confounds from inflammation-driven changes in movement, which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching used to match distributions of movement magnitude between baseline and LPS. Results: LPS produces increases in cortical cytokines and behavioral quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: {chi}2(4)=21.51, p=0.00057), but not connectivity ({chi}2(4)=6.39, p=0.17). Increases in SWA associate with IL6 (p<0.001) and MCP-1 (p=0.001) and are suppressed by piroxicam (p<0.001) and caffeine (p=0.046). Aged animals compared to adult show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence. Conclusions: Cytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signaling may link inflammation to neural changes and hence delirium.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    Serum Metabolites Associate with Brain Amyloid Beta Deposition, Cognitive Dysfunction, and Alzheimers Disease Progression

    RATIONALE: Metabolomics in the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort provides a powerful tool for mapping biochemical changes in AD, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-{beta} deposition in AD. OBJECTIVES: We examined 140 serum metabolites and their associations with brain amyloid-{beta} deposition, cognition, and conversion from mild cognitive impairment (MCI) to AD. FINDINGS: Serum-based targeted metabolite levels were measured in 1,531 ADNI participants. We performed association analysis of metabolites with brain amyloid-{beta} deposition measured from [18F] Florbetapir PET scans. We identified nine metabolites as significantly associated with amyloid-{beta} deposition after FDR-based multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-{beta} accumulation. However, higher levels of seven phosphatidylcholines (PC) were associated with increased amyloid deposition. In addition, PC ae C44:4 was significantly associated with cognition and conversion from MCI to AD dementia. CONCLUSION: Perturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid-{beta} deposition and cognitive performance.

    in bioRxiv: Neuroscience on November 27, 2020 12:00 AM.

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    The homeostatic homunculus: rethinking deprivation-triggered reorganisation

    Publication date: April 2021

    Source: Current Opinion in Neurobiology, Volume 67

    Author(s): Dollyane Muret, Tamar R Makin

    in Current Opinion in Neurobiology on November 26, 2020 07:00 PM.

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    Passages 2021

    in Journal of Comparative Neurology on November 26, 2020 06:35 PM.

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    Chronic stress has different immediate and delayed effects on hippocampal calretinin‐ and somatostatin‐positive cells

    Abstract

    Past studies find that chronic stress alters inhibitory, GABAergic circuitry of neurons in distinct hippocampal subregions. Less clear is whether these effects persist weeks after chronic stress ends, and whether these effects involve changes in the total number of hippocampal GABAergic neurons or modulates the function of specific GABAergic subtypes. A transgenic mouse line (VGAT:Cre Ai9) containing an indelible marker for GABAergic neurons (tdTomato) throughout the brain was used to determine whether chronic stress alters total GABAergic neuronal number or the expression of two key GABAergic cell subtypes, calretinin expressing (CR+) and somatostatin expressing (SOM+) neurons, and whether these changes endure weeks later. Male and female mice were chronically stressed in wire mesh restrainers for 6h/d/21d (Str) or not (Con), and then allowed a 3 week rest period (Str‐Rest) and compared to those without a rest period (Str‐NoRest). Epifluorescent microscope images of immunohistochemistry‐processed brains were quantified to estimate the total number of fluorescently‐labeled hippocampal GABAergic neurons and the proportion that were CR+ or SOM+. Neither chronic stress nor sex altered the total number of GABAergic cells. In contrast, chronic stress reduced the expression of CR+ in the CA3 region of the hippocampus in both males and females, with robust reductions in the DG region of males, but not females, and these changes reversed following a rest period. Chronic stress also reduced the proportion of hippocampal SOM+ neurons and this reduction persisted even with a rest period. These results show chronic stress dynamically reduced CR expression without changing total inhibitory neuronal number and point to CR as a potential new lead to understand mechanisms by which chronic stress alters hippocampal function.

    in Hippocampus on November 26, 2020 01:10 PM.

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    Cover Image, Volume 30, Issue 12

    Cover Image, Volume 30, Issue 12

    Cover legend: The cover image is based on the Research Article Hebbian and non‐Hebbian timing‐dependent plasticity in the hippocampal CA3 region by Meyer B. Jackson, https://doi.org/10.1002/hipo.23252.


    in Hippocampus on November 26, 2020 01:01 PM.

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    Conjunctive representation of what and when in monkey hippocampus and lateral prefrontal cortex during an associative memory task

    Abstract

    Adaptive memory requires the organism to form associations that bridge between events separated in time. Many studies show interactions between hippocampus (HPC) and prefrontal cortex (PFC) during formation of such associations. We analyze neural recording from monkey HPC and PFC during a memory task that requires the monkey to associate stimuli separated by about a second in time. After the first stimulus was presented, large numbers of units in both HPC and PFC fired in sequence. Many units fired only when a particular stimulus was presented at a particular time in the past. These results indicate that both HPC and PFC maintain a temporal record of events that could be used to form associations across time. This temporal record of the past is a key component of the temporal coding hypothesis, a hypothesis in psychology that memory not only encodes what happened, but when it happened.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Introduction to part two of the special issue on computational models of hippocampus and related structures

    Abstract

    Extensive computational modeling has focused on the hippocampal formation and related cortical structures. This introduction describes the topics addressed by individual articles in part two of this special issue of the journal Hippocampus on the topic of computational models of the hippocampus and related structures.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Retraction: Hippocampal BDNF regulates a shift from flexible, goal‐directed to habit memory system function following cocaine abstinence

    in Hippocampus on November 26, 2020 01:01 PM.

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    NMDA receptors promote hippocampal sharp‐wave ripples and the associated coactivity of CA1 pyramidal cells

    Abstract

    Hippocampal sharp‐wave ripples (SWRs) support the reactivation of memory representations, relaying information to neocortex during “offline” and sleep‐dependent memory consolidation. While blockade of NMDA receptors (NMDAR) is known to affect both learning and subsequent consolidation, the specific contributions of NMDAR activation to SWR‐associated activity remain unclear. Here, we combine biophysical modeling with in vivo local field potential (LFP) and unit recording to quantify changes in SWR dynamics following inactivation of NMDAR. In a biophysical model of CA3‐CA1 SWR activity, we find that NMDAR removal leads to reduced SWR density, but spares SWR properties such as duration, cell recruitment and ripple frequency. These predictions are confirmed by experiments in which NMDAR‐mediated transmission in rats was inhibited using three different NMDAR antagonists, while recording dorsal CA1 LFP. In the model, loss of NMDAR‐mediated conductances also induced a reduction in the proportion of cell pairs that co‐activate significantly above chance across multiple events. Again, this prediction is corroborated by dorsal CA1 single‐unit recordings, where the NMDAR blocker ketamine disrupted correlated spiking during SWR. Our results are consistent with a framework in which NMDA receptors both promote activation of SWR events and organize SWR‐associated spiking content. This suggests that, while SWR are short‐lived events emerging in fast excitatory‐inhibitory networks, slower network components including NMDAR‐mediated currents contribute to ripple density and promote consistency in the spiking content across ripples, underpinning mechanisms for fine‐tuning of memory consolidation processes.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Interindividual differences in memory system local field potential activity predict behavioral strategy on a dual‐solution T‐maze

    Abstract

    Individuals can use diverse behavioral strategies to navigate their environment including hippocampal‐dependent place strategies reliant upon cognitive maps and striatal‐dependent response strategies reliant upon egocentric body turns. The existence of multiple memory systems appears to facilitate successful navigation across a wide range of environmental and physiological conditions. The mechanisms by which these systems interact to ultimately generate a unitary behavioral response, however, remain unclear. We trained 20 male, Sprague–Dawley rats on a dual‐solution T‐maze while simultaneously recording local field potentials that were targeted to the dorsolateral striatum and dorsal hippocampus. Eight rats spontaneously exhibited a place strategy while the remaining 12 rats exhibited a response strategy. Interindividual differences in behavioral strategy were associated with distinct patterns of LFP activity between the dorsolateral striatum and dorsal hippocampus. Specifically, striatal‐hippocampal theta activity was in‐phase in response rats and out‐of‐phase in place rats and response rats exhibited elevated striatal‐hippocampal coherence across a wide range of frequency bands. These contrasting striatal‐hippocampal activity regimes were (a) present during both maze‐learning and a 30 min premaze habituation period and (b) could be used to train support vector machines to reliably predict behavioral strategy. Distinct patterns of neuronal activity across multiple memory systems, therefore, appear to bias behavioral strategy selection and thereby contribute to interindividual differences in behavior.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Developmental onset of enduring long‐term potentiation in mouse hippocampus

    Abstract

    Analysis of long‐term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L‐LTP), lasting >3 hr, occurs abruptly at postnatal day 12 (P12) in the stratum radiatum of rat hippocampal area CA1. The goal here was to determine the developmental profile of synaptic plasticity leading to L‐LTP in the mouse hippocampus. Two mouse strains and two mutations known to affect synaptic plasticity were chosen: C57BL/6J and Fmr1 −/y on the C57BL/6J background, and 129SVE and Hevin −/− (Sparcl1 −/−) on the 129SVE background. Like rats, hippocampal slices from all of the mice showed test pulse‐induced depression early during development that was gradually resolved with maturation by 5 weeks. All the mouse strains showed a gradual progression between P10‐P35 in the expression of short‐term potentiation (STP), lasting ≤1 hr. In the 129SVE mice, L‐LTP onset (>25% of slices) occurred by 3 weeks, reliable L‐LTP (>50% slices) was achieved by 4 weeks, and Hevin −/− advanced this profile by 1 week. In the C57BL/6J mice, L‐LTP onset occurred significantly later, over 3–4 weeks, and reliability was not achieved until 5 weeks. Although some of the Fmr1 −/y mice showed L‐LTP before 3 weeks, reliable L‐LTP also was not achieved until 5 weeks. L‐LTP onset was not advanced in any of the mouse genotypes by multiple bouts of theta‐burst stimulation at 90 or 180 min intervals. These findings show important species differences in the onset of STP and L‐LTP, which occur at the same age in rats but are sequentially acquired in mice.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Recurrent amplification of grid‐cell activity

    Abstract

    High‐level cognitive abilities such as navigation and spatial memory are thought to rely on the activity of grid cells in the medial entorhinal cortex (MEC), which encode the animal's position in space with periodic triangular patterns. Yet the neural mechanisms that underlie grid‐cell activity are still unknown. Recent in vitro and in vivo experiments indicate that grid cells are embedded in highly structured recurrent networks. But how could recurrent connectivity become structured during development? And what is the functional role of these connections? With mathematical modeling and simulations, we show that recurrent circuits in the MEC could emerge under the supervision of weakly grid‐tuned feedforward inputs. We demonstrate that a learned excitatory connectivity could amplify grid patterns when the feedforward sensory inputs are available and sustain attractor states when the sensory cues are lost. Finally, we propose a Fourier‐based measure to quantify the spatial periodicity of grid patterns: the grid‐tuning index.

    in Hippocampus on November 26, 2020 01:01 PM.

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    The function of medial temporal lobe and posterior middle temporal gyrus in forming creative associations

    Abstract

    Although the function of the hippocampus and adjacent medial temporal lobe (MTL) areas in forming associations is generally recognized, how MTL contributes to form creative associations that could result in novel and appropriate functions or meanings remains unclear. In this study, we compared highly creative combinations (HCCs) of two objects (e.g., that of “lifejacket” and “distress signal device”) that resulted in genuine innovative designs comprising additionally unprecedented functions (the “1 + 1 > 2” effects) with the lowly creative combinations (LCCs, e.g., the combination of “set‐top box” and “jewelry box”) that resulted in nothing more than simple “1 + 1 = 2” effects. The event‐related functional magnetic resonance imaging (fMRI) study found that during the “early binding phase,” when the combinations of the two objects were initially encoded, the right parahippocampus was more intensively activated during the encoding of HCC relative to LCC trials. However, during the “late integration phase,” when participants finally formed a holistic mental representation of new products based on the two‐object combinations, both HCCs and LCCs were found to be associated with significantly increased hippocampal and parahippocampal activation relative to the baseline condition, but at a similar level. In this “late integration phase,” the functional areas appeared to be more intensively activated in HCCs relative to LCCs located in the posterior middle temporal gyrus (pMTG), the area known to mediate category‐related processing. Consistently, our supplementary behavioral study found that, relative to LCCs, HCCs had a higher possibility of resulting in some new conceptual expansions that differed from each of the original two objects that constituted the combinations. These findings indicate that the formation of creative combinations not only require MTL‐based novel association‐formation, but also pMTG‐based novel concept‐expansion.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Hebbian and non‐Hebbian timing‐dependent plasticity in the hippocampal CA3 region

    Abstract

    The timing between synaptic inputs has been proposed to play a role in the induction of plastic changes that enable neural circuits to store information. In the case of spike timing‐dependent plasticity (STDP), this relates to the interval between a synaptic input and a postsynaptic spike, thus providing a conceptual link to the Hebb learning rule. Experiments have documented STDP in many synapses and brain regions, and computational models have tested its utility in many neural network functions. However, questions remain about whether timing plays a role in plasticity during natural activity, and whether it can function in information storage. The present study used imaging with voltage sensitive dye to investigate the effectiveness of input timing in the plasticity of responses in the CA3 region of hippocampal slices. Plasticity was induced by sequential dual‐site stimulation at 10 ms intervals of either synaptic inputs and cell bodies (synaptic–somatic induction) or of two sets of synaptic inputs (synaptic–synaptic induction). Both protocols potentiated responses, with greater potentiation of responses to the first stimulation of the sequence than the second. Neither of these protocols induced depression. Synaptic–somatic stimulation was much more effective than synaptic–synaptic stimulation in evoking somatic action potentials, but both protocols potentiated responses equally well. This suggests that sequential dual‐site stimulation can potentiate equally well with very different degrees of somatic action potential firing. With synaptic–somatic induction, potentiation was focused at the sites of stimulation. In contrast, with synaptic–synaptic induction, the distribution of potentiation varied greatly. Changes in the spatial distribution of responses indicated that sequential dual‐site stimulation functions poorly in the storage of activity patterns. These results suggest that in the hippocampal CA3 region, timed sequential activation of two inputs is less effective than theta bursts, both in the induction of LTP and in the storage of information.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Neurobiological successor features for spatial navigation

    Abstract

    The hippocampus has long been observed to encode a representation of an animal's position in space. Recent evidence suggests that the nature of this representation is somewhat predictive and can be modeled by learning a successor representation (SR) between distinct positions in an environment. However, this discretization of space is subjective making it difficult to formulate predictions about how some environmental manipulations should impact the hippocampal representation. Here, we present a model of place and grid cell firing as a consequence of learning a SR from a basis set of known neurobiological features—boundary vector cells (BVCs). The model describes place cell firing as the successor features of the SR, with grid cells forming a low‐dimensional representation of these successor features. We show that the place and grid cells generated using the BVC‐SR model provide a good account of biological data for a variety of environmental manipulations, including dimensional stretches, barrier insertions, and the influence of environmental geometry on the hippocampal representation of space.

    in Hippocampus on November 26, 2020 01:01 PM.

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    Issue Information ‐ TOC

    in Hippocampus on November 26, 2020 01:01 PM.

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    Issue Information ‐ Editorial Board

    in Hippocampus on November 26, 2020 01:01 PM.

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    Network Fingerprint of Stimulation‐Induced Speech Impairment in Essential Tremor

    Objective

    This study was undertaken to gain insights into structural networks associated with stimulation‐induced dysarthria (SID) and to predict stimulation‐induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS).

    Methods

    Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation‐induced worsening of intelligibility in a structural connectome. The resulting fiber‐based atlas structure was then validated in a leave‐one‐out design.

    Results

    Fibers determined as discriminative for stimulation‐induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al‐Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p < 0.001) of the variance of stimulation‐induced change in intelligibility in a leave‐one‐out analysis.

    Interpretation

    This study demonstrates that SID in essential tremor patients is associated with both motor cortex and cerebellar connectivity. Furthermore, the identified fiber‐based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in essential tremor patients with thalamic DBS. ANN NEUROL 2020

    in Annals of Neurology on November 26, 2020 11:51 AM.

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    Unsupervised Object Keypoint Learning using Local Spatial Predictability. (arXiv:2011.12930v1 [cs.CV])

    We propose PermaKey, a novel approach to representation learning based on object keypoints. It leverages the predictability of local image regions from spatial neighborhoods to identify salient regions that correspond to object parts, which are then converted to keypoints. Unlike prior approaches, it utilizes predictability to discover object keypoints, an intrinsic property of objects. This ensures that it does not overly bias keypoints to focus on characteristics that are not unique to objects, such as movement, shape, colour etc. We demonstrate the efficacy of PermaKey on Atari where it learns keypoints corresponding to the most salient object parts and is robust to certain visual distractors. Further, on downstream RL tasks in the Atari domain we demonstrate how agents equipped with our keypoints outperform those using competing alternatives, even on challenging environments with moving backgrounds or distractor objects.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 26, 2020 01:30 AM.

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    Contrastive Representation Learning for Whole Brain Cytoarchitectonic Mapping in Histological Human Brain Sections. (arXiv:2011.12865v1 [eess.IV])

    Cytoarchitectonic maps provide microstructural reference parcellations of the brain, describing its organization in terms of the spatial arrangement of neuronal cell bodies as measured from histological tissue sections. Recent work provided the first automatic segmentations of cytoarchitectonic areas in the visual system using Convolutional Neural Networks. We aim to extend this approach to become applicable to a wider range of brain areas, envisioning a solution for mapping the complete human brain. Inspired by recent success in image classification, we propose a contrastive learning objective for encoding microscopic image patches into robust microstructural features, which are efficient for cytoarchitectonic area classification. We show that a model pre-trained using this learning task outperforms a model trained from scratch, as well as a model pre-trained on a recently proposed auxiliary task. We perform cluster analysis in the feature space to show that the learned representations form anatomically meaningful groups.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Anytime Prediction as a Model of Human Reaction Time. (arXiv:2011.12859v1 [cs.AI])

    Neural networks today often recognize objects as well as people do, and thus might serve as models of the human recognition process. However, most such networks provide their answer after a fixed computational effort, whereas human reaction time varies, e.g. from 0.2 to 10 s, depending on the properties of stimulus and task. To model the effect of difficulty on human reaction time, we considered a classification network that uses early-exit classifiers to make anytime predictions. Comparing human and MSDNet accuracy in classifying CIFAR-10 images in added Gaussian noise, we find that the network equivalent input noise SD is 15 times higher than human, and that human efficiency is only 0.6\% that of the network. When appropriate amounts of noise are present to bring the two observers (human and network) into the same accuracy range, they show very similar dependence on duration or FLOPS, i.e. very similar speed-accuracy tradeoff. We conclude that Anytime classification (i.e. early exits) is a promising model for human reaction time in recognition tasks.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Low Latency CMOS Hardware Acceleration for Fully Connected Layers in Deep Neural Networks. (arXiv:2011.12839v1 [cs.AR])

    We present a novel low latency CMOS hardware accelerator for fully connected (FC) layers in deep neural networks (DNNs). The FC accelerator, FC-ACCL, is based on 128 8x8 or 16x16 processing elements (PEs) for matrix-vector multiplication, and 128 multiply-accumulate (MAC) units integrated with 128 High Bandwidth Memory (HBM) units for storing the pretrained weights. Micro-architectural details for CMOS ASIC implementations are presented and simulated performance is compared to recent hardware accelerators for DNNs for AlexNet and VGG 16. When comparing simulated processing latency for a 4096-1000 FC8 layer, our FC-ACCL is able to achieve 48.4 GOPS (with a 100 MHz clock) which improves on a recent FC8 layer accelerator quoted at 28.8 GOPS with a 150 MHz clock. We have achieved this considerable improvement by fully utilizing the HBM units for storing and reading out column-specific FClayer weights in 1 cycle with a novel colum-row-column schedule, and implementing a maximally parallel datapath for processing these weights with the corresponding MAC and PE units. When up-scaled to 128 16x16 PEs, for 16x16 tiles of weights, the design can reduce latency for the large FC6 layer by 60 % in AlexNet and by 3 % in VGG16 when compared to an alternative EIE solution which uses compression.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 26, 2020 01:30 AM.

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    External Electromagnetic Wave Excitation of a PreSynaptic Neuron Based on LIF model. (arXiv:2011.12832v1 [q-bio.NC])

    Interaction of electromagnetic (EM) waves with human tissue has been a longstanding research topic for electrical and biomedical engineers. However, few numbers of publications discuss the impacts of external EM-waves on neural stimulation and communication through the nervous system. In fact, complex biological neural channels are a main barrier for intact and comprehensive analyses in this area. One of the everpresent challenges in neural communication responses is dependency of vesicle release probability on the input spiking pattern. In this regard, this study sheds light on consequences of changing the frequency of external EM-wave excitation on the post-synaptic neuron's spiking rate. It is assumed that the penetration depth of the wave in brain does not cover the postsynaptic neuron. Consequently, we model neurotransmission of a bipartite chemical synapse. In addition, the way that external stimulation affects neurotransmission is examined. Unlike multiple frequency component EM-waves, the monochromatic incident wave does not face frequency shift and distortion in dispersive media. In this manner, a single frequency signal is added as external current in the modified leaky integrated-andfire (LIF) model. The results demonstrate existence of a node equilibrium point in the first order dynamical system of LIF model. A fold bifurcation (for presupposed LIF model values) occurs when the external excitation frequency is near 200 Hz. The outcomes provided in this paper enable us to select proper frequency excitation for neural signaling. Correspondingly, the cut-off frequency reliance on elements' values in LIF circuit is found.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Computational Model of Motion Sickness Describing the Effects of Learning Exogenous Motion Dynamics. (arXiv:2011.12826v1 [q-bio.QM])

    The existing computational models used to estimate motion sickness are incapable of describing the fact that the predictability of motion patterns affects motion sickness. Therefore, the present study proposes a computational model to describe the effect of the predictability of dynamics or the pattern of motion stimuli on motion sickness. In the proposed model, a submodel, in which a recursive Gaussian process regression is used to represent human features of online learning and future prediction of motion dynamics, is combined with a conventional model of motion sickness based on an observer theory. A simulation experiment was conducted in which the proposed model predicted motion sickness caused by a 900 s horizontal movement. The movement was composed of a 9 m repetitive back-and-forth movement pattern with a pause. Regarding the motion condition, the direction and timing of the motion were varied as follows: a) Predictable motion (M_P): the direction of the motion and duration of the pause were set to 8 s; b) Motion with unpredicted direction (M_dU): the pause duration was fixed as in (P), but the motion direction was randomly determined; c) Motion with unpredicted timing (M_tU): the motion direction was fixed as in (M_P), but the pause duration was randomly selected from 4 to 12 s. The results obtained using the proposed model demonstrated that the predicted motion sickness incidence for (M_P) was smaller than those for (M_dU) and (M_tU). This tendency agrees with the sickness patterns observed in a previous experimental study in which the human participants were subject to motion conditions similar to those used in our simulations. Moreover, no significant differences were found in the predicted motion sickness incidences at different conditions when the conventional model was used.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Postnatal functional inactivation of the ventral subiculum enhances dopaminergic responses in the core part of the nucleus accumbens following ketamine injection in adult rats. (arXiv:2011.12789v1 [q-bio.NC])

    For almost two decades schizophrenia has been considered to be a functional disconnection disorder. This functional disconnectivity between several brain regions could have a neurodevelopmental origin. Various approaches suggest the ventral subiculum (SUB) is a particular target region for neurodevelopemental disturbances in schizophrenia. It is also commonly acknowledged that there is a striatal dopaminergic (DA) dysregulation in schizophrenia which may depend on a subiculo-striatal disconnection involving glutamatergic NMDA receptors. The present study was designed to investigate, in adult rats, the effects of the non-competitive NMDA receptor antagonist ketamine on DA responses in the ventral striatum, or, more specifically, the core part of the nucleus accumbens (Nacc), following postnatal functional inactivation of the SUB. Functional inactivation of the left SUB was carried out by local tetrodotoxin (TTX) microinjection at postnatal day 8 (PND8), i.e. at a critical point in the neurodevelopmental period. DA variations were recorded using in vivo voltammetry in freely moving adult rats (11 weeks). Locomotor activity was recorded simultaneously with the extracellular levels of DA in the core part of the Nacc. Data obtained during the present study showed that after administration of ketamine, the two indexes were higher in TTX animals than PBS animals, the suggestion being that animals microinjected with TTX in the left SUB at PND8 present greater reactivity to ketamine than animals microinjected with PBS. These findings could provide new information regarding the involvement of NMDA glutamatergic receptors in the core part of the Nacc in the pathophysiology of schizophrenia.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Great expectations in music: violation of rhythmic expectancies elicits late frontal gamma activity nested in theta oscillations. (arXiv:2011.12676v1 [q-bio.NC])

    Rhythm processing involves building expectations according to the hierarchical temporal structure of auditory events. Although rhythm processing has been addressed in the context of predictive coding, the properties of the oscillatory response in different cortical areas is still not clear. We explored the oscillatory properties of the neural response to rhythmic incongruence and explored the cross-frequency coupling between multiple frequencies to provide links between the concepts of predictive coding and rhythm perception. We designed an experiment to investigate the neural response to rhythmic deviations in which the tone either arrived earlier than expected or the tone in the same metrical position was omitted. These two manipulations modulate the rhythmic structure differently, with the former creating a larger violation of the general structure of the musical stimulus than the latter. Both deviations resulted in an MMN response, whereas only the rhythmic deviant resulted in a subsequent P3a. Rhythmic deviants due to the early occurrence of a tone, but not omission deviants, elicited a late high gamma response (60-80 Hz) at the end of the P3a over the left frontal region, which, interestingly, correlated with the P3a amplitude over the same region and was also nested in theta oscillations. The timing of the elicited high-frequency gamma oscillations related to rhythmic deviation suggests that it might be related to the update of the predictive neural model, corresponding to the temporal structure of the events in higher-level cortical areas.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Modeling the Evolution of Retina Neural Network. (arXiv:2011.12448v1 [cs.NE])

    Vital to primary visual processing, retinal circuitry shows many similar structures across a very broad array of species, both vertebrate and non-vertebrate, especially functional components such as lateral inhibition. This surprisingly conservative pattern raises a question of how evolution leads to it, and whether there is any alternative that can also prompt helpful preprocessing. Here we design a state-of-the-art method using genetic algorithm that, with many degrees of freedom, leads to architectures whose functions are similar to biological retina, as well as effective alternatives that are different in structures and functions. We compare this state-of-the-art model to natural evolution and discuss how our framework can come into goal-driven search and sustainable enhancement of neural network models in machine learning.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 26, 2020 01:30 AM.

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    PeleNet: A Reservoir Computing Framework for Loihi. (arXiv:2011.12338v1 [cs.NE])

    High-level frameworks for spiking neural networks are a key factor for fast prototyping and efficient development of complex algorithms. Such frameworks have emerged in the last years for traditional computers, but programming neuromorphic hardware is still a challenge. Often low level programming with knowledge about the hardware of the neuromorphic chip is required. The PeleNet framework aims to simplify reservoir computing for the neuromorphic hardware Loihi. It is build on top of the NxSDK from Intel and is written in Python. The framework manages weight matrices, parameters and probes. In particular, it provides an automatic and efficient distribution of networks over several cores and chips. With this, the user is not confronted with technical details and can concentrate on experiments.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 26, 2020 01:30 AM.

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    Persistence of hierarchical network organization and emergent topologies in models of functional connectivity. (arXiv:2003.04741v2 [cond-mat.dis-nn] UPDATED)

    Functional networks provide a topological description of activity patterns in the brain, as they stem from the propagation of neural activity on the anatomical, or structural network of synaptic connections. This last is well known to be organized in hierarchical and modular way. While it is assumed that structural networks shape their functional counterparts, it is also hypothesized that alterations of brain dynamics come with transformations of functional connectivity. In this computational study, we introduce a novel methodology to monitor the persistence and breakdown of hierarchical order in functional networks, generated from computational models of activity spreading on both synthetic and real structural connectomes. We show that hierarchical connectivity appears in functional networks in a persistent way if the dynamics is set to be in the quasi-critical regime associated with optimal processing capabilities and normal brain function, while it breaks down in other (supercritical) dynamical regimes, often associated with pathological conditions. Our results offer important clues for the study of optimal neurocomputing architectures and processes, which are capable of controlling patterns of activity and information flow. We conclude that functional connectivity patterns achieve optimal balance between local specialized processing and global integration, by inheriting the hierarchical organization of the underlying structural architecture.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 26, 2020 01:30 AM.

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    Publisher Correction: HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-20152-w

    Publisher Correction: HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains

    in Nature Communications on November 26, 2020 12:00 AM.

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    Author Correction: Chemical trends of deep levels in van der Waals semiconductors

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-20151-x

    Author Correction: Chemical trends of deep levels in van der Waals semiconductors

    in Nature Communications on November 26, 2020 12:00 AM.

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    Author Correction: Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-20129-9

    Author Correction: Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy

    in Nature Communications on November 26, 2020 12:00 AM.

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    Scalable thermoelectric fibers for multifunctional textile-electronics

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19867-7

    Despite the potential of incorporating thermoelectric (TE) fibers into textile electronics for green energy harvesting, existing fabrication methods are not commercially viable. Here, the authors report a scalable gelation extrusion fabrication strategy for realizing alternating p/n-type TE fibers.

    in Nature Communications on November 26, 2020 12:00 AM.

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    Rapid de novo evolution of lysis genes in single-stranded RNA phages

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19860-0

    Leviviruses are phages with ssRNA genomes that encode a protein (Sgl) that induces host autolysis by interfering with bacterial cell wall synthesis. Identification of sgl genes is complicated by their small size and lack of sequence similarity. Here, Chamakura et al. use bioinformatic and experimental approaches to identify sgl genes in 244 leviviral genomes.

    in Nature Communications on November 26, 2020 12:00 AM.

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    Empowering alcohols as carbonyl surrogates for Grignard-type reactions

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19857-9

    Alcohols are more naturally abundant than carbonyl compounds, which in turn are well known for their reactivity in Grignard reactions. Here, the authors showcase a distinct Grignard-like reactivity by using alcohols as coupling partners with hydrazones and synthesize more complex alcohols under ruthenium catalysis.

    in Nature Communications on November 26, 2020 12:00 AM.

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    Unraveling the influence of non-fullerene acceptor molecular packing on photovoltaic performance of organic solar cells

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19853-z

    Non-fullerene acceptors are crucial for realising efficient charge transport and high power conversion in organic solar cells, yet the relationship of molecular packing and carrier transport is not well-understood. Here, the authors study the effect of side-chain engineering on the backbone assembly and the corresponding charge transport pathway.

    in Nature Communications on November 26, 2020 12:00 AM.

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    Atomically precise nanoclusters with reversible isomeric transformation for rotary nanomotors

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19789-4

    Atomically precise metal nanoclusters are an emerging class of precision nanomaterials and hold potential in many applications. Here, the authors devise a [Au13Ag12(PPh3)10Cl8]+ nanocluster with two conformational isomers that can reversibly convert in response to temperature, and hence acts as a rotary nanomotor.

    in Nature Communications on November 26, 2020 12:00 AM.

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    Direct RNA sequencing reveals m6A modifications on adenovirus RNA are necessary for efficient splicing

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19787-6

    Adenovirus transcripts contain N6-methyladenosine (m6A) modification. Here the authors profile m6A modification sites on adenovirus mRNAs using Illumina meRIP-Seq and nanopore direct RNA sequencing, and showcase a role for m6A in splicing of viral late mRNAs.

    in Nature Communications on November 26, 2020 12:00 AM.

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    A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

    Nature Communications, Published online: 26 November 2020; doi:10.1038/s41467-020-19782-x

    Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells.

    in Nature Communications on November 26, 2020 12:00 AM.

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    Daily briefing: Japan’s ‘cluster busting’ COVID strategy might have hit its limits

    Nature, Published online: 26 November 2020; doi:10.1038/d41586-020-03363-5

    Is Japan’s COVID lucky streak nearing its end? Plus, questions besiege the Oxford–AstraZeneca COVID vaccine and how to build an unofficial board of mentors.

    in Nature on November 26, 2020 12:00 AM.

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    How I run a lab and work as a PhD student simultaneously

    Nature, Published online: 26 November 2020; doi:10.1038/d41586-020-03358-2

    Oday Abushalbaq outlines his experience leading a team of neuroscience researchers from 9,000 kilometres away — while completing his PhD training.

    in Nature on November 26, 2020 12:00 AM.

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    How mud volcanoes are born under the sea

    Nature, Published online: 26 November 2020; doi:10.1038/d41586-020-03346-6

    Trapped gas causes buried sediments to flow like water, rising and erupting dangerously at the sea floor.

    in Nature on November 26, 2020 12:00 AM.

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    Hopf Bifurcation in Mean Field Explains Critical Avalanches in Excitation-Inhibition Balanced Neuronal Networks: A Mechanism for Multiscale Variability

    Cortical neural circuits display highly irregular spiking in individual neurons but variably sized collective firing, oscillations and critical avalanches at the population level, all of which have functional importance for information processing. Theoretically, the balance of excitation and inhibition inputs is thought to account for spiking irregularity and critical avalanches may originate from an underlying phase transition. However, the theoretical reconciliation of these multilevel dynamic aspects in neural circuits remains an open question. Herein, we study excitation-inhibition (E-I) balanced neuronal network with biologically realistic synaptic kinetics. It can maintain irregular spiking dynamics with different levels of synchrony and critical avalanches emerge near the synchronous transition point. We propose a novel semi-analytical mean-field theory to derive the field equations governing the network macroscopic dynamics. It reveals that the E-I balanced state of the network manifesting irregular individual spiking is characterized by a macroscopic stable state, which can be either a fixed point or a periodic motion and the transition is predicted by a Hopf bifurcation in the macroscopic field. Furthermore, by analyzing public data, we find the coexistence of irregular spiking and critical avalanches in the spontaneous spiking activities of mouse cortical slice in vitro, indicating the universality of the observed phenomena. Our theory unveils the mechanism that permits complex neural activities in different spatiotemporal scales to coexist and elucidates a possible origin of the criticality of neural systems. It also provides a novel tool for analyzing the macroscopic dynamics of E-I balanced networks and its relationship to the microscopic counterparts, which can be useful for large-scale modeling and computation of cortical dynamics.

    in Frontiers in Systems Neuroscience on November 26, 2020 12:00 AM.

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    BrainWave Nets: Are Sparse Dynamic Models Susceptible to Brain Manipulation Experimentation?

    Sparse time series models have shown promise in estimating contemporaneous and ongoing brain connectivity. This paper was motivated by a neuroscience experiment using EEG signals as the outcome of our established interventional protocol, a new method in neurorehabilitation toward developing a treatment for visual verticality disorder in post-stroke patients. To analyze the [complex outcome measure (EEG)] that reflects neural-network functioning and processing in more specific ways regarding traditional analyses, we make a comparison among sparse time series models (classic VAR, GLASSO, TSCGM, and TSCGM-modified with non-linear and iterative optimizations) combined with a graphical approach, such as a Dynamic Chain Graph Model (DCGM). These dynamic graphical models were useful in assessing the role of estimating the brain network structure and describing its causal relationship. In addition, the class of DCGM was able to visualize and compare experimental conditions and brain frequency domains [using finite impulse response (FIR) filter]. Moreover, using multilayer networks, the results corroborate with the susceptibility of sparse dynamic models, bypassing the false positives problem in estimation algorithms. We conclude that applying sparse dynamic models to EEG data may be useful for describing intervention-relocated changes in brain connectivity.

    in Frontiers in Systems Neuroscience on November 26, 2020 12:00 AM.

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    Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

    Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

    in Frontiers in Molecular Neuroscience on November 26, 2020 12:00 AM.

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    A Functional Comparison of Homopentameric Nicotinic Acetylcholine Receptors (ACR-16) Receptors From Necator americanus and Ancylostoma ceylanicum

    Effective control of hookworm infections in humans and animals relies on using a small group of anthelmintics. Many of these drugs target cholinergic ligand-gated ion channels, yet the direct activity of anthelmintics has only been studied in a subset of these receptors, primarily in the non-parasitic nematode, Caenorhabditis elegans. Here we report the characterization of a homopentameric ionotropic acetylcholine receptor (AChR), ACR-16, from Necator americanus and Ancylostoma ceylanicum, the first known characterization of human hookworm ion channels. We used two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes to determine the pharmacodynamics of cholinergics and anthelmintics on ACR-16 from both species of hookworm. The A. ceylanicum receptor (Ace-ACR-16) was more sensitive to acetylcholine (EC50 = 20.64 ± 0.32 μM) and nicotine (EC50 = 24.37 ± 2.89 μM) than the N. americanus receptor (Nam-ACR-16) (acetylcholine EC50 = 170.1 ± 19.23 μM; nicotine EC50 = 597.9 ± 59.12 μM), at which nicotine was a weak partial agonist (% maximal acetylcholine response = 30.4 ± 7.4%). Both receptors were inhibited by 500 μM levamisole (Ace-ACR-16 = 65.1 ± 14.3% inhibition, Nam-ACR-16 = 79.5 ± 7.7% inhibition), and responded to pyrantel, but only Ace-ACR-16 responded to oxantel. We used in silico homology modeling to investigate potential structural differences that account for the differences in agonist binding and identified a loop E isoleucine 130 of Nam-ACR-16 as possibly playing a role in oxantel insensitivity. These data indicate that key functional differences exist among ACR-16 receptors from closely related species and suggest mechanisms for differential drug sensitivity.

    in Frontiers in Molecular Neuroscience on November 26, 2020 12:00 AM.

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    A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade

    Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and Amyotrophic Lateral Sclerosis. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.

    in Frontiers in Molecular Neuroscience on November 26, 2020 12:00 AM.

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    Local Secretory Trafficking Pathways in Neurons and the Role of Dendritic Golgi Outposts in Different Cell Models

    A fundamental characteristic of neurons is the relationship between the architecture of the polarized neuron and synaptic transmission between neurons. Intracellular membrane trafficking is paramount to establish and maintain neuronal structure; perturbation in trafficking results in defects in neurodevelopment and neurological disorders. Given the physical distance from the cell body to the distal sites of the axon and dendrites, transport of newly synthesized membrane proteins from the central cell body to their functional destination at remote, distal sites represents a conundrum. With the identification of secretory organelles in dendrites, including endoplasmic reticulum (ER) and Golgi outposts (GOs), recent studies have proposed local protein synthesis and trafficking distinct from the conventional anterograde transport pathways of the cell body. A variety of different model organisms, including Drosophila, zebrafish, and rodents, have been used to probe the organization and function of the local neuronal secretory network. Here, we review the evidence for local secretory trafficking pathways in dendrites in a variety of cell-based neuronal systems and discuss both the similarities and differences in the organization and role of the local secretory organelles, especially the GOs. In addition, we identify the gaps in the current knowledge and the potential advances using human induced pluripotent stem cells (iPSCs) in defining local membrane protein trafficking in human neurons and in understanding the molecular basis of neurological diseases.

    in Frontiers in Molecular Neuroscience on November 26, 2020 12:00 AM.

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    Evaluating Sensory Integration/Sensory Processing Treatment: Issues and Analysis

    For more than 50 years, “Sensory Integration” has been a theoretical framework for diagnosing and treating disabilities in children under the umbrella of “sensory integration dysfunction” (SID). More recently, the approach has been reframed as “the dimensions of sensory processing” or SPD in place of SID, so the review herein describes this collective framework as sensory integration/sensory processing treatment (SI/SP-T) for ASD. This review is not focused on diagnosis of SI/SPD. Broadly, the SI/SPD intervention approach views a plethora of disabilities such as ADHD, ASD, and disruptive behavior as being exacerbated by difficulties in modulating and integrating sensory input with a primary focus on contributions from tactile, proprioceptive, and vestibular systems which are hypothesized to contribute to core symptoms of the conditions (e.g., ASD). SI/SP intervention procedures include sensory protocols designed to enhance tactile, proprioceptive, and vestibular experiences. SI/SP-T procedures utilize equipment (e.g., lycra swings, balance beams, climbing walls, and trampolines), specific devices (e.g., weighted vests, sensory brushes) and activities (e.g., placing hands in messy substances such as shaving cream, sequenced movements) hypothesized to enhance sensory integration and sensory processing. The approach is reviewed herein to provide a framework for testing SI/SP-T using widely accepted clinical trials and event coding methods used in applied behavior analysis (ABA) and other behavioral interventions. Also, a related but distinct neuroscientific paradigm, multisensory integration, is presented as an independent test of whether SI/SP-T differentially impacts sensory integration and/or multisensory integration. Finally, because SI/SP-T activities include many incidental behavioral events that are known as developmental facilitators (e.g., contingent verbal models/recasts during verbal interactions), there is a compelling need to control for confounds to study the unique impact of sensory-based interventions. Note that SI/SP-T includes very specific and identifiable procedures and materials, so it is reasonable to expect high treatment fidelity when testing the approach. A patient case is presented that illustrates this confound with a known facilitator (recast intervention) and a method for controlling potential confounds in order to conduct unbiased studies of the effects of SI/SP-T approaches that accurately represent SI/SP-T theories of change.

    in Frontiers in Integrative Neuroscience on November 26, 2020 12:00 AM.

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    Comparing the Impact of Laparoscopic Sleeve Gastrectomy and Gastric Cancer Surgery on Resting-State Brain Activity and Functional Connectivity

    Laparoscopic sleeve gastrectomy (LSG) is one of the most performed bariatric surgeries in clinical practice. Growing neuroimaging evidence shows that LSG induces brain functional and structural alterations accompany with sustained weight-loss. Meanwhile, for clinical treatment of gastric cancer, stomach removal surgery is a similar procedure to LSG. It is unclear if the gastric cancer surgery (GCS) would induce the similar alterations in brain functions and structures as LSG, and it would help to clarify the specificity of the LSG. We recruited 24 obese patients who received LSG in the LSG group and 16 normal weight patients with gastric cancer who received GCS as the control group. Functional magnetic resonance imaging was employed to investigate the differences and similarity of surgery’s impact on resting-state brain activity and functional connectivity (RSFC) between LSG and GCS groups. Both LSG and GCS groups showed increased activities in the posterior cingulate cortex (PCC) and supplementary motor area (SMA) as well as the decreased RSFC of PCC- dorsomedial prefrontal cortex and SMA- dorsolateral prefrontal cortex. There were decreased resting-state activity of hippocampus and putamen in LSG group and increases in GCS group. In LSG group, resting-state activities of hippocampus and putamen were correlated with craving for high-caloric food and body mass index after surgery, respectively. These findings suggest LSG induced alterations in resting-state activity and RSFC of hippocampus and putamen specifically regulate the obese state and overeating behaviors in obese patients.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 26, 2020 12:00 AM.

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    Is So Called “Split Alpha” in EEG Spectral Analysis a Result of Methodological and Interpretation Errors?

    This paper attempts to explain some methodological issues regarding EEG signal analysis which might lead to misinterpretation and therefore to unsubstantiated conclusions. The so called “split-alpha,” a “new phenomenon” in EEG spectral analysis described lately in few papers is such a case. We have shown that spectrum feature presented as a “split alpha” can be the result of applying improper means of analysis of the spectrum of the EEG signal that did not take into account the significant properties of the applied Fast Fourier Transform (FFT) method. Analysis of the shortcomings of the FFT method applied to EEG signal such as limited duration of analyzed signal, dependence of frequency resolution on time window duration, influence of window duration and shape, overlapping and spectral leakage was performed. Our analyses of EEG data as well as simulations indicate that double alpha spectra called as “split alpha” can appear, as spurious peaks, for short signal window when the EEG signal being studied shows multiple frequencies and frequency bands. These peaks have no relation to any frequencies of the signal and are an effect of spectrum leakage. Our paper is intended to explain the reasons underlying a spectrum pattern called as a “split alpha” and give some practical indications for using spectral analysis of EEG signal that might be useful for readers and allow to avoid EEG spectrum misinterpretation in further studies and publications as well as in clinical practice.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 26, 2020 12:00 AM.

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    Association of Odor Identification Ability With Amyloid-β and Tau Burden: A Systematic Review and Meta-Analysis

    Background: The associations between olfactory identification (OI) ability and the Alzheimer's disease biomarkers were not clear.

    Objective: This meta-analysis aimed to examine the associations between OI and Aβ and tau burden.

    Methods: Electronic databases (PubMed, Embase, PsycINFO, and Google Scholar) were searched until June 2019 to identify studies that reported correlation coefficients or regression coefficients between OI and Aβ or tau levels measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Pooled Pearson correlation coefficients were computed for the PET imaging and CSF biomarkers, with subgroup analysis for subjects classified into different groups.

    Results: Nine studies met the inclusion criteria. Of these, five studies (N = 494) involved Aβ PET, one involved tau PET (N = 26), and four involved CSF Aβ or tau (N = 345). OI was negatively associated with Aβ PET in the mixed (r = −0.25, P = 0.008) and cognitively normal groups (r = −0.15, P = 0.004) but not in the mild cognitive impairment group. A similar association with CSF total tau in the mixed group was also observed. No association was found between OI and CSF phosphorylated tau or Aβ42 in the subgroup analysis of the CSF biomarkers. Due to a lack of data, no pooled r value could be computed for the association between the OI and tau PET.

    Conclusion: The associations between OI ability and Aβ and CSF tau burden in older adults are negligible. While current evidence does not support the association, further studies using PET tau imaging are warranted.

    in Frontiers in Neuroscience: Neurodegeneration on November 26, 2020 12:00 AM.

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    Molecular Mechanisms of Glutamate Toxicity in Parkinson’s Disease

    Parkinson’s disease (PD) is a common neurodegenerative disease, the pathological features of which include the presence of Lewy bodies and the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. However, until recently, research on the pathogenesis and treatment of PD have progressed slowly. Glutamate and dopamine are both important central neurotransmitters in mammals. A lack of enzymatic decomposition of extracellular glutamate results in glutamate accumulating at synapses, which is mainly absorbed by excitatory amino acid transporters (EAATs). Glutamate exerts its physiological effects by binding to and activating ligand-gated ion channels [ionotropic glutamate receptors (iGluRs)] and a class of G-protein-coupled receptors [metabotropic glutamate receptors (mGluRs)]. Timely clearance of glutamate from the synaptic cleft is necessary because high levels of extracellular glutamate overactivate glutamate receptors, resulting in excitotoxic effects in the central nervous system. Additionally, increased concentrations of extracellular glutamate inhibit cystine uptake, leading to glutathione depletion and oxidative glutamate toxicity. Studies have shown that oxidative glutamate toxicity in neurons lacking functional N-methyl-D-aspartate (NMDA) receptors may represent a component of the cellular death pathway induced by excitotoxicity. The association between inflammation and excitotoxicity (i.e., immunoexcitotoxicity) has received increased attention in recent years. Glial activation induces neuroinflammation and can stimulate excessive release of glutamate, which can induce excitotoxicity and, additionally, further exacerbate neuroinflammation. Glutamate, as an important central neurotransmitter, is closely related to the occurrence and development of PD. In this review, we discuss recent progress on elucidating glutamate as a relevant neurotransmitter in PD. Additionally, we summarize the relationship and commonality among glutamate excitotoxicity, oxidative toxicity, and immunoexcitotoxicity in order to posit a holistic view and molecular mechanism of glutamate toxicity in PD.

    in Frontiers in Neuroscience: Neurodegeneration on November 26, 2020 12:00 AM.

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    Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction

    Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and optic nerve damage. In the current study, we investigate the use of codon-optimized versions of OPA1 isoform 1 and 7 as potential therapeutic interventions in a range of in vitro and in vivo models of mitochondrial dysfunction. We demonstrate that both isoforms perform equally well in ameliorating mitochondrial dysfunction in OPA1 knockout mouse embryonic fibroblast cells but that OPA1 expression levels require tight regulation for optimal benefit. Of note, we demonstrate for the first time that both OPA1 isoform 1 and 7 can be used independently to protect spatial visual function in a murine model of retinal ganglion cell degeneration caused by mitochondrial dysfunction, as well as providing benefit to mitochondrial bioenergetics in DOA patient derived fibroblast cells. These results highlight the potential value of OPA1-based gene therapy interventions.

    in Frontiers in Neuroscience: Neurodegeneration on November 26, 2020 12:00 AM.

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    An in vitro Model of Human Retinal Detachment Reveals Successive Death Pathway Activations

    Purpose

    was to create an in vitro model of human retinal detachment (RD) to study the mechanisms of photoreceptor death.

    Methods

    Human retinas were obtained through eye globe donations for research purposes and cultivated as explants. Cell death was investigated in retinas with (control) and without retinal pigment epithelium (RPE) cells to mimic RD. Tissues were studied at different time points and immunohistological analyses for TUNEL, Cleaved caspase3, AIF, CDK4 and the epigenetic mark H3K27me3 were performed. Human and monkey eye globes with retinal detachment served as controls.

    Results

    The number of TUNEL-positive cells, compared between 1 and 7 days, increased with time in both retinas with RPE (from 1.2 ± 0.46 to 8 ± 0.89, n = 4) and without RPE (from 2.6 ± 0.73 to 16.3 ± 1.27, p < 0.014). In the group without RPE, cell death peaked at day 3 (p = 0.014) and was high until day 7. Almost no Cleaved-Caspase3 signal was observed, whereas a transient augmentation at day 3 of AIF-positive cells was observed to be about 10-fold in comparison to the control group (n = 2). Few CDK4-positive cells were found in both groups, but significantly more in the RD group at day 7 (1.8 ± 0.24 vs. 4.7 ± 0.58, p = 0.014). The H3K27me3 mark increased by 7-fold after 5 days in the RD group (p = 0.014) and slightly decreased at day 7 and was also observed to be markedly increased in human and monkey detached retina samples.

    Conclusion

    AIF expression coincides with the first peak of cell death, whereas the H3K27me3 mark increases during the cell death plateau, suggesting that photoreceptor death is induced by different successive pathways after RD. This in vitro model should permit the identification of neuroprotective drugs with clinical relevance.

    in Frontiers in Neuroscience: Neurodegeneration on November 26, 2020 12:00 AM.

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    Decreased Proliferation in the Neurogenic Niche, Disorganized Neuroblast Migration, and Increased Oligodendrogenesis in Adult Netrin-5-Deficient Mice

    In the adult mouse brain, neurogenesis occurs mainly in the ventricular-subventricular zone (V-SVZ) and the subgranular zone of the hippocampal dentate gyrus. Neuroblasts generated in the V-SVZ migrate to the olfactory bulb via the rostral migratory stream (RMS) in response to guidance molecules, such as netrin-1. We previously showed that the related netrin-5 (NTN5) is expressed in Mash1-positive transit-amplifying cells and doublecortin-positive neuroblasts in the granule cell layer of the olfactory bulb, the RMS, and the subgranular zone of the adult mouse brain. However, the precise role of NTN5 in adult neurogenesis has not been investigated. In this study, we show that proliferation in the neurogenic niche is impaired in NTN5 knockout mice. The number of proliferating (EdU-labeled) cells in NTN5 KO mice was significantly lower in the V-SVZ, whereas the number of Ki67-positive proliferating cells was unchanged, suggesting a longer cell cycle and decreased cell division in NTN5 KO mice. The number of EdU-labeled cells in the RMS and olfactory bulb was unchanged. By contrast, the numbers of EdU-labeled cells in the cortex, basal ganglia/lateral septal nucleus, and corpus callosum/anterior commissure were increased, which largely represented oligodendrocyte lineage cells. Lastly, we found that chain migration in the RMS of NTN5 KO mice was disorganized. These findings suggest that NTN5 may play important roles in promoting proliferation in the V-SVZ niche, organizing proper chain migration in the RMS, and suppressing oligodendrogenesis in the brain.

    in Frontiers in Neuroscience: Neurogenesis on November 26, 2020 12:00 AM.

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    Zero Echo Time MRAC on FDG-PET/MR Maintains Diagnostic Accuracy for Alzheimer’s Disease; A Simulation Study Combining ADNI-Data

    Aim

    Attenuation correction using zero-echo time (ZTE) – magnetic resonance imaging (MRI) (ZTE-MRAC) has become one of the standard methods for brain-positron emission tomography (PET) on commercial PET/MR scanners. Although the accuracy of the net tracer-uptake quantification based on ZTE-MRAC has been validated, that of the diagnosis for dementia has not yet been clarified, especially in terms of automated statistical analysis. The aim of this study was to clarify the impact of ZTE-MRAC on the diagnosis of Alzheimer’s disease (AD) by performing simulation study.

    Methods

    We recruited 27 subjects, who underwent both PET/computed tomography (CT) and PET/MR (GE SIGNA) examinations. Additionally, we extracted 107 subjects from the Alzheimer Disease Neuroimaging Initiative (ADNI) dataset. From the PET raw data acquired on PET/MR, three FDG-PET series were generated, using two vendor-provided MRAC methods (ZTE and Atlas) and CT-based AC. Following spatial normalization to Montreal Neurological Institute (MNI) space, we calculated each patient’s specific error maps, which correspond to the difference between the PET image corrected using the CTAC method and the PET images corrected using the MRAC methods. To simulate PET maps as if ADNI data had been corrected using MRAC methods, we multiplied each of these 27 error maps with each of the 107 ADNI cases in MNI space. To evaluate the probability of AD in each resulting image, we calculated a cumulative t-value using a fully automated method which had been validated not only in the original ADNI dataset but several multi-center studies. In the method, PET score = 1 is the 95% prediction limit of AD. PET score and diagnostic accuracy for the discrimination of AD were evaluated in simulated images using the original ADNI dataset as reference.

    Results

    Positron emission tomography score was slightly underestimated both in ZTE and Atlas group compared with reference CTAC (−0.0796 ± 0.0938 vs. −0.0784 ± 0.1724). The absolute error of PET score was lower in ZTE than Atlas group (0.098 ± 0.075 vs. 0.145 ± 0.122, p < 0.001). A higher correlation to the original PET score was observed in ZTE vs. Atlas group (R2: 0.982 vs. 0.961). The accuracy for the discrimination of AD patients from normal control was maintained in ZTE and Atlas compared to CTAC (ZTE vs. Atlas. vs. original; 82.5% vs. 82.1% vs. 83.2% (CI 81.8–84.5%), respectively).

    Conclusion

    For FDG-PET images on PET/MR, attenuation correction using ZTE-MRI had superior accuracy to an atlas-based method in classification for dementia. ZTE maintains the diagnostic accuracy for AD.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 26, 2020 12:00 AM.

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    SARA-GAN: Self-Attention and Relative Average Discriminator Based Generative Adversarial Networks for Fast Compressed Sensing MRI Reconstruction

    Research on undersampled magnetic resonance image (MRI) reconstruction can increase the speed of MRI imaging and reduce patient suffering. In this paper, an undersampled MRI reconstruction method based on Generative Adversarial Networks with the Self-Attention mechanism and the Relative Average discriminator (SARA-GAN) is proposed. In our SARA-GAN, the relative average discriminator theory is applied to make full use of the prior knowledge, in which half of the input data of the discriminator is true and half is fake. At the same time, a self-attention mechanism is incorporated into the high-layer of the generator to build long-range dependence of the image, which can overcome the problem of limited convolution kernel size. Besides, spectral normalization is employed to stabilize the training process. Compared with three widely used GAN-based MRI reconstruction methods, i.e., DAGAN, DAWGAN, and DAWGAN-GP, the proposed method can obtain a higher peak signal-to-noise ratio (PSNR) and structural similarity index measure(SSIM), and the details of the reconstructed image are more abundant and more realistic for further clinical scrutinization and diagnostic tasks.

    in Frontiers in Neuroinformatics on November 26, 2020 12:00 AM.

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    Loss of Smell in COVID-19 Patients: Lessons and Opportunities

    in Frontiers in Human Neuroscience on November 26, 2020 12:00 AM.

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    Brain Metabolite Levels in Sedentary Women and Non-contact Athletes Differ From Contact Athletes

    White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy (MRS) in the prefrontal white matter at the beginning (In-Season) and end (Off-Season) of season in contact (N = 54, rugby players) and non-contact (N = 23, swimmers and rowers) varsity athletes. Sedentary women (N = 23) were scanned once, at a time equivalent to the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline.

    in Frontiers in Human Neuroscience on November 26, 2020 12:00 AM.

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    Integration of Convergent Sensorimotor Inputs Within Spinal Reflex Circuits in Healthy Adults

    The output from motor neuron pools is influenced by the integration of synaptic inputs originating from descending corticomotor and spinal reflex pathways. In this study, using paired non-invasive brain and peripheral nerve stimulation, we investigated how descending corticomotor pathways influence the physiologic recruitment order of the soleus Hoffmann (H-) reflex. Eleven neurologically unimpaired adults (9 females; mean age 25 ± 3 years) completed an assessment of transcranial magnetic stimulation (TMS)-conditioning of the soleus H-reflex over a range of peripheral nerve stimulation (PNS) intensities. Unconditioned H-reflex recruitment curves were obtained by delivering PNS pulses to the posterior tibial nerve. Subsequently, TMS-conditioned H-reflex recruitment curves were obtained by pairing PNS with subthreshold TMS at short (−1.5 ms) and long (+10 ms) intervals. We evaluated unconditioned and TMS-conditioned H-reflex amplitudes along the ascending limb, peak, and descending limb of the H-reflex recruitment curve. Our results revealed that, for long-interval facilitation, TMS-conditioned H-reflex amplitudes were significantly larger than unconditioned H-reflex amplitudes along the ascending limb and peak of the H-reflex recruitment curve. Additionally, significantly lower PNS intensities were needed to elicit peak H-reflex amplitude (Hmax) for long-interval facilitation compared to unconditioned. These findings suggest that the influence of descending corticomotor pathways, particularly those mediating long-interval facilitation, contribute to changing the recruitment gain of the motor neuron pool, and can inform future methodological protocols for TMS-conditioning of H-reflexes. By characterizing and inducing short-term plasticity in circuitry mediating short- and long-interval TMS-conditioning of H-reflex amplitudes, future studies can investigate supraspinal and spinal circuit contributions to abnormal motor control, as well as develop novel therapeutic targets for neuromodulation.

    in Frontiers in Human Neuroscience on November 26, 2020 12:00 AM.

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    Factors Influencing Saccadic Reaction Time: Effect of Task Modality, Stimulus Saliency, Spatial Congruency of Stimuli, and Pupil Size

    It is often assumed that the reaction time of a saccade toward visual and/or auditory stimuli reflects the sensitivities of our oculomotor-orienting system to stimulus saliency. Endogenous factors, as well as stimulus-related factors, would also affect the saccadic reaction time (SRT). However, it was not clear how these factors interact and to what extent visual and auditory-targeting saccades are accounted for by common mechanisms. The present study examined the effect of, and the interaction between, stimulus saliency and audiovisual spatial congruency on the SRT for visual- and for auditory-target conditions. We also analyzed pre-target pupil size to examine the relationship between saccade preparation and pupil size. Pupil size is considered to reflect arousal states coupling with locus-coeruleus (LC) activity during a cognitive task. The main findings were that (1) the pattern of the examined effects on the SRT varied between visual- and auditory-auditory target conditions, (2) the effect of stimulus saliency was significant for the visual-target condition, but not significant for the auditory-target condition, (3) Pupil velocity, not absolute pupil size, was sensitive to task set (i.e., visual-targeting saccade vs. auditory-targeting saccade), and (4) there was a significant correlation between the pre-saccade absolute pupil size and the SRTs for the visual-target condition but not for the auditory-target condition. The discrepancy between target modalities for the effect of pupil velocity and between the absolute pupil size and pupil velocity for the correlation with SRT may imply that the pupil effect for the visual-target condition was caused by a modality-specific link between pupil size modulation and the SC rather than by the LC-NE (locus coeruleus-norepinephrine) system. These results support the idea that different threshold mechanisms in the SC may be involved in the initiation of saccades toward visual and auditory targets.

    in Frontiers in Human Neuroscience on November 26, 2020 12:00 AM.

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    Learning-Dependent Dendritic Spine Plasticity Is Reduced in the Aged Mouse Cortex

    Aging is accompanied by a progressive decrease in learning and memory function. Synaptic loss, one of the hallmarks of normal aging, likely plays an important role in age-related cognitive decline. But little is known about the impact of advanced age on synaptic plasticity and neuronal function in vivo. In this study, we examined the structural dynamics of postsynaptic dendritic spines as well as calcium activity of layer 5 pyramidal neurons in the cerebral cortex of young and old mice. Using transcranial two-photon microscopy, we found that in both sensory and motor cortices, the elimination rates of dendritic spines were comparable between young (3–5 months) and mature adults (8–10 months), but seemed higher in old mice (>20 months), contributing to a reduction of total spine number in the old brain. During the process of motor learning, old mice compared to young mice had fewer new spines formed in the primary motor cortex. Motor training-evoked somatic calcium activity in layer 5 pyramidal neurons of the motor cortex was also lower in old than young mice, which was associated with the decline of motor learning ability during aging. Together, these results demonstrate the effects of aging on learning-dependent synapse remodeling and neuronal activity in the living cortex and suggest that synaptic deficits may contribute to age-related learning impairment.

    in Frontiers in Neural Circuits on November 26, 2020 12:00 AM.

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    The Paradox of Astroglial Ca2 + Signals at the Interface of Excitation and Inhibition

    Astroglial networks constitute a non-neuronal communication system in the brain and are acknowledged modulators of synaptic plasticity. A sophisticated set of transmitter receptors in combination with distinct secretion mechanisms enables astrocytes to sense and modulate synaptic transmission. This integrative function evolved around intracellular Ca2+ signals, by and large considered as the main indicator of astrocyte activity. Regular brain physiology meticulously relies on the constant reciprocity of excitation and inhibition (E/I). Astrocytes are metabolically, physically, and functionally associated to the E/I convergence. Metabolically, astrocytes provide glutamine, the precursor of both major neurotransmitters governing E/I in the central nervous system (CNS): glutamate and γ-aminobutyric acid (GABA). Perisynaptic astroglial processes are structurally and functionally associated with the respective circuits throughout the CNS. Astonishingly, in astrocytes, glutamatergic as well as GABAergic inputs elicit similar rises in intracellular Ca2+ that in turn can trigger the release of glutamate and GABA as well. Paradoxically, as gliotransmitters, these two molecules can thus strengthen, weaken or even reverse the input signal. Therefore, the net impact on neuronal network function is often convoluted and cannot be simply predicted by the nature of the stimulus itself. In this review, we highlight the ambiguity of astrocytes on discriminating and affecting synaptic activity in physiological and pathological state. Indeed, aberrant astroglial Ca2+ signaling is a key aspect of pathological conditions exhibiting compromised network excitability, such as epilepsy. Here, we gather recent evidence on the complexity of astroglial Ca2+ signals in health and disease, challenging the traditional, neuro-centric concept of segregating E/I, in favor of a non-binary, mutually dependent perspective on glutamatergic and GABAergic transmission.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Receptoral Mechanisms for Fast Cholinergic Transmission in Direction-Selective Retinal Circuitry

    Direction selectivity represents an elementary sensory computation that can be related to underlying synaptic mechanisms. In mammalian retina, direction-selective ganglion cells (DSGCs) respond strongly to visual motion in a “preferred” direction and weakly to motion in the opposite, “null” direction. The DS mechanism depends on starburst amacrine cells (SACs), which provide null direction-tuned GABAergic inhibition and untuned cholinergic excitation to DSGCs. GABAergic inhibition depends on conventional synaptic transmission, whereas cholinergic excitation apparently depends on paracrine (i.e., non-synaptic) transmission. Despite its paracrine mode of transmission, cholinergic excitation is more transient than GABAergic inhibition, yielding a temporal difference that contributes essentially to the DS computation. To isolate synaptic mechanisms that generate the distinct temporal properties of cholinergic and GABAergic transmission from SACs to DSGCs, we optogenetically stimulated SACs while recording postsynaptic currents (PSCs) from DSGCs in mouse retina. Direct recordings from channelrhodopsin-2-expressing (ChR2+) SACs during quasi-white noise (WN) (0-30 Hz) photostimulation demonstrated precise, graded optogenetic control of SAC membrane current and potential. Linear systems analysis of ChR2-evoked PSCs recorded in DSGCs revealed cholinergic transmission to be faster than GABAergic transmission. A deconvolution-based analysis showed that distinct postsynaptic receptor kinetics fully account for the temporal difference between cholinergic and GABAergic transmission. Furthermore, GABAA receptor blockade prolonged cholinergic transmission, identifying a new functional role for GABAergic inhibition of SACs. Thus, fast cholinergic transmission from SACs to DSGCs arises from at least two distinct mechanisms, yielding temporal properties consistent with conventional synapses despite its paracrine nature.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

    Store-operated calcium channels (SOCs) are widely expressed in excitatory and non-excitatory cells where they mediate significant store-operated calcium entry (SOCE), an important pathway for calcium signaling throughout the body. While the activity of SOCs has been well studied in non-excitable cells, attention has turned to their role in neurons and glia in recent years. In particular, the role of SOCs in the nervous system has been extensively investigated, with links to their dysregulation found in a wide variety of neurological diseases from Alzheimer’s disease (AD) to pain. In this review, we provide an overview of their molecular components, expression, and physiological role in the nervous system and describe how the dysregulation of those roles could potentially lead to various neurological disorders. Although further studies are still needed to understand how SOCs are activated under physiological conditions and how they are linked to pathological states, growing evidence indicates that SOCs are important players in neurological disorders and could be potential new targets for therapies. While the role of SOCE in the nervous system continues to be multifaceted and controversial, the study of SOCs provides a potentially fruitful avenue into better understanding the nervous system and its pathologies.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Mechanisms Underlying Memory Consolidation by Adult-Born Neurons During Sleep

    The mammalian hippocampus generates new neurons that incorporate into existing neuronal networks throughout the lifespan, which bestows a unique form of cellular plasticity to the memory system. Recently, we found that hippocampal adult-born neurons (ABNs) that were active during learning reactivate during subsequent rapid eye movement (REM) sleep and provided causal evidence that ABN activity during REM sleep is necessary for memory consolidation. Here, we describe the potential underlying mechanisms by highlighting distinct characteristics of ABNs including decoupled firing from local oscillations and ability to undergo profound synaptic remodeling in response to experience. We further discuss whether ABNs constitute the conventional definition of engram cells by focusing on their active and passive roles in the memory system. This synthesis of evidence helps advance our thinking on the unique mechanisms by which ABNs contribute to memory consolidation.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Subarachnoid Hemorrhage Increases Level of Heme Oxygenase-1 and Biliverdin Reductase in the Choroid Plexus

    Subarachnoid hemorrhage is a specific, life-threatening form of hemorrhagic stroke linked to high morbidity and mortality. It has been found that the choroid plexus of the brain ventricles forming the blood-cerebrospinal fluid barrier plays an important role in subarachnoid hemorrhage pathophysiology. Heme oxygenase-1 and biliverdin reductase are two of the key enzymes of the hemoglobin degradation cascade. Therefore, the aim of present study was to investigate changes in protein levels of heme oxygenase-1 and biliverdin reductase in the rat choroid plexus after experimental subarachnoid hemorrhage induced by injection of non-heparinized autologous blood to the cisterna magna. Artificial cerebrospinal fluid of the same volume as autologous blood was injected to mimic increased intracranial pressure in control rats. Immunohistochemical and Western blot analyses were used to monitor changes in the of heme oxygenase-1 and biliverdin reductase levels in the rat choroid plexus after induction of subarachnoid hemorrhage or artificial cerebrospinal fluid application for 1, 3, and 7 days. We found increased levels of heme oxygenase-1 and biliverdin reductase protein in the choroid plexus over the entire period following subarachnoid hemorrhage induction. The level of heme oxygenase-1 was the highest early (1 and 3 days) after subarachnoid hemorrhage indicating its importance in hemoglobin degradation. Increased levels of heme oxygenase-1 were also observed in the choroid plexus epithelial cells at all time points after application of artificial cerebrospinal fluid. Biliverdin reductase protein was detected mainly in the choroid plexus epithelial cells, with levels gradually increasing during subarachnoid hemorrhage. Our results suggest that heme oxygenase-1 and biliverdin reductase are involved not only in hemoglobin degradation but probably also in protecting choroid plexus epithelial cells and the blood-cerebrospinal fluid barrier from the negative effects of subarachnoid hemorrhage.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Effects of Exosomes on Neurological Function Recovery for Ischemic Stroke in Pre-clinical Studies: A Meta-analysis

    Background: Exosomes, especially stem cell-derived exosomes, have been widely studied in pre-clinical research of ischemic stroke. However, their pooled effects remain inconclusive.

    Methods: Relevant literature concerning the effects of exosomes on neurological performance in a rodent model of ischemic stroke was identified via searching electronic databases, including PubMed, Embase, and Web of Science. The primary outcomes included neurological function scores (NFS) and infarct volume (IV), and the secondary outcomes were several pro-inflammatory factors and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells. Subgroup analyses regarding several factors potentially influencing the effects of exosomes on NFS and IV were also conducted.

    Results: We identified 21 experiments from 18 studies in the meta-analysis. Pooled analyses showed the positive and significant effects of exosomes on NFS (standardized mean difference −2.79; 95% confidence interval −3.81 to −1.76) and IV (standardized mean difference −3.16; 95% confidence interval −4.18 to −2.15). Our data revealed that the effects of exosomes on neurological outcomes in rodent stroke models might be related to routes of administration and exosomes sources. In addition, there was significant attenuation in pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and interleukin-1β, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells when undergoing exosomes treatment.

    Conclusion: Cell-derived exosomes treatment demonstrated statistically significant improvements in structural and neurological function recovery in animal models of ischemic stroke. Our results also provide relatively robust evidence supporting cell-derived exosomes as a promising therapy to promote neurological recovery in stroke individuals.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Corticotrophin-Releasing Factor Modulates the Facial Stimulation-Evoked Molecular Layer Interneuron-Purkinje Cell Synaptic Transmission in vivo in Mice

    Corticotropin-releasing factor (CRF) is an important neuromodulator in central nervous system that modulates neuronal activity via its receptors during stress responses. In cerebellar cortex, CRF modulates the simple spike (SS) firing activity of Purkinje cells (PCs) has been previously demonstrated, whereas the effect of CRF on the molecular layer interneuron (MLI)–PC synaptic transmission is still unknown. In this study, we examined the effect of CRF on the facial stimulation–evoked cerebellar cortical MLI-PC synaptic transmission in urethane-anesthetized mice by in vivo cell-attached recording, neurobiotin juxtacellular labeling, immunohistochemistry techniques, and pharmacological method. Cell-attached recordings from cerebellar PCs showed that air-puff stimulation of ipsilateral whisker pad evoked a sequence of tiny parallel fiber volley (N1) followed by MLI-PC synaptic transmission (P1). Microapplication of CRF in cerebellar cortical molecular layer induced increases in amplitude of P1 and pause of SS firing. The CRF decreases in amplitude of P1 waveform were in a dose-dependent manner with the EC50 of 241 nM. The effects of CRF on amplitude of P1 and pause of SS firing were abolished by either a non-selective CRF receptor antagonist, α-helical CRF-(9-14), or a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM), but were not prevented by a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Notably, application CRF not only induced a significant increase in spontaneous spike firing rate, but also produced a significant increase in the number of the facial stimulation–evoked action potential in MLIs. The effect of CRF on the activity of MLIs was blocked by the selective CRF-R1 antagonist, and the MLIs expressed the CRF-R1 imunoreactivity. These results indicate that CRF increases excitability of MLIs via CRF-R1, resulting in an enhancement of the facial stimulation–evoked MLI-PC synaptic transmission in vivo in mice.

    in Frontiers in Cellular Neuroscience on November 26, 2020 12:00 AM.

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    Whole-Brain Three-Dimensional Profiling Reveals Brain Region Specific Axon Vulnerability in 5xFAD Mouse Model

    Axonopathy is a pathological feature observed in both Alzheimer’s disease (AD) patients and animal models. However, identifying the temporal and regional progression of axonopathy during AD development remains elusive. Using the fluorescence micro-optical sectioning tomography system, we acquired whole-brain datasets in the early stage of 5xFAD/Thy1-GFP-M mice. We reported that among GFP labeled axons, GFP-positive axonopathy first formed in the lateral septal nucleus, subiculum, and medial mammillary nucleus. The axonopathy further increased in most brain regions during aging. However, most of the axonopathic varicosities disappeared significantly in the medial mammillary nucleus after 8 weeks old. Continuous three-dimensional datasets showed that axonopathy in the medial mammillary nucleus was mainly located on axons from hippocampal GFP-positive neurons. Using the rabies viral tracer in combination with immunohistochemistry, we found that axons in the medial mammillary nucleus from the subiculum were susceptible to lesions that prior to the occurrence of behavioral disorders. In conclusion, we created an early-stage spatiotemporal map of axonopathy in 5xFAD/Thy1-GFP-M mice and identified specific neural circuits which are vulnerable to axon lesions in an AD mouse model. These findings underline the importance of early interventions for AD, and may contribute to the understanding of its progression and its early symptom treatment.

    in Frontiers in Neuroanatomy on November 26, 2020 12:00 AM.

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    Developmental Genes and Malformations in the Hypothalamus

    The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly mediated by the pituitary gland. In the updated prosomeric model, the hypothalamus represents the rostralmost forebrain, composed of two segmental regions (terminal and peduncular hypothalamus), which extend respectively into the non-evaginated preoptic telencephalon and the evaginated pallio-subpallial telencephalon. Complex genetic cascades of transcription factors and signaling molecules rule their development. Alterations of some of these molecular mechanisms acting during forebrain development are associated with more or less severe hypothalamic and pituitary dysfunctions, which may be associated with brain malformations such as holoprosencephaly or septo-optic dysplasia. Studies on transgenic mice with mutated genes encoding critical transcription factors implicated in hypothalamic-pituitary development are contributing to understanding the high clinical complexity of these pathologies. In this review article, we will analyze first the complex molecular genoarchitecture of the hypothalamus resulting from the activity of previous morphogenetic signaling centers and secondly some malformations related to alterations in genes implicated in the development of the hypothalamus.

    in Frontiers in Neuroanatomy on November 26, 2020 12:00 AM.

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    Differences in Noradrenaline Receptor Expression Across Different Neuronal Subtypes in Macaque Frontal Eye Field

    Cognitive functions such as attention and working memory are modulated by noradrenaline receptors in the prefrontal cortex (PFC). The frontal eye field (FEF) has been shown to play an important role in visual spatial attention. However, little is known about the underlying circuitry. The aim of this study was to characterize the expression of noradrenaline receptors on different pyramidal neuron and inhibitory interneuron subtypes in macaque FEF. Using immunofluorescence, we found broad expression of noradrenaline receptors across all layers of the FEF. Differences in the expression of different noradrenaline receptors were observed across different inhibitory interneuron subtypes. No significant differences were observed in the expression of noradrenaline receptors across different pyramidal neuron subtypes. However, we found that putative long-range projecting pyramidal neurons expressed all noradrenaline receptor subtypes at a much higher proportion than any of the other neuronal subtypes. Nearly all long-range projecting pyramidal neurons expressed all types of noradrenaline receptor, suggesting that there is no receptor-specific machinery acting on these long-range projecting pyramidal neurons. This pattern of expression among long-range projecting pyramidal neurons suggests a mechanism by which noradrenergic modulation of FEF activity influences attention and working memory.

    in Frontiers in Neuroanatomy on November 26, 2020 12:00 AM.

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    Multimodal Imaging and Analysis of the Neuroanatomical Organization of the Primary Olfactory Inputs in the Brownbanded Bamboo Shark, Chiloscyllium punctatum

    There is currently a limited understanding of the morphological and functional organization of the olfactory system in cartilaginous fishes, particularly when compared to bony fishes and terrestrial vertebrates. In this fish group, there is a clear paucity of information on the characterization, density, and distribution of olfactory receptor neurons (ORNs) within the sensory olfactory epithelium lining the paired olfactory rosettes, and their functional implications with respect to the hydrodynamics of incurrent water flow into the nares. This imaging study examines the brownbanded bamboo shark Chiloscyllium punctatum (Elasmobranchii) and combines immunohistochemical labeling using antisera raised against five G-protein α-subunits (Gαs/olf, Gαq/11/14, Gαi–1/2/3, Gαi–3, Gαo) with light and electron microscopy, to characterize the morphological ORN types present. Three main ORNs (“long”, “microvillous” and “crypt-like”) are confirmed and up to three additional microvilli-bearing types are also described; “Kappe-like” (potential or homologous “Kappe” as in teleosts), “pear-shaped” and “teardrop-shaped” cells. These morphotypes will need to be confirmed molecularly in the future. Using X-ray diffusible iodine-based contrast-enhanced computed tomography (diceCT), high-resolution scans of the olfactory rosettes, olfactory bulbs (OBs), peduncles, and telencephalon reveal a lateral segregation of primary olfactory inputs within the OBs, with distinct medial and lateral clusters of glomeruli, suggesting a potential somatotopic organization. However, most ORN morphotypes are found to be ubiquitously distributed within the medial and lateral regions of the olfactory rosette, with at least three microvilli-bearing ORNs labeled with anti-Gαo found in significantly higher densities in lateral lamellae [in lateral lamellae] and on the anterior portion of lamellae (facing the olfactory cavity). These microvilli-bearing ORN morphotypes (microvillous, “Kappe-like,” “pear-shaped,” and “teardrop-shaped”) are the most abundant across the olfactory rosette of this species, while ciliated ORNs are less common and crypt cells are rare. Spatial simulations of the fluid dynamics of the incurrent water flow into the nares and within the olfactory cavities indicate that the high densities of microvilli-bearing ORNs located within the lateral region of the rosette are important for sampling incoming odorants during swimming and may determine subsequent tracking behavior.

    in Frontiers in Neuroanatomy on November 26, 2020 12:00 AM.

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    Declining Trends of Heart Rate Variability According to Aging in Healthy Asian Adults

    Heart rate variability (HRV) indices correlate with aging and are related to the autonomic nervous system. However, the trend of HRV with age has not been explored for the Asian population. Therefore, we proposed a linear regression model of HRV indices that decreased with aging in healthy Asian adults. HRV parameters [High frequency (HF), Low frequency (LF), Very low frequency (VLF), Total power (TP), HRV triangular index (HRV-index), Standard deviation of the normal-to-normal interval (SDNN), and Proportion of normal-to-normal intervals greater than 50 ms (pNN50)] were measured in a total of 300 healthy participants (150 men and 150 women) aged 19–69 years stratified into five age groups: 19–29, 30–39, 40–49, 50–59, and 60–69 years comprising 60 people each in Seoul, South Korea. A simple regression analysis was performed to reveal the linear declining trend of HRV indices with age. Independent t-tests were conducted to investigate the gender differences in HRV values depending on each age group. The values of all HRV indices showed a decreasing trend with age in healthy Korean adults, as observed in the Western population (P < 0.001 for all indices); HF (Y = −0.039x + 6.833, R2 = 0.287), LF (Y = −0.047x + 7.197, R2 = 0.414), VLF (Y = −0.025x + 6.861, R2 = 0.177), TP (Y = −0.034x + 8.082, R2 = 0.352), HRV-index (Y = −0.125x + 15.628, R2 = 0.298), SDNN (Y = −0.502x + 53.907, R2 = 0.343), and pNN50 (Y = −0.650x + 53.852, R2 = 0.345) all decreased with age. There was no significant gender difference in any HRV parameter. A linear regression model of various HRV indices has been presented considering the age of healthy Asians, which may be useful to prevent diseases related to the autonomic nervous system by estimating or tracking autonomic functional degeneration in the Asian population.

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer’s Disease Pathogenesis

    Background: The pathogenesis of Alzheimer’s disease (AD) remains to be elucidated. This study aimed to identify the hub genes in AD pathogenesis and determine their functions and pathways.

    Methods: A co-expression network for an AD gene dataset with 401 samples was constructed, and the AD status-related genes were screened. The hub genes of the network were identified and validated by an independent cohort. The functional pathways of hub genes were analyzed.

    Results: The co-expression network revealed a module that related to the AD status, and 101 status-related genes were screened from the trait-related module. Gene enrichment analysis indicated that these status-related genes are involved in synaptic processes and pathways. Four hub genes (ENO2, ELAVL4, SNAP91, and NEFM) were identified from the module, and these hub genes all participated in AD-related pathways, but the associations of each gene with clinical features were variable. An independent dataset confirmed the different expression of hub genes between AD and controls.

    Conclusions: Four novel genes associated with AD pathogenesis were identified and validated, which provided novel therapeutic targets for AD.

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Amantadine Alleviates Postoperative Cognitive Dysfunction Possibly by Preserving Neurotrophic Factor Expression and Dendritic Arborization in the Hippocampus of Old Rodents

    Objectives

    Amantadine has been shown to attenuate postoperative learning and memory dysfunction in young adult rats. However, postoperative cognitive dysfunction often occurs in elderly patients. We aimed to determine whether amantadine attenuated postoperative learning and memory dysfunction and whether these effects were associated with improved dendritic arborization in old rodents.

    Methods

    Eighteen-month old male C57BL/6J mice or Fischer 344 rats were subjected to right carotid artery exposure (surgery) under isoflurane anesthesia. This age represents an early old stage in rodents. Carotid artery exposure was used to simulate commonly performed carotid endarterectomy in elderly patients. Amantadine was injected intraperitoneally at 25 μg/g once a day for 3 days with the first dose at 15 min before surgery. The animals were tested by Barnes maze and fear conditioning starting one week after the surgery. Hippocampus was harvested for Western blotting and Golgi staining.

    Results

    Surgery and anesthesia impaired the learning and memory in old mice and rats. Surgery reduced the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), dendritic arborization and spine density in the hippocampus of old rats. These effects were attenuated by amantadine. The effects of amantadine were blocked by intracerebroventricular injection of anti-BDNF antibody or anti-GDNF antibody.

    Conclusion

    Surgery and anesthesia impaired learning, memory and dendritic arborization in old rodents that are age relevant to postoperative cognitive dysfunction. These effects may be attenuated by amantadine via preserving the expression of neurotrophic factors.

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Acupuncture Therapy for Cognitive Impairment: A Delphi Expert Consensus Survey

    Background

    Current research evidence challenges clinical decision-making when acupuncture is taken into consideration in the treatment of cognitive impairment (CI). Aiming to provide some viable recommendations for acupuncture practitioners in dealing with actual clinic issues, an expert consensus study was conducted.

    Methods

    A clinical question investigation among 47 acupuncturists yielded 24 initial items. Subsequently, systematic reviews on acupuncture for CI were searched within three online databases. A panel of 30 authoritative experts were requested to respond with agreement, neutrality, or disagreement for each item. Consensus establishment was defined as the percentage of agreement on a given item >80%.

    Results

    Following a 2-round Delphi survey, there were 21 items reaching consensus and three items resulting in no consensus; of which 10 items reached 90∼100% agreement, and 80∼90% expert agreement was achieved for 11 items. These items could be roughly categorized into six domains: (1) therapeutic effects of acupuncture, (2) therapeutic principles, (3) acupoint selection and combination, (4) acupuncture parameters, (5) considerable combined therapies, and (6) possible adverse events.

    Conclusion

    Without ready-made guidelines, this expert consensus may be conducive to guide acupuncturists in implementing clinical acupuncture practice for CI. Moreover, given the lack of high-quality research evidence and plenty of unresolved clinical issues in this field, it is of necessity to carry out more studies to better clarify the treatment algorithm.

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Age Effects on Distraction in a Visual Task Requiring Fast Reactions: An Event-Related Potential Study

    We investigated the effects of distractors in older and younger participants in choice and simple reaction time tasks with concurrent registration of event-related potentials. In the task the participants had to prevent a disk from falling into a bin after a color or luminosity change (target stimuli). Infrequently, task-irrelevant stimuli (schematic faces or threatening objects) were superimposed on the target stimuli (distractors), or the bin disappeared which required no response (Nogo trials). Reaction time was delayed to the distractors, but this effect was similar in the two age groups. As a robust age-related difference, in the older group a large anterior positivity and posterior negativity emerged to the distractors within the 100–200 ms post-stimulus range, and these components were larger for schematic faces than for threatening objects. sLORETA localized the age-specific effect to the ventral stream of the visual system and to anterior structures considered as parts of the executive system. The Nogo stimuli elicited a late positivity (Nogo P3) with longer latency in the older group. We interpreted the age-related differences as decreased but compensated resistance to task-irrelevant change of the target stimuli.

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Frontal and Cerebellar Atrophy Supports FTSD-ALS Clinical Continuum

    Background

    Frontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic, and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS, and ALS patients to further understand this clinical continuum.

    Methods

    We used voxel-based morphometry on structural magnetic resonance images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, and 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness (CT¯) to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency, and semantic fluency.

    Results

    Common (mainly frontal) and specific areas with reduced volume were detected between FTSD, FTSD-ALS, and ALS patients, confirming suggestions of a clinical continuum, while at the same time defining morphological specificities for each clinical group (e.g., a difference of cerebral and cerebellar involvement between FTSD and ALS). CT¯ values suggested extensive network disruption in the pathological process, with indications of a correlation between cerebral and cerebellar volumes and CT¯ in ALS. The analysis of the neuropsychological scores indeed pointed toward an important role for the cerebellum, along with fronto-temporal areas, in explaining impairment of executive, and linguistic functions.

    Conclusion

    We identified common elements that explain the FTSD-ALS clinical continuum, while also identifying specificities of each group, partially explained by different cerebral and cerebellar involvement.

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Editorial: Proteomics as a Tool for Biomarker and Drug Target Discovery: Improving the Diagnosis and Treatment of Neurodegenerative Diseases

    in Frontiers in Ageing Neuroscience on November 26, 2020 12:00 AM.

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    Modelling how antimicrobial resistance spreads between wards

    Moving patients between wards and prescribing high levels of antibiotics increases the spread of bacterial infections that are resistant to treatment in hospitals.

    in eLife on November 26, 2020 12:00 AM.

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    A novel haemocytometric COVID-19 prognostic score developed and validated in an observational multicentre European hospital-based study

    COVID-19 induces haemocytometric changes. Complete blood count changes, including new cell activation parameters, from 982 confirmed COVID-19 adult patients from 11 European hospitals were retrospectively analysed for distinctive patterns based on age, gender, clinical severity, symptom duration and hospital days. The observed haemocytometric patterns formed the basis to develop a multi-haemocytometric-parameter prognostic score to predict, during the first three days after presentation, which patients will recover without ventilation or deteriorate within a two-week timeframe, needing intensive care or with fatal outcome. The prognostic score, with ROC curve AUC at baseline of 0.753 (95% CI 0.723-0.781) increasing to 0.875 (95% CI 0.806-0.926) on day 3, was superior to any individual parameter at distinguishing between clinical severity. Findings were confirmed in a validation cohort. Aim is that the score and haemocytometry results are simultaneously provided by analyser software, enabling wide applicability of the score as haemocytometry is commonly requested in COVID-19 patients.

    in eLife on November 26, 2020 12:00 AM.

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    Science Forum: A survey of research quality in core facilities

    Core facilities are an effective way of making expensive experimental equipment available to a large number of researchers, and are thus well placed to contribute to efforts to promote good research practices. Here we report the results of a survey that asked core facilities in Europe about their approaches to the promotion of good research practices, and about their interactions with users from the first contact to the publication of the results. Based on 253 responses we identified four ways that good research practices could be encouraged: i) motivating users to follow the advice and procedures for best research practice; ii) providing clear guidance on data-management practices; iii) improving communication along the whole research process; and iv) clearly defining the responsibilities of each party.

    in eLife on November 26, 2020 12:00 AM.

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    Magnesium efflux from Drosophila Kenyon Cells is critical for normal and diet-enhanced long-term memory

    Dietary magnesium (Mg2+) supplementation can enhance memory in young and aged rats. Memory-enhancing capacity was largely ascribed to increases in hippocampal synaptic density and elevated expression of the NR2B subunit of the NMDA-type glutamate receptor. Here we show that Mg2+ feeding also enhances long-term memory in Drosophila. Normal and Mg2+ enhanced fly memory appears independent of NMDA receptors in the mushroom body and instead requires expression of a conserved CNNM-type Mg2+-efflux transporter encoded by the unextended (uex) gene. UEX contains a putative cyclic nucleotide-binding homology domain and its mutation separates a vital role for uex from a function in memory. Moreover, UEX localization in mushroom body Kenyon Cells is altered in memory defective flies harboring mutations in cAMP-related genes. Functional imaging suggests that UEX-dependent efflux is required for slow rhythmic maintenance of Kenyon Cell Mg2+. We propose that regulated neuronal Mg2+ efflux is critical for normal and Mg2+ enhanced memory.

    in eLife on November 26, 2020 12:00 AM.

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    Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction

    Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of stochastic growth and retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.

    in eLife on November 26, 2020 12:00 AM.

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    Tracking prototype and exemplar representations in the brain across learning

    There is a long-standing debate about whether categories are represented by individual category members (exemplars) or by the central tendency abstracted from individual members (prototypes). Neuroimaging studies have shown neural evidence for either exemplar representations or prototype representations, but not both. Presently, we asked whether it is possible for multiple types of category representations to exist within a single task. We designed a categorization task to promote both exemplar and prototype representations and tracked their formation across learning. We found only prototype correlates during the final test. However, interim tests interspersed throughout learning showed prototype and exemplar representations across distinct brain regions that aligned with previous studies: prototypes in ventromedial prefrontal cortex and anterior hippocampus and exemplars in inferior frontal gyrus and lateral parietal cortex. These findings indicate that, under the right circumstances, individuals may form representations at multiple levels of specificity, potentially facilitating a broad range of future decisions.

    in eLife on November 26, 2020 12:00 AM.

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    Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy

    Dementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here, we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head-direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wild-type mice are tightly linked to running speed, was invariant in rTg4510 mice during locomotion. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.

    in eLife on November 26, 2020 12:00 AM.

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    Sequential activation of transcriptional repressors promotes progenitor commitment by silencing stem cell identity genes

    Stem cells that indirectly generate differentiated cells through intermediate progenitors drives vertebrate brain evolution. Due to a lack of lineage information, how stem cell functionality, including the competency to generate intermediate progenitors, becomes extinguished during progenitor commitment remains unclear. Type II neuroblasts in fly larval brains divide asymmetrically to generate a neuroblast and a progeny that commits to an intermediate progenitor (INP) identity. We identified Tailless (Tll) as a master regulator of type II neuroblast functional identity, including the competency to generate INPs. Successive expression of transcriptional repressors functions through Hdac3 to silence tll during INP commitment. Reducing repressor activity allows re-activation of Notch in INPs to ectopically induce tll expression driving supernumerary neuroblast formation. Knocking down hdac3 function prevents downregulation of tll during INP commitment. We propose that continual inactivation of stem cell identity genes allows intermediate progenitors to stably commit to generating diverse differentiated cells during indirect neurogenesis.

    in eLife on November 26, 2020 12:00 AM.

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    The cerebellum is involved in internal and external speech error monitoring

    An fMRI study examined how speakers inspect their own speech for errors. In a word production task, we observed enhanced involvement of the right posterior cerebellum for trials that were correct, but on which participants were more likely to make a word- as compared to a non-word error. Furthermore, comparing errors to correctly produced utterances, we observed increased activation of the same cerebellar region, in addition to temporal and medial frontal regions. Within the framework associating the cerebellum to forward modelling of upcoming actions, this indicates that forward models of verbal actions contain information about word representations that are used for error monitoring even before articulation (internal monitoring). Additional resources relying on speech perception and conflict monitoring are deployed during articulation to detect overt errors (external monitoring). In summary, speech monitoring seems to recruit a network of brain regions serving domain general purposes, even for abstract levels of processing.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

    The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four- to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Hippocampal Egr1-dependent neuronal ensemblesnegatively regulate motor learning

    Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here we show that mice receiving a long-term training in the accelerating rotarod display marked transcriptional changes in the striatum and hippocampus when compared with short-term trained mice. We identify Egr1 as a modulator of gene expression in the hippocampus during motor learning. Using mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion we identify ensembles of Egr1-expressing pyramidal neurons in CA1 activated in short- and long-term trained mice in the rotarod task. When Egr1 is downregulated or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit motor learning.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Basal ganglia and cerebellar contributions to vocal emotion processing: a high resolution fMRI study

    Until recently, brain networks underlying emotional voice prosody decoding and processing were focused on modulations in primary and secondary auditory, ventral frontal and prefrontal cortices, and the amygdala. Growing interest for a specific role of the basal ganglia and cerebellum was recently brought into the spotlight. In the present study, we aimed at characterizing the role of such subcortical brain regions in vocal emotion processing, at the level of both brain activation and functional and effective connectivity, using high resolution functional magnetic resonance imaging. Variance explained by low-level acoustic parameters (fundamental frequency, voice energy) was also modelled. Wholebrain data revealed expected contributions of the temporal and frontal cortices, basal ganglia and cerebellum to vocal emotion processing, while functional connectivity analyses highlighted correlations between basal ganglia and cerebellum, especially for angry voices. Seed-to-seed and seed-to-voxel effective connectivity revealed direct connections within the basal ganglia especially between the putamen and external globus pallidus and between the subthalamic nucleus and the cerebellum. Our results speak in favour of crucial contributions of the basal ganglia, especially the putamen, external globus pallidus and subthalamic nucleus, and several cerebellar lobules and nuclei for an efficient decoding of and response to vocal emotions.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Frontoparietal, cerebellum network codes for accurate intention prediction in altered perceptual conditions

    Integrating and predicting intentions and actions of others are crucial components of social interactions, but the behavioral and neural underpinnings of such mechanisms in altered perceptual conditions remain poorly understood. We demonstrated that expertise was necessary to successfully understand and evaluate communicative intent in spatially and temporally altered visual representations of music plays, recruiting frontoparietal regions and several sub-areas of the cerebellum. Functional connectivity between these brain areas revealed widespread organization, especially in the cerebellum. This network may be essential to assess communicative intent in ambiguous or complex visual scenes.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Left frontal motor delta oscillations reflect the temporal integration of multimodal speech

    During multimodal speech perception, slow delta oscillations (~1 - 3 Hz) in the listener's brain synchronize with speech signal, likely reflecting signal decomposition at the service of comprehension. In particular, fluctuations imposed onto the speech amplitude envelope by a speaker's prosody seem to temporally align with articulatory and body gestures, thus providing two complementary sensations to the speech signal's temporal structure. Further, endogenous delta oscillations in the left motor cortex align with speech and music beat, suggesting a role in the temporal integration of (quasi)-rhythmic stimulations. We propose that delta activity facilitates the temporal alignment of a listener's oscillatory activity with the prosodic fluctuations in a speaker's speech during multimodal speech perception. We recorded EEG responses in an audiovisual synchrony detection task while participants watched videos of a speaker. To test the temporal alignment of visual and auditory prosodic features, we filtered the speech signal to remove verbal content. Results confirm (i) that participants accurately detected audiovisual synchrony, and (ii) greater delta power in left frontal motor regions in response to audiovisual asynchrony. The latter effect correlated with behavioural performance, and (iii) decreased delta-beta coupling in the left frontal motor regions when listeners could not accurately integrate visual and auditory prosodies. Together, these findings suggest that endogenous delta oscillations align fluctuating prosodic information conveyed by distinct sensory modalities onto a common temporal organisation in multimodal speech perception.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Multimodal imaging evidence for the brain basis of cognitive dysfunction in older HIV+ men

    Objective: This study used converging methods to define the structural and functional characteristics of the neural substrates underlying variation in cognitive ability in older men with well-controlled HIV infection. Methods: Seventy-six HIV+ men treated with combination antiretrovirals completed attention and inhibitory control tasks tapping different cortico-subcortical circuits while time-locked high-density EEG was acquired. Fifty-four also underwent structural MRI. We investigated relationships between task-evoked EEG responses, cognitive ability and immunocompromise. MRI suggested a subcortical basis for the observed EEG effects. Results: EEG activity was associated with cognitive ability at later (P300) but not earlier processing stages of both tasks. However, only the P300 evoked by the attention task was associated with past HIV infection severity. Source localization confirmed that the tasks engaged different brain circuits. Thalamus volumes correlated with P300 amplitudes evoked by the attention task, while globus pallidus volumes were related to the P300 in both tasks. Interpretation: This is the first study to combine structural and functional imaging in an overlapping sample to address the neural circuits related to cognitive dysfunction in HIV. Neural substrates of attention were more affected than those supporting inhibitory control. Preliminary evidence suggests these differences may relate to vulnerability of the thalamus to the effects of HIV. Our results suggest high-yield tasks and circuit targets for future work.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects

    Chromodomain helicase DNA-binding 8 (CHD8) is one of the most frequently mutated genes causative of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly and hence implicates cortical abnormalities in this form of ASD, the neurodevelopmental impact of human CHD8 haploinsufficiency remains unexplored. Here we combined human cerebral organoids and single cell transcriptomics to define the effect of ASD-linked CHD8 mutations on human cortical development. We found that CHD8 haploinsufficiency causes a major disruption of neurodevelopmental trajectories with an accelerated generation of inhibitory neurons and a delayed production of excitatory neurons alongside the ensuing protraction of the proliferation phase. This imbalance leads to a significant enlargement of cerebral organoids aligned to the macrocephaly observed in patients with CHD8 mutations. By adopting an isogenic design of patient-specific mutations and mosaic cerebral organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Finally, our results assign different CHD8-dependent molecular defects to particular cell types, pointing to an abnormal and extended program of proliferation and alternative splicing specifically affected in, respectively, the radial glial and immature neuronal compartments. By identifying temporally restricted cell-type specific effects of human CHD8 mutations, our study uncovers developmental alterations as reproducible endophenotypes for neurodevelopmental disease modelling.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Phasic inhibition of dopamine neurons is an instrumental punisher

    It is well established that the activity of VTA dopamine neurons is sufficient to serve as a Pavlovian reinforcer but whether this activity can also serve as instrumental reinforcer is less well understood. Here we studied the effects of optogenetic inhibition of VTA dopamine neurons in instrumental conditioning preparations. We show that optogenetic inhibition of VTA dopamine neurons causes a response-specific, contingency-sensitive suppression of instrumental responding. This suppression was due to instrumental response, not Pavlovian stimulus, learning and could not be attributed to deepened instrumental extinction learning. These effects of optogenetic inhibition of VTA dopamine neurons on instrumental responding are formally similar to the effects of aversive events in instrumental preparations and show that optogenetic inhibition of VTA dopamine neurons is sufficient to serve as an instrumental punisher.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    NMDA receptor signalling controls R-type calcium channel levels at the neuronal synapse

    Regulation of extracellular Ca++ influx by neuronal activity is a key mechanism underlying synaptic plasticity. At the neuronal synapse, activity-dependent Ca++ entry involves NMDA-type glutamate receptors (NMDARs) and voltage-gated calcium channels (VGCCs); the relationship between NMDARs and VGCCs, however, is poorly understood. Here, I report that neuronal activity specifically regulates synaptic levels of R-type VGCCs through synaptic NMDAR signalling and protein translation. This finding reveals a link between two key neuronal signalling pathways, suggesting a feedback mode for regulation of Ca++ signalling at the synapse.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Plume dynamics structure the spatiotemporal activity of glomerular networks in the mouse olfactory bulb

    Although mice locate resources using turbulent airborne odor plumes, the stochasticity and intermittency of fluctuating plumes create challenges for interpreting odor cues in natural environments. Population activity within the olfactory bulb (OB), is thought to process this complex spatial and temporal information, but how plume dynamics impact odor representation in this early stage of the mouse olfactory system is not known. Limitations in odor detection technology have made it impossible to measure plume fluctuations while simultaneously recording from the mouse's brain. Thus, previous studies have measured OB activity following controlled odor pulses of varying profiles or frequencies, but this approach only captures a subset of features found within olfactory plumes. Adequately sampling this feature space is difficult given a lack of knowledge regarding which features the brain extracts during exposure to natural olfactory scenes. Here we measured OB responses to naturally fluctuating odor plumes using a miniature, adapted odor sensor combined with wide-field GCaMP6f signaling from the dendrites of mitral and tufted (MT) cells imaged in olfactory glomeruli of head-fixed mice. We precisely tracked plume dynamics and imaged glomerular responses to this fluctuating input, while varying flow conditions across a range of ethologically-relevant values. We found that a consistent portion of MT activity in glomeruli follows odor concentration dynamics, and the strongest responding glomeruli are the best at following fluctuations within odor plumes. Further, the reliability and average response magnitude of glomerular populations of MT cells are affected by the flow condition in which the animal samples the plume, with the fidelity of plume following by MT cells increasing in conditions of higher flow velocity where odor dynamics result in intermittent whiffs of stronger concentration. Thus, the flow environment in which an animal encounters an odor has a large-scale impact on the temporal representation of an odor plume in the OB. Additionally, across flow conditions odor dynamics are a major driver of activity in many glomerular networks. Taken together, these data demonstrate that plume dynamics structure olfactory representations in the first stage of odor processing in the mouse olfactory system.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Changes in presynaptic gene expression during homeostatic compensation at a central synapse

    Homeostatic matching of pre- and postsynaptic function has been observed in many species and neural structures, but whether transcriptional changes contribute to this form of trans-synaptic coordination remains unknown. To identify genes whose expression is altered in presynaptic neurons as a result of perturbing postsynaptic excitability, we applied a transcriptomics-friendly, temperature-inducible Kir2.1-based activity clamp at the first synaptic relay of the Drosophila olfactory system, a central synapse known to exhibit trans-synaptic homeostatic matching. Twelve hours after adult-onset suppression of activity in postsynaptic antennal lobe projection neurons, we detected changes in the expression of many genes in the third antennal segment, which houses the somata of presynaptic olfactory receptor neurons. These changes affected genes with roles in synaptic vesicle release and synaptic remodeling, including several genes implicated in homeostatic plasticity at the neuromuscular junction. At 48 hours and beyond, the transcriptional landscape was tilted toward proteostasis, energy metabolism, and cellular stress defenses, indicating that the system had been pushed to its homeostatic limits. Our data provide insights into the nature of homeostatic compensation at a central synapse and identify many genes engaged in synaptic homeostasis. The presynaptic transcriptional response to genetically targeted postsynaptic perturbations could be exploited for the construction of novel connectivity tracing tools.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Different contrast encoding in ON and OFF visual pathways

    Subjective visual experience builds on sensory encoding of light reflected by different objects in our environment. Most retinal ganglion cells encode changes in light intensity, quantified as contrast, rather than the absolute intensity. Mathematically, contrast is often defined as a relative change in light intensity. Activity in the visual system and perceptual responses are usually explained with such definitions of contrast. Here, for the first time, we explicitly explored how contrast is actually represented in the visual system. Using mouse retina electrophysiology, we show that response strength of OFF retinal ganglion cells does not represent relative, but absolute changes in light intensity. ON RGC response strength is governed by a combination of absolute and relative change in light intensity. This is true for a wide range of ambient light levels, at least from scotopic to high mesopic regimes. Consequently, light decrements and increments are represented asymmetrically in the retina, which may explain the asymmetries in responses to negative and positive contrast observed throughout the visual system. These findings may help to more thoroughly design and interpret vision science studies where responses are driven by contrast of the visual stimuli.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

    The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer's disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on {beta}-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6-9 month old male wild type and TgF344-AD rats, we discovered that loss of LC-NA axons co-insides with heightened {beta}-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG) that is responsible for the increase in LTP magnitude at MPP-DCG synapses we previously reported in TgF344-AD rats. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires {beta}-ARs, and pharmacological blockade of {beta}-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on {beta}-ARs in both behaviors. Thus, a compensatory increase in {beta}-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    Intronic enhancer region governs transcript-specific BDNF expression in neurons

    Brain-derived neurotrophic factor (BDNF) controls the survival, growth, and function of neurons both during the development and in the adult nervous system. BDNF gene is transcribed from several distinct promoters generating transcripts with alternative 5' exons. BDNF transcripts initiated at the first cluster of exons have been associated with the regulation of body weight and various aspects of social behavior, but the mechanisms driving the expression of these transcripts have remained poorly understood. Here, we identify an evolutionarily conserved intronic enhancer region inside the BDNF gene that regulates both basal and stimulus-dependent expression of the BDNF transcripts starting from the first cluster of 5' exons in neurons. We further uncover a functional E-box element in the enhancer region, linking the expression of BDNF and various pro-neural basic helix-loop-helix transcription factors. Collectively, our results shed new light on the cell type- and stimulus-specific regulation of the important neurotrophic factor BDNF.

    in bioRxiv: Neuroscience on November 26, 2020 12:00 AM.

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    In silico prediction of ARB resistance: A first step in creating personalized ARB therapy

    by Shane D. Anderson, Asna Tabassum, Jae Kyung Yeon, Garima Sharma, Priscilla Santos, Tik Hang Soong, Yin Win Thu, Isaac Nies, Tomomi Kurita, Andrew Chandler, Abdelaziz Alsamarah, Rhye-Samuel Kanassatega, Yun L. Luo, Wesley M. Botello-Smith, Bradley T. Andresen

    Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 –L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.

    in PLoS Computational Biology on November 25, 2020 10:00 PM.

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    Learning about cell lineage, cellular diversity and evolution of the human brain through stem cell models

    Publication date: February 2021

    Source: Current Opinion in Neurobiology, Volume 66

    Author(s): Romain Le Bail, Antonela Bonafina, Ira Espuny-Camacho, Laurent Nguyen

    in Current Opinion in Neurobiology on November 25, 2020 07:00 PM.

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    Community effects allow bioelectrical reprogramming of cell membrane potentials in multicellular aggregates: Model simulations

    Author(s): Javier Cervera, Patricio Ramirez, Michael Levin, and Salvador Mafe

    Bioelectrical patterns are established by spatiotemporal correlations of cell membrane potentials at the multicellular level, being crucial to development, regeneration, and tumorigenesis. We have conducted multicellular simulations on bioelectrical community effects and intercellular coupling in mu...


    [Phys. Rev. E 102, 052412] Published Wed Nov 25, 2020

    in Physical Review E: Biological physics on November 25, 2020 10:00 AM.

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    Cell type‐ and layer‐specific convergence in core and shell neurons of the dorsal lateral geniculate nucleus

    Cell type‐ and layer‐specific convergence in core and shell neurons of the dorsal lateral geniculate nucleus

    Rabies virus‐based monosynaptic circuit tracing allows the exploration of cell‐type specificity of both long‐distance and local connections in the central nervous system. We provide anatomical evidence of the cell type‐and layer‐specific convergence in dLGN core and shell neurons. These findings suggest that dLGN core neurons integrate and process more multimodal information along with visual information than dLGN shell neurons and that LGN core and shell neurons integrate different types of information, send their own convergent information to discrete populations of the V1, and differentially contribute to visual perception and behavior.


    Abstract

    Over 40 distinct types of retinal ganglion cells (RGCs) generate parallel processing pathways in the visual system. In mice, two subdivisions of the dorsal lateral geniculate nucleus (dLGN), the core and the shell, organize distinct parallel channels to transmit visual information from the retina to the primary visual cortex (V1). To investigate how the dLGN core and shell differentially integrate visual information and other modalities, we mapped synaptic input sources to each dLGN subdivision at the cell‐type level with G‐deleted rabies viral vectors. The monosynaptic circuit tracing revealed that dLGN core neurons received inputs from alpha‐RGCs, layer 6 neurons of the V1, the superficial and intermediate layers of the superior colliculus (SC), the internal ventral LGN, the lower layer of the external ventral LGN (vLGNe), the intergeniculate leaf, the thalamic reticular nucleus (TRN), and the pretectal nucleus (PT). Conversely, shell neurons received inputs from alpha‐RGCs and direction‐selective ganglion cells of the retina, layer 6 neurons of the V1, the superficial layer of the SC, the superficial and lower layers of the vLGNe, the TRN, the PT, and the parabigeminal nucleus. The present study provides anatomical evidence of the cell type‐ and layer‐specific convergence in dLGN core and shell neurons. These findings suggest that dLGN core neurons integrate and process more multimodal information along with visual information than shell neurons and that LGN core and shell neurons integrate different types of information, send their own convergent information to discrete populations of the V1, and differentially contribute to visual perception and behavior.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on November 25, 2020 09:44 AM.

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    Dendritic trafficking: synaptic scaling and structural plasticity. (arXiv:2011.12067v1 [q-bio.NC])

    Neuronal circuits internally regulate electrical signaling via a host of homeostatic mechanisms. Two prominent mechanisms, synaptic scaling and structural plasticity, are believed to maintain average activity within an operating range by modifying the strength and spatial extent of network connectivity using negative feedback. However, both mechanisms operate on relatively slow timescales and thus face fundamental limits due to delays. We show that these mechanisms fulfill complementary roles in maintaining stability in a large network. In particular, even relatively, slow growth dynamics improves performance significantly beyond synaptic scaling alone.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 25, 2020 01:30 AM.

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    Role of inhibitory neurons in temporal correlations of critical and supercritical spontaneous activity. (arXiv:2011.12050v1 [q-bio.NC])

    Experimental and numerical results suggest that the brain can be viewed as a system acting close to a critical point, as confirmed by scale-free distributions of relevant quantities in a variety of different systems and models. Less attention has received the investigation of the temporal correlation functions in brain activity in different, healthy and pathological, conditions. Here we perform this analysis by means of a model with short and long-term plasticity which implements the novel feature of different recovery rates for excitatory and inhibitory neurons, found experimentally. We evidence the important role played by inhibitory neurons in the supercritical state: We detect an unexpected oscillatory behaviour of the correlation decay, whose frequency depends on the fraction of inhibitory neurons and their connectivity degree. This behaviour can be rationalized by the observation that bursts in activity become more frequent and with a smaller amplitude as inhibition becomes more relevant.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 25, 2020 01:30 AM.

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    Efficient Sampling for Predictor-Based Neural Architecture Search. (arXiv:2011.12043v1 [cs.LG])

    Recently, predictor-based algorithms emerged as a promising approach for neural architecture search (NAS). For NAS, we typically have to calculate the validation accuracy of a large number of Deep Neural Networks (DNNs), what is computationally complex. Predictor-based NAS algorithms address this problem. They train a proxy model that can infer the validation accuracy of DNNs directly from their network structure. During optimization, the proxy can be used to narrow down the number of architectures for which the true validation accuracy must be computed, what makes predictor-based algorithms sample efficient. Usually, we compute the proxy for all DNNs in the network search space and pick those that maximize the proxy as candidates for optimization. However, that is intractable in practice, because the search spaces are often very large and contain billions of network architectures. The contributions of this paper are threefold: 1) We define a sample efficiency gain to compare different predictor-based NAS algorithms. 2) We conduct experiments on the NASBench-101 dataset and show that the sample efficiency of predictor-based algorithms decreases dramatically if the proxy is only computed for a subset of the search space. 3) We show that if we choose the subset of the search space on which the proxy is evaluated in a smart way, the sample efficiency of the original predictor-based algorithm that has access to the full search space can be regained. This is an important step to make predictor-based NAS algorithms useful, in practice.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    A More Biologically Plausible Local Learning Rule for ANNs. (arXiv:2011.12012v1 [cs.NE])

    The backpropagation algorithm is often debated for its biological plausibility. However, various learning methods for neural architecture have been proposed in search of more biologically plausible learning. Most of them have tried to solve the "weight transport problem" and try to propagate errors backward in the architecture via some alternative methods. In this work, we investigated a slightly different approach that uses only the local information which captures spike timing information with no propagation of errors. The proposed learning rule is derived from the concepts of spike timing dependant plasticity and neuronal association. A preliminary evaluation done on the binary classification of MNIST and IRIS datasets with two hidden layers shows comparable performance with backpropagation. The model learned using this method also shows a possibility of better adversarial robustness against the FGSM attack compared to the model learned through backpropagation of cross-entropy loss. The local nature of learning gives a possibility of large scale distributed and parallel learning in the network. And finally, the proposed method is a more biologically sound method that can probably help in understanding how biological neurons learn different abstractions.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    Hyper parameter estimation method with particle swarm optimization. (arXiv:2011.11944v1 [cs.LG])

    Particle swarm optimization (PSO) method cannot be directly used in the problem of hyper-parameter estimation since the mathematical formulation of the mapping from hyper-parameters to loss function or generalization accuracy is unclear. Bayesian optimization (BO) framework is capable of converting the optimization of the hyper-parameters into the optimization of an acquisition function. The acquisition function is non-convex and multi-peak. So the problem can be better solved by the PSO. The proposed method in this paper uses the particle swarm method to optimize the acquisition function in the BO framework to get better hyper-parameters. The performances of proposed method in both of the classification and regression models are evaluated and demonstrated. The results on several benchmark problems are improved.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    Multi-task Language Modeling for Improving Speech Recognition of Rare Words. (arXiv:2011.11715v2 [cs.CL] UPDATED)

    End-to-end automatic speech recognition (ASR) systems are increasingly popular due to their relative architectural simplicity and competitive performance. However, even though the average accuracy of these systems may be high, the performance on rare content words often lags behind hybrid ASR systems. To address this problem, second-pass rescoring is often applied. In this paper, we propose a second-pass system with multi-task learning, utilizing semantic targets (such as intent and slot prediction) to improve speech recognition performance. We show that our rescoring model with trained with these additional tasks outperforms the baseline rescoring model, trained with only the language modeling task, by 1.4% on a general test and by 2.6% on a rare word test set in term of word-error-rate relative (WERR).

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    Natural-gradient learning for spiking neurons. (arXiv:2011.11710v1 [q-bio.NC])

    In many normative theories of synaptic plasticity, weight updates implicitly depend on the chosen parametrization of the weights. This problem relates, for example, to neuronal morphology: synapses which are functionally equivalent in terms of their impact on somatic firing can differ substantially in spine size due to their different positions along the dendritic tree. Classical theories based on Euclidean gradient descent can easily lead to inconsistencies due to such parametrization dependence. The issues are solved in the framework of Riemannian geometry, in which we propose that plasticity instead follows natural gradient descent. Under this hypothesis, we derive a synaptic learning rule for spiking neurons that couples functional efficiency with the explanation of several well-documented biological phenomena such as dendritic democracy, multiplicative scaling and heterosynaptic plasticity. We therefore suggest that in its search for functional synaptic plasticity, evolution might have come up with its own version of natural gradient descent.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    DeepClimGAN: A High-Resolution Climate Data Generator. (arXiv:2011.11705v1 [cs.NE])

    Earth system models (ESMs), which simulate the physics and chemistry of the global atmosphere, land, and ocean, are often used to generate future projections of climate change scenarios. These models are far too computationally intensive to run repeatedly, but limited sets of runs are insufficient for some important applications, like adequately sampling distribution tails to characterize extreme events. As a compromise, emulators are substantially less expensive but may not have all of the complexity of an ESM. Here we demonstrate the use of a conditional generative adversarial network (GAN) to act as an ESM emulator. In doing so, we gain the ability to produce daily weather data that is consistent with what ESM might output over any chosen scenario. In particular, the GAN is aimed at representing a joint probability distribution over space, time, and climate variables, enabling the study of correlated extreme events, such as floods, droughts, or heatwaves.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    Transient chaotic dimensionality expansion by recurrent networks. (arXiv:2002.11006v3 [cond-mat.dis-nn] UPDATED)

    Cortical neurons communicate with spikes, which are discrete events in time. Even if the timings of the individual events are strongly chaotic (microscopic chaos), the rate of events might still be non-chaotic or at the edge of what is known as rate chaos. Such edge-of-chaos dynamics are beneficial to the computational power of neuronal networks. We analyze both types of chaotic dynamics in densely connected networks of asynchronous binary neurons, by developing and applying a model-independent field theory for neuronal networks. We find a strongly size-dependent transition to microscopic chaos. We then expose the conceptual difficulty at the heart of the definition of rate chaos, identify two reasonable definitions, and show that for neither of them the binary network dynamics crosses a transition to rate chaos.

    The analysis of diverging trajectories in chaotic networks also allows us to study classification of linearly non-separable classes of stimuli in a reservoir computing approach. We show that microscopic chaos rapidly expands the dimensionality of the representation while, crucially, the number of dimensions corrupted by noise lags behind. This translates to a transient peak in the networks' classification performance even deeply in the chaotic regime, challenging the view that computational performance is always optimal near the edge of chaos. This is a general effect in high dimensional chaotic systems, and not specific to binary networks: We also demonstrate it in a continuous 'rate' network, a spiking LIF network, and an LSTM network. For binary and LIF networks, classification performance peaks rapidly within one activation per participating neuron, demonstrating fast event-based computation that may be exploited by biological neural systems, for which we propose testable predictions.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 25, 2020 01:30 AM.

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    Complex Sparse Code Priors Improve the Statistical Models of Neurons in Primate Primary Visual Cortex. (arXiv:1911.08241v2 [q-bio.QM] UPDATED)

    System identification techniques---projection pursuit regression models (PPR) and convolutional neural networks (CNNs)---provide state-of-the-art performance in predicting visual cortical neurons' responses to arbitrary input stimuli. However, the constituent kernels recovered by these methods, particularly those of CNNs, are often noisy and lack coherent structure, making it difficult to understand the underlying component features of a neuron's receptive field. In this paper, we show that using a dictionary of complex sparse codes, which are learned from natural scenes based on efficient coding theory, as the front-end for PPR and CNNs can improve their performance in neuronal response prediction. More importantly, this approach makes the constituent kernels of these models substantially more coherent and interpretable. Extensive experimental results also indicate that these interpretable kernels provide important information on the component features of a neuron's receptive field. In addition, we find that models with a complex sparse code front-end are significantly better than models with a standard orientation-selective Gabor filter front-end for modeling V1 neurons that have been found to exhibit complex pattern selectivity. This observation adds further credence to the sparse coding theory as well as empirical findings of complex feature selectivity in V1.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 25, 2020 01:30 AM.

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    Deep Evidential Regression. (arXiv:1910.02600v2 [cs.LG] UPDATED)

    Deterministic neural networks (NNs) are increasingly being deployed in safety critical domains, where calibrated, robust, and efficient measures of uncertainty are crucial. In this paper, we propose a novel method for training non-Bayesian NNs to estimate a continuous target as well as its associated evidence in order to learn both aleatoric and epistemic uncertainty. We accomplish this by placing evidential priors over the original Gaussian likelihood function and training the NN to infer the hyperparameters of the evidential distribution. We additionally impose priors during training such that the model is regularized when its predicted evidence is not aligned with the correct output. Our method does not rely on sampling during inference or on out-of-distribution (OOD) examples for training, thus enabling efficient and scalable uncertainty learning. We demonstrate learning well-calibrated measures of uncertainty on various benchmarks, scaling to complex computer vision tasks, as well as robustness to adversarial and OOD test samples.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 25, 2020 01:30 AM.

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    Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-3015-0

    Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery

    in Nature on November 25, 2020 12:00 AM.

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    Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-3014-1

    Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

    in Nature on November 25, 2020 12:00 AM.

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    Author Correction: Combinatorial expression of GPCR isoforms affects signalling and drug responses

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2999-9

    Author Correction: Combinatorial expression of GPCR isoforms affects signalling and drug responses

    in Nature on November 25, 2020 12:00 AM.

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    Commensal-driven immune zonation of the liver promotes host defence

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2977-2

    The authors show that zonation extends to hepatic immune cells and that this spatial patterning is mediated by microbiome sensing by liver sinusoidal endothelial cells, and provide evidence that immune zonation is required to protect the host from the dissemination of blood-borne pathogens.

    in Nature on November 25, 2020 12:00 AM.

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    Functional adaptive landscapes predict terrestrial capacity at the origin of limbs

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2974-5

    Analysis of humeri from fossils that span the fin-to-limb transition reveal that the change in the humerus shape is driven by both ecology and phylogeny, and is associated with functional trade-offs related to locomotor performance.

    in Nature on November 25, 2020 12:00 AM.

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    Neural circuit mechanisms of sexual receptivity in Drosophila females

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2972-7

    In Drosophila melanogaster, female mating decisions are governed by female-specific descending neurons that integrate input from auditory neurons that respond to features of the song of a conspecific male and central neurons that encode the mating status of the female.

    in Nature on November 25, 2020 12:00 AM.

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    The gut microbiota is associated with immune cell dynamics in humans

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2971-8

    Influence of the gut microbiome on the human immune system is revealed by systems analysis of vast clinical data from decades of electronic health records paired with massive longitudinal microbiome sequencing.

    in Nature on November 25, 2020 12:00 AM.

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    Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2968-3

    Inhibition of YBX1, a downstream target of the Janus kinase JAK2, sensitizes myeloproliferative neoplasm cells to JAK and could provide a means to eradicate such cells in human haematopoietic cancers.

    in Nature on November 25, 2020 12:00 AM.

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    A map of cis-regulatory elements and 3D genome structures in zebrafish

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2962-9

    A comprehensive map of transcriptomes, cis-regulatory elements, heterochromatin structure, the methylome and 3D genome organization in the zebrafish (Danio rerio) enables identification of species-specific and evolutionarily conserved regulatory features, and provides a foundation for modelling studies on human disease and development.

    in Nature on November 25, 2020 12:00 AM.

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    Multiple wheat genomes reveal global variation in modern breeding

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2961-x

    Comparison of multiple genome assemblies from wheat reveals extensive diversity that results from the complex breeding history of wheat and provides a basis for further potential improvements to this important food crop.

    in Nature on November 25, 2020 12:00 AM.

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    TRF2-independent chromosome end protection during pluripotency

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2960-y

    Experiments in mouse pluripotent embryonic and epiblast stem cells show that TRF2 is dispensable for telomere protection specifically specifically in the pluripotent cells that form during early embryonic development, when cells form T-loops independently of this protein.

    in Nature on November 25, 2020 12:00 AM.

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    TRF2-mediated telomere protection is dispensable in pluripotent stem cells

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2959-4

    Depletion of TRF2—an essential mediator of telomere protection in most mammalian cells—in mouse embryonic stem cells activates a compensatory transcriptional program that renders TRF2 dispensable for their survival and proliferation.

    in Nature on November 25, 2020 12:00 AM.

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    Retraction Note: Living annulative π-extension polymerization for graphene nanoribbon synthesis

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2950-0

    Retraction Note: Living annulative π-extension polymerization for graphene nanoribbon synthesis

    in Nature on November 25, 2020 12:00 AM.

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    The barley pan-genome reveals the hidden legacy of mutation breeding

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2947-8

    Chromosome-scale sequence assemblies of 20 diverse varieties of barley are used to construct a first-generation pan-genome, revealing previously hidden genetic variation that can be used by studies aimed at crop improvement

    in Nature on November 25, 2020 12:00 AM.

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    Late Cretaceous bird from Madagascar reveals unique development of beaks

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2945-x

    A crow-sized stem bird, Falcatakely forsterae, possesses a long and deep rostrum—a beak morphology that was previously unknown among Mesozoic birds and is similar to that of some crown-group birds, such as toucans.

    in Nature on November 25, 2020 12:00 AM.

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    A network of grassroots reserves protects tropical river fish diversity

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2944-y

    A network of small, community-run river reserves in Thailand increases local fish biomass, diversity and richness.

    in Nature on November 25, 2020 12:00 AM.

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    Fibrosis: from mechanisms to medicines

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2938-9

    This review discusses how single-cell profiling and other technological advances are increasing our understanding of the mechanisms of fibrosis, thereby accelerating the discovery, development and testing of new treatments.

    in Nature on November 25, 2020 12:00 AM.

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    Observing the emergence of a quantum phase transition shell by shell

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2936-y

    An atomic simulator formed of a few ultracold fermionic atoms trapped in a two-dimensional harmonic potential exhibits precursors of a quantum phase transition, revealing the onset of collective quantum many-body phenomena in a few-body system.

    in Nature on November 25, 2020 12:00 AM.

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    Experimental evidence of neutrinos produced in the CNO fusion cycle in the Sun

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2934-0

    Direct experimental evidence of the carbon–nitrogen–oxygen fusion cycle in the Sun is provided by the detection of neutrinos emitted during this process.

    in Nature on November 25, 2020 12:00 AM.

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    Discoveries in structure and physiology of mechanically activated ion channels

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2933-1

    This Review summarizes developments in the field of mechanically activated ion channels, which have been driven by the increasing breadth of structural studies.

    in Nature on November 25, 2020 12:00 AM.

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    Lanthanide-doped inorganic nanoparticles turn molecular triplet excitons bright

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2932-2

    Optically dark (non-emitting) triplet excitons on organic molecules may be rendered bright by coupling the molecules to lanthanide-doped nanoparticles, providing a way to control such excitons in optoelectronic systems.

    in Nature on November 25, 2020 12:00 AM.

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    Spin-enhanced nanodiamond biosensing for ultrasensitive diagnostics

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2917-1

    Lateral-flow in vitro diagnostic assays based on fluorescent nanodiamonds, in which microwave-based spin manipulation is used to increase sensitivity, are demonstrated using the biotin–avidin model and by the single-copy detection of HIV-1 RNA.

    in Nature on November 25, 2020 12:00 AM.

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    Antarctic ice dynamics amplified by Northern Hemisphere sea-level forcing

    Nature, Published online: 25 November 2020; doi:10.1038/s41586-020-2916-2

    Changes in Northern Hemisphere ice-sheet size during ice-age cycles enhance the advance and retreat of the grounding line of the Antarctic Ice Sheet, owing to interhemispheric sea-level forcing.

    in Nature on November 25, 2020 12:00 AM.

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    Mechanisms of node of Ranvier assembly

    Nature Reviews Neuroscience, Published online: 25 November 2020; doi:10.1038/s41583-020-00406-8

    The formation of the nodes of Ranvier in myelinated axons involves a specific clustering of ion channels. In this Review, Rasband and Peles describe two independent, glia-directed mechanisms that converge on the axonal cytoskeleton to cluster and maintain nodal ion channels.

    in Nature Reviews on November 25, 2020 12:00 AM.

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    Publisher Correction: A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-20120-4

    Publisher Correction: A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

    in Nature Communications on November 25, 2020 12:00 AM.

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    Author Correction: Quantum clocks and the temporal localisability of events in the presence of gravitating quantum systems

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-20105-3

    Author Correction: Quantum clocks and the temporal localisability of events in the presence of gravitating quantum systems

    in Nature Communications on November 25, 2020 12:00 AM.

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    Retraction Note: Air-stable superparamagnetic metal nanoparticles entrapped in graphene oxide matrix

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19968-3

    Retraction Note: Air-stable superparamagnetic metal nanoparticles entrapped in graphene oxide matrix

    in Nature Communications on November 25, 2020 12:00 AM.

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    Breaking boundaries in subduction science

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19930-3

    Subduction is the primary driver of plate tectonics, yet we still do not fully understand how subduction zones initiate or the budgets of life-supporting elements recycled via subduction. At Nature Communications, we advocate for more transdisciplinary initiatives and collaborative projects, which are essential if we are to continue to bring new dynamics to subduction research.

    in Nature Communications on November 25, 2020 12:00 AM.

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    No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19818-2

    SARS-CoV-2 has emerged recently and may still adapt to the human host. Here the authors show that none of the so far identified recurrent mutations in SARS-CoV-2 are significantly associated with increased viral transmission.

    in Nature Communications on November 25, 2020 12:00 AM.

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    High-resolution sampling of beam-driven plasma wakefields

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19811-9

    Controlled particle acceleration in plasmas requires precise measurements of the excited wakefield. Here the authors report and demonstrate a high-resolution method to measure the effective longitudinal electric field of a beam-driven plasma-wakefield accelerator.

    in Nature Communications on November 25, 2020 12:00 AM.

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    Biased localization of actin binding proteins by actin filament conformation

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19768-9

    The assembly of actin filaments into distinct cytoskeletal structures plays a critical role in cell physiology. Here, the authors use a combination of live cell imaging and in vitro single molecule binding measurements to show that tandem calponin homology domains (CH1–CH2) are sensitive to actin filament conformation, biasing their subcellular localization.

    in Nature Communications on November 25, 2020 12:00 AM.

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    Vibrational couplings and energy transfer pathways of water’s bending mode

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19759-w

    Vibrational energy transfer in water involves intermolecular coupling of O-H stretching modes, but much less is known about the role of the bending modes. Here the authors, combining static and femtosecond infrared, Raman, and hyper-Raman spectroscopy and ab initio molecular dynamics simulations, provide insight into the energy dynamics of the bend vibrations.

    in Nature Communications on November 25, 2020 12:00 AM.

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    The genetic architecture of sporadic and multiple consecutive miscarriage

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19742-5

    Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.

    in Nature Communications on November 25, 2020 12:00 AM.

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    Intelligent non-colorimetric indicators for the perishable supply chain by non-wovens with photo-programmed thermal response

    Nature Communications, Published online: 25 November 2020; doi:10.1038/s41467-020-19676-y

    High-performance and low-cost indicators are important in food and cosmetics industry but market uptake is low due to several challenges such as toxicity, cost and unclear reading. Here, the authors report on optically-programmed, non-colorimetric indicators based on nanotextured organic non-wovens, encoded by controlling their cross-linking degree.

    in Nature Communications on November 25, 2020 12:00 AM.

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    Daily briefing: ‘Serendipity’ boosted Oxford–AstraZeneca vaccine’s efficacy

    Nature, Published online: 25 November 2020; doi:10.1038/d41586-020-03353-7

    Mistake led to striking improvement for COVID vaccine, how Iceland hammered COVID with science and ways Joe Biden can achieve his ambitious climate agenda.

    in Nature on November 25, 2020 12:00 AM.

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    Adult Mouse Retina Explants: From ex vivo to in vivo Model of Central Nervous System Injuries

    In mammals, adult neurons fail to regenerate following any insult to adult central nervous system (CNS), which leads to a permanent and irreversible loss of motor and cognitive functions. For a long time, much effort has been deployed to uncover mechanisms of axon regeneration in the CNS. Even if some cases of functional recovery have been reported, there is still a discrepancy regarding the functionality of a neuronal circuit upon lesion. Today, there is a need not only to identify new molecules implicated in adult CNS axon regeneration, but also to decipher the fine molecular mechanisms associated with regeneration failure. Here, we propose to use cultures of adult retina explants to study all molecular and cellular mechanisms that occur during CNS regeneration. We show that adult retinal explant cultures have the advantages to (i) recapitulate all the features observed in vivo, including axon regeneration induced by intrinsic factors, and (ii) be an ex vivo set-up with high accessibility and many downstream applications. Thanks to several examples, we demonstrate that adult explants can be used to address many questions, such as axon guidance, growth cone formation and cytoskeleton dynamics. Using laser guided ablation of a single axon, axonal injury can be performed at a single axon level, which allows to record early and late molecular events that occur after the lesion. Our model is the ideal tool to study all molecular and cellular events that occur during CNS regeneration at a single-axon level, which is currently not doable in vivo. It is extremely valuable to address unanswered questions of neuroprotection and neuroregeneration in the context of CNS lesion and neurodegenerative diseases.

    in Frontiers in Molecular Neuroscience on November 25, 2020 12:00 AM.

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    Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation

    Embryofetal development is a critical process that needs a strict epigenetic control, however, perturbations in this balance might lead to the occurrence of congenital anomalies. It is known that anticonvulsants potentially affect epigenetics-related genes, however, it is not comprehended whether this unbalance could explain the anticonvulsants-induced fetal syndromes. In the present study, we aimed to evaluate the expression of epigenetics-related genes in valproic acid, carbamazepine, or phenytoin exposure. We selected these three anticonvulsants exposure assays, which used murine or human embryonic stem-cells and were publicly available in genomic databases. We performed a differential gene expression (DGE) and weighted gene co-expression network analysis (WGCNA), focusing on epigenetics-related genes. Few epigenetics genes were differentially expressed in the anticonvulsants’ exposure, however, the WGCNA strategy demonstrated a high enrichment of chromatin remodeling genes for the three drugs. We also identified an association of 46 genes related to Fetal Valproate Syndrome, containing SMARCA2 and SMARCA4, and nine genes to Fetal Hydantoin Syndrome, including PAX6, NEUROD1, and TSHZ1. The evaluation of stem-cells under drug exposure can bring many insights to understand the drug-induced damage to the embryofetal development. The candidate genes here presented are potential biomarkers that could help in future strategies for the prevention of congenital anomalies.

    in Frontiers in Neuroscience: Systems Biology on November 25, 2020 12:00 AM.

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    Organ Cultures for Retinal Diseases

    The successful development of novel therapies is closely linked with understanding the underlying pathomechanisms of a disease. To do so, model systems that reflect human diseases and allow for the evaluation of new therapeutic approaches are needed. Yet, preclinical animal studies often have limited success in predicting human physiology, pathology, and therapeutic responses. Moreover, animal testing is facing increasing ethical and bureaucratic hurdles, while human cell cultures are limited in their ability to represent in vivo situations due to the lack of the tissue microenvironment, which may alter cellular responses. To overcome these struggles, organ cultures, especially those of complex organs such as the retina, can be used to study physiological reactions to substances or stressors. Human and animal organ cultures are now well established and recognized. This mini-review discusses how retinal organ cultures can be used to preserve tissue architecture more realistically and therefore better represent disease-related changes. It also shows how molecular biological, biochemical, and histological techniques can be combined to investigate how anatomical localization may alter cellular responses. Examples for the use of retinal organ cultures, including models to study age-related macular degeneration (AMD), retinitis pigmentosa (RP), central artery occlusion (CRAO), and glaucoma are presented, and their advantages and disadvantages are discussed. We conclude that organ cultures significantly improve our understanding of complex retinal diseases and may advance treatment testing without the need for animal testing.

    in Frontiers in Neuroscience: Neurodegeneration on November 25, 2020 12:00 AM.

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    Alterations in Sub-Axonal Architecture Between Normal Aging and Parkinson’s Diseased Human Brains Using Label-Free Cryogenic X-ray Nanotomography

    Gaining insight to pathologically relevant processes in continuous volumes of unstained brain tissue is important for a better understanding of neurological diseases. Many pathological processes in neurodegenerative disorders affect myelinated axons, which are a critical part of the neuronal circuitry. Cryo ptychographic X-ray computed tomography in the multi-keV energy range is an emerging technology providing phase contrast at high sensitivity, allowing label-free and non-destructive three dimensional imaging of large continuous volumes of tissue, currently spanning up to 400,000 μm3. This aspect makes the technique especially attractive for imaging complex biological material, especially neuronal tissues, in combination with downstream optical or electron microscopy techniques. A further advantage is that dehydration, additional contrast staining, and destructive sectioning/milling are not required for imaging. We have developed a pipeline for cryo ptychographic X-ray tomography of relatively large, hydrated and unstained biological tissue volumes beyond what is typical for the X-ray imaging, using human brain tissue and combining the technique with complementary methods. We present four imaged volumes of a Parkinson’s diseased human brain and five volumes from a non-diseased control human brain using cryo ptychographic X-ray tomography. In both cases, we distinguish neuromelanin-containing neurons, lipid and melanic pigment, blood vessels and red blood cells, and nuclei of other brain cells. In the diseased sample, we observed several swellings containing dense granular material resembling clustered vesicles between the myelin sheaths arising from the cytoplasm of the parent oligodendrocyte, rather than the axoplasm. We further investigated the pathological relevance of such swollen axons in adjacent tissue sections by immunofluorescence microscopy for phosphorylated alpha-synuclein combined with multispectral imaging. Since cryo ptychographic X-ray tomography is non-destructive, the large dataset volumes were used to guide further investigation of such swollen axons by correlative electron microscopy and immunogold labeling post X-ray imaging, a possibility demonstrated for the first time. Interestingly, we find that protein antigenicity and ultrastructure of the tissue are preserved after the X-ray measurement. As many pathological processes in neurodegeneration affect myelinated axons, our work sets an unprecedented foundation for studies addressing axonal integrity and disease-related changes in unstained brain tissues.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 25, 2020 12:00 AM.

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    Effects of Visual Attentional Load on the Tactile Sensory Memory Indexed by Somatosensory Mismatch Negativity

    Auditory sensory memory indexed by mismatch negativity has been broadly studied over the past century, but far less attention has been directed to tactile sensory memory. To investigate whether tactile sensory memory is affected by attention, we recorded somatosensory mismatch negativity (sMMN) from 24 healthy adults in two experiments to distinguish sustained attention from non-sustained attention. Using the roving somatosensory oddball paradigm, we analyzed the average dynamic changes in the amplitude and latency of sMMN amplitude and found a clear sMMN component at the central region at a 100–300 ms interval. The sMMN amplitude, which indexes the early detection of tactile stimuli with the sensory memory trace, was larger in the tactile attentional task. Additionally, the sMMN latency increased with the increasing visual attentional load, which indicates a decay of tactile sensory memory. Our results indicate that the more attention resources are allocated for a tactile sensation, the more favorable it is to the generation of tactile sensory memory.

    in Frontiers in Neuroinformatics on November 25, 2020 12:00 AM.

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    Editorial: Coding for Spatial Orientation in Humans and Animals: Behavior, Circuits and Neurons

    in Frontiers in Neural Circuits on November 25, 2020 12:00 AM.

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    Corrigendum: Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity

    in Frontiers in Cellular Neuroscience on November 25, 2020 12:00 AM.

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    Phase Coupled Firing of Prefrontal Parvalbumin Interneuron With High Frequency Oscillations

    The prefrontal cortex (PFC) plays a central role in executive functions and inhibitory control over many cognitive behaviors. Dynamic changes in local field potentials (LFPs), such as gamma oscillation, have been hypothesized to be important for attentive behaviors and modulated by local interneurons such as parvalbumin (PV) cells. However, the precise relationships between the firing patterns of PV interneurons and temporal dynamics of PFC activities remains elusive. In this study, by combining in vivo electrophysiological recordings with optogenetics, we investigated the activities of prefrontal PV interneurons and categorized them into three subtypes based on their distinct firing rates under different behavioral states. Interestingly, all the three subtypes of interneurons showed strong phase-locked firing to cortical high frequency oscillations (HFOs), but not to theta or gamma oscillations, despite of behavior states. Moreover, we showed that sustained optogenetic stimulation (over a period of 10 s) of PV interneurons can consequently modulate the activities of local pyramidal neurons. Interestingly, such optogenetic manipulations only showed moderate effects on LFPs in the PFC. We conclude that prefrontal PV interneurons are consist of several subclasses of cells with distinct state-dependent modulation of firing rates, selectively coupled to HFOs.

    in Frontiers in Cellular Neuroscience on November 25, 2020 12:00 AM.

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    Motor Skill Learning-Induced Functional Plasticity in the Primary Somatosensory Cortex: A Comparison Between Young and Older Adults

    While in young adults (YAs) the underlying neural mechanisms of motor learning are well-studied, studies on the involvement of the somatosensory system during motor skill learning in older adults (OAs) remain sparse. Therefore, the aim of the present study was to investigate motor learning-induced neuroplasticity in the primary somatosensory cortex (S1) in YAs and OAs. Somatosensory evoked potentials (SEPs) were used to quantify somatosensory activation prior and immediately after motor skill learning in 20 right-handed healthy YAs (age range: 19–35 years) and OAs (age range: 57–76 years). Participants underwent a single session of a 30-min co-contraction task of the abductor pollicis brevis (APB) and deltoid muscle. To assess the effect of motor learning, muscle onset asynchrony (MOA) between the onsets of the contractions of both muscles was measured using electromyography monitoring. In both groups, MOA shortened significantly during motor learning, with YAs showing bigger reductions. No changes were found in SEP amplitudes after motor learning in both groups. However, a correlation analysis revealed an association between baseline SEP amplitudes of the N20/P25 and N30 SEP component and the motor learning slope in YAs such that higher amplitudes are related to higher learning. Hence, the present findings suggest that SEP amplitudes might serve as a predictor of individual motor learning success, at least in YAs. Additionally, our results suggest that OAs are still capable of learning complex motor tasks, showing the importance of motor training in higher age to remain an active part of our society as a prevention for care dependency.

    in Frontiers in Ageing Neuroscience on November 25, 2020 12:00 AM.

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    Overview of Meta-Analyses of Five Non-pharmacological Interventions for Alzheimer's Disease

    Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory deficits, cognitive decline, and spatial disorientation. Non-pharmacological interventions to treat AD have been reported in many meta-analyses (MAs), but robust conclusions have not been made because of variations in the scope, quality, and findings of these reviews.

    Objective: This work aimed to review existing MAs to provide an overview of existing evidence on the effects of five non-pharmacological interventions in AD patients on three outcomes: Mini-Mental State Examination (MMSE), activities of daily living (ADL), and Alzheimer's Disease Assessment Scale-cognitive section (ADAS-cog).

    Methods: The databases PubMed, Cochrane Library, Embase, and Web of Science were searched to collect MAs of non-pharmacological interventions for AD. Two reviewers independently conducted literature screening, data extraction, and quality assessment. We assessed the quality of MAs with the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 and assessed the evidence quality for significant outcomes using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.

    Results: We found 10 eligible MAs, which included between three (133 patients) and 15 randomized trials (1,217 patients), and five non-pharmacological interventions, namely, acupuncture therapy (40%), exercise intervention (30%), music therapy (10%), cognitive intervention (10%), and repetitive transcranial magnetic stimulation (rTMS) (10%). All the included MAs were critically low to low quality by AMSTAR 2. Acupuncture therapy and exercise intervention showed the preliminary potential to improve ADL and MMSE. rTMS and acupuncture therapy show benefits in decreasing ADAS-cog, and there were some evidence of improved MMSE with cognitive intervention. All these outcomes scored very low quality to moderate quality of evidence on the GRADE system.

    Conclusions: Non-pharmacological therapy shows promise for the treatment of AD, but there is still a lack of high-quality evidence. In the future, the quality of the original research needs to be improved, and strictly designed MAs should be carried out following methodological requirements.

    in Frontiers in Ageing Neuroscience on November 25, 2020 12:00 AM.

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    Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients

    Membrane protein biogenesis in the endoplasmic reticulum (ER) is complex and failure-prone. The ER membrane protein complex (EMC), comprising eight conserved subunits, has emerged as a central player in this process. Yet, we have limited understanding of how EMC enables insertion and integrity of diverse clients, from tail-anchored to polytopic transmembrane proteins. Here, yeast and human EMC cryo-EM structures reveal conserved intricate assemblies and human-specific features associated with pathologies. Structure-based functional studies distinguish between two separable EMC activities, as an insertase regulating tail-anchored protein levels and a broader role in polytopic membrane protein biogenesis. These depend on mechanistically coupled yet spatially distinct regions including two lipid-accessible membrane cavities which confer client-specific regulation, and a non-insertase EMC function mediated by the EMC lumenal domain. Our studies illuminate the structural and mechanistic basis of EMC's multifunctionality and point to its role in differentially regulating the biogenesis of distinct client protein classes.

    in eLife on November 25, 2020 12:00 AM.

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    Structure of bacterial phospholipid transporter MlaFEDB with substrate bound

    In double-membraned bacteria, phospholipid transport across the cell envelope is critical to maintain the outer membrane barrier, which plays a key role in virulence and antibiotic resistance. An MCE transport system called Mla has been implicated in phospholipid trafficking and outer membrane integrity, and includes an ABC transporter, MlaFEDB. The transmembrane subunit, MlaE, has minimal sequence similarity to other transporters, and the structure of the entire inner-membrane MlaFEDB complex remains unknown. Here we report the cryo-EM structure of MlaFEDB at 3.05 Å resolution, revealing distant relationships to the LPS and MacAB transporters, as well as the eukaryotic ABCA/ABCG families. A continuous transport pathway extends from the MlaE substrate-binding site, through the channel of MlaD, and into the periplasm. Unexpectedly, two phospholipids are bound to MlaFEDB, suggesting that multiple lipid substrates may be transported each cycle. Our structure provides mechanistic insight into substrate recognition and transport by MlaFEDB.

    in eLife on November 25, 2020 12:00 AM.

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    Autophagy compensates for Lkb1 loss to maintain adult mice homeostasis and survival

    Liver Kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11) is the major energy sensor for cells to respond to metabolic stress. Autophagy degrades and recycles proteins, macromolecules, and organelles for cells to survive starvation. To access the role and cross-talk between autophagy and Lkb1 in normal tissue homeostasis, we generated genetically engineered mouse models where we can conditionally delete Stk11 and autophagy essential gene, Atg7, respectively or simultaneously, throughout the adult mice. We found that Lkb1 was essential for the survival of adult mice, and autophagy activation could temporarily compensate for the acute loss of Lkb1 and extend mouse life span. We further found that acute deletion of Lkb1 in adult mice led to impaired intestinal barrier function, hypoglycemia, and abnormal serum metabolism, which was partly rescued by the Lkb1 loss-induced autophagy upregulation via inhibiting p53 induction. Taken together, we demonstrated that autophagy and Lkb1 work synergistically to maintain adult mouse homeostasis and survival.

    in eLife on November 25, 2020 12:00 AM.

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    Proteomic analysis of young and old mouse hematopoietic stem cells and their progenitors reveals post-transcriptional regulation in stem cells

    The balance of hematopoietic stem cell (HSC) self-renewal and differentiation is critical for a healthy blood supply; imbalances underlie hematological diseases. The importance of HSCs and their progenitors have led to their extensive characterization at genomic and transcriptomic levels. However, the proteomics of hematopoiesis remains incompletely understood. Here we report a proteomics resource from mass spectrometry of mouse young adult and old adult mouse HSCs, multipotent progenitors and oligopotent progenitors; 12 cell types in total. We validated differential protein levels, including confirmation that Dnmt3a protein levels are undetected in young adult mouse HSCs until forced into cycle. Additionally, through integrating proteomics and RNA-sequencing datasets, we identified a subset of genes with apparent post-transcriptional repression in young adult mouse HSCs. In summary, we report proteomic coverage of young and old mouse HSCs and progenitors, with broader implications for understanding mechanisms for stem cell maintenance, niche interactions and fate determination.

    in eLife on November 25, 2020 12:00 AM.

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    Efficient mate finding in planktonic copepods swimming in turbulence

    Zooplankton live in dynamic environments where turbulence may challenge their limited swimming abilities. How this interferes with fundamental behavioral processes remains elusive. We reconstruct simultaneously the trajectories of flow tracers and calanoid copepods and we quantify their ability to find mates when ambient flow imposes physical constrains on their motion and impairs their olfactory orientation. We show that copepods achieve high encounter rates in turbulence due to the contribution of advection and vigorous swimming. Males further convert encounters within the perception radius to contacts and then to mating via directed motion toward nearby organisms within the short time frame of the encounter. Inertial effects do not result in preferential concentration, reducing the geometric collision kernel to the clearance rate, which we model accurately by superposing turbulent velocity and organism motion. This behavioral and physical coupling mechanism may account for the ability of copepods to reproduce in turbulent environments.

    in eLife on November 25, 2020 12:00 AM.

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    Structural basis of TRPC4 regulation by calmodulin and pharmacological agents

    Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin. Molecular details of both calmodulin and drug binding have remained elusive so far. Here we report structures of TRPC4 in complex with three pyridazinone-based inhibitors and calmodulin. The structures reveal that all the inhibitors bind to the same cavity of the voltage-sensing-like domain and allow us to describe how structural changes from the ligand binding site can be transmitted to the central ion-conducting pore of TRPC4. Calmodulin binds to the rib helix of TRPC4, which results in the ordering of a previously disordered region, fixing the channel in its closed conformation. This represents a novel calmodulin-induced regulatory mechanism of canonical TRP channels.

    in eLife on November 25, 2020 12:00 AM.

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    The Arabidopsis V-ATPase is localized to the TGN/EE via a seed plant specific motif

    The V-ATPase is a versatile proton-pump found in a range of endomembrane compartments yet the mechanisms governing its differential targeting remain to be determined. In Arabidopsis, VHA-a1 targets the V-ATPase to the TGN/EE whereas VHA-a2 and VHA-a3 are localized to the tonoplast. We report here that the VHA-a1 targeting domain serves as both an ER-exit and as a TGN/EE-retention motif and is conserved among seed plants. In contrast, Marchantia encodes a single VHA-isoform that localizes to the TGN/EE and the tonoplast in Arabidopsis. Analysis of CRISPR/Cas9 generated null alleles revealed that VHA-a1 has an essential for male gametophyte development but acts redundantly with the tonoplast isoforms during vegetative growth. We propose that in the absence of VHA-a1, VHA-a3 is partially re-routed to the TGN/EE. Our findings contribute to understanding the evolutionary origin of V-ATPase targeting and provide a striking example that differential localization does not preclude functional redundancy.

    in eLife on November 25, 2020 12:00 AM.

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    In silico analysis of myeloid cells across animal kingdom reveal neutrophil evolution by colony stimulating factors

    Neutrophils constitute the largest population of phagocytic granulocytes in the blood of mammals. The development and function of neutrophils and monocytes is primarily governed by the granulocyte colony-stimulating factor receptor family (CSF3R/CSF3) and macrophage colony-stimulating factor receptor family (CSF1R/IL34/CSF1) respectively. Using various techniques this study considered how the emergence of receptor:ligand pairings shaped the distribution of blood myeloid cell populations. Comparative gene analysis supported the ancestral pairings of CSF1R/IL34 and CSF3R/CSF3, and the emergence of CSF1 later in lineages after the advent of Jawed/Jawless fish. Further analysis suggested that the emergence of CSF3 lead to reorganisation of granulocyte distribution between amphibian and early reptiles. However, the advent of endothermy likely contributed to the dominance of the neutrophil/heterophil in modern-day mammals and birds. In summary, we show that the emergence of CSF3R/CSF3 was a key factor in the subsequent evolution of the modern-day mammalian neutrophil.

    in eLife on November 25, 2020 12:00 AM.

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    Wnt3 distribution in the zebrafish brain is determined by expression, diffusion and multiple molecular interactions

    Wnt3 proteins are lipidated and glycosylated, secreted signaling molecules that play an important role in zebrafish neural patterning and brain development. However, the transport mechanism of lipid-modified Wnts through the hydrophilic extracellular environment for long-range action remains unresolved. Here, we determine how Wnt3 accomplishes long-range distribution in the zebrafish brain. First, we characterize the Wnt3-producing source and Wnt3-receiving target regions. Subsequently, we analyze Wnt3 mobility at different length scales by fluorescence correlation spectroscopy and fluorescence recovery after photobleaching. We demonstrate that Wnt3 spreads extracellularly and interacts with heparan sulfate proteoglycans (HSPG). We then determine the binding affinity of Wnt3 to its receptor, Frizzled1 (Fzd1), using fluorescence cross-correlation spectroscopy, and show that the co-receptor, low-density lipoprotein receptor-related protein 5 (Lrp5), is required for Wnt3-Fzd1 interaction. Our results are consistent with the extracellular distribution of Wnt3 by a diffusive mechanism that is modified by tissue morphology, interactions with HSPG and Lrp5-mediated receptor binding, to regulate zebrafish brain development.

    in eLife on November 25, 2020 12:00 AM.

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    Zebrafish Posterior Lateral Line primordium migration requires interactions between a superficial sheath of motile cells and the skin

    The Zebrafish Posterior Lateral Line primordium migrates in a channel between the skin and somites. Its migration depends on the coordinated movement of its mesenchymal-like leading cells and trailing cells, which form epithelial rosettes, or protoneuromasts. We describe a superficial population of flat primordium cells that wrap around deeper epithelialized cells and extend polarized lamellipodia to migrate apposed to the overlying skin. Polarization of lamellipodia extended by both superficial and deeper protoneuromast-forming cells depends on Fgf signaling. Removal of the overlying skin has similar effects on superficial and deep cells: lamellipodia are lost, blebs appear instead, and collective migration fails. When skinned embryos are embedded in Matrigel, basal and superficial lamellipodia are recovered; however, only the directionality of basal protrusions is recovered, and migration is not rescued. These observations support a key role played by superficial primordium cells and the skin in directed migration of the Posterior Lateral Line primordium.

    in eLife on November 25, 2020 12:00 AM.

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    Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behaviour

    Low-intensity transcranial ultrasound (TUS) can non-invasively modulate human neural activity. We investigated how different fundamental sonication parameters influence the effects of TUS on the motor cortex (M1) of 16 healthy subjects by probing cortico-cortical excitability and behaviour. A low-intensity 500 kHz TUS transducer was coupled to a transcranial magnetic stimulation (TMS) coil. TMS was delivered 10 ms before the end of TUS to the left M1 hotspot of the first dorsal interosseous muscle. Varying acoustic parameters (pulse repetition frequency, duty cycle and sonication duration) on motor-evoked potential amplitude were examined. Paired-pulse measures of cortical inhibition and facilitation, and performance on a visuomotor task was also assessed. TUS safely suppressed TMS-elicited motor cortical activity, with longer sonication durations and shorter duty cycles when delivered in a blocked paradigm. TUS increased GABAA-mediated short-interval intracortical inhibition and decreased reaction time on visuomotor task but not when controlled with TUS at near-somatosensory threshold intensity.

    in eLife on November 25, 2020 12:00 AM.

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    Sex-dimorphic neuroestradiol regulation of ventromedial hypothalamic nucleus glucoregulatory transmitter and glycogen metabolism enzyme protein expression in the rat

    Ventromedial hypothalamic nucleus (VMN) gluco-regulatory transmission is subject to sex-specific control by estradiol. The VMN is characterized by high levels of aromatase expression.

    in BMC Neuroscience on November 25, 2020 12:00 AM.

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    Transforming the study of organisms: Phenomic data models and knowledge bases

    by Anne E. Thessen, Ramona L. Walls, Lars Vogt, Jessica Singer, Robert Warren, Pier Luigi Buttigieg, James P. Balhoff, Christopher J. Mungall, Deborah L. McGuinness, Brian J. Stucky, Matthew J. Yoder, Melissa A. Haendel

    The rapidly decreasing cost of gene sequencing has resulted in a deluge of genomic data from across the tree of life; however, outside a few model organism databases, genomic data are limited in their scientific impact because they are not accompanied by computable phenomic data. The majority of phenomic data are contained in countless small, heterogeneous phenotypic data sets that are very difficult or impossible to integrate at scale because of variable formats, lack of digitization, and linguistic problems. One powerful solution is to represent phenotypic data using data models with precise, computable semantics, but adoption of semantic standards for representing phenotypic data has been slow, especially in biodiversity and ecology. Some phenotypic and trait data are available in a semantic language from knowledge bases, but these are often not interoperable. In this review, we will compare and contrast existing ontology and data models, focusing on nonhuman phenotypes and traits. We discuss barriers to integration of phenotypic data and make recommendations for developing an operationally useful, semantically interoperable phenotypic data ecosystem.

    in PLoS Computational Biology on November 24, 2020 10:00 PM.

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    Epidemics on the move: Climate change and infectious disease

    by Matthew B. Thomas

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Improved genetically encoded near-infrared fluorescent calcium ion indicators for <i>in vivo</i> imaging

    by Yong Qian, Danielle M. Orozco Cosio, Kiryl D. Piatkevich, Sarah Aufmkolk, Wan-Chi Su, Orhan T. Celiker, Anne Schohl, Mitchell H. Murdock, Abhi Aggarwal, Yu-Fen Chang, Paul W. Wiseman, Edward S. Ruthazer, Edward S. Boyden, Robert E. Campbell

    Near-infrared (NIR) genetically encoded calcium ion (Ca2+) indicators (GECIs) can provide advantages over visible wavelength fluorescent GECIs in terms of reduced phototoxicity, minimal spectral cross talk with visible light excitable optogenetic tools and fluorescent probes, and decreased scattering and absorption in mammalian tissues. Our previously reported NIR GECI, NIR-GECO1, has these advantages but also has several disadvantages including lower brightness and limited fluorescence response compared to state-of-the-art visible wavelength GECIs, when used for imaging of neuronal activity. Here, we report 2 improved NIR GECI variants, designated NIR-GECO2 and NIR-GECO2G, derived from NIR-GECO1. We characterized the performance of the new NIR GECIs in cultured cells, acute mouse brain slices, and Caenorhabditis elegans and Xenopus laevis in vivo. Our results demonstrate that NIR-GECO2 and NIR-GECO2G provide substantial improvements over NIR-GECO1 for imaging of neuronal Ca2+ dynamics.

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Climate change and disease in plant communities

    by Jeremy J. Burdon, Jiasui Zhan

    Climate change is triggering similar effects on the incidence and severity of disease for crops in agriculture and wild plants in natural communities. The complexity of natural ecosystems, however, generates a complex array of interactions between wild plants and pathogens in marked contrast to those generated in the structural and species simplicity of most agricultural crops. Understanding the different impacts of climate change on agricultural and natural ecosystems requires accounting for the specific interactions between an individual pathogen and its host(s) and their subsequent effects on the interplay between the host and other species in the community. Ultimately, progress will require looking past short-term fluctuations to multiyear trends to understand the nature and extent of plant and pathogen evolutionary adaptation and determine the fate of plants under future climate change.

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Understanding how temperature shifts could impact infectious disease

    by Jason R. Rohr, Jeremy M. Cohen

    Climate change is expected to have complex effects on infectious diseases, causing some to increase, others to decrease, and many to shift their distributions. There have been several important advances in understanding the role of climate and climate change on wildlife and human infectious disease dynamics over the past several years. This essay examines 3 major areas of advancement, which include improvements to mechanistic disease models, investigations into the importance of climate variability to disease dynamics, and understanding the consequences of thermal mismatches between host and parasites. Applying the new information derived from these advances to climate–disease models and addressing the pressing knowledge gaps that we identify should improve the capacity to predict how climate change will affect disease risk for both wildlife and humans.

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils

    by Young Mi Kwon, Kevin Gori, Naomi Park, Nicole Potts, Kate Swift, Jinhong Wang, Maximilian R. Stammnitz, Naomi Cannell, Adrian Baez-Ortega, Sebastien Comte, Samantha Fox, Colette Harmsen, Stewart Huxtable, Menna Jones, Alexandre Kreiss, Clare Lawrence, Billie Lazenby, Sarah Peck, Ruth Pye, Gregory Woods, Mona Zimmermann, David C. Wedge, David Pemberton, Michael R. Stratton, Rodrigo Hamede, Elizabeth P. Murchison

    Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Building resilience to mosquito-borne diseases in the Caribbean

    by Rachel Lowe, Sadie J. Ryan, Roché Mahon, Cedric J. Van Meerbeeck, Adrian R. Trotman, Laura-Lee G. Boodram, Mercy J. Borbor-Cordova, Anna M. Stewart-Ibarra

    Small island developing states in the Caribbean are among the most vulnerable countries on the planet to climate variability and climate change. In the last 3 decades, the Caribbean region has undergone frequent and intense heat waves, storms, floods, and droughts. This has had a detrimental impact on population health and well-being, including an increase in infectious disease outbreaks. Recent advances in climate science have enhanced our ability to anticipate hydrometeorological hazards and associated public health challenges. Here, we discuss progress towards bridging the gap between climate science and public health decision-making in the Caribbean to build health system resilience to extreme climatic events. We focus on the development of climate services to help manage mosquito-transmitted disease epidemics. There are numerous areas of ongoing biological research aimed at better understanding the direct and indirect impacts of climate change on the transmission of mosquito-borne diseases. Here, we emphasise additional factors that affect our ability to operationalise this biological understanding. We highlight a lack of financial resources, technical expertise, data sharing, and formalised partnerships between climate and health communities as major limiting factors to developing sustainable climate services for health. Recommendations include investing in integrated climate, health and mosquito surveillance systems, building regional and local human resource capacities, and designing national and regional cross-sectoral policies and national action plans. This will contribute towards achieving the Sustainable Development Goals (SDGs) and maximising regional development partnerships and co-benefits for improved health and well-being in the Caribbean.

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Effects of climate change on parasites and disease in estuarine and nearshore environments

    by James E. Byers

    Information on parasites and disease in marine ecosystems lags behind terrestrial systems, increasing the challenge of predicting responses of marine host–parasite systems to climate change. However, here I examine several generalizable aspects and research priorities. First, I advocate that quantification and comparison of host and parasite thermal performance curves is a smart approach to improve predictions of temperature effects on disease. Marine invertebrate species are ectothermic and should be highly conducive to this approach given their generally short generation times. Second, in marine systems, shallow subtidal and intertidal areas will experience the biggest temperature swings and thus likely see the most changes to host–parasite dynamics. Third, for some responses like parasite intensity, as long as the lethal limit of the parasite is not crossed, on average, there may be a biological basis to expect temperature-dependent intensification of impacts on hosts. Fourth, because secondary mortality effects and indirect effects of parasites can be very important, we need to study temperature effects on host–parasite dynamics in a community context to truly know their bottom line effects. This includes examining climate-influenced effects of parasites on ecosystem engineers given their pivotal role in communities. Finally, other global change factors, especially hypoxia, salinity, and ocean acidity, covary with temperature change and need to be considered and evaluated when possible for their contributing effects on host–parasite systems. Climate change–disease interactions in nearshore marine environments are complex; however, generalities are possible and continued research, especially in the areas outlined here, will improve our understanding.

    in PLoS Biology on November 24, 2020 10:00 PM.

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    Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy

    Objective

    This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations.

    Methods

    We performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database–DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death.

    Results

    Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty‐two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty‐four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001).

    Interpretation

    Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2020

    in Annals of Neurology on November 24, 2020 08:11 PM.

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    EIF2AK2 missense variants associated with early‐onset generalized dystonia

    Objective

    To identify a monogenic cause of early‐onset, generalized dystonia.

    Methods

    Genome‐wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain MRI, and protein expression studies in skin fibroblasts from patients.

    Results

    We identified a heterozygous variant, c.388G>A, p.Gly130Arg in the Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2 (EIF2AK2) gene, segregating with early‐onset isolated generalized dystonia in five patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded two unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These three missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In three patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (PKR) that phosphorylates the Eukaryotic Translation Initiation Factor 2 Alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR‐mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA, the product of another gene causing monogenic dystonia.

    Interpretation

    We identified EIF2AK2 variants implicated in early‐onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 24, 2020 08:00 PM.

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    Passages 2021

    in Annals of Neurology on November 24, 2020 07:46 PM.

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    Correction for Goldstein and Lee, Demographic perspectives on the mortality of COVID-19 and other epidemics [Correction]

    SOCIAL SCIENCES Correction for “Demographic perspectives on the mortality of COVID-19 and other epidemics,” by Joshua R. Goldstein and Ronald D. Lee, which was first published August 20, 2020; 10.1073/pnas.2006392117 (Proc. Natl. Acad. Sci. U.S.A. 117, 22035–22041). The authors note that on page 22037, left column, fourth paragraph, second sentence,...

    in PNAS on November 24, 2020 06:46 PM.

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    Correction for Kossin et al., Global increase in major tropical cyclone exceedance probability over the past four decades [Correction]

    EARTH, ATMOSPHERIC, AND PLANETARY SCIENCES Correction for “Global increase in major tropical cyclone exceedance probability over the past four decades,” by James P. Kossin, Kenneth R. Knapp, Timothy L. Olander, and Christopher S. Velden, which was first published May 18, 2020; 10.1073/pnas.1920849117 (Proc. Natl. Acad. Sci. U.S.A. 117, 11975–11980). The...

    in PNAS on November 24, 2020 06:46 PM.

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    Correction for Huang et al., Mechanism of water extraction from gypsum rock by desert colonizing microorganisms [Correction]

    BIOPHYSICS AND COMPUTATIONAL BIOLOGY, MICROBIOLOGY Correction for “Mechanism of water extraction from gypsum rock by desert colonizing microorganisms,” by Wei Huang, Emine Ertekin, Taifeng Wang, Luz Cruz, Micah Dailey, Jocelyne DiRuggiero, and David Kisailus, which was first published May 4, 2020; 10.1073/pnas.2001613117 (Proc. Natl. Acad. Sci. U.S.A. 117, 10681–10687). The...

    in PNAS on November 24, 2020 06:46 PM.

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    Correction for Polymenidou et al., Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection [Correction]

    Colloquium Correction for “Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection,” by Magdalini Polymenidou, Frank L. Heppner, Erica C. Pellicioli, Eduard Urich, Gino Miele, Nathalie Braun, Franziska Wopfner, Hermann M. Schätzl, Burkhard Becher, and Adriano Aguzzi, which was first published August 3, 2004; 10.1073/pnas.0404772101 (Proc. Natl....

    in PNAS on November 24, 2020 06:46 PM.

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    Rerouting of ribosomal proteins into splicing in plant organelles [Plant Biology]

    Production and expression of RNA requires the action of multiple RNA-binding proteins (RBPs). New RBPs are most often created by novel combinations of dedicated RNA-binding modules. However, recruiting existing genes to create new RBPs is also an important evolutionary strategy. In this report, we analyzed the eight-member uL18 ribosomal protein...

    in PNAS on November 24, 2020 06:46 PM.

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    Selectivity filter ion binding affinity determines inactivation in a potassium channel [Physiology]

    Potassium channels can become nonconducting via inactivation at a gate inside the highly conserved selectivity filter (SF) region near the extracellular side of the membrane. In certain ligand-gated channels, such as BK channels and MthK, a Ca2+-activated K+ channel from Methanobacterium thermoautotrophicum, the SF has been proposed to play a...

    in PNAS on November 24, 2020 06:46 PM.

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    Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist [Pharmacology]

    Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970...

    in PNAS on November 24, 2020 06:46 PM.

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    Characteristics of sequential activity in networks with temporally asymmetric Hebbian learning [Neuroscience]

    Sequential activity has been observed in multiple neuronal circuits across species, neural structures, and behaviors. It has been hypothesized that sequences could arise from learning processes. However, it is still unclear whether biologically plausible synaptic plasticity rules can organize neuronal activity to form sequences whose statistics match experimental observations. Here,...

    in PNAS on November 24, 2020 06:46 PM.

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    The potassium channel subunit Kv{beta}1 serves as a maȷor control point for synaptic facilitation [Neuroscience]

    Analysis of the presynaptic action potential’s (APsyn) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca2+ in cultured hippocampal neurons. These recordings revealed a critical and...

    in PNAS on November 24, 2020 06:46 PM.

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    Oscillations in the central brain of Drosophila are phase locked to attended visual features [Neuroscience]

    Object-based attention describes the brain’s capacity to prioritize one set of stimuli while ignoring others. Human research suggests that the binding of diverse stimuli into one attended percept requires phase-locked oscillatory activity in the brain. Even insects display oscillatory brain activity during visual attention tasks, but it is unclear if...

    in PNAS on November 24, 2020 06:46 PM.

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    Stac protein regulates release of neuropeptides [Neuroscience]

    Neuropeptides are important for regulating numerous neural functions and behaviors. Release of neuropeptides requires long-lasting, high levels of cytosolic Ca2+. However, the molecular regulation of neuropeptide release remains to be clarified. Recently, Stac3 was identified as a key regulator of L-type Ca2+ channels (CaChs) and excitation–contraction coupling in vertebrate skeletal...

    in PNAS on November 24, 2020 06:46 PM.

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    Reshaping circadian metabolism in the suprachiasmatic nucleus and prefrontal cortex by nutritional challenge [Neuroscience]

    Food is a powerful entrainment cue for circadian clocks in peripheral tissues, and changes in the composition of nutrients have been demonstrated to metabolically reprogram peripheral clocks. However, how food challenges may influence circadian metabolism of the master clock in the suprachiasmatic nucleus (SCN) or in other brain areas is...

    in PNAS on November 24, 2020 06:46 PM.

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    Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding [Neuroscience]

    Transmembrane channel-like protein 1 (TMC1) and lipoma HMGIC fusion partner-like 5 (LHFPL5) are recognized as two critical components of the mechanotransduction complex in inner-ear hair cells. However, the physical and functional interactions of TMC1 and LHFPL5 remain largely unexplored. We examined the interaction between TMC1 and LHFPL5 by using multiple...

    in PNAS on November 24, 2020 06:46 PM.

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    Neuropsychological and neuropathological observations of a long-studied case of memory impairment [Neuroscience]

    We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and...

    in PNAS on November 24, 2020 06:46 PM.

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    A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex [Neuroscience]

    The prefrontal cortex encodes and stores numerous, often disparate, schemas and flexibly switches between them. Recent research on artificial neural networks trained by reinforcement learning has made it possible to model fundamental processes underlying schema encoding and storage. Yet how the brain is able to create new schemas while preserving...

    in PNAS on November 24, 2020 06:46 PM.

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    Type I interferon remodels lysosome function and modifies intestinal epithelial defense [Microbiology]

    Organelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen Salmonella led us to discover that type I IFN (IFN-I) remodels lysosomes. Even in the...

    in PNAS on November 24, 2020 06:46 PM.

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    Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis [Microbiology]

    Kinetoplastids are unicellular eukaryotic parasites responsible for such human pathologies as Chagas disease, sleeping sickness, and leishmaniasis. They have a single large mitochondrion, essential for the parasite survival. In kinetoplastid mitochondria, most of the molecular machineries and gene expression processes have significantly diverged and specialized, with an extreme example being...

    in PNAS on November 24, 2020 06:46 PM.

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    Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach [Microbiology]

    Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant pathogens for which new treatments are desperately needed. Carbapenemases and other types of antibiotic resistance genes are carried almost exclusively on large, low-copy-number plasmids (pCRE). Accordingly, small molecules that efficiently evict pCRE plasmids should restore much-needed treatment options. We therefore designed a high-throughput screen to...

    in PNAS on November 24, 2020 06:46 PM.

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    Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection [Microbiology]

    Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries...

    in PNAS on November 24, 2020 06:46 PM.

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    Excess of the NF-ĸB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1- and chemokines-mediated mechanisms [Medical Sciences]

    Nuclear factor–ĸB (NF-ĸB) transcription factor is a family of essential regulators of the immune response and cell proliferation and transformation. A typical factor is a heterodimer made of either p50 or p52, which are limited processing products of either p105 or p100, respectively, and a member of the Rel family...

    in PNAS on November 24, 2020 06:46 PM.

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    Type 1 interferon-dependent repression of NLRC4 and iPLA2 licenses down-regulation of Salmonella flagellin inside macrophages [Immunology and Inflammation]

    Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether this innate sensing mechanism has any regulatory effect on the expression of stimulatory ligands by the pathogen. During infection with Salmonella and many other pathogens, flagellin is a major...

    in PNAS on November 24, 2020 06:46 PM.

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    Identification of a brainstem locus that inhibits tumor necrosis factor [Immunology and Inflammation]

    In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other...

    in PNAS on November 24, 2020 06:46 PM.

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    Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide [Immunology and Inflammation]

    Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A Neisseria meningitidis (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To...

    in PNAS on November 24, 2020 06:46 PM.

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    Oncogenic allelic interaction in Xiphophorus highlights hybrid incompatibility [Genetics]

    Mixing genomes of different species by hybridization can disrupt species-specific genetic interactions that were adapted and fixed within each species population. Such disruption can predispose the hybrids to abnormalities and disease that decrease the overall fitness of the hybrids and is therefore named as hybrid incompatibility. Interspecies hybridization between southern...

    in PNAS on November 24, 2020 06:46 PM.

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    The evolutionary origin and domestication history of goldfish (Carassius auratus) [Genetics]

    Goldfish have been subjected to over 1,000 y of intensive domestication and selective breeding. In this report, we describe a high-quality goldfish genome (2n = 100), anchoring 95.75% of contigs into 50 pseudochromosomes. Comparative genomics enabled us to disentangle the two subgenomes that resulted from an ancient hybridization event. Resequencing...

    in PNAS on November 24, 2020 06:46 PM.

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    Selection on phenotypic plasticity favors thermal canalization [Evolution]

    Climate change affects organisms worldwide with profound ecological and evolutionary consequences, often increasing population extinction risk. Climatic factors can increase the strength, variability, or direction of natural selection on phenotypic traits, potentially driving adaptive evolution. Phenotypic plasticity in relation to temperature can allow organisms to maintain fitness in response to...

    in PNAS on November 24, 2020 06:46 PM.

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    Exploitative leaders incite intergroup warfare in a social mammal [Evolution]

    Collective conflicts among humans are widespread, although often highly destructive. A classic explanation for the prevalence of such warfare in some human societies is leadership by self-serving individuals that reap the benefits of conflict while other members of society pay the costs. Here, we show that leadership of this kind...

    in PNAS on November 24, 2020 06:46 PM.

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    Marine wild-capture fisheries after nuclear war [Sustainability Science]

    Nuclear war, beyond its devastating direct impacts, is expected to cause global climatic perturbations through injections of soot into the upper atmosphere. Reduced temperature and sunlight could drive unprecedented reductions in agricultural production, endangering global food security. However, the effects of nuclear war on marine wild-capture fisheries, which significantly contribute...

    in PNAS on November 24, 2020 06:46 PM.

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    Seasonal and diel patterns of abundance and activity of viruses in the Red Sea [Ecology]

    Virus–microbe interactions have been studied in great molecular details for many years in cultured model systems, yielding a plethora of knowledge on how viruses use and manipulate host machinery. Since the advent of molecular techniques and high-throughput sequencing, methods such as cooccurrence, nucleotide composition, and other statistical frameworks have been...

    in PNAS on November 24, 2020 06:46 PM.

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    A climatic dipole drives short- and long-term patterns of postfire forest recovery in the western United States [Ecology]

    Researchers are increasingly examining patterns and drivers of postfire forest recovery amid growing concern that climate change and intensifying fires will trigger ecosystem transformations. Diminished seed availability and postfire drought have emerged as key constraints on conifer recruitment. However, the spatial and temporal extent to which recurring modes of climatic...

    in PNAS on November 24, 2020 06:46 PM.

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    What Are the Odds?

    in Annals of Neurology on November 24, 2020 06:21 PM.

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    Parafovea change and dopamine loss in the retina with Parkinson's disease

    in Annals of Neurology on November 24, 2020 02:39 PM.

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    Learning sparse and meaningful representations through embodiment

    Publication date: Available online 23 November 2020

    Source: Neural Networks

    Author(s): Viviane Clay, Peter König, Kai-Uwe Kühnberger, Gordon Pipa

    in Neural Networks on November 24, 2020 02:00 PM.

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    Tunability enhancement of gene regulatory motifs through competition for regulatory protein resources

    Author(s): Swetamber Das and Sandeep Choubey

    Gene regulatory networks (GRNs) orchestrate the spatiotemporal levels of gene expression, thereby regulating various cellular functions ranging from embryonic development to tissue homeostasis. Some patterns called “motifs” recurrently appear in the GRNs. Owing to the prevalence of these motifs they...


    [Phys. Rev. E 102, 052410] Published Tue Nov 24, 2020

    in Physical Review E: Biological physics on November 24, 2020 10:00 AM.

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    Contours information and the perception of various visual illusions. (arXiv:2011.11495v1 [q-bio.NC])

    The simplicity principle states that the human visual system prefers the simplest interpretation. However, conventional coding models could not resolve the incompatibility between predictions from the global minimum principle and the local minimum principle. By quantitatively evaluating the total information content of all possible visual interpretations, we show that the perceived pattern is always the one with the simplest local completion as well as the least total surprisal globally, thus solving this apparent conundrum. Our proposed framework consist of (1) the information content of visual contours, (2) direction of visual contour, and (3) the von Mises distribution governing human visual expectation. We used it to explain the perception of prominent visual illusions such as Kanizsa triangle, Ehrenstein cross, and Rubin's vase. This provides new insight into the celebrated simplicity principle and could serve as a fundamental explanation of the perception of illusory boundaries and the bi-stability of perceptual grouping.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 24, 2020 01:30 AM.

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    Language guided machine action. (arXiv:2011.11400v1 [cs.AI])

    Here we build a hierarchical modular network called Language guided machine action (LGMA), whose modules process information stream mimicking human cortical network that allows to achieve multiple general tasks such as language guided action, intention decomposition and mental simulation before action execution etc. LGMA contains 3 main systems: (1) primary sensory system that multimodal sensory information of vision, language and sensorimotor. (2) association system involves and Broca modules to comprehend and synthesize language, BA14/40 module to translate between sensorimotor and language, midTemporal module to convert between language and vision, and superior parietal lobe to integrate attended visual object and arm state into cognitive map for future spatial actions. Pre-supplementary motor area (pre-SMA) can converts high level intention into sequential atomic actions, while SMA can integrate these atomic actions, current arm and attended object state into sensorimotor vector to apply corresponding torques on arm via pre-motor and primary motor of arm to achieve the intention. The high-level executive system contains PFC that does explicit inference and guide voluntary action based on language, while BG is the habitual action control center.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 24, 2020 01:30 AM.

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    Usage and Scaling of an Open-Source Spiking Multi-Area Model of Monkey Cortex. (arXiv:2011.11335v1 [q-bio.NC])

    We are entering an age of `big' computational neuroscience, in which neural network models are increasing in size and in numbers of underlying data sets. Consolidating the zoo of models into large-scale models simultaneously consistent with a wide range of data is only possible through the effort of large teams, which can be spread across multiple research institutions. To ensure that computational neuroscientists can build on each other's work, it is important to make models publicly available as well-documented code. This chapter describes such an open-source model, which relates the connectivity structure of all vision-related cortical areas of the macaque monkey with their resting-state dynamics. We give a brief overview of how to use the executable model specification, which employs NEST as simulation engine, and show its runtime scaling. The solutions found serve as an example for organizing the workflow of future models from the raw experimental data to the visualization of the results, expose the challenges, and give guidance for the construction of ICT infrastructure for neuroscience.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 24, 2020 01:30 AM.

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    Evolutionary Planning in Latent Space. (arXiv:2011.11293v1 [cs.LG])

    Planning is a powerful approach to reinforcement learning with several desirable properties. However, it requires a model of the world, which is not readily available in many real-life problems. In this paper, we propose to learn a world model that enables Evolutionary Planning in Latent Space (EPLS). We use a Variational Auto Encoder (VAE) to learn a compressed latent representation of individual observations and extend a Mixture Density Recurrent Neural Network (MDRNN) to learn a stochastic, multi-modal forward model of the world that can be used for planning. We use the Random Mutation Hill Climbing (RMHC) to find a sequence of actions that maximize expected reward in this learned model of the world. We demonstrate how to build a model of the world by bootstrapping it with rollouts from a random policy and iteratively refining it with rollouts from an increasingly accurate planning policy using the learned world model. After a few iterations of this refinement, our planning agents are better than standard model-free reinforcement learning approaches demonstrating the viability of our approach.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 24, 2020 01:30 AM.

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    V3H: Incomplete Multi-view Clustering via View Variation and View Heredity. (arXiv:2011.11194v1 [cs.LG])

    Real data often appear in the form of multiple incomplete views, and incomplete multi-view clustering is an effective method to integrate these incomplete views. Previous methods only learn the consistent information between different views and ignore the unique information of each view, which limits their clustering performance and generalizations. To overcome this limitation, we propose a novel View Variation and View Heredity approach (V 3 H). Inspired by the variation and the heredity in genetics, V 3 H first decomposes each subspace into a variation matrix for the corresponding view and a heredity matrix for all the views to represent the unique information and the consistent information respectively. Then, by aligning different views based on their cluster indicator matrices, V3H integrates the unique information from different views to improve the clustering performance. Finally, with the help of the adjustable low-rank representation based on the heredity matrix, V3H recovers the underlying true data structure to reduce the influence of the large incompleteness. More importantly, V3H presents possibly the first work to introduce genetics to clustering algorithms for learning simultaneously the consistent information and the unique information from incomplete multi-view data. Extensive experimental results on fifteen benchmark datasets validate its superiority over other state-of-the-arts.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 24, 2020 01:30 AM.

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    Deep Learning in EEG: Advance of the Last Ten-Year Critical Period. (arXiv:2011.11128v1 [eess.SP])

    Deep learning has achieved excellent performance in a wide range of domains, especially in speech recognition and computer vision. Relatively less work has been done for EEG, but there is still significant progress attained in the last decade. Due to the lack of a comprehensive survey for deep learning in EEG, we attempt to summarize recent progress to provide an overview, as well as perspectives for future developments. We first briefly mention the artifacts removal for EEG signal and then introduce deep learning models that have been utilized in EEG processing and classification. Subsequently, the applications of deep learning in EEG are reviewed by categorizing them into groups such as brain-computer interface, disease detection, and emotion recognition. They are followed by the discussion, in which the pros and cons of deep learning are presented and future directions and challenges for deep learning in EEG are proposed. We hope that this paper could serve as a summary of past work for deep learning in EEG and the beginning of further developments and achievements of EEG studies based on deep learning.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 24, 2020 01:30 AM.

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    Investigating Emotion-Color Association in Deep Neural Networks. (arXiv:2011.11058v1 [cs.NE])

    It has been found that representations learned by Deep Neural Networks (DNNs) correlate very well to neural responses measured in primates' brains and psychological representations exhibited by human similarity judgment. On another hand, past studies have shown that particular colors can be associated with specific emotion arousal in humans. Do deep neural networks also learn this behavior? In this study, we investigate if DNNs can learn implicit associations in stimuli, particularly, an emotion-color association between image stimuli. Our study was conducted in two parts. First, we collected human responses on a forced-choice decision task in which subjects were asked to select a color for a specified emotion-inducing image. Next, we modeled this decision task on neural networks using the similarity between deep representation (extracted using DNNs trained on object classification tasks) of the images and images of colors used in the task. We found that our model showed a fuzzy linear relationship between the two decision probabilities. This results in two interesting findings, 1. The representations learned by deep neural networks can indeed show an emotion-color association 2. The emotion-color association is not just random but involves some cognitive phenomena. Finally, we also show that this method can help us in the emotion classification task, specifically when there are very few examples to train the model. This analysis can be relevant to psychologists studying emotion-color associations and artificial intelligence researchers modeling emotional intelligence in machines or studying representations learned by deep neural networks.

    in arXiv: Computer Science: Neural and Evolutionary Computing on November 24, 2020 01:30 AM.

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    Autonomous learning of nonlocal stochastic neuron dynamics. (arXiv:2011.10955v1 [q-bio.NC])

    Neuronal dynamics is driven by externally imposed or internally generated random excitations/noise, and is often described by systems of stochastic ordinary differential equations. A solution to these equations is the joint probability density function (PDF) of neuron states. It can be used to calculate such information-theoretic quantities as the mutual information between the stochastic stimulus and various internal states of the neuron (e.g., membrane potential), as well as various spiking statistics. When random excitations are modeled as Gaussian white noise, the joint PDF of neuron states satisfies exactly a Fokker-Planck equation. However, most biologically plausible noise sources are correlated (colored). In this case, the resulting PDF equations require a closure approximation. We propose two methods for closing such equations: a modified nonlocal large-eddy-diffusivity closure and a data-driven closure relying on sparse regression to learn relevant features. The closures are tested for stochastic leaky integrate-and-fire (LIF) and FitzHugh-Nagumo (FHN) neurons driven by sine-Wiener noise. Mutual information and total correlation between the random stimulus and the internal states of the neuron are calculated for the FHN neuron.

    in arXiv: Quantitative Biology: Neurons and Cognition on November 24, 2020 01:30 AM.

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    Author Correction: 15 years of Nature Physics

    Nature Physics, Published online: 24 November 2020; doi:10.1038/s41567-020-01113-y

    Author Correction: 15 years of Nature Physics

    in Nature Physics on November 24, 2020 12:00 AM.

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    Author Correction: Enhancement of trans-cleavage activity of Cas12a with engineered crRNA enables amplified nucleic acid detection

    Nature Communications, Published online: 24 November 2020; doi:10.1038/s41467-020-20117-z

    Author Correction: Enhancement of trans-cleavage activity of Cas12a with engineered crRNA enables amplified nucleic acid detection

    in Nature Communications on November 24, 2020 12:00 AM.

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    Author Correction: Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

    Nature Communications, Published online: 24 November 2020; doi:10.1038/s41467-020-20098-z

    Author Correction: Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

    in Nature Communications on November 24, 2020 12:00 AM.

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    Refinement of High-Gamma EEG Features From TBI Patients With Hemicraniectomy Using an ICA Informed by Simulated Myoelectric Artifacts

    Recent studies have shown the ability to record high-γ signals (80–160 Hz) in electroencephalogram (EEG) from traumatic brain injury (TBI) patients who have had hemicraniectomies. However, extraction of the movement-related high-γ remains challenging due to a confounding bandwidth overlap with surface electromyogram (EMG) artifacts related to facial and head movements. In our previous work, we described an augmented independent component analysis (ICA) approach for removal of EMG artifacts from EEG, and referred to as EMG Reduction by Adding Sources of EMG (ERASE). Here, we tested this algorithm on EEG recorded from six TBI patients with hemicraniectomies while they performed a thumb flexion task. ERASE removed a mean of 52 ± 12% (mean ± S.E.M) (maximum 73%) of EMG artifacts. In contrast, conventional ICA removed a mean of 27 ± 19% (mean ± S.E.M) of EMG artifacts from EEG. In particular, high-γ synchronization was significantly improved in the contralateral hand motor cortex area within the hemicraniectomy site after ERASE was applied. A more sophisticated measure of high-γ complexity is the fractal dimension (FD). Here, we computed the FD of EEG high-γ on each channel. Relative FD of high-γ was defined as that the FD in move state was subtracted by FD in idle state. We found relative FD of high-γ over hemicraniectomy after applying ERASE were strongly correlated to the amplitude of finger flexion force. Results showed that significant correlation coefficients across the electrodes related to thumb flexion averaged ~0.76, while the coefficients across the homologous electrodes in non-hemicraniectomy areas were nearly 0. After conventional ICA, a correlation between relative FD of high-γ and force remained high in both hemicraniectomy areas (up to 0.86) and non-hemicraniectomy areas (up to 0.81). Across all subjects, an average of 83% of electrodes significantly correlated with force was located in the hemicraniectomy areas after applying ERASE. After conventional ICA, only 19% of electrodes with significant correlations were located in the hemicraniectomy. These results indicated that the new approach isolated electrophysiological features during finger motor activation while selectively removing confounding EMG artifacts. This approach removed EMG artifacts that can contaminate high-gamma activity recorded over the hemicraniectomy.

    in Frontiers in Neuroscience: Neural Technology on November 24, 2020 12:00 AM.

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    Predicting Response to Group Cognitive Behavioral Therapy in Asthma by a Small Number of Abnormal Resting-State Functional Connections

    Group cognitive behavioral therapy (GCBT) is a successful psychotherapy for asthma. However, response varies considerably among individuals, and identifying biomarkers of GCBT has been challenging. Thus, the aim of this study was to predict an individual’s potential response by using machine learning algorithms and functional connectivity (FC) and to improve the personalized treatment of GCBT. We use the lasso method to make the feature selection in the functional connections between brain regions, and we utilize t-test method to test the significant difference of these selected features. The feature selections are performed between controls (size = 20) and pre-GCBT patients (size = 20), pre-GCBT patients (size = 10) and post-GCBT patients (size = 10), and post-GCBT patients (size = 10) and controls (size = 10). Depending on these features, support vector classification was used to classify controls and pre- and post-GCBT patients. Pearson correlation analysis was employed to analyze the associations between clinical symptoms and the selected discriminated FCs in post-GCBT patients. At last, linear support vector regression was applied to predict the therapeutic effect of GCBT. After feature selection and significant analysis, five discriminated FC regarding neuroimaging biomarkers of GCBT were discovered, which are also correlated with clinical symptoms. Using these discriminated functional connections, we could accurately classify the patients before and after GCBT (classification accuracy, 80%) and predict the therapeutic effect of GCBT in asthma (predicted accuracy, 67.8%). The findings in this study would provide a novel sight toward GCBT response prediction and further confirm neural underpinnings of asthma. Moreover, our findings had clinical implications for personalized treatment by identifying asthmatic patients who will be appropriate for GCBT.

    Clinical Trial Registration

    The brain mechanisms of group cognitive behavioral therapy to improve the symptoms of asthma (Registration number: Chi-CTR-15007442, http://www.chictr.org.cn/index.aspx).

    in Frontiers in Neuroscience: Brain Imaging Methods on November 24, 2020 12:00 AM.

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    Studying the Factors of Human Carotid Atherosclerotic Plaque Rupture, by Calculating Stress/Strain in the Plaque, Based on CEUS Images: A Numerical Study

    Carotid plaque neovascularization is one of the major factors for the classification of vulnerable plaque, but the axial force effects of the pulsatile blood flow on the plaque with neovessel and intraplaque hemorrhage was unclear. Together with the severity of stenosis, the fibrous cap thickness, large lipid core, and the neovascularization followed by intraplaque hemorrhage (IPH) have been regarded as high-risk features of plaque rupture. In this work, the effects of these factors were evaluated on the progression and rupture of the carotid atherosclerotic plaques. Five geometries of carotid artery plaque were developed based on contrast-enhanced ultrasound (CEUS) images, which contain two types of neovessel and IPH, and geometry without neovessel and IPH. A one-way fluid-structure interaction model was applied to compute the maximum principal stress and strain in the plaque. For that hyper-elastic and non-linear material, Yeoh 3rd Order strain energy density function was used for components of the plaque. The simulation results indicated that the maximum principal stress of plaque in the carotid artery was higher when the degree of the luminal stenosis increased and the thickness of the fibrous cap decreased. The neovessels within the plaque could introduce a 2.5% increments of deformation in the plaque under the pulsatile blood flow pressure. The IPH also contributed to the increased risk of plaque rupture that a gain of stress was 8.983, 14.526, and 34.47 kPa for the plaque with 50, 65, and 75%, respectively, when comparing stress in the plaque with IPH distributed at the middle to the shoulder of the plaque. In conclusion, neovascularization in the plaque could reduce the stability of the plaque by increasing the stress within the plaque. Also, the risk of plaque rupture increased when large luminal stenosis, thin fibrous cap, and IPH were observed.

    in Frontiers in Neuroinformatics on November 24, 2020 12:00 AM.

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    Increases in Bdnf DNA Methylation in the Prefrontal Cortex Following Aversive Caregiving Are Reflected in Blood Tissue

    Child maltreatment not only leads to epigenetic changes, but also increases the risk of related behavioral deficits and mental disorders. These issues presumably are most closely associated with epigenetic changes in the brain, but epigenetic changes in peripheral tissues like blood are often examined instead, due to their accessibility. As such, the reliability of using the peripheral epigenome as a proxy for that of the brain is imperative. Previously, our lab has found aberrant methylation at the Brain-derived neurotrophic factor (Bdnf) gene in the prefrontal cortex of rats following aversive caregiving. The current study examined whether aversive caregiving alters Bdnf DNA methylation in the blood compared to the prefrontal cortex. It was revealed that DNA methylation associated with adversity increased in both tissues, but this methylation was not correlated between tissues. These findings indicate that group trends in Bdnf methylation between blood and the brain are comparable, but variation exists among individual subjects.

    in Frontiers in Human Neuroscience on November 24, 2020 12:00 AM.

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    On the Relationship Between White Matter Structure and Subjective Pain. Lessons From an Acute Surgical Pain Model

    Background: Pain has been associated with structural changes of the brain. However, evidence regarding white matter changes in response to acute pain protocols is still scarce. In the present study, we assess the existence of differences in brain white matter related to pain intensity reported by patients undergoing surgical removal of a mandibular impacted third molar using diffusion tensor imaging (DTI) analysis.

    Methods: 30 participants reported their subjective pain using a visual analog scale at three postsurgical stages: under anesthesia, in pain, and after the administration of an analgesic. The diffusion data were acquired prior to surgery.

    Results: DTI analysis yielded significant positive associations of fractional anisotropy in white matter areas related to pain processing (corticospinal tract, corona radiata, corpus callosum) with the differences in pain between the three postsurgery stages. Extent and location of these associations depended on the magnitude of the subjective pain differences. Tractography analysis indicated that some pain–tract associations are significant only when pain stage is involved in the contrast (posterior corona radiata), while others (middle cerebellar peduncle, pontine crossing) are only when anesthesia is involved in the contrast.

    Conclusions: The association of white matter fractional anisotropy and connectivity, measured before the pain stages, with subjective pain depends on the magnitude of the differences in pain scores.

    in Frontiers in Human Neuroscience on November 24, 2020 12:00 AM.

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    LncRNA-T199678 Mitigates α-Synuclein-Induced Dopaminergic Neuron Injury via miR-101-3p

    Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by dopaminergic neuron death and the abnormal accumulation and aggregation of α-synuclein (α-Syn) in the substantia nigra (SN). Although the abnormal accumulation of α-Syn can solely promote and accelerate the progress of PD, the underlying molecular mechanisms remain unknown. Mounting evidence confirms that the abnormal expression of long non-coding RNA (lncRNA) plays an important role in PD. Our previous study found that exogenous α-Syn induced the downregulation of lncRNA-T199678 in SH-SY5Y cells via a gene microarray analysis. This finding suggested that lncRNA-T199678 might have a potential pathological role in the pathogenesis of PD. This study aimed to explore the influence of lncRNA-T199678 on α-Syn-induced dopaminergic neuron injury. Overexpression of lncRNA-T199678 ameliorated the neuron injury induced by α-Syn via regulating oxidative stress, cell cycle, and apoptosis. Studies indicate lncRNAs could regulate posttranscriptional gene expression via regulating the downstream microRNA (miRNA). To discover the downstream molecular target of lncRNA-T199678, the following experiment found out that miR-101-3p was a potential target for lncRNA-T199678. Further study showed that the upregulation of lncRNA-T199678 reduced α-Syn-induced neuronal damage through miR-101-3p in SH-SY5Y cells and lncRNA-T199678 was responsible for the α-Syn-induced intracellular oxidative stress, dysfunction of the cell cycle, and apoptosis. All in all, lncRNA-T199678 mitigated the α-Syn-induced dopaminergic neuron injury via targeting miR-101-3p, which contributed to promote PD. Our results highlighted the role of lncRNA-T199678 in mitigating dopaminergic neuron injury in PD and revealed a new molecular target for PD.

    in Frontiers in Ageing Neuroscience on November 24, 2020 12:00 AM.

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    Resveratrol Modulates the Gut-Brain Axis: Focus on Glucagon-Like Peptide-1, 5-HT, and Gut Microbiota

    Resveratrol is a natural polyphenol that has anti-aging and anti-inflammatory properties against stress condition. It is reported that resveratrol has beneficial functions in various metabolic and central nervous system (CNS) diseases, such as obesity, diabetes, depression, and dementia. Recently, many researchers have emphasized the connection between the brain and gut, called the gut–brain axis, for treating both CNS neuropathologies and gastrointestinal diseases. Based on previous findings, resveratrol is involved in glucagon-like peptide 1 (GLP-1) secreted by intestine L cells, the patterns of microbiome in the intestine, the 5-hydroxytryptamine (5-HT) level, and CNS inflammation. Here, we review recent evidences concerning the relevance and regulatory function of resveratrol in the gut–brain axis from various perspectives. Here, we highlight the necessity for further study on resveratrol's specific mechanism in the gut–brain axis. We present the potential of resveratrol as a natural therapeutic substance for treating both neuropathology and gastrointestinal dysfunction.

    in Frontiers in Ageing Neuroscience on November 24, 2020 12:00 AM.

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    COVID-19 research risks ignoring important host genes due to pre-established research patterns

    It is known that research into human genes is heavily skewed towards genes that have been widely studied for decades, including many genes that were being studied before the productive phase of the Human Genome Project. This means that the genes most frequently investigated by the research community tend to be only marginally more important to human physiology and disease than a random selection of genes. Based on an analysis of 10,395 research publications about SARS-CoV-2 that mention at least one human gene, we report here that the COVID-19 literature up to mid-October 2020 follows a similar pattern. This means that a large number of host genes that have been implicated in SARS-CoV-2 infection by four genome-wide studies remain unstudied. While quantifying the consequences of this neglect is not possible, they could be significant.

    in eLife on November 24, 2020 12:00 AM.

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    Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner

    The mechanisms linking maternal stress in pregnancy with infant neurodevelopment in a sexually dimorphic manner are poorly understood. We tested the hypothesis that maternal hypothalamic-pituitary-adrenal axis activity, measured by hair cortisol concentration (HCC), is associated with microstructure, structural connectivity, and volume of the infant amygdala. In 78 mother-infant dyads, maternal hair was sampled postnatally, and infants underwent magnetic resonance imaging at term-equivalent age. We found a relationship between maternal HCC and amygdala development that differed according to infant sex. Higher HCC was associated with higher left amygdala fractional anisotropy (β = 0.677, p=0.010), lower left amygdala orientation dispersion index (β = −0.597, p=0.034), and higher fractional anisotropy in connections between the right amygdala and putamen (β = 0.475, p=0.007) in girls compared to boys. Furthermore, altered amygdala microstructure was only observed in boys, with connectivity changes restricted to girls. Maternal cortisol during pregnancy is related to newborn amygdala architecture and connectivity in a sexually dimorphic manner. Given the fundamental role of the amygdala in the emergence of emotion regulation, these findings offer new insights into mechanisms linking maternal health with neuropsychiatric outcomes of children.

    in eLife on November 24, 2020 12:00 AM.

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    A lung-on-chip model of early M. tuberculosis infection reveals an essential role for alveolar epithelial cells in controlling bacterial growth

    We establish a murine lung-on-chip infection model and use time-lapse imaging to reveal the dynamics of host-Mycobacterium tuberculosis interactions at an air-liquid interface with a spatiotemporal resolution unattainable in animal models and to probe the direct role of pulmonary surfactant in early infection. Surfactant deficiency results in rapid and uncontrolled bacterial growth in both macrophages and alveolar epithelial cells. In contrast, under normal surfactant levels, a significant fraction of intracellular bacteria are non-growing. The surfactant-deficient phenotype is rescued by exogenous addition of surfactant replacement formulations, which have no effect on bacterial viability in the absence of host cells. Surfactant partially removes virulence-associated lipids and proteins from the bacterial cell surface. Consistent with this mechanism, the attenuation of bacteria lacking the ESX-1 secretion system is independent of surfactant levels. These findings may partly explain why smokers and elderly persons with compromised surfactant function are at increased risk of developing active tuberculosis.

    in eLife on November 24, 2020 12:00 AM.

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    High neural activity accelerates the decline of cognitive plasticity with age in Caenorhabditis elegans

    The ability to learn progressively declines with age. Neural hyperactivity has been implicated in impairing cognitive plasticity with age, but the molecular mechanisms remain elusive. Here, we show that chronic excitation of the Caenorhabditis elegans O2-sensing neurons during ageing causes a rapid decline of experience-dependent plasticity in response to environmental O2 concentration, whereas sustaining lower activity of O2-sensing neurons retains plasticity with age. We demonstrate that neural activity alters the ageing trajectory in the transcriptome of O2-sensing neurons, and our data suggest that high-activity neurons redirect resources from maintaining plasticity to sustaining continuous firing. Sustaining plasticity with age requires the K+-dependent Na+/Ca2+ (NCKX) exchanger, whereas the decline of plasticity with age in high-activity neurons acts through calmodulin and the scaffold protein Kidins220. Our findings demonstrate directly that the activity of neurons alters neuronal homeostasis to govern the age-related decline of neural plasticity and throw light on the mechanisms involved.

    in eLife on November 24, 2020 12:00 AM.

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    Lipocalin-2 is an anorexigenic signal in primates

    In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.

    in eLife on November 24, 2020 12:00 AM.

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    Semiochemical responsive olfactory sensory neurons are sexually dimorphic and plastic

    Understanding how genes and experiences work in concert to generate phenotypic variability will provide a better understanding of individuality. Here, we considered this in the main olfactory epithelium, a chemosensory structure with over a thousand distinct cell types in mice. We identified a subpopulation of olfactory sensory neurons, defined by receptor expression, whose abundances were sexually dimorphic. This subpopulation of olfactory sensory neurons was over-represented in sex-separated mice and robustly responsive to sex-specific semiochemicals. Sex-combined housing led to an attenuation of the dimorphic representations. Single-cell sequencing analysis revealed an axis of activity-dependent gene expression amongst a subset of the dimorphic OSN populations. Finally, the pro-apoptotic gene Bax is necessary to generate the dimorphic representations. Altogether, our results suggest a role of experience and activity in influencing homeostatic mechanisms to generate a robust sexually dimorphic phenotype in the main olfactory epithelium.

    in eLife on November 24, 2020 12:00 AM.

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    A dual-feedback loop model of the mammalian circadian clock for multi-input control of circadian phase

    by Lindsey S. Brown, Francis J. Doyle III

    The molecular circadian clock is driven by interlocked transcriptional-translational feedback loops, producing oscillations in the expressions of genes and proteins to coordinate the timing of biological processes throughout the body. Modeling this system gives insight into the underlying processes driving oscillations in an activator-repressor architecture and allows us to make predictions about how to manipulate these oscillations. The knockdown or upregulation of different cellular components using small molecules can disrupt these rhythms, causing a phase shift, and we aim to determine the dosing of such molecules with a model-based control strategy. Mathematical models allow us to predict the phase response of the circadian clock to these interventions and time them appropriately but only if the model has enough physiological detail to describe these responses while maintaining enough simplicity for online optimization. We build a control-relevant, physiologically-based model of the two main feedback loops of the mammalian molecular clock, which provides sufficient detail to consider multi-input control. Our model captures experimentally observed peak to trough ratios, relative abundances, and phase differences in the model species, and we independently validate this model by showing that the in silico model reproduces much of the behavior that is observed in vitro under genetic knockout conditions. Because our model produces valid phase responses, it can be used in a model predictive control algorithm to determine inputs to shift phase. Our model allows us to consider multi-input control through small molecules that act on both feedback loops, and we find that changes to the parameters of the negative feedback loop are much stronger inputs for shifting phase. The strongest inputs predicted by this model provide targets for new experimental small molecules and suggest that the function of the positive feedback loop is to stabilize the oscillations while linking the circadian system to other clock-controlled processes.

    in PLoS Computational Biology on November 23, 2020 10:00 PM.

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    Within-host mechanisms of immune regulation explain the contrasting dynamics of two helminth species in both single and dual infections

    by Chiara Vanalli, Lorenzo Mari, Lorenzo Righetto, Renato Casagrandi, Marino Gatto, Isabella M. Cattadori

    Variation in the intensity and duration of infections is often driven by variation in the network and strength of host immune responses. While many of the immune mechanisms and components are known for parasitic helminths, how these relationships change from single to multiple infections and impact helminth dynamics remains largely unclear. Here, we used laboratory data from a rabbit-helminth system and developed a within-host model of infection to investigate different scenarios of immune regulation in rabbits infected with one or two helminth species. Model selection suggests that the immunological pathways activated against Trichostrongylus retortaeformis and Graphidium strigosum are similar. However, differences in the strength of these immune signals lead to the contrasting dynamics of infections, where the first parasite is rapidly cleared and the latter persists with high intensities. In addition to the reactions identified in single infections, rabbits with both helminths also activate new pathways that asymmetrically affect the dynamics of the two species. These new signals alter the intensities but not the general trend of the infections. The type of interactions described can be expected in many other host-helminth systems. Our immune framework is flexible enough to capture different mechanisms and their complexity, and provides essential insights to the understanding of multi-helminth infections.

    in PLoS Computational Biology on November 23, 2020 10:00 PM.

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    Integrative analysis of structural variations using short-reads and linked-reads yields highly specific and sensitive predictions

    by Riccha Sethi, Julia Becker, Jos de Graaf, Martin Löwer, Martin Suchan, Ugur Sahin, David Weber

    Genetic diseases are driven by aberrations of the human genome. Identification of such aberrations including structural variations (SVs) is key to our understanding. Conventional short-reads whole genome sequencing (cWGS) can identify SVs to base-pair resolution, but utilizes only short-range information and suffers from high false discovery rate (FDR). Linked-reads sequencing (10XWGS) utilizes long-range information by linkage of short-reads originating from the same large DNA molecule. This can mitigate alignment-based artefacts especially in repetitive regions and should enable better prediction of SVs. However, an unbiased evaluation of this technology is not available. In this study, we performed a comprehensive analysis of different types and sizes of SVs predicted by both the technologies and validated with an independent PCR based approach. The SVs commonly identified by both the technologies were highly specific, while validation rate dropped for uncommon events. A particularly high FDR was observed for SVs only found by 10XWGS. To improve FDR and sensitivity, statistical models for both the technologies were trained. Using our approach, we characterized SVs from the MCF7 cell line and a primary breast cancer tumor with high precision. This approach improves SV prediction and can therefore help in understanding the underlying genetics in various diseases.

    in PLoS Computational Biology on November 23, 2020 10:00 PM.

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    Breaking the circularity in circular analyses: Simulations and formal treatment of the flattened average approach

    by Howard Bowman, Joseph L. Brooks, Omid Hajilou, Alexia Zoumpoulaki, Vladimir Litvak

    There has been considerable debate and concern as to whether there is a replication crisis in the scientific literature. A likely cause of poor replication is the multiple comparisons problem. An important way in which this problem can manifest in the M/EEG context is through post hoc tailoring of analysis windows (a.k.a. regions-of-interest, ROIs) to landmarks in the collected data. Post hoc tailoring of ROIs is used because it allows researchers to adapt to inter-experiment variability and discover novel differences that fall outside of windows defined by prior precedent, thereby reducing Type II errors. However, this approach can dramatically inflate Type I error rates. One way to avoid this problem is to tailor windows according to a contrast that is orthogonal (strictly parametrically orthogonal) to the contrast being tested. A key approach of this kind is to identify windows on a fully flattened average. On the basis of simulations, this approach has been argued to be safe for post hoc tailoring of analysis windows under many conditions. Here, we present further simulations and mathematical proofs to show exactly why the Fully Flattened Average approach is unbiased, providing a formal grounding to the approach, clarifying the limits of its applicability and resolving published misconceptions about the method. We also provide a statistical power analysis, which shows that, in specific contexts, the fully flattened average approach provides higher statistical power than Fieldtrip cluster inference. This suggests that the Fully Flattened Average approach will enable researchers to identify more effects from their data without incurring an inflation of the false positive rate.

    in PLoS Computational Biology on November 23, 2020 10:00 PM.

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    Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human brain

    by Gareth Ball, Jakob Seidlitz, Jonathan O’Muircheartaigh, Ralica Dimitrova, Daphna Fenchel, Antonios Makropoulos, Daan Christiaens, Andreas Schuh, Jonathan Passerat-Palmbach, Jana Hutter, Lucilio Cordero-Grande, Emer Hughes, Anthony Price, Jo V. Hajnal, Daniel Rueckert, Emma C. Robinson, A David Edwards

    Interruption to gestation through preterm birth can significantly impact cortical development and have long-lasting adverse effects on neurodevelopmental outcome. We compared cortical morphology captured by high-resolution, multimodal magnetic resonance imaging (MRI) in n = 292 healthy newborn infants (mean age at birth = 39.9 weeks) with regional patterns of gene expression in the fetal cortex across gestation (n = 156 samples from 16 brains, aged 12 to 37 postconceptional weeks [pcw]). We tested the hypothesis that noninvasive measures of cortical structure at birth mirror areal differences in cortical gene expression across gestation, and in a cohort of n = 64 preterm infants (mean age at birth = 32.0 weeks), we tested whether cortical alterations observed after preterm birth were associated with altered gene expression in specific developmental cell populations. Neonatal cortical structure was aligned to differential patterns of cell-specific gene expression in the fetal cortex. Principal component analysis (PCA) of 6 measures of cortical morphology and microstructure showed that cortical regions were ordered along a principal axis, with primary cortex clearly separated from heteromodal cortex. This axis was correlated with estimated tissue maturity, indexed by differential expression of genes expressed by progenitor cells and neurons, and engaged in stem cell differentiation, neuron migration, and forebrain development. Preterm birth was associated with altered regional MRI metrics and patterns of differential gene expression in glial cell populations. The spatial patterning of gene expression in the developing cortex was thus mirrored by regional variation in cortical morphology and microstructure at term, and this was disrupted by preterm birth. This work provides a framework to link molecular mechanisms to noninvasive measures of cortical development in early life and highlights novel pathways to injury in neonatal populations at increased risk of neurodevelopmental disorder.

    in PLoS Biology on November 23, 2020 10:00 PM.

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    Reply to “Letter to the editor concerning Barton and Ranalli”

    in Annals of Neurology on November 23, 2020 06:57 PM.

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    Projections of ipRGCs and conventional RGCs to retinorecipient brain nuclei

    Projections of ipRGCs and conventional RGCs to retinorecipient brain nuclei

    A dual recombinase fluorescent reporter strategy reveals that many retinorecipient brain regions associated with nonimage forming vision are innervated by retinal projections from both image and non‐image forming retinal ganglion cells.


    Abstract

    Retinal ganglion cells (RGCs), the output neurons of the retina, allow us to perceive our visual environment. RGCs respond to rod/cone input through the retinal circuitry, however, a small population of RGCs are in addition intrinsically photosensitive (ipRGCs) and project to unique targets in the brain to modulate a broad range of subconscious visual behaviors such as pupil constriction and circadian photoentrainment. Despite the discovery of ipRGCs nearly two decades ago, there is still little information about how or if conventional RGCs (non‐ipRGCs) target ipRGC‐recipient nuclei to influence subconscious visual behavior. Using a dual recombinase fluorescent reporter strategy, we showed that conventional RGCs innervate many subconscious ipRGC‐recipient nuclei, apart from the suprachiasmatic nucleus. We revealed previously unrecognized stratification patterns of retinal innervation from ipRGCs and conventional RGCs in the ventral portion of the lateral geniculate nucleus. Further, we found that the percent innervation of ipRGCs and conventional RGCs across ipsi‐ and contralateral nuclei differ. Our data provide a blueprint to understand how conventional RGCs and ipRGCs innervate different brain regions to influence subconscious visual behaviors.

    in Journal of Comparative Neurology on November 23, 2020 12:47 PM.

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    Laminar distribution of cortical projection neurons to the pulvinar: a comparative study in cats and mice

    Laminar distribution of cortical projection neurons to the pulvinar: a comparative study in cats and mice

    The laminar distribution of corticothalamic (CT) neurons projecting to the pulvinar thalamic nucleus was assessed in two species: cats and mice. Following injections of the retrograde tracer fragment B of cholera toxin (CTb) in the pulvinar, the morphology and distribution of labelled neurons in the infragranular layers of the visual cortex was compared between the two species. In cats, CT neurons were mostly distributed in layer 6 in all extrastriate areas. The exception was area 17 that labelled neurons where almost exclusively located in layer 5. In mice, CT neurons were mostly located in layer 6 across all areas, including V1. Our findings show a distinct pattern of CT projections in mice in comparison to the one in cats suggesting that the pulvinar nucleus plays distinct roles in the transthalamic transmission of visual information in these species.


    Abstract

    The cortical processing of visual information is thought to follow a hierarchical framework. This framework of connections between visual areas is based on the laminar patterns of direct feedforward and feedback cortico‐cortical projections. However, this view ignores the cortico‐thalamo‐cortical projections to the pulvinar nucleus in the thalamus, which provides an alternative transthalamic information transfer between cortical areas. It was proposed that corticothalamic (CT) pathways follow a similar hierarchical pattern as cortico‐cortical connections. Two main types of CT projections have been recognized: drivers and modulators. Drivers originate mainly in layer 5 whereas modulators are from layer 6. Little is known about the laminar distribution of these projections to the pulvinar across visual cortical areas. Here, we analyzed the distribution of CT neurons projecting to the lateral posterior (LP) thalamus in two species: cats and mice. Injections of the retrograde tracer fragment B of cholera toxin (CTb) were performed in the LP. The morphology and cortical laminar distribution of CTb‐labelled neurons was assessed. In cats, neurons were mostly found in layer 6 except in area 17, where they were mostly in layer 5. In contrast, CT neurons in mice were mostly located in layer 6 across all areas. Thus, our results demonstrate that CT projections in mice do not follow the same organization as cats suggesting that the transthalamic pathways play distinct roles in these species.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on November 23, 2020 10:19 AM.

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    Multicellular sensing at a feedback-induced critical point

    Author(s): Michael Vennettilli, Amir Erez, and Andrew Mugler

    Some biological systems have been found to operate near criticality. This work uses a simple model of a multicellular biological system to probe implications of criticality for information sensing. The authors investigate tradeoffs between precision and rate of acquisition of information about an external signal and discuss implications for several well-studied biological systems.


    [Phys. Rev. E 102, 052411] Published Mon Nov 23, 2020

    in Physical Review E: Biological physics on November 23, 2020 10:00 AM.

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    Focus on neuroscience methods

    Nature Neuroscience, Published online: 23 November 2020; doi:10.1038/s41593-020-00750-z

    In this special issue, we present a series of reviews, perspectives and commentaries that highlight advances in methods and analytical approaches and provide guidelines and best practices in various areas of neuroscience.

    in Nature Neuroscience on November 23, 2020 12:00 AM.

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    An offset ON–OFF receptive field is created by gap junctions between distinct types of retinal ganglion cells

    Nature Neuroscience, Published online: 23 November 2020; doi:10.1038/s41593-020-00747-8

    Cooler and Schwartz describe a retinal ganglion cell type with receptive field properties generated by asymmetric morphology and an electrical connection, via gap junctions, to a different type of retinal ganglion cell.

    in Nature Neuroscience on November 23, 2020 12:00 AM.

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    Neuronal correlates of strategic cooperation in monkeys

    Nature Neuroscience, Published online: 23 November 2020; doi:10.1038/s41593-020-00746-9

    Ong et al. analyzed behavior, gaze patterns and neuronal activity of monkeys playing the game ‘chicken’. Monkeys seemed to develop models of the behavior of the partner, and neurons in the mSTS and the ACCg signaled strategic information to guide their decisions.

    in Nature Neuroscience on November 23, 2020 12:00 AM.

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    Parameterizing neural power spectra into periodic and aperiodic components

    Nature Neuroscience, Published online: 23 November 2020; doi:10.1038/s41593-020-00744-x

    A method for parameterizing electrophysiological neural power spectra into periodic and aperiodic components is introduced, addressing limitations of common approaches. The method is validated in simulation and demonstrated on real data applications.

    in Nature Neuroscience on November 23, 2020 12:00 AM.

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    Auditory activity is diverse and widespread throughout the central brain of Drosophila

    Nature Neuroscience, Published online: 23 November 2020; doi:10.1038/s41593-020-00743-y

    Pacheco et al. present new methods for the unbiased recording and cataloging of sensory activity throughout the Drosophila brain and across trials and individuals. They find auditory activity is temporally diverse but present in neurons throughout nearly all central brain regions.

    in Nature Neuroscience on November 23, 2020 12:00 AM.

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    Acute social isolation evokes midbrain craving responses similar to hunger

    Nature Neuroscience, Published online: 23 November 2020; doi:10.1038/s41593-020-00742-z

    When people are isolated, they crave social interactions. Midbrain craving regions were activated by food in hungry people, and by social interactions in people mandated to be isolated.

    in Nature Neuroscience on November 23, 2020 12:00 AM.

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    Simultaneous profiling of chromatin accessibility and methylation on human cell lines with nanopore sequencing

    Nature Methods, Published online: 23 November 2020; doi:10.1038/s41592-020-01000-7

    Using nanopore sequencing as readout, nanoNOMe–seq enables chromosome-level allele-specific profiles of CpG methylation and chromatin accessibility on human cells, in which the chromatin accessibility is profiled through exogenous GpC methylation introduced by a GpC methyltransferase.

    in Nature Methods on November 23, 2020 12:00 AM.

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    Quantitative shotgun proteome analysis by direct infusion

    Nature Methods, Published online: 23 November 2020; doi:10.1038/s41592-020-00999-z

    Direct infusion–shotgun proteome analysis (DI-SPA) using data-independent acquisition mass spectrometry (DIA-MS) achieves fast and reproducible results by omitting the liquid-chromatography fractionation step and directly performing gas-phase peptide fractionation by ion mobility.

    in Nature Methods on November 23, 2020 12:00 AM.

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    Living proof of effective defects

    Nature Physics, Published online: 23 November 2020; doi:10.1038/s41567-020-01084-0

    A class of biological matter including elongated cells and filaments can be understood in the framework of active nematic liquid crystals. Within these systems, topological defects emerge and give rise to remarkable collective behaviours.

    in Nature Physics on November 23, 2020 12:00 AM.

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    Topological defects in the nematic order of actin fibres as organization centres of Hydra morphogenesis

    Nature Physics, Published online: 23 November 2020; doi:10.1038/s41567-020-01083-1

    Topological defects in the nematic order of actin fibres in a regenerating organism are shown to be tied to key feature formation. Fibre alignment sets the regenerated body axis and defect sites form organizing centres for the developing body plan.

    in Nature Physics on November 23, 2020 12:00 AM.

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    Bacteria solve the problem of crowding by moving slowly

    Nature Physics, Published online: 23 November 2020; doi:10.1038/s41567-020-01070-6

    Bacteria are able to move as vast, dense collectives. Here the authors show that slow movement is key to this collective behaviour because faster bacteria cause topological defects to collide together and trap cells in place.

    in Nature Physics on November 23, 2020 12:00 AM.

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    Topological defects promote layer formation in Myxococcus xanthus colonies

    Nature Physics, Published online: 23 November 2020; doi:10.1038/s41567-020-01056-4

    Topological defects in active nematic systems such as epithelial tissues and neural progenitor cells can be associated with biological functions. Here, the authors show that defects can play a role in the layer formation of the soil bacterium Myxococcus xanthus.

    in Nature Physics on November 23, 2020 12:00 AM.

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    High-harmonic generation from topological surface states

    Nature Physics, Published online: 23 November 2020; doi:10.1038/s41567-020-01052-8

    High-harmonic generation up to the seventh harmonic is observed from the intrinsic three-dimensional topological insulator BiSbTeSe2. The parallel components of the even-order harmonics arise directly from the topological surface states.

    in Nature Physics on November 23, 2020 12:00 AM.

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    Real-space observation of vibrational strong coupling between propagating phonon polaritons and organic molecules

    Nature Photonics, Published online: 23 November 2020; doi:10.1038/s41566-020-00725-3

    Real-space mid-infrared nanoimaging reveals vibrational strong coupling between molecules and propagating phonon polaritons in unstructured, thin hexagonal boron nitride layers, which could provide a platform for testing strong coupling and local control of chemical properties.

    in Nature Photomics on November 23, 2020 12:00 AM.

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    Editorial: The Therapeutic Potential of Transcranial Magnetic Stimulation in Addiction

    in Frontiers in Neuroscience: Neural Technology on November 23, 2020 12:00 AM.

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    Functional Connectivity Combined With a Machine Learning Algorithm Can Classify High-Risk First-Degree Relatives of Patients With Schizophrenia and Identify Correlates of Cognitive Impairments

    Schizophrenia (SCZ) is an inherited disease, with the familial risk being among the most important factors when evaluating an individual’s risk for SCZ. However, robust imaging biomarkers for the disease that can be used for diagnosis and determination of the prognosis are lacking. Here, we explore the potential of functional connectivity (FC) for use as a biomarker for the early detection of high-risk first-degree relatives (FDRs). Thirty-eight first-episode SCZ patients, 38 healthy controls (HCs), and 33 FDRs were scanned using resting-state functional magnetic resonance imaging. The subjects’ brains were parcellated into 200 regions using the Craddock atlas, and the FC between each pair of regions was used as a classification feature. Multivariate pattern analysis using leave-one-out cross-validation achieved a correct classification rate of 88.15% [sensitivity 84.06%, specificity 92.18%, and area under the receiver operating characteristic curve (AUC) 0.93] for differentiating SCZ patients from HCs. FC located within the default mode, frontal-parietal, auditory, and sensorimotor networks contributed mostly to the accurate classification. The FC patterns of each FDR were input into each classification model as test data to obtain a corresponding prediction label (a total of 76 individual classification scores), and the averaged individual classification score was then used as a robust measure to characterize whether each FDR showed an SCZ-type or HC-type FC pattern. A significant negative correlation was found between the average classification scores of the FDRs and their semantic fluency scores. These findings suggest that FC combined with a machine learning algorithm could help to predict whether FDRs are likely to show an SCZ-specific or HC-specific FC pattern.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 23, 2020 12:00 AM.

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    A Perspective of International Collaboration Through Web-Based Telecommunication–Inspired by COVID-19 Crisis

    The tsunami effect of the COVID-19 pandemic is affecting many aspects of scientific activities. Multidisciplinary experimental studies with international collaborators are hindered by the closing of the national borders, logistic issues due to lockdown, quarantine restrictions, and social distancing requirements. The full impact of this crisis on science is not clear yet, but the above-mentioned issues have most certainly restrained academic research activities. Sharing innovative solutions between researchers is in high demand in this situation. The aim of this paper is to share our successful practice of using web-based communication and remote control software for real-time long-distance control of brain stimulation. This solution may guide and encourage researchers to cope with restrictions and has the potential to help expanding international collaborations by lowering travel time and costs.

    in Frontiers in Human Neuroscience on November 23, 2020 12:00 AM.

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    Effects of Electrical Stimulation of NAc Afferents on VP Neurons’ Tonic Firing

    Afferents from the nucleus accumbens (NAc) are a major source of input into the ventral pallidum (VP). Research reveals that these afferents are GABAergic, however, stimulation of these afferents induces both excitatory and inhibitory responses within the VP. These are likely to be partially mediated by enkephalin and substance P (SP), which are also released by these afferents, and are known to modulate VP neurons. However, less is known about the potentially differential effects stimulation of these afferents has on subpopulations of neurons within the VP and the cellular mechanisms by which they exert their effects. The current study aimed to research this further using brain slices containing the VP, stimulation of the NAc afferents, and multi-electrode array (MEA) recordings of their VP targets. Stimulation of the NAc afferents induced a pause in the tonic firing in 58% of the neurons studied in the VP, while 42% were not affected. Measures used to reveal the electrophysiological difference between these groups found no significant differences in firing frequency, coefficient of variation, and spike half-width. There were however significant differences in the pause duration between neurons in the dorsal and ventral VP, with stimulation of NAc afferents producing a significantly longer pause (0.48 ± 0.06 s) in tonic firing in dorsal VP neurons, compared to neurons in the ventral VP (0.21 ± 0.09 s). Pauses in the tonic firing of VP neurons, as a result of NAc afferent stimulation, were found to be largely mediated by GABAA receptors, as the application of picrotoxin significantly reduced their duration. Opioid agonists and antagonists were found to have no significant effects on the pause in tonic activity induced by NAc afferent stimulation. However, NK-1 receptor antagonists caused significant decreases in the pause duration, suggesting that SP may contribute to the inhibitory effect of NAc afferent stimulation via activation of NK-1 receptors.

    in Frontiers in Cellular Neuroscience on November 23, 2020 12:00 AM.

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    Methylmercury Impact on Adult Neurogenesis: Is the Worst Yet to Come From Recent Brazilian Environmental Disasters?

    Worldwide environmental tragedies of anthropogenic origin causing massive release of metals and other pollutants have been increasing considerably. These pollution outbreaks affect the ecosystems and impact human health. Among those tragedies, recent large-scale environmental disasters in Brazil strongly affected riverside populations, leading to high-risk exposure to methylmercury (MeHg). MeHg is highly neurotoxic to the developing brain. This toxicant causes neural stem cell dysfunction and neurodevelopmental abnormalities. However, less is known about the effects of MeHg in the postnatal neurogenic niche, which harbors neural stem cells and their progeny, in the adult brain. Therefore, taking in consideration the impact of MeHg in human health it is urgent to clarify possible associations between exposure to mercury, accelerated cognitive decline, and neurodegenerative diseases. In this perspectives paper, we discuss the neurotoxic mechanisms of MeHg on postnatal neurogenesis and the putative implications associated with accelerated brain aging and early-onset cognitive decline in populations highly exposed to this environmental neurotoxicant.

    in Frontiers in Ageing Neuroscience on November 23, 2020 12:00 AM.

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    Classifying Parkinson’s Disease Patients With Syntactic and Socio-emotional Verbal Measures

    Frontostriatal disorders, such as Parkinson’s disease (PD), are characterized by progressive disruption of cortico-subcortical dopaminergic loops involved in diverse higher-order domains, including language. Indeed, syntactic and emotional language tasks have emerged as potential biomarkers of frontostriatal disturbances. However, relevant studies and models have typically considered these linguistic dimensions in isolation, overlooking the potential advantages of targeting multidimensional markers. Here, we examined whether patient classification can be improved through the joint assessment of both dimensions using sentential stimuli. We evaluated 31 early PD patients and 24 healthy controls via two syntactic measures (functional-role assignment, parsing of long-distance dependencies) and a verbal task tapping social emotions (envy, Schadenfreude) and compared their classification accuracy when analyzed in isolation and in combination. Complementarily, we replicated our approach to discriminate between patients on and off medication. Results showed that specific measures of each dimension were selectively impaired in PD. In particular, joint analysis of outcomes in functional-role assignment and Schadenfreude improved the classification accuracy of patients and controls, irrespective of their overall cognitive and affective state. These results suggest that multidimensional linguistic assessments may better capture the complexity and multi-functional impact of frontostriatal disruptions, highlighting their potential contributions in the ongoing quest for sensitive markers of PD.

    in Frontiers in Ageing Neuroscience on November 23, 2020 12:00 AM.

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    Acupuncture Improves White Matter Perfusion and Integrity in Rat Model of Vascular Dementia: An MRI-Based Imaging Study

    White matter lesions induced by chronic cerebral hypoperfusion are associated with cognitive impairment in vascular dementia (VaD). Previous studies have shown that acupuncture can ameliorate the cognitive deficits of individuals with VaD. However, the neuroimaging mechanisms of acupuncture on white matter perfusion and integrity remain elusive. In this study, the VaD model was induced by bilateral common carotid arteries occlusion (BCCAO) in rats. Novel object recognition task and Morris water maze were performed to evaluate short-term memory and spatial learning and memory. Arterial spin labeling and diffusion tensor imaging (DTI) were used to measure the cerebral blood flow (CBF) and the white matter integrity. Pathological examinations detected the myelin loss and concomitant neuroinflammation. The results demonstrate that BCCAO rats with reduced CBF exhibited worse performance and altered DTI parameters, including decreased fractional anisotropy, increased radial diffusivity, and axial diffusivity in white matter regions. Acupuncture ameliorated cognitive impairment, increased CBF, and protected the myelin sheath integrity but not the axons of BCCAO rats. These protective effects of acupuncture on white matter were significantly correlated with improved CBF. Pathological examination confirmed that the loss of myelin basic protein and microglial accumulation associated IL-1β and IL-6 production were attenuated by acupuncture treatment. Our findings suggest that acupuncture protects cognitive function of BCCAO rats by improving white matter perfusion and integrity.

    in Frontiers in Ageing Neuroscience on November 23, 2020 12:00 AM.

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    LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation

    Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

    in Frontiers in Ageing Neuroscience on November 23, 2020 12:00 AM.

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    Alpha-Synuclein Accumulation and Its Phosphorylation in the Enteric Nervous System of Patients Without Neurodegeneration: An Explorative Study

    Alpha-synuclein (α-Syn) is widely distributed and involved in the regulation of the nervous system. The phosphorylation of α-Syn at serine 129 (pSer129α-Syn) is known to be closely associated with α-Synucleinopathies, especially Parkinson's disease (PD). The present study aimed to explore the α-Syn accumulation and its phosphorylation in the enteric nervous system (ENS) in patients without neurodegeneration. Patients who underwent colorectal surgery for either malignant or benign tumors that were not suitable for endoscopic resection (n = 19) were recruited to obtain normal intestinal specimens, which were used to assess α-Syn immunoreactivity patterns using α-Syn and pSer129α-Syn antibodies. Furthermore, the sub-location of α-Syn in neurons was identified by α-Syn/neurofilament double staining. Semi-quantitative counting was used to evaluate the expression of α-Syn and pSer129α-Syn in the ENS. Positive staining of α-Syn was detected in all intestinal layers in patients with non-neurodegenerative diseases. There was no significant correlation between the distribution of α-Syn and age (p = 0.554) or tumor stage (p = 0.751). Positive staining for pSer129α-Syn was only observed in the submucosa and myenteric plexus layers. The accumulation of pSer129α-Syn increased with age. In addition, we found that the degenerative changes of the ENS were related to the degree of tumor malignancy (p = 0.022). The deposits of α-Syn were present in the ENS of patients with non-neurodegenerative disorders; particularly the age-dependent expression of pSer129α-Syn in the submucosa and myenteric plexus. The current findings of α-Syn immunostaining in the ENS under near non-pathological conditions weaken the basis of using α-Syn pathology as a suitable hallmark to diagnose α-Synucleinopathies including PD. However, our data provided unique perspectives to study gastrointestinal dysfunction in non-neurodegenerative disorders. These findings provide new evidence to elucidate the neuropathological characteristics and α-Syn pathology pattern of the ENS in non-neurodegenerative conditions.

    in Frontiers in Ageing Neuroscience on November 23, 2020 12:00 AM.

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    Distinct Brain Functional Impairment Patterns Between Suspected Non-Alzheimer Disease Pathophysiology and Alzheimer’s Disease: A Study Combining Static and Dynamic Functional Magnetic Resonance Imaging

    Background: Suspected non-Alzheimer disease pathophysiology (SNAP) refers to the subjects who feature negative β-amyloid (Aβ) but positive tau or neurodegeneration biomarkers. It accounts for a quarter of the elderly population and is associated with cognitive decline. However, the underlying pathophysiology is still unclear.

    Methods: We included 111 non-demented subjects, then classified them into three groups using cerebrospinal fluid (CSF) Aβ 1–42 (A), phosphorylated tau 181 (T), and total tau (N). Specifically, we identified the normal control (NC; subjects with normal biomarkers, A-T-N-), SNAP (subjects with normal amyloid but abnormal tau, A−T+), and predementia Alzheimer’s disease (AD; subjects with abnormal amyloid and tau, A+T+). Then, we used the static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance to reflect the intrinsic functional network strength and stability, respectively. Further, we performed a correlation analysis to explore the possible relationship between intrinsic brain activity changes and cognition.

    Results: SNAP showed decreased sALFF in left superior frontal gyrus (SFG) while increased sALFF in left insula as compared to NC. Regarding the dynamic metric, SNAP showed a similarly decreased dALFF in the left SFG and left paracentral lobule as compared to NC. By contrast, when compared to NC, predementia AD showed decreased sALFF in left inferior parietal gyrus (IPG) and right precuneus, while increased sALFF in the left insula, with more widely distributed decreased dALFF variance across the frontal, parietal and occipital lobe. When directly compared to SNAP, predementia AD showed decreased sALFF in left middle occipital gyrus and IPG, while showing decreased dALFF variance in the left temporal pole. Further correlation analysis showed that increased sALFF in the insula had a negative correlation with the general cognition in the SNAP group. Besides, sALFF and dALFF variance in the right precuneus negatively correlated with attention in the predementia AD group.

    Conclusion: SNAP and predementia AD show distinct functional impairment patterns. Specifically, SNAP has functional impairments that are confined to the frontal region, which is usually spared in early-stage AD, while predementia AD exhibits widely distributed functional damage involving the frontal, parietal and occipital cortex.

    in Frontiers in Ageing Neuroscience on November 23, 2020 12:00 AM.

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    Shedding light on those who provide support

    An eLife survey explores the experiences of those in the research community who support colleagues struggling with their mental health.

    in eLife on November 23, 2020 12:00 AM.

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    Osmolarity-independent electrical cues guide rapid response to injury in zebrafish epidermis

    The ability of epithelial tissues to heal after injury is essential for animal life, yet the mechanisms by which epithelial cells sense tissue damage are incompletely understood. In aquatic organisms such as zebrafish, osmotic shock following injury is believed to be an early and potent activator of a wound response. We find that, in addition to sensing osmolarity, basal skin cells in zebrafish larvae are also sensitive to changes in the particular ionic composition of their surroundings after wounding, specifically the concentration of sodium chloride in the immediate vicinity of the wound. This sodium chloride-specific wound detection mechanism is independent of cell swelling, and instead is suggestive of a mechanism by which cells sense changes in the transepithelial electrical potential generated by the transport of sodium and chloride ions across the skin. Consistent with this hypothesis, we show that electric fields directly applied within the skin are sufficient to initiate actin polarization and migration of basal cells in their native epithelial context in vivo, even overriding endogenous wound signaling. This suggests that, in order to mount a robust wound response, skin cells respond to both osmotic and electrical perturbations arising from tissue injury.

    in eLife on November 23, 2020 12:00 AM.

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    Autistic traits are associated with the functional connectivity of between—but not within—attention systems in the general population

    Previous studies have demonstrated that individuals with autism spectrum disorder (ASD) exhibit dysfunction in the three attention systems (i.e., alerting, orienting, and executive control) as well as atypical re...

    in BMC Neuroscience on November 23, 2020 12:00 AM.

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    Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

    Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 par...

    in BMC Neuroscience on November 23, 2020 12:00 AM.

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    Occipital repetitive transcranial magnetic stimulation does not affect multifocal visual evoked potentials

    To identify mechanisms of cortical plasticity of the visual cortex and to quantify their significance, sensitive parameters are warranted. In this context, multifocal visual evoked potentials (mfVEPs) can make...

    in BMC Neuroscience on November 23, 2020 12:00 AM.

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    Emotion regulation through bifocal processing of fear inducing and disgust inducing stimuli

    We present first-time evidence for the immediate neural and behavioral effects of bifocal emotional processing via visualized tapping for two different types of negative emotions (fear and disgust) in a sample...

    in BMC Neuroscience on November 23, 2020 12:00 AM.

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    Distant Supervision Relation Extraction via adaptive dependency-path and additional knowledge graph supervision

    Publication date: Available online 21 November 2020

    Source: Neural Networks

    Author(s): Yong Shi, Yang Xiao, Pei Quan, MingLong Lei, Lingfeng Niu

    in Neural Networks on November 22, 2020 07:00 PM.

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    Axonal branch patterning and neuronal shape diversity: roles in developmental circuit assembly: Axonal branch patterning and neuronal shape diversity in developmental circuit assembly

    Publication date: February 2021

    Source: Current Opinion in Neurobiology, Volume 66

    Author(s): Ann-Kristin Hoersting, Dietmar Schmucker

    in Current Opinion in Neurobiology on November 22, 2020 07:00 PM.

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    An isomorphic three‐dimensional cortical model of the pig rostrum

    An isomorphic three‐dimensional cortical model of the pig rostrum

    Body‐brain isomorphism of pig rostrum and cortical rostrum gyrus


    Abstract

    Physiological studies of the last century mapped a somatosensory cortical gyrus representing the pig’s rostrum. Here we describe the extraordinary correspondence of this gyrus to the rostrum. The pig rostrum is packed with microvibrissae (~470 per hemi‐rostrum) and innervated by a prominent infra‐orbital nerve, containing about 80000 axons. The pig’s rostrum has three major skin‐folds. The nostrils have a rectangular medial wall and a funnel‐like lateral opening, nasal channels run obliquely from lateral (surface) to medial (inside). The rostrum gyrus mimics rostrum geometry in great detail. The putative representation of skin folds coincides with blood sinus and folds of the rostrum gyrus. The putative nostril representation is an oblique sulcus running from lateral (surface) to medial (inside). As observed in rodents, layer 4 is thin in the nostril sulcus. The side of the nostril sulcus representing the medial wall of the nostril is rectangular, whereas the side of the nostril sulcus representing the lateral wall is funnel‐like. Proportions and geometry of the rostrum and the rostrum gyrus are similar, albeit with a collapsed nostril and a larger inter‐individual variability in the gyrus. The pig’s cortical rostrum gyrus receives dense thalamic innervation, has a thin layer 1 and contains roughly 8 million neurons. With all that, the rostrum gyrus looks like a model of the pig rostrum at a scale of ~1:2. Our findings are reminiscent of the raccoon cortex with its forepaw‐like somatosensory forepaw‐representation. Representing highly relevant afferents in three‐dimensional body‐part‐models might facilitate isomorphic cortical computations in large‐brained tactile specialists.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on November 22, 2020 04:03 PM.

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    Development and Validation of the Pediatric CMT Quality of Life Outcome Measure

    Objective

    Charcot‐Marie‐Tooth disease (CMT) reduces health‐related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT‐specific QOL outcome measure (pCMT‐QOL).

    Methods

    Development and validation of the pCMT‐QOL patient‐reported outcome measure was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus‐group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia.

    Results

    We conducted systematic literature reviews and analysis of generic QOL measures to identify six domains relevant to QOL in children with CMT. 60 items corresponding to those domains were developed de novo, or identified from literature review and CMT‐specific modification of items from the pediatric Neuro‐QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT‐QOL measure. From 2010‐2016, the pCMT‐QOL working version was administered to 398 children ages 8‐18 seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test‐retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final pCMT‐QOL patient‐reported outcome measure.

    Interpretation

    The pCMT‐QOL patient‐reported outcome measure is a reliable, valid, and sensitive measure of health‐related QOL for children with CMT.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 22, 2020 12:26 PM.

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    Modality independent adversarial network for generalized zero shot image classification

    Publication date: Available online 21 November 2020

    Source: Neural Networks

    Author(s): Haofeng Zhang, Yinduo Wang, Yang Long, Longzhi Yang, Ling Shao

    in Neural Networks on November 21, 2020 07:00 PM.

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    Behavior and lineage progression of neural progenitors in the mammalian cortex

    Publication date: February 2021

    Source: Current Opinion in Neurobiology, Volume 66

    Author(s): Yang Lin, Jiajun Yang, Zhongfu Shen, Jian Ma, Benjamin D Simons, Song-Hai Shi

    in Current Opinion in Neurobiology on November 21, 2020 07:00 PM.

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    Multicenter validation of the max‐ICH Score in intracerebral hemorrhage

    Objective

    Outcome prognostication unbiased by early care limitations(ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage(ICH). This study aims to determine whether the max‐ICH Score provides improved and clinically useful prognostic estimation of functional long‐term outcomes after ICH.

    Methods

    This multicenter validation study compared the max‐ICH Score’s vs the ICH Score’s prognostication regarding diagnostic accuracy (discrimination, calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients(n=4,677) from two retrospective German‐wide studies(RETRACE I+II; anticoagulation‐associated ICH only) conducted at 22 participating centers, one German prospective single‐center study(UKER‐ICH; non‐anticoagulation‐associated ICH only), and one U.S.‐based prospective longitudinal single‐center study(MGH; both anticoagulation‐ and non‐anticoagulation‐associated ICH), treated between January 2006 and December 2015.

    Results

    Of 4,677 included ICH patients, 1,017(21.7%) were affected by ECL[German‐cohort:15.6%(440/2377); MGH:31.0%(577/1283)]. Validation of long‐term functional outcome prognostication by the max‐ICH Score provided good and superior discrimination in patients without ECL compared to the ICH Score[Area under the receiver operating curve(AUROC),German‐cohort:0.81(0.78‐0.83) vs 0.74(0.72‐0.77),p<0.01; MGH:0.85(0.81‐0.89) vs 0.78(0.74‐0.82),p<0.01], and for the entire cohort[AUROC,German‐cohort:0.84(0.82‐0.86) vs 0.80(0.77‐0.82),p<0.01; MGH:0.83(0.81‐0.85) vs 0.77(0.75‐0.79),p<0.01]. Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed at high threshold probabilities(0.8, aiming to avoid false‐positive poor outcome attribution), that the max‐ICH Score provided a clinical net‐benefit compared to the ICH Score(14.1 vs 2.1 net‐predicted poor outcomes per 100 patients).

    Interpretation

    The max‐ICH score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net‐benefit in minimizing false poor outcome attribution may potentially prevent unwarranted care limitations in patients with ICH.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 21, 2020 06:21 PM.

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    Hyperkinesias and Echolalia in Primary Familial Brain Calcification

    in Annals of Neurology on November 21, 2020 03:29 PM.

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    Morphological identification of thoracolumbar spinal afferent nerve endings in mouse uterus

    Morphological identification of thoracolumbar spinal afferent nerve endings in mouse uterus

    Here, we provide the first detailed description of spinal afferent nerve endings in the uterus of a vertebrate. This was achieved using an in vivo anterograde tracing technique from thoracolumbar (T13‐L3) dorsal root ganglia in female mice. Our key findings revealed that at least three distinct morphological types of spinal afferent nerve ending can be readily identified throughout multiple layers of the uterine wall; the vast majority of which are peptidergic (immunoreactive to calcitonin gene‐related peptide).


    Abstract

    Major sensory innervation to the uterus is provided by spinal afferent nerves, whose cell bodies lie predominantly in thoracolumbar dorsal root ganglia (DRG). While the origin of the cell bodies of uterine spinal afferents is clear, the identity of their sensory endings has remained unknown. Hence, our major aim was to identify the location, morphology, and calcitonin gene‐related peptide (CGRP)‐immunoreactivity of uterine spinal afferent endings supplied by thoracolumbar DRG. We also sought to determine the degree of uterine afferent innervation provided by the vagus nerve. Using an anterograde tracing technique, nulliparous female C57BL/6 mice were injected unilaterally with biotinylated dextran into thoracolumbar DRG (T13‐L3). After 7–9 days, uterine horns were stained to visualize traced nerve axons and endings immunoreactive to CGRP. Whole uteri from a separate cohort of animals were injected with retrograde neuronal tracer (DiI) and dye uptake in nodose ganglia was examined. Anterogradely labeled axons innervated each uterine horn, these projected rostrally or caudally from their site of entry, branching to form varicose endings in the myometrium and/or vascular plexus. Most spinal afferent endings were CGRP‐immunoreactive and morphologically classified as “simple‐type.” Rarely, uterine nerve cell bodies were labeled in nodose ganglia. Here, we provide the first detailed description of spinal afferent nerve endings in the uterus of a vertebrate. Distinct morphological types of spinal afferent nerve endings were identified throughout multiple anatomical layers of the uterine wall. Compared to other visceral organs, uterine spinal afferent endings displayed noticeably less morphological diversity. Few neurons in nodose ganglia innervate the uterus.

    in Journal of Comparative Neurology on November 21, 2020 10:12 AM.

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    The Impact of SARS‐CoV‐2 on Stroke Epidemiology and Care: A Meta‐analysis

    Objective

    Emerging data indicates an increased risk for cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus and highlights the potential impact of coronavirus disease (COVID‐19) on the management and outcomes of acute stroke. We conducteda systematic review and meta‐analysis to evaluate the aforementioned considerations.

    Methods

    We performed a meta‐analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS‐CoV‐2 infection status. We used a random‐effects model. Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (95%CI).

    Results

    We identified 18 cohort studies including 67,845 patients. Among patients with SARS‐CoV‐2, 1.3% (95%CI:0.9‐1.6%;I2=87%) were hospitalized for cerebrovascular events, 1.1% (95%CI:0.8‐1.3%;I2=85%) for ischemic stroke, and 0.2% (95%CI:0.1‐0.3%; I2=64%) for hemorrhagic stroke. Compared to non‐infected contemporary or historical controls, patients with SARS‐CoV‐2 infection had increased odds of ischemic stroke (OR=3.58,95%CI:1.43‐8.92; I2=43%) and cryptogenic stroke (OR=3.98,95%CI:1.62‐9.77;I2=0%). Diabetes mellitus was found to be more prevalent among SARS‐CoV‐2 stroke patients compared to non‐infected contemporary or historical controls (OR=1.39, 95%CI:1.04‐1.86; I2=0%). SARS‐CoV‐2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR=1.42,95%CI:0.65‐3.10; I2=0%) or endovascular thrombectomy (OR=0.78,95%CI:0.35‐1.74; I2=0%) among hospitalized ischemic stroke patients during the COVID‐19 pandemic. Odds for in‐hospital mortality were higher among SARS‐CoV‐2stroke patients compared to non‐infected contemporary or historical stroke patients (OR=5.60,95%CI:3.19‐9.80;I2=45%).

    Interpretation

    SARS‐CoV‐2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular. It may also be related to an increased mortality risk.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 21, 2020 09:28 AM.

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    <i>EventEpi</i>—A natural language processing framework for event-based surveillance

    by Auss Abbood, Alexander Ullrich, Rüdiger Busche, Stéphane Ghozzi

    According to the World Health Organization (WHO), around 60% of all outbreaks are detected using informal sources. In many public health institutes, including the WHO and the Robert Koch Institute (RKI), dedicated groups of public health agents sift through numerous articles and newsletters to detect relevant events. This media screening is one important part of event-based surveillance (EBS). Reading the articles, discussing their relevance, and putting key information into a database is a time-consuming process. To support EBS, but also to gain insights into what makes an article and the event it describes relevant, we developed a natural language processing framework for automated information extraction and relevance scoring. First, we scraped relevant sources for EBS as done at the RKI (WHO Disease Outbreak News and ProMED) and automatically extracted the articles’ key data: disease, country, date, and confirmed-case count. For this, we performed named entity recognition in two steps: EpiTator, an open-source epidemiological annotation tool, suggested many different possibilities for each. We extracted the key country and disease using a heuristic with good results. We trained a naive Bayes classifier to find the key date and confirmed-case count, using the RKI’s EBS database as labels which performed modestly. Then, for relevance scoring, we defined two classes to which any article might belong: The article is relevant if it is in the EBS database and irrelevant otherwise. We compared the performance of different classifiers, using bag-of-words, document and word embeddings. The best classifier, a logistic regression, achieved a sensitivity of 0.82 and an index balanced accuracy of 0.61. Finally, we integrated these functionalities into a web application called EventEpi where relevant sources are automatically analyzed and put into a database. The user can also provide any URL or text, that will be analyzed in the same way and added to the database. Each of these steps could be improved, in particular with larger labeled datasets and fine-tuning of the learning algorithms. The overall framework, however, works already well and can be used in production, promising improvements in EBS. The source code and data are publicly available under open licenses.

    in PLoS Computational Biology on November 20, 2020 10:00 PM.

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    Poisson balanced spiking networks

    by Camille E. Rullán Buxó, Jonathan W. Pillow

    An important problem in computational neuroscience is to understand how networks of spiking neurons can carry out various computations underlying behavior. Balanced spiking networks (BSNs) provide a powerful framework for implementing arbitrary linear dynamical systems in networks of integrate-and-fire neurons. However, the classic BSN model requires near-instantaneous transmission of spikes between neurons, which is biologically implausible. Introducing realistic synaptic delays leads to an pathological regime known as “ping-ponging”, in which different populations spike maximally in alternating time bins, causing network output to overshoot the target solution. Here we document this phenomenon and provide a novel solution: we show that a network can have realistic synaptic delays while maintaining accuracy and stability if neurons are endowed with conditionally Poisson firing. Formally, we propose two alternate formulations of Poisson balanced spiking networks: (1) a “local” framework, which replaces the hard integrate-and-fire spiking rule within each neuron by a “soft” threshold function, such that firing probability grows as a smooth nonlinear function of membrane potential; and (2) a “population” framework, which reformulates the BSN objective function in terms of expected spike counts over the entire population. We show that both approaches offer improved robustness, allowing for accurate implementation of network dynamics with realistic synaptic delays between neurons. Both Poisson frameworks preserve the coding accuracy and robustness to neuron loss of the original model and, moreover, produce positive correlations between similarly tuned neurons, a feature of real neural populations that is not found in the deterministic BSN. This work unifies balanced spiking networks with Poisson generalized linear models and suggests several promising avenues for future research.

    in PLoS Computational Biology on November 20, 2020 10:00 PM.

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    Structure of the Lifeact–F-actin complex

    by Alexander Belyy, Felipe Merino, Oleg Sitsel, Stefan Raunser

    Lifeact is a short actin-binding peptide that is used to visualize filamentous actin (F-actin) structures in live eukaryotic cells using fluorescence microscopy. However, this popular probe has been shown to alter cellular morphology by affecting the structure of the cytoskeleton. The molecular basis for such artefacts is poorly understood. Here, we determined the high-resolution structure of the Lifeact–F-actin complex using electron cryo-microscopy (cryo-EM). The structure reveals that Lifeact interacts with a hydrophobic binding pocket on F-actin and stretches over 2 adjacent actin subunits, stabilizing the DNase I-binding loop (D-loop) of actin in the closed conformation. Interestingly, the hydrophobic binding site is also used by actin-binding proteins, such as cofilin and myosin and actin-binding toxins, such as a hypervariable region of TccC3 (TccC3HVR) from Photorhabdus luminescens and ExoY from Pseudomonas aeruginosa. In vitro binding assays and activity measurements demonstrate that Lifeact indeed competes with these proteins, providing an explanation for the altering effects of Lifeact on cell morphology in vivo. Finally, we demonstrate that the affinity of Lifeact to F-actin can be increased by introducing mutations into the peptide, laying the foundation for designing improved actin probes for live cell imaging.

    in PLoS Biology on November 20, 2020 10:00 PM.

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    SCRINSHOT enables spatial mapping of cell states in tissue sections with single-cell resolution

    by Alexandros Sountoulidis, Andreas Liontos, Hong Phuong Nguyen, Alexandra B. Firsova, Athanasios Fysikopoulos, Xiaoyan Qian, Werner Seeger, Erik Sundström, Mats Nilsson, Christos Samakovlis

    Changes in cell identities and positions underlie tissue development and disease progression. Although single-cell mRNA sequencing (scRNA-Seq) methods rapidly generate extensive lists of cell states, spatially resolved single-cell mapping presents a challenging task. We developed SCRINSHOT (Single-Cell Resolution IN Situ Hybridization On Tissues), a sensitive, multiplex RNA mapping approach. Direct hybridization of padlock probes on mRNA is followed by circularization with SplintR ligase and rolling circle amplification (RCA) of the hybridized padlock probes. Sequential detection of RCA-products using fluorophore-labeled oligonucleotides profiles thousands of cells in tissue sections. We evaluated SCRINSHOT specificity and sensitivity on murine and human organs. SCRINSHOT quantification of marker gene expression shows high correlation with published scRNA-Seq data over a broad range of gene expression levels. We demonstrate the utility of SCRINSHOT by mapping the locations of abundant and rare cell types along the murine airways. The amenability, multiplexity, and quantitative qualities of SCRINSHOT facilitate single-cell mRNA profiling of cell-state alterations in tissues under a variety of native and experimental conditions.

    in PLoS Biology on November 20, 2020 10:00 PM.

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    Perfusion‐dependent cerebral autoregulation impairment in hemispheric stroke

    Objective

    Loss of cerebral autoregulation (CA) plays a key role in secondary neurologic injury. However, the regional distribution of CA impairment after acute cerebral injury remains unclear because in clinical practice, CA is only assessed within a limited compartment. Here, we performed large‐scale regional mapping of cortical perfusion and CA in patients undergoing decompressive surgery for malignant hemispheric stroke.

    Methods

    In 24 patients, autoregulation over the affected hemisphere was calculated based on direct, 15‐20‐minute cortical perfusion measurement with intraoperative Laser Speckle Imaging and mean arterial blood pressure (MAP) recording. Cortical perfusion was normalized against non‐infarcted tissue and 6 perfusion categories from 0% to >100% were defined. The interaction between cortical perfusion and MAP was estimated using a linear random slope model and Pearson correlation.

    Results

    Cortical perfusion and CA impairment were heterogeneously distributed across the entire hemisphere. The degree of CA impairment was significantly greater in areas with critical hypoperfusion (40‐60%: 0.42% per mmHg and 60‐80%: 0.46% per mmHg) than in non‐infarcted (>100%: 0.22% per mmHg) or infarcted (0‐20%: 0.29% per mmHg) areas (*p<0.001). Pearson correlation confirmed greater CA impairment at critically reduced perfusion (20‐40%: r=0.67; 40‐60%: r=0.68; 60‐80%: r=0.68) compared to perfusion >100% (r=0.36; *p<0.05). Tissue integrity had no impact on the degree of CA impairment.

    Interpretation

    In hemispheric stroke, CA is impaired across the entire hemisphere to a variable extent. Autoregulation impairment was greatest in hypoperfused and potentially viable tissue, suggesting that precise localization of such regions is essential for effective tailoring of perfusion pressure‐based treatment strategies.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 20, 2020 08:00 PM.

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    The Mouse Dorsal Raphe Nucleus as Understood by Temporal Fgf8 Lineage Analysis

    The Mouse Dorsal Raphe Nucleus as Understood by Temporal Fgf8 Lineage Analysis

    Serotonin neurons (dots) depicted in sagittal section (left) and coronal section (right), color‐coded by Fgf8‐lineage captured at different time‐points in development. The arrows indicate the approximate level of the coronal section. Serotonin neurons arising from progenitors expressing Fgf8 at later ages in development progressively populate more rostral and dorsal locations in the dorsal raphe, with serotonin neurons arising from the latest Fgf8 expressers also located in the lateral wings.


    Abstract

    Fgf8 is expressed transiently during embryogenesis at the midbrain‐hindbrain border, an area that gives rise to a variety of neuronal populations including the dorsal raphe nucleus (DR). Using an inducible Fgf8‐cre allele we identified the populations of neurons defined by Fgf8 lineage at different stages of development. When Fgf8‐cre expression is induced at embryonic day 7.5 (T‐E7.5), in the adult the entire DR and part of the median raphe (MnR) has Fgf8 lineage. When induced at later timepoints, Fgf8 lineage progressively ebbs from the caudal and ventral aspect of this domain, particularly on the midline. Successively excluded from Fgf8‐ lineage at T‐E9.5 are serotonin neurons in the MnR and caudal‐intrafascicular DR, followed at T‐E11.5 by ventral‐middle and caudal‐dorsal DR. The last to show Fgf8 lineage are those serotonin neurons in the lateral wings and those at the rostral‐dorsal pole of dorsal raphe nucleus. Thus the temporal succession of Fgf8 lineage correlates with organizational features of serotonin neurons in these nuclei.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on November 20, 2020 07:55 PM.

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    A prodromal brain‐clinical pattern of cognition in synucleinopathies

    Objective

    Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Biomarkers are lacking to predict conversion to a dementia‐ or a motor‐first phenotype. Here, we aimed at identifying a brain‐clinical signature that predicts dementia in iRBD.

    Methods

    A brain‐clinical signature was identified in 48 polysomnography‐confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 iRBD patients followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from iRBD patients were compared to 207 patients with PD, DLB or prodromal DLB to assess if scores were higher in DLB compared to PD.

    Results

    One latent variable explained 31% of the brain‐clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p=0.036, odds ratio: 2.249; 95% CI: 1.053‐4.803), specifically to DLB (odds ratio: 4.754; 95% CI: 1.283‐17.618, p=0.020) and not PD (p=0.286). iRBD patients who developed dementia had scores similar to clinical and prodromal DLB patients but higher scores compared to PD patients. The deformation score also predicted cognitive performance over one, two, and four years in PD patients.

    Interpretation

    We identified a brain‐clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 20, 2020 06:43 PM.

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    Association between Computed Tomographic Biomarkers of Cerebral Small Vessel Diseases and Long‐Term Outcome after Spontaneous Intracerebral Hemorrhage

    Objective

    A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long‐term outcome after intracerebral hemorrhage.

    Methods

    We performed a prospective, community‐based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May 31, 2013. A neuroradiologist rated the diagnostic brain CT for acute intracerebral hemorrhage features and SVD biomarkers. We used severity of white matter lucencies and cerebral atrophy, and the number of lacunes to calculate the CT SVD score. We assessed the association between CT SVD biomarkers and either death, or death or dependence (modified Rankin Scale scores = 4–6) 1 year after first‐ever intracerebral hemorrhage using logistic regression, adjusting for known predictors of outcome.

    Results

    Within 1 year of intracerebral hemorrhage, 224 (56%) of 402 patients died. In separate models, 1‐year death was associated with severe atrophy (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.44–4.49, p = 0.001) but not lacunes or severe white matter lucencies, and CT SVD sum score ≥ 1 (aOR = 2.50, 95% CI = 1.40–4.45, p = 0.002). Two hundred seventy‐seven (73%) of 378 patients with modified Rankin Scale data were dead or dependent at 1 year. In separate models, 1‐year death or dependence was associated with severe atrophy (aOR = 3.67, 95% CI = 1.71–7.89, p = 0.001) and severe white matter lucencies (aOR = 2.18, 95% CI = 1.06–4.51, p = 0.035) but not lacunes, and CT SVD sum score ≥ 1 (aOR = 2.81, 95% CI = 1.45–5.46, p = 0.002).

    Interpretation

    SVD biomarkers on the diagnostic brain CT are associated with 1‐year death and dependence after intracerebral hemorrhage, independent of known predictors of outcome. ANN NEUROL 2020

    in Annals of Neurology on November 20, 2020 06:43 PM.

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    Timeline of Rapid Eye Movement Sleep Behavior Disorder in Overt Alpha‐Synucleinopathies

    Objective

    The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha‐synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age‐ and sex‐matched controls in a population‐based incident‐cohort study.

    Methods

    We used a population‐based, 1991 to 2010 incident‐cohort study of alpha‐synucleinopathies. A movement‐disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream‐enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined.

    Results

    Among the 444 incident cases of alpha‐synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha‐synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha‐synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0–217.2, p < 0.0001), higher in dementia with Lewy bodies than in Parkinson disease (OR = 2.57, 95% CI: 1.50–4.40, p = 0.0004), and higher in men than in women with Parkinson disease, dementia with Lewy bodies, or Parkinson disease dementia (OR = 3.70, 95% CI: 2.07–6.62, p < 0.0001), but did not increase mortality risk.

    Interpretation

    Our cohort had RBD incidence of 3.4%. Overall RBD increased to 23.8% after 15 years, with an overall incidence of 2.5 cases per 100 person‐years. With 53 times greater lifetime incidence in alpha‐synucleinopathy patients than in controls, RBD was more likely to develop in dementia with Lewy bodies than in Parkinson disease or Parkinson disease dementia, and in men than in women, but did not increase mortality risk within our cohort. ANN NEUROL 2020

    in Annals of Neurology on November 20, 2020 06:40 PM.

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    Diagnostic Accuracy of Amyloid versus FDG PET in Autopsy‐Confirmed Dementia

    Objective

    To compare the diagnostic accuracy of antemortem [11C]Pittsburgh Compound B (PIB) and [18F]Flurodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.

    Methods

    101 participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by three raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention while FDG scans were read as showing an Alzheimer’s disease (AD) or non‐AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate‐high AD Neuropathological Changes (ADNC).

    Results

    101 participants were included (mean age 67.2; 41 females; MMSE 21.9; PET‐to‐autopsy 4.4 years). At autopsy, 32 patients showed primary AD, 56 non‐AD neuropathology (primarily frontotemporal lobar degeneration (FTLD)) and 13 mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate‐high ADNC (96% [95% confidence interval: 89‐100%] vs 80% [68‐92%], p=0.02), but equivalent specificity (86% [76‐95%] vs. 84% [74‐93%], p=0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% [92‐100%] and specificity 98% [93‐100%]. Nine of 24 patients with incongruent reads were found to have co‐occurrence of AD and non‐AD pathologies.

    Interpretation

    In our sample enriched for younger‐onset cognitive impairment, PIB‐PET had higher sensitivity than FDG‐PET for intermediate‐high ADNC with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, while mixed pathology should be considered when PIB and FDG are incongruent.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 20, 2020 03:50 PM.

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    Short‐term Cessation of Dabigatran Causes a Paradoxical Prothrombotic State

    Objective

    It is unclear if stopping treatment with dabigatran, a new oral anticoagulant (NOAC), induces a paradoxical rebound prothrombotic state. We investigated if short‐term (1‐3 days) dabigatran cessation is associated with a higher thrombus volume than expected from a simple reversal of the anticoagulant effect.

    Methods

    Ten‐week‐old C57Bl/6 mice (n=338) received one of the following oral treatments: phosphate‐buffered saline (PBS), dabigatran for 7 days with or without 1‐4 day cessation, and aspirin in either a single dose or daily for 7 days. Some of the animals that ceased dabigatran for 1‐3 days received single‐dose aspirin. Thereafter, we induced FeCl3‐mediated carotid thrombosis in 130 mice, after which we performed microCT thrombus imaging. The other 208 mice underwent coagulation assays or platelet function tests. As an explorative pilot study, we reviewed the medical records of 18 consecutive patients with NOAC cessation‐related cerebral infarction in a large acute stroke cohort.

    Results

    We observed a higher volume of carotid thrombus after dabigatran cessation at 1‐3 days than after vehicle treatment and showed that this effect could be prevented by single‐dose aspirin pretreatment. Dabigatran cessation unduly increased platelet aggregability for 2 days after drug cessation, an effect mediated through arachidonic acid or thrombin, which effect was significantly attenuated by single‐dose aspirin pretreatment. In patients, short‐term (3 day) cessation of NOAC therapy, compared with longer‐term (≥5 days) cessation, tended to be associated with relatively high stroke severity.

    Interpretation

    We provide the first preclinical evidence that a rebound prothrombotic state follows short‐term cessation of dabigatran therapy.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 20, 2020 03:33 PM.

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    Effects of adolescent intermittent ethanol on hippocampal expression of glutamate homeostasis and astrocyte‐neuronal tethering proteins in male and female rats

    Effects of adolescent intermittent ethanol on hippocampal expression of glutamate homeostasis and astrocyte‐neuronal tethering proteins in male and female rats

    Male and female rats were exposed to adolescent intermittent ethanol (AIE; PND 30–45) and aged into adulthood (PND 70). Dorsal and ventral hippocampi were harvested for analysis of synaptic membrane protein expression. AIE caused adult hippocampal glial and synaptic protein expression alterations in a sex‐ and region‐dependent manner. EphA4, ephrin receptor tyrosine kinase A4; GLAST, glutamate aspartate transporter 1; GLT‐1, glutamate transporter 1; GluN2A, NMDA receptor subunit 2A; PSD‐95, postsynaptic density 95; xCT, cystine‐glutamate antiporter


    Abstract

    Adolescent alcohol drinking is widely recognized as a significant public health problem, and evidence is accumulating that sufficient levels of consumption during this critical period of brain development have an enduring impact on neural and behavioral function. Recent studies have indicated that adolescent intermittent ethanol (AIE) exposure alters astrocyte function, astrocyte–neuronal interactions, and related synaptic regulation and activity. However, few of those studies have included female animals, and a broader assessment of AIE effects on the proteins mediating astrocyte‐mediated glutamate dynamics and synaptic function is needed. We measured synaptic membrane expression of several such proteins in the dorsal and ventral regions of the hippocampal formation (DH, VH) from male and female rats exposed to AIE or adolescent intermittent water. In the DH, AIE caused elevated expression of glutamate transporter 1 (GLT‐1) in both males and females, elevated postsynaptic density 95 expression in females only, and diminished NMDA receptor subunit 2A expression in males only. AIE and sex interactively altered ephrin receptor A4 (EphA4) expression in the DH. In the VH, AIE elevated expression of the cystine/glutamate antiporter and the glutamate aspartate transporter 1 (GLAST) in males only. Compared to males, female animals expressed lower levels of GLT‐1 in the DH and greater levels of ephrin receptor B6 (EphB6) in the VH, in the absence of AIE effects. These results support the growing literature indicating that adolescent alcohol exposure produces long‐lasting effects on astrocyte function and astrocyte‐neuronal interactions. The sex and subregion specificity of these effects have mechanistic implications for our understanding of AIE effects generally.

    in Journal of Neuroscience Research on November 20, 2020 12:15 PM.

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    Severe acute respiratory syndrome coronavirus 2 infection reaches the human nervous system: How?

    Abstract

    Without protective and/or therapeutic agents the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection known as coronavirus disease 2019 is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS‐CoV‐2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS‐CoV‐2 components could use to reach the CNS and PNS, utilizing the within‐body cross talk between organs. The majority of SARS‐CoV‐2–infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune‐mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood–endothelial barrier may be considered as the main route for SARS‐CoV‐2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.

    in Journal of Neuroscience Research on November 20, 2020 11:59 AM.

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    Morphological diversity of acoustic and electric communication systems of mochokid catfish

    Morphological diversity of acoustic and electric communication systems of mochokid catfish

    This study provides an anatomical characterization of motor and premotor neurons associated with the muscle producing swim bladder sounds and/or electric discharges in five mochokid catfish. Even though the same muscle and neuronal populations are associated with these behaviors across all species, our results suggest that behavioral differences are associated with quantitative differences, mainly in the size of the protractor muscle and associated skeletal elements, and the number, size and location of motoneurons.


    Abstract

    Mochokid catfish offer a distinct opportunity to study a communication system transitioning to a new signaling channel because some produce sounds and others electric discharges. Both signals are generated using an elastic spring system (ESS), which includes a protractor muscle innervated by motoneurons within the protractor nucleus that also has a motoneuron afferent population. Synodontis grandiops and S. nigriventris produce sounds and electric discharges, respectively, and their ESSs show several morphological and physiological differences. The extent to which these differences explain different signal types remains unclear. Here, we compare ESS morphologies and behavioral phenotypes among five mochokids. S. grandiops and S. nigriventris were compared with Synodontis eupterus that is known to produce both signal types, and representative members of two sister genera, Microsynodontis cf. batesii and Mochokiella paynei, for which no data were available. We provide support for the hypothesis that peripheral and central components of the ESS are conserved among mochokids. We also show that the two nonsynodontids are only sonic, consistent with sound production being an ancestral character for mochokids. Even though the three sound producing‐only species differ in some ESS characters, several are similar and likely associated with only sound production. We propose that the ability of S. eupterus to generate both electric discharges and sounds may depend on a protractor muscle intermediate in morphology between sound producing‐only and electric discharge‐only species, and two separate populations of protractor motoneurons. Our results further suggest that an electrogenic ESS in synodontids is an exaptation of a sound producing ESS.

    in Journal of Comparative Neurology on November 20, 2020 10:45 AM.

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    Modeling multicellular dynamics regulated by extracellular-matrix-mediated mechanical communication via active particles with polarized effective attraction

    Author(s): Yu Zheng, Qihui Fan, Christopher Z. Eddy, Xiaochen Wang, Bo Sun, Fangfu Ye, and Yang Jiao

    Collective cell migration is crucial to many physiological and pathological processes such as embryo development, wound healing, and cancer invasion. Recent experimental studies have indicated that the active traction forces generated by migrating cells in a fibrous extracellular matrix (ECM) can me...


    [Phys. Rev. E 102, 052409] Published Fri Nov 20, 2020

    in Physical Review E: Biological physics on November 20, 2020 10:00 AM.

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    Author Correction: Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion

    Nature Neuroscience, Published online: 20 November 2020; doi:10.1038/s41593-020-00760-x

    Author Correction: Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion

    in Nature Neuroscience on November 20, 2020 12:00 AM.

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    Making the case for place cells

    Nature Reviews Neuroscience, Published online: 20 November 2020; doi:10.1038/s41583-020-00414-8

    Optogenetic stimulation of place cells alters memory-guided spatial navigation in mice, providing evidence for a causal role for these cells in spatial cognition.

    in Nature Reviews on November 20, 2020 12:00 AM.

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    Reply to ‘Non-reciprocal propagation versus non-reciprocal control’

    Nature Photonics, Published online: 20 November 2020; doi:10.1038/s41566-020-00724-4

    Reply to ‘Non-reciprocal propagation versus non-reciprocal control’

    in Nature Photomics on November 20, 2020 12:00 AM.

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    Non-reciprocal propagation versus non-reciprocal control

    Nature Photonics, Published online: 20 November 2020; doi:10.1038/s41566-020-00723-5

    Non-reciprocal propagation versus non-reciprocal control

    in Nature Photomics on November 20, 2020 12:00 AM.

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    Guiding light to non-classicality

    Nature Photonics, Published online: 20 November 2020; doi:10.1038/s41566-020-00719-1

    The manipulation of the quantum properties of light involves its technically challenging strong interaction with matter. Now, an experiment shows that when light propagates through a waveguide it only takes a weakly coupled line of atoms to single out its photons, or bunch them together, unveiling and controlling its quantum nature.

    in Nature Photomics on November 20, 2020 12:00 AM.

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    Effects of GABAA Receptor α3 Subunit Epilepsy Mutations on Inhibitory Synaptic Signaling

    Missense mutations T166M, Q242L, T336M, and Y474C in the GABAA receptor (GABAAR) α3 subunit gene are associated with epileptic seizures, dysmorphic features, intellectual disability, and developmental delay. When incorporated into GABAARs expressed in oocytes, all mutations are known to reduce GABA-evoked whole-cell currents. However, their impact on the properties of inhibitory synaptic currents (IPSCs) is unknown, largely because it is difficult to establish, much less control, the stoichiometry of GABAAR expressed in native neuronal synapses. To circumvent this problem, we employed a HEK293 cell-neuron co-culture expression system that permits the recording of IPSCs mediated by a pure population of GABAARs with a defined stoichiometry. We first demonstrated that IPSCs mediated by α3-containing GABAARs (α3β3γ2) decay significantly slower than those mediated by α1-containing isoforms (α1β2γ2 or α1β3γ2). GABAAR α3 mutations did not affect IPSC peak amplitudes or 10–90% rise times, but three of the mutations affected IPSC decay. T336M significantly accelerated the IPSC decay rate whereas T166M and Y474C had the opposite effect. The acceleration of IPSC decay kinetics caused by the T366M mutation was returned to wild-type-like values by the anti-epileptic medication, midazolam. Quantification experiments in HEK293 cells revealed a significant reduction in cell-surface expression for all mutants, in agreement with previous oocyte data. Taken together, our results show that impaired surface expression and altered IPSC decay rates could both be significant factors underlying the pathologies associated with these mutations.

    in Frontiers in Molecular Neuroscience on November 20, 2020 12:00 AM.

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    Neuroinflammation-Induced Upregulation of Glial Cathepsin X Expression and Activity in vivo

    Neuroinflammation is an important factor in the pathogenesis of neurodegenerative diseases. Microglia-derived lysosomal cathepsins have been increasingly recognized as important inflammatory mediators that trigger signaling pathways that aggravate neuroinflammation. In vitro, a contribution to neuroinflammation processes has been shown for cathepsin X: however, the expression patterns and functional role of cathepsin X in neuroinflammatory brain pathology remain elusive. In this study we analyzed the expression, activity, regional distribution and cellular localization of cathepsin X in the rat brain with neuroinflammation-induced neurodegeneration. The unilateral injection of lipopolysaccharide (LPS) induced a strong upregulation of cathepsin X expression and its activity in the ipsilateral striatum. In addition to the striatum, cathepsin X overexpression was detected in other brain areas such as the cerebral cortex, corpus callosum, subventricular zone and external globus pallidus, whereas the upregulation was mainly restricted to activated microglia and reactive astrocytes. Continuous administration of the cathepsin X inhibitor AMS36 indicated protective effects against LPS-induced striatal degeneration, as seen by the attenuated LPS-mediated dilation of the lateral ventricles and partial decreased extent of striatal lesion. Taken together, our results indicate that cathepsin X plays a role as a pathogenic factor in neuroinflammation-induced neurodegeneration and represents a potential therapeutic target for neurodegenerative diseases associated with neuroinflammation.

    in Frontiers in Molecular Neuroscience on November 20, 2020 12:00 AM.

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    High-Resolution 3D in vivo Brain Diffusion Tensor Imaging at Ultrahigh Fields: Following Maturation on Juvenile and Adult Mice

    Diffusion tensor imaging (DTI) is a well-established technique for mapping brain microstructure and white matter tracts in vivo. High resolution DTI, however, is usually associated with low intrinsic sensitivity and therefore long acquisition times. By increasing sensitivity, high magnetic fields can alleviate these demands, yet high fields are also typically associated with significant susceptibility-induced image distortions. This study explores the potential arising from employing new pulse sequences and emerging hardware at ultrahigh fields, to overcome these limitations. To this end, a 15.2 T MRI instrument equipped with a cryocooled surface transceiver coil was employed, and DTI experiments were compared between SPatiotemporal ENcoding (SPEN), a technique that tolerates well susceptibility-induced image distortions, and double-sampled Spin-Echo Echo-Planar Imaging (SE-EPI) methods. Following optimization, SE-EPI afforded whole brain DTI maps at 135 μm isotropic resolution that possessed higher signal-to-noise ratios (SNRs) than SPEN counterparts. SPEN, however, was a better alternative to SE-EPI when focusing on challenging regions of the mouse brain –including the olfactory bulb and the cerebellum. In these instances, the higher robustness of fully refocused SPEN acquisitions coupled to its built-in zooming abilities, provided in vivo DTI maps with 75 μm nominal isotropic spatial resolution. These DTI maps, and in particular the mean diffusion direction (MDD) details, exhibited variations that matched very well the anatomical features known from histological brain Atlases. Using these capabilities, the development of the olfactory bulb (OB) in live mice was followed from week 1 post-partum, until adulthood. The diffusivity of this organ showed a systematic decrease in its overall isotropic value and increase in its fractional anisotropy with age; this maturation was observed for all regions used in the OB's segmentation but was most evident for the lobules' centers, in particular for the granular cell layer. The complexity of the OB neuronal connections also increased during maturation, as evidenced by the growth in directionalities arising in the mean diffusivity direction maps.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 20, 2020 12:00 AM.

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    Electroacupuncture Protects Cognition by Regulating Tau Phosphorylation and Glucose Metabolism via the AKT/GSK3β Signaling Pathway in Alzheimer’s Disease Model Mice

    Background

    Alzheimer’s disease (AD) is mainly manifested as a continuous and progressive decline in cognitive ability. Neurofibrillary tangles (NFTs) are pathological hallmarks of AD and due to accumulated phosphorylated Tau. Glycogen synthase kinase-3β (GSK3β), as a major Tau kinase and a downstream target of the serine protein kinase B (AKT) signaling pathway, can regulate Tau phosphorylation in AD. Importantly, the AKT/GSK3β signaling pathway is involved in glucose metabolism, and abnormal glucose metabolism is found in the AD brain. Numerous studies have shown that electroacupuncture (EA), which is thought to be a potential complementary therapeutic approach for AD, can protect cognitive ability to a certain extent.

    Objective

    The purpose of this experiment was to investigate whether the protective and beneficial mechanism of EA on cognition was mediated by the AKT/GSK3β signaling pathway, thereby improving glucose metabolism and Tau phosphorylation in the brain.

    Methods

    EA was applied to the Baihui (GV20) and Yintang (GV29) acupoints of 6-month-old amyloid precursor protein (APP)/presenilin-1 (PS1) mice for 20 min, and then quickly prick Shuigou (GV26) acupoint. The intervention was performed once every other day for 28 days. The Morris water maze (MWM) test was performed on C57BL/6N (Non-Tg) mice, APP/PS1 (Tg) mice and EA-treated Tg (Tg + EA) mice to evaluate the effect of EA therapy on cognitive function. 18F-FDG positron emission tomography (PET), immunohistochemistry, and western blotting (WB) were used to investigate the possible mechanism underlying the effect of EA on AD.

    Results

    EA treatment significantly improved the cognition of APP/PS1 mice and the glucose uptake rate in the hippocampus. Furthermore, EA inhibited the phosphorylation of Tau (Ser199 and Ser202) proteins by inducing AKT (Ser473) and GSK3β (Ser9) phosphorylation.

    Conclusion

    These results demonstrate that EA intervention protects cognition by enhancing glucose metabolism and inhibiting abnormal phosphorylation of Tau protein in the AD model mice, and the AKT/GSK3β pathway might play an irreplaceable role in the regulation process.

    in Frontiers in Neuroscience: Neurodegeneration on November 20, 2020 12:00 AM.

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    P300 Analysis Using High-Density EEG to Decipher Neural Response to rTMS in Patients With Schizophrenia and Auditory Verbal Hallucinations

    Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 20, 2020 12:00 AM.

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    Review of Deep Learning Approaches for the Segmentation of Multiple Sclerosis Lesions on Brain MRI

    In recent years, there have been multiple works of literature reviewing methods for automatically segmenting multiple sclerosis (MS) lesions. However, there is no literature systematically and individually review deep learning-based MS lesion segmentation methods. Although the previous review also included methods based on deep learning, there are some methods based on deep learning that they did not review. In addition, their review of deep learning methods did not go deep into the specific categories of Convolutional Neural Network (CNN). They only reviewed these methods in a generalized form, such as supervision strategy, input data handling strategy, etc. This paper presents a systematic review of the literature in automated multiple sclerosis lesion segmentation based on deep learning. Algorithms based on deep learning reviewed are classified into two categories through their CNN style, and their strengths and weaknesses will also be given through our investigation and analysis. We give a quantitative comparison of the methods reviewed through two metrics: Dice Similarity Coefficient (DSC) and Positive Predictive Value (PPV). Finally, the future direction of the application of deep learning in MS lesion segmentation will be discussed.

    in Frontiers in Neuroinformatics on November 20, 2020 12:00 AM.

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    SSVEP BCI and Eye Tracking Use by Individuals With Late-Stage ALS and Visual Impairments

    Access to communication is critical for individuals with late-stage amyotrophic lateral sclerosis (ALS) and minimal volitional movement, but they sometimes present with concomitant visual or ocular motility impairments that affect their performance with eye tracking or visual brain-computer interface (BCI) systems. In this study, we explored the use of modified eye tracking and steady state visual evoked potential (SSVEP) BCI, in combination with the Shuffle Speller typing interface, for this population. Two participants with late-stage ALS, visual impairments, and minimal volitional movement completed a single-case experimental research design comparing copy-spelling performance with three different typing systems: (1) commercially available eye tracking communication software, (2) Shuffle Speller with modified eye tracking, and (3) Shuffle Speller with SSVEP BCI. Participant 1 was unable to type any correct characters with the commercial system, but achieved accuracies of up to 50% with Shuffle Speller eye tracking and 89% with Shuffle Speller BCI. Participant 2 also had higher maximum accuracies with Shuffle Speller, typing with up to 63% accuracy with eye tracking and 100% accuracy with BCI. However, participants’ typing accuracy for both Shuffle Speller conditions was highly variable, particularly in the BCI condition. Both the Shuffle Speller interface and SSVEP BCI input show promise for improving typing performance for people with late-stage ALS. Further development of innovative BCI systems for this population is needed.

    in Frontiers in Human Neuroscience on November 20, 2020 12:00 AM.

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    Measuring the Cognitive Workload During Dual-Task Walking in Young Adults: A Combination of Neurophysiological and Subjective Measures

    Background: Walking while performing a secondary task (dual-task (DT) walking) increases cognitive workload in young adults. To date, few studies have used neurophysiological measures in combination to subjective measures to assess cognitive workload during a walking task. This combined approach can provide more insights into the amount of cognitive resources in relation with the perceived mental effort involving in a walking task.

    Research Question: The objective was to examine cognitive workload in young adults during walking conditions varying in complexity.

    Methods: Twenty-five young adults (mean = 24.4 ± 5.4) performed four conditions: (1) usual walking, (2) simple DT walking, (3) complex DT walking and (4) standing while subtracting. During the walking task, mean speed, cadence, stride time, stride length, and their respective coefficient of variation (CV) were recorded. Cognitive workload will be measured through changes in oxy- and deoxy-hemoglobin (ΔHbO2 and ΔHbR) during walking in the dorsolateral prefrontal cortex (DLPFC) and perceived mental demand score from NASA-TLX questionnaire.

    Results: In young adults, ΔHbO2 in the DLPFC increased from usual walking to both DT walking conditions and standing while subtracting condition. ΔHbO2 did not differ between the simple and complex DT and between the complex DT and standing while subtracting condition. Perceived mental demand gradually increased with walking task complexity. As expected, all mean values of gait parameters were altered according to task complexity. CV of speed, cadence and stride time were significantly higher during DT walking conditions than during usual walking whereas CV of stride length was only higher during complex DT walking than during usual walking.

    Significance: Young adults had greater cognitive workload in the two DT walking conditions compared to usual walking. However, only the mental demand score from NASA-TLX questionnaire discriminated simple from complex DT walking. Subjective measure provides complementary information to objective one on changes in cognitive workload during challenging walking tasks in young adults. These results may be useful to improve our understanding of cognitive workload during walking.

    in Frontiers in Human Neuroscience on November 20, 2020 12:00 AM.

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    Modification of Eye–Head Coordination With High Frequency Random Noise Stimulation

    The vestibulo-ocular reflex (VOR) plays an important role in controlling the gaze at a visual target. Although patients with vestibular hypofunction aim to improve their VOR function, some retain dysfunction for a long time. Previous studies have explored the effects of direct current stimulation on vestibular function; however, the effects of random noise stimulation on eye–head coordination have not previously been tested. Therefore, we aimed to clarify the effects of high frequency noisy vestibular stimulation (HF-nVS) on eye–head coordination related to VOR function. Thirteen healthy young adult participants with no serious disease took part in our study. The current amplitude and density used were 0.4 mA and 0.2 mA/cm2, respectively, with a random noise frequency of 100–640 Hz. The electrodes were located on both mastoid processes. The stimulus duration and fade in/out duration were 600 and 10 s, respectively. Subjects oscillated their head horizontally, gazing at the fixation point, at 1 Hz (0.5 cycles/s) for 30 repetitions. The coordination of eye–head movements was measured by eye-tracking and a motion capture system. Peak-to-peak angles for eye and head movement and deviation of the visual line from the fixation target revealed no significant differences between HF-nVS and sham. The lag time between the eye and head movement with HF-nVS post-stimulation was significantly shorter than that of the sham. We found that HF-nVS can reduce the lag time between eye and head movement and improve coordination, contributing to a clear retinal image. This technique could be applied as a form of VOR training for patients with vestibular hypofunction.

    in Frontiers in Human Neuroscience on November 20, 2020 12:00 AM.

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    Deep Brain Stimulation of the Subthalamic Nucleus Modulates Reward-Related Behavior: A Systematic Review

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for the motor symptoms of movement disorders including Parkinson's Disease (PD). Despite its therapeutic benefits, STN-DBS has been associated with adverse effects on mood and cognition. Specifically, apathy, which is defined as a loss of motivation, has been reported to emerge or to worsen following STN-DBS. However, it is often challenging to disentangle the effects of STN-DBS per se from concurrent reduction of dopamine replacement therapy, from underlying PD pathology or from disease progression. To this end, pre-clinical models allow for the dissociation of each of these factors, and to establish neural substrates underlying the emergence of motivational symptoms following STN-DBS. Here, we performed a systematic analysis of rodent studies assessing the effects of STN-DBS on reward seeking, reward motivation and reward consumption across a variety of behavioral paradigms. We find that STN-DBS decreases reward seeking in the majority of experiments, and we outline how design of the behavioral task and DBS parameters can influence experimental outcomes. While an early hypothesis posited that DBS acts as a “functional lesion,” an analysis of lesions and inhibition of the STN revealed no consistent pattern on reward-related behavior. Thus, we discuss alternative mechanisms that could contribute to the amotivational effects of STN-DBS. We also argue that optogenetic-assisted circuit dissection could yield important insight into the effects of the STN on motivated behavior in health and disease. Understanding the mechanisms underlying the effects of STN-DBS on motivated behavior-will be critical for optimizing the clinical application of STN-DBS.

    in Frontiers in Human Neuroscience on November 20, 2020 12:00 AM.

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    Think Hard or Think Smart: Network Reconfigurations After Divergent Thinking Associate With Creativity Performance

    Evidence suggests divergent thinking is the cognitive basis of creative thoughts. Neuroimaging literature using resting-state functional connectivity (RSFC) has revealed network reorganizations during divergent thinking. Recent studies have revealed the changes of network organizations when performing creativity tasks, but such brain reconfigurations may be prolonged after task and be modulated by the trait of creativity. To investigate the dynamic reconfiguration, 40 young participants were recruited to perform consecutive Alternative Uses Tasks (AUTs) for divergent thinking and two resting-state scans (before and after AUT) were used for mapping the brain reorganizations after AUT. We split participants into high- and low-creative groups based on creative achievement questionnaire (CAQ) and targeted on reconfigurations of the two brain networks: (1) default-mode network (DMN) and (2) the network seeded at the left inferior frontal gyrus (IFG) because the between-group difference of AUT-induced brain activation located at the left IFG. The changes of post-AUT RSFCs (DMN and IFGN) indicated the prolonged effect of divergent thinking. More specifically, the alterations of RSFCIFG−AG and RSFCIFG−IPL (AG: angular gyrus, IPG: inferior parietal lobule) in the high-creative group had positive relationship with their AUT performances (originality and fluency), but not found in the low-creative group. Furthermore, the RSFC changes of DMN did not present significant relationships with AUT performances. The findings not only confirmed the possibility of brain dynamic reconfiguration following divergent thinking, but also suggested the distinct IFGN reconfiguration between individuals with different creativity levels.

    in Frontiers in Human Neuroscience on November 20, 2020 12:00 AM.

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    Topographic Organization of Correlation Along the Longitudinal and Transverse Axes in Rat Hippocampal CA3 Due to Excitatory Afferents

    The topographic organization of afferents to the hippocampal CA3 subfield are well-studied, but their role in influencing the spatiotemporal dynamics of population activity is not understood. Using a large-scale, computational neuronal network model of the entorhinal-dentate-CA3 system, the effects of the perforant path, mossy fibers, and associational system on the propagation and transformation of network spiking patterns were investigated. A correlation map was constructed to characterize the spatial structure and temporal evolution of pairwise correlations which underlie the emergent patterns found in the population activity. The topographic organization of the associational system gave rise to changes in the spatial correlation structure along the longitudinal and transverse axes of the CA3. The resulting gradients may provide a basis for the known functional organization observed in hippocampus.

    in Frontiers in Computational Neuroscience on November 20, 2020 12:00 AM.

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    Fano Factor: A Potentially Useful Information

    The Fano factor, defined as the variance-to-mean ratio of spike counts in a time window, is often used to measure the variability of neuronal spike trains. However, despite its transparent definition, careless use of the Fano factor can easily lead to distorted or even wrong results. One of the problems is the unclear dependence of the Fano factor on the spiking rate, which is often neglected or handled insufficiently. In this paper we aim to explore this problem in more detail and to study the possible solution, which is to evaluate the Fano factor in the operational time. We use equilibrium renewal and Markov renewal processes as spike train models to describe the method in detail, and we provide an illustration on experimental data.

    in Frontiers in Computational Neuroscience on November 20, 2020 12:00 AM.

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    Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

    Multiple sclerosis (MS) is a complex auto-immune disorder of the central nervous system (CNS) that involves a range of CNS and immune cells. MS is characterized by chronic neuroinflammation, demyelination, and neuronal loss, but the molecular causes of this disease remain poorly understood. One cellular process that could provide insight into MS pathophysiology and also be a possible therapeutic avenue, is autophagy. Autophagy is an intracellular degradative pathway essential to maintain cellular homeostasis, particularly in neurons as defects in autophagy lead to neurodegeneration. One of the functions of autophagy is to maintain cellular homeostasis by eliminating defective or superfluous proteins, complexes, and organelles, preventing the accumulation of potentially cytotoxic damage. Importantly, there is also an intimate and intricate interplay between autophagy and multiple aspects of both innate and adaptive immunity. Thus, autophagy is implicated in two of the main hallmarks of MS, neurodegeneration, and inflammation, making it especially important to understand how this pathway contributes to MS manifestation and progression. This review summarizes the current knowledge about autophagy in MS, in particular how it contributes to our understanding of MS pathology and its potential as a novel therapeutic target.

    in Frontiers in Cellular Neuroscience on November 20, 2020 12:00 AM.

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    Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models

    Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury.

    in Frontiers in Cellular Neuroscience on November 20, 2020 12:00 AM.

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    The CSF-Contacting Nucleus Receives Anatomical Inputs From the Cerebral Cortex: A Combination of Retrograde Tracing and 3D Reconstruction Study in Rat

    Objective

    This study aimed to investigate the direct monosynaptic projections from cortical functional regions to the cerebrospinal fluid (CSF)-contacting nucleus for understanding the functions of the CSF-contacting nucleus.

    Methods

    The Sprague–Dawley rats received cholera toxin B subunit (CB) injections into the CSF-contacting nucleus. After 7–10 days of survival time, the rats were perfused, and the whole brain and spinal cord were sliced under a freezing microtome at 40 μm. All sections were treated with the CB immunofluorescence reaction. The retrogradely labeled neurons in different cortical areas were revealed under a confocal microscope. The distribution features were further illustrated under 3D reconstruction.

    Results

    The retrogradely labeled neurons were identified in the olfactory, orbital, cingulate, insula, retrosplenial, somatosensory, motor, visual, auditory, association, rhinal, and parietal cortical areas. A total of 12 functional areas and 34 functional subregions showed projections to the CSF-contacting nucleus in different cell intensities.

    Conclusion

    According to the connectivity patterns, we conclude that the CSF-contacting nucleus participates in cognition, emotion, pain, visceral activity, etc. The present study firstly reveals the cerebral cortex→CSF-contacting nucleus connections, which implies the multiple functions of this special nucleus in neural and body fluid regulations.

    in Frontiers in Neuroanatomy on November 20, 2020 12:00 AM.

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    Comparison of Transparency and Shrinkage During Clearing of Insect Brains Using Media With Tunable Refractive Index

    Improvement of imaging quality has the potential to visualize previously unseen building blocks of the brain and is therefore one of the great challenges in neuroscience. Rapid development of new tissue clearing techniques in recent years have attempted to solve imaging compromises in thick brain samples, particularly for high resolution optical microscopy, where the clearing medium needs to match the high refractive index of the objective immersion medium. These problems are exacerbated in insect tissue, where numerous (initially air-filled) tracheal tubes branching throughout the brain increase the scattering of light. To date, surprisingly few studies have systematically quantified the benefits of such clearing methods using objective transparency and tissue shrinkage measurements. In this study we compare a traditional and widely used insect clearing medium, methyl salicylate combined with permanent mounting in Permount (“MS/P”) with several more recently applied clearing media that offer tunable refractive index (n): 2,2′-thiodiethanol (TDE), “SeeDB2” (in variants SeeDB2S and SeeDB2G matched to oil and glycerol immersion, n = 1.52 and 1.47, respectively) and Rapiclear (also with n = 1.52 and 1.47). We measured transparency and tissue shrinkage by comparing freshly dissected brains with cleared brains from dipteran flies, with or without addition of vacuum or ethanol pre-treatments (dehydration and rehydration) to evacuate air from the tracheal system. The results show that ethanol pre-treatment is very effective for improving transparency, regardless of the subsequent clearing medium, while vacuum treatment offers little measurable benefit. Ethanol pre-treated SeeDB2G and Rapiclear brains show much less shrinkage than using the traditional MS/P method. Furthermore, at lower refractive index, closer to that of glycerol immersion, these recently developed media offer outstanding transparency compared to TDE and MS/P. Rapiclear protocols were less laborious compared to SeeDB2, but both offer sufficient transparency and refractive index tunability to permit super-resolution imaging of local volumes in whole mount brains from large insects, and even light-sheet microscopy. Although long-term permanency of Rapiclear stored samples remains to be established, our samples still showed good preservation of fluorescence after storage for more than a year at room temperature.

    in Frontiers in Neuroanatomy on November 20, 2020 12:00 AM.

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    Quantification of the Cannabinoid Type 1 Receptor Availability in the Mouse Brain

    Introduction: The endocannabinoid system is involved in several diseases such as addictive disorders, schizophrenia, post-traumatic stress disorder, and eating disorders. As often mice are used as the preferred animal model in translational research, in particular when using genetically modified mice, this study aimed to provide a systematic analysis of in vivo cannabinoid type 1 (CB1) receptor ligand-binding capacity using positron emission tomography (PET) using the ligand [18F]MK-9470. We then compared the PET results with literature data from immunohistochemistry (IHC) to review the consistency between ex vivo protein expression and in vivo ligand binding.

    Methods: Six male C57BL/6J (6–9 weeks) mice were examined with the CB1 receptor ligand [18F]MK-9470 and small animal PET. Different brain regions were evaluated using the parameter %ID/ml. The PET results of the [18F]MK-9470 accumulation in the mouse brain were compared with immunohistochemical literature data.

    Results: The ligand [18F]MK-9470 was taken up into the mouse brain within 5 min after injection and exhibited slow kinetics. It accumulated highly in most parts of the brain. PET and IHC classifications were consistent for most parts of the telencephalon, while brain regions of the diencephalon, mesencephalon, and rhombencephalon were rated higher with PET than IHC.

    Conclusions: This preclinical [18F]MK-9470 study demonstrated the radioligand’s applicability for imaging the region-specific CB1 receptor availability in the healthy adult mouse brain and thus offers the potential to study CB1 receptor availability in pathological conditions.

    in Frontiers in Neuroanatomy on November 20, 2020 12:00 AM.

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    Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

    cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.

    in Frontiers in Neuroanatomy on November 20, 2020 12:00 AM.

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    Various Diseases and Clinical Heterogeneity Are Associated With “Hot Cross Bun”

    Objective: To characterize the clinical phenotypes associated with the “hot cross bun” sign (HCBs) on MRI and identify correlations between neuroimaging and clinical characteristics.

    Methods: Firstly, we screened a cohort of patients with HCBs from our radiologic information system (RIS) in our center. Secondly, we systematically reviewed published cases on HCBs and classified all these cases according to their etiologies. Finally, we characterized all HCBs cases in detail and classified the disease spectra and their clinical heterogeneity.

    Results: Out of a total of 3,546 patients who were screened, we identified 40 patients with HCBs imaging sign in our cohort; systemic literature review identified 39 cases, which were associated with 14 diseases. In our cohort, inflammation [neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS), and acute disseminated encephalomyelitis (ADEM)] and toxicants [toxic encephalopathy caused by phenytoin sodium (TEPS)] were some of the underlying etiologies. Published cases by systemic literature review were linked to metabolic abnormality, degeneration, neoplasm, infection, and stroke. We demonstrated that the clinical phenotype, neuroimaging characteristics, and HCBs response to therapy varied greatly depending on underlying etiologies.

    Conclusion: This is the first to report HCBs spectra in inflammatory and toxication diseases. Our study and systemic literature review demonstrated that the underpinning disease spectrum may be broader than previously recognized.

    in Frontiers in Ageing Neuroscience on November 20, 2020 12:00 AM.

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    Apolipoprotein E ε4 Is Associated With the Development of Incident Dementia in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients With p.Arg544Cys Mutation

    Background and Purpose

    To identify clinical, laboratory, and magnetic resonance imaging (MRI) features in predicting incident stroke and dementia in Korean patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

    Materials and Methods

    We enrolled 87 Korean CADASIL patients who had undergone baseline clinical, laboratory, and MRI examinations between March 2012 and February 2015. The primary outcome of this study is the occurrence of stroke and dementia during the study period. The occurrence of incident stroke was confirmed by neuroimaging study, and dementia was defined by the diagnostic and statistical manual of mental disorders, fourth edition, criteria.

    Results

    Of the 87 patients, 57.5% were men, and the mean age was 63 ± 13 years (range 34–90 years), and 82 patients (94.3%) had p.Arg544Cys mutation. During an average follow-up of 67 months (interquartile range: 53–69 months), incident stroke occurred in 14 of 87 patients (16.1%) and incident dementia in 7 of 70 non-demented patients (10.0%). In adjusted analysis, increased systolic blood pressure was associated with increased risk of incident stroke [for every 10-mmHg increase; hazard ratio, 1.44 (1.02–2.03)]. Apolipoprotein E ε4 genotype was associated with an increased risk of incident dementia [hazard ratio, 10.70 (1.27–89.88)].

    Conclusion

    In this study, apolipoprotein E ε4 genotype was associated with the development of incident dementia, and higher blood pressure was associated with increased risk of incident stroke in CADASIL patients with predominant p.Arg544Cys mutation.

    in Frontiers in Ageing Neuroscience on November 20, 2020 12:00 AM.

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    Crossed cerebellar diaschisis after stroke detected noninvasively by arterial spin-labeling MR imaging

    As a noninvasive perfusion-weighted MRI technique, arterial spin-labeling (ASL) was becoming increasingly used to evaluate cerebral hemodynamics in many studies. The relation between ASL-MRI and crossed cerebe...

    in BMC Neuroscience on November 20, 2020 12:00 AM.

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    Evolution of multicellular life cycles under costly fragmentation

    by Yuriy Pichugin, Arne Traulsen

    A fascinating wealth of life cycles is observed in biology, from unicellularity to the concerted fragmentation of multicellular units. However, the understanding of factors driving their evolution is still limited. We show that costs of fragmentation have a major impact on the evolution of life cycles due to their influence on the growth rates of the associated populations. We model a group structured population of undifferentiated cells, where cell clusters reproduce by fragmentation. Fragmentation events are associated with a cost expressed by either a fragmentation delay, an additional risk, or a cell loss. The introduction of such fragmentation costs vastly increases the set of possible life cycles. Based on these findings, we suggest that the evolution of life cycles involving splitting into multiple offspring can be directly associated with the fragmentation cost. Moreover, the impact of this cost alone is strong enough to drive the emergence of multicellular units that eventually split into many single cells, even under scenarios that strongly disfavour collectives compared to solitary individuals.

    in PLoS Computational Biology on November 19, 2020 10:00 PM.

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    Ten simple rules for starting research in your late teens

    by Cameron Mura, Mike Chalupa, Abigail M. Newbury, Jack Chalupa, Philip E. Bourne

    in PLoS Computational Biology on November 19, 2020 10:00 PM.

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    Ten simple rules for increased lab resilience

    by Matthias C. Rillig, Milos Bielcik, V. Bala Chaudhary, Leonie Grünfeld, Stefanie Maaß, India Mansour, Masahiro Ryo, Stavros D. Veresoglou

    When running a lab we do not think about calamities, since they are rare events for which we cannot plan while we are busy with the day-to-day management and intellectual challenges of a research lab. No lab team can be prepared for something like a pandemic such as COVID-19, which has led to shuttered labs around the globe. But many other types of crises can also arise that labs may have to weather during their lifetime. What can researchers do to make a lab more resilient in the face of such exterior forces? What systems or behaviors could we adjust in ‘normal’ times that promote lab success, and increase the chances that the lab will stay on its trajectory? We offer 10 rules, based on our current experiences as a lab group adapting to crisis.

    in PLoS Computational Biology on November 19, 2020 10:00 PM.

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    Modeling HIV-1 infection in the brain

    by Colin T. Barker, Naveen K. Vaidya

    While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggests that the brain can be an important reservoir causing long-term viral persistence.

    in PLoS Computational Biology on November 19, 2020 10:00 PM.

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    Transmissible cancers and the evolution of sex under the Red Queen hypothesis

    by Thomas G. Aubier, Matthias Galipaud, E. Yagmur Erten, Hanna Kokko

    The predominance of sexual reproduction in eukaryotes remains paradoxical in evolutionary theory. Of the hypotheses proposed to resolve this paradox, the ‘Red Queen hypothesis’ emphasises the potential of antagonistic interactions to cause fluctuating selection, which favours the evolution and maintenance of sex. Whereas empirical and theoretical developments have focused on host-parasite interactions, the premises of the Red Queen theory apply equally well to any type of antagonistic interactions. Recently, it has been suggested that early multicellular organisms with basic anticancer defences were presumably plagued by antagonistic interactions with transmissible cancers and that this could have played a pivotal role in the evolution of sex. Here, we dissect this argument using a population genetic model. One fundamental aspect distinguishing transmissible cancers from other parasites is the continual production of cancerous cell lines from hosts’ own tissues. We show that this influx dampens fluctuating selection and therefore makes the evolution of sex more difficult than in standard Red Queen models. Although coevolutionary cycling can remain sufficient to select for sex under some parameter regions of our model, we show that the size of those regions shrinks once we account for epidemiological constraints. Altogether, our results suggest that horizontal transmission of cancerous cells is unlikely to cause fluctuating selection favouring sexual reproduction. Nonetheless, we confirm that vertical transmission of cancerous cells can promote the evolution of sex through a separate mechanism, known as similarity selection, that does not depend on coevolutionary fluctuations.

    in PLoS Biology on November 19, 2020 10:00 PM.

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    Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms

    Objective

    Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here.

    Methods

    In the tetrodotoxin model, we used 16‐channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasm patients.

    Results

    Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow wave sleep. In addition, the ensuing interictal up states of slow wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations, as it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp‐up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasm patients.

    Interpretation

    Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies. ANN NEUROL 2020

    in Annals of Neurology on November 19, 2020 03:35 PM.

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    Episodic memory governs choices: An RNN-based reinforcement learning model for decision-making task

    Publication date: Available online 18 November 2020

    Source: Neural Networks

    Author(s): Xiaohan Zhang, Lu Liu, Guodong Long, Jing Jiang, Shenquan Liu

    in Neural Networks on November 19, 2020 02:00 PM.

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    Silent new brain MRI lesions in children with MOG‐antibody associated disease.

    Anti‐myelin oligodendrocyte glycoprotein antibodies (MOG‐IgG) are associated clinically with either a monophasic or relapsing disease course. We investigated the frequency and clinical importance of acquired asymptomatic brain MRI lesions in a prospective incident cohort of 74 MOG‐IgG positive children with serial MRI scans over a median of 5 years from presentation. Silent new lesions were detected in 14% of MOG‐IgG positive participants, most commonly within the first months post‐onset, with a positive predictive value for clinically relapsing disease of only 20%. Detection of asymptomatic lesions alone need not prompt initiation of chronic immunotherapy.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on November 19, 2020 12:50 PM.

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    Author Correction: Highly specific multiplexed RNA imaging in tissues with split-FISH

    Nature Methods, Published online: 19 November 2020; doi:10.1038/s41592-020-01019-w

    Author Correction: Highly specific multiplexed RNA imaging in tissues with split-FISH

    in Nature Methods on November 19, 2020 12:00 AM.

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    Linking lapsed attention and memory

    Nature Reviews Neuroscience, Published online: 19 November 2020; doi:10.1038/s41583-020-00413-9

    Linking lapsed attention and memory

    in Nature Reviews on November 19, 2020 12:00 AM.

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    A microcephaly-screening method

    Nature Reviews Neuroscience, Published online: 19 November 2020; doi:10.1038/s41583-020-00412-w

    A microcephaly-screening method

    in Nature Reviews on November 19, 2020 12:00 AM.

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    Crop growth

    Nature Reviews Neuroscience, Published online: 19 November 2020; doi:10.1038/s41583-020-00411-x

    Crop growth

    in Nature Reviews on November 19, 2020 12:00 AM.

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    Touch to taste

    Nature Reviews Neuroscience, Published online: 19 November 2020; doi:10.1038/s41583-020-00410-y

    Touch to taste

    in Nature Reviews on November 19, 2020 12:00 AM.

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    Mixture Coding and Segmentation in the Anterior Piriform Cortex

    Coding of odorous stimuli has been mostly studied using single isolated stimuli. However, a single sniff of air in a natural environment is likely to introduce airborne chemicals emitted by multiple objects into the nose. The olfactory system is therefore faced with the task of segmenting odor mixtures to identify objects in the presence of rich and often unpredictable backgrounds. The piriform cortex is thought to be the site of object recognition and scene segmentation, yet the nature of its responses to odorant mixtures is largely unknown. In this study, we asked two related questions. (1) How are mixtures represented in the piriform cortex? And (2) Can the identity of individual mixture components be read out from mixture representations in the piriform cortex? To answer these questions, we recorded single unit activity in the piriform cortex of naïve mice while sequentially presenting single odorants and their mixtures. We find that a normalization model explains mixture responses well, both at the single neuron, and at the population level. Additionally, we show that mixture components can be identified from piriform cortical activity by pooling responses of a small population of neurons—in many cases a single neuron is sufficient. These results indicate that piriform cortical representations are well suited to perform figure-background segmentation without the need for learning.

    in Frontiers in Systems Neuroscience on November 19, 2020 12:00 AM.

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    Single-Trial EEG Connectivity of Default Mode Network Before and During Encoding Predicts Subsequent Memory Outcome

    The successful memory process produces specific activity in the brain network. As the brain activity of the prestimulus and encoding phases has a crucial effect on subsequent memory outcomes (e.g., remembered or forgotten), previous studies have tried to predict the memory performance in this period. Conventional studies have used the spectral power or event-related potential of specific regions as the classification feature. However, as multiple brain regions work collaboratively to process memory, it could be a better option to use functional connectivity within the memory-related brain network to predict subsequent memory performance. In this study, we acquired the EEG signals while performing an associative memory task that remembers scene–word pairs. For the connectivity analysis, we estimated the cross–mutual information within the default mode network with the time–frequency spectra at the prestimulus and encoding phases. Then, we predicted the success or failure of subsequent memory outcome with the connectivity features. We found that the classifier with support vector machine achieved the highest classification accuracy of 80.83% ± 12.65% (mean ± standard deviation) using the beta (13–30 Hz) connectivity at encoding phase among the multiple frequency bands and task phases. Using the prestimulus beta connectivity, the classification accuracy of 72.45% ± 12.52% is also achieved. Among the features, the connectivity related to the dorsomedial prefrontal cortex was found to contribute to successful memory encoding. The connectivity related to the posterior cingulate cortex was found to contribute to the failure of memory encoding. The present study showed for the first time the successful prediction with high accuracy of subsequent memory outcome using single-trial functional connectivity.

    in Frontiers in Systems Neuroscience on November 19, 2020 12:00 AM.

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    Epidural Electrical Stimulation of the Lumbosacral Spinal Cord Improves Trunk Stability During Seated Reaching in Two Humans With Severe Thoracic Spinal Cord Injury

    Background: Quality of life measurements indicate that independent performance of activities of daily living, such as reaching to manipulate objects, is a high priority of individuals living with motor impairments due to spinal cord injury (SCI). In a small number of research participants with SCI, electrical stimulation applied to the dorsal epidural surface of the spinal cord, termed epidural spinal electrical stimulation (ES), has been shown to improve motor functions, such as standing and stepping. However, the impact of ES on seated reaching performance, as well as the approach to identifying stimulation parameters that improve reaching ability, have yet to be described.

    Objective: Herein, we characterize the effects of ES on seated reaching performance in two participants with chronic, complete loss of motor and sensory functions below thoracic-level SCI. Additionally, we report the effects of delivering stimulation to discrete cathode/anode locations on a 16-contact electrode array spanning the lumbosacral spinal segments on reach distance while participants were seated on a mat and/or in their wheelchair.

    Methods: Two males with mid-thoracic SCI due to trauma, each of which occurred more than 3 years prior to study participation, were enrolled in a clinical trial at Mayo Clinic, Rochester, MN, USA. Reaching performance was assessed, with and without ES, at several time points throughout the study using the modified functional reach test (mFRT). Altogether, participant 1 performed 1,164 reach tests over 26-time points. Participant 2 performed 480 reach tests over 17-time points.

    Results: Median reach distances during ES were higher for both participants compared to without ES. Forward reach distances were greater than lateral reach distances in all environments, mat or wheelchair, for both participants. Stimulation delivered in the caudal region of the array resulted in improved forward reach distance compared to stimulation in the rostral region. For both participants, when stimulation was turned off, no significant changes in reach distance were observed throughout the study.

    Conclusion: ES enhanced seated reaching-performance of individuals with chronic SCI. Additionally, electrode configurations delivering stimulation in caudal regions of the lumbosacral spinal segments may improve reaching ability compared to rostral regions.

    in Frontiers in Systems Neuroscience on November 19, 2020 12:00 AM.

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    AMI, an Indazole Derivative, Improves Parkinson’s Disease by Inhibiting Tau Phosphorylation

    Dopaminergic neuronal loss is the main pathological character of Parkinson’s disease (PD). Abnormal tau hyperphosphorylation will lead to dopaminergic neuronal loss. An indazole derivative 6-amino-1-methyl-indazole (AMI) successfully synthesized to inhibit tau hyperphosphorylation may exert a neuroprotective effect. The in vitro study showed that AMI effectively increased cell viability and alleviated the apoptosis induced by MPP+ in SH-SY5Y cells. In addition, AMI treatment significantly decreased the expression of p-tau and upstream kinases GSK-3β. In the MPTP-induced PD mice models, we found AMI apparently preserved dopaminergic neurons in the substantia nigra and improved the PD behavioral symptoms. Our results demonstrate that AMI exerts a neuroprotective effect by inhibiting tau hyperphosphorylation, representing a promising new candidate for PD treatment.

    in Frontiers in Molecular Neuroscience on November 19, 2020 12:00 AM.

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    Spinal Manipulative Therapy Alters Brain Activity in Patients With Chronic Low Back Pain: A Longitudinal Brain fMRI Study

    Background: Spinal manipulative therapy (SMT) helps to reduce chronic low back pain (cLBP). However, the underlying mechanism of pain relief and the neurological response to SMT remains unclear. We utilized brain functional magnetic resonance imaging (fMRI) upon the application of a real-time spot pressure mechanical stimulus to assess the effects of SMT on patients with cLBP.

    Methods: Patients with cLBP (Group 1, n = 14) and age-matched healthy controls without cLBP (Group 2, n = 20) were prospectively enrolled. Brain fMRI was performed for Group 1 at three time points: before SMT (TP1), after the first SMT session (TP2), and after the sixth SMT session (TP3). The healthy controls (Group 2) did not receive SMT and underwent only one fMRI scan. During fMRI scanning, a real-time spot pressure mechanical stimulus was applied to the low back area of all participants. Participants in Group 1 completed clinical questionnaires assessing pain and quality of life using a visual analog scale (VAS) and the Chinese Short Form Oswestry Disability Index (C-SFODI), respectively.

    Results: Before SMT (TP1), there were no significant differences in brain activity between Group 1 and Group 2. After the first SMT session (TP2), Group 1 showed significantly greater brain activity in the right parahippocampal gyrus, right dorsolateral prefrontal cortex, and left precuneus compared to Group 2 (P < 0.05). After the sixth SMT session (TP3), Group 1 showed significantly greater brain activity in the posterior cingulate gyrus and right inferior frontal gyrus compared to Group 2 (P < 0.05). After both the first and sixth SMT sessions (TP2 and TP3), Group 1 had significantly lower VAS pain scores and C-SFODI scores than at TP1 (P < 0.001).

    Conclusion: We observed alterations in brain activity in regions of the default mode network in patients with cLBP after SMT. These findings suggest the potential utility of the default mode network as a neuroimaging biomarker for pain management in patients with cLBP.

    Clinical Trial Registration:Chinese Clinical Trial Registry, identifier ChiCTR1800015620.

    in Frontiers in Integrative Neuroscience on November 19, 2020 12:00 AM.

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    Dendritic Degeneration of Human Auditory Nerve Fibers and Its Impact on the Spiking Pattern Under Regular Conditions and During Cochlear Implant Stimulation

    Due to limitations of human in vivo studies, detailed computational models enable understanding the neural signaling in the degenerated auditory system and cochlear implants (CIs). Four human cochleae were used to quantify hearing levels depending on dendritic changes in diameter and myelination thickness from type I of the auditory nerve fibers (ANFs). Type I neurons transmit the auditory information as spiking pattern from the inner hair cells (IHCs) to the cochlear nucleus. The impact of dendrite diameter and degree of myelination on neural signal transmission was simulated for (1) synaptic excitation via IHCs and (2) stimulation from CI electrodes. An accurate three-dimensional human cochlear geometry, along with 30 auditory pathways, mimicked the CI environment. The excitation properties of electrical potential distribution induced by two CI were analyzed. Main findings: (1) The unimodal distribution of control dendrite diameters becomes multimodal for hearing loss cases; a group of thin dendrites with diameters between 0.3 and 1 μm with a peak at 0.5 μm appeared. (2) Postsynaptic currents from IHCs excite such thin dendrites easier and earlier than under control conditions. However, this advantage is lost as their conduction velocity decreases proportionally with the diameter and causes increased spike latency and jitter in soma and axon. Firing probability reduces through the soma passage due to the low intracellular current flow in thin dendrites during spiking. (3) Compared with dendrite diameter, variations in myelin thickness have a small impact on spiking performance. (4) Contrary to synaptic excitation, CIs cause several spike initiation sites in dendrite, soma region, and axon; moreover, fiber excitability reduces with fiber diameter. In a few cases, where weak stimuli elicit spikes of a target neuron (TN) in the axon, dendrite diameter reduction has no effect. However, in many cases, a spike in a TN is first initiated in the dendrite, and consequently, dendrite degeneration demands an increase in threshold currents. (5) Threshold currents of a TN and co-stimulation of degenerated ANFs in other frequency regions depend on the electrode position, including its distance to the outer wall, the cochlear turn, and the three-dimensional pathway of the TN.

    in Frontiers in Neuroscience: Neural Technology on November 19, 2020 12:00 AM.

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    Hematoma Ventricle Distance on Computed Tomography Predicts Poor Outcome in Intracerebral Hemorrhage

    Objective

    To investigate the relationship between hematoma ventricle distance (HVD) and clinical outcome in patients with intracerebral hemorrhage (ICH).

    Methods

    We prospectively enrolled consecutive patients with ICH in a tertiary academic hospital between July 2011 and April 2018. We retrospectively reviewed images for all patients receiving a computed tomography (CT) within 6 h after onset of symptoms and at least one follow-up CT scan within 36 h. The minimum distance of hematoma border to nearest ventricle was measured as HVD. Youden index was used to evaluate the cutoff of HVD predicting functional outcome. Logistic regression model was used to assess the HVD data and clinical poor outcome (modified Rankin Scale 4–6) at 90 days.

    Results

    A total of 325 patients were included in our final analysis. The median HVD was 2.4 mm (interquartile range, 0–5.7 mm), and 119 (36.6%) patients had poor functional outcome at 3 months. After adjusting for age, admission Glasgow coma scale, intraventricular hemorrhage, baseline ICH volume, admission systolic blood pressure, blood glucose, hematoma expansion, withdrawal of care, and hypertension, HVD ≤ 2.5 mm was associated with increased odds of clinical poor outcome [odd ratio, 3.59, (95%CI = 1.72–7.50); p = 0.001] in multivariable logistic regression analysis.

    Conclusion

    Hematoma ventricle distance allows physicians to quickly select and stratify patients in clinical trials and thereby serve as a novel and useful addition to predict ICH prognosis.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 19, 2020 12:00 AM.

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    Microglia Play an Essential Role in Synapse Development and Neuron Maturation in Tissue-Engineered Neural Tissues

    In the process of constructing engineered neural tissues, we often use mixed primary neural cells, which contain microglia in the cell culture. However, the role that microglia play in the construction of engineered neural tissue has not been well studied. Here, we generated three-dimensional (3D) engineered neural tissues by silk fibroin/collagen composite scaffolds and primary mixed cortical cells. We depleted microglial cells by magnetic separation. Then, we analyzed the neural growth, development, mature and synapse-related gene, and protein expressions compared with the control engineered neural tissues with the microglia-depleted engineered neural tissues. We found that the engineered neural tissues constructed by magnetic separation to remove microglia showed a decrease in the number of synaptic proteins and mature neurons. These findings link microglia to neuron and synaptic maturation and suggest the importance of microglia in constructing engineered neural tissues in vitro.

    in Frontiers in Neuroscience: Neural Technology on November 19, 2020 12:00 AM.

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    Electrical Imaging of Light-Induced Signals Across and Within Retinal Layers

    The mammalian retina processes sensory signals through two major pathways: a vertical excitatory pathway, which involves photoreceptors, bipolar cells, and ganglion cells, and a horizontal inhibitory pathway, which involves horizontal cells, and amacrine cells. This concept explains the generation of an excitatory center—inhibitory surround sensory receptive fields—but fails to explain the modulation of the retinal output by stimuli outside the receptive field. Electrical imaging of light-induced signal propagation at high spatial and temporal resolution across and within different retinal layers might reveal mechanisms and circuits involved in the remote modulation of the retinal output. Here we took advantage of a high-density complementary metal oxide semiconductor-based microelectrode array and investigated the light-induced propagation of local field potentials (LFPs) in vertical mouse retina slices. Surprisingly, the LFP propagation within the different retinal layers depends on stimulus duration and stimulus background. Application of the same spatially restricted light stimuli to flat-mounted retina induced ganglion cell activity at remote distances from the stimulus center. This effect disappeared if a global background was provided or if gap junctions were blocked. We hereby present a neurotechnological approach and demonstrated its application, in which electrical imaging evaluates stimulus-dependent signal processing across different neural layers.

    in Frontiers in Neuroscience: Neural Technology on November 19, 2020 12:00 AM.

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    Multiclass Classification Based on Combined Motor Imageries

    Motor imagery (MI) allows the design of self-paced brain–computer interfaces (BCIs), which can potentially afford an intuitive and continuous interaction. However, the implementation of non-invasive MI-based BCIs with more than three commands is still a difficult task. First, the number of MIs for decoding different actions is limited by the constraint of maintaining an adequate spacing among the corresponding sources, since the electroencephalography (EEG) activity from near regions may add up. Second, EEG generates a rather noisy image of brain activity, which results in a poor classification performance. Here, we propose a solution to address the limitation of identifiable motor activities by using combined MIs (i.e., MIs involving 2 or more body parts at the same time). And we propose two new multilabel uses of the Common Spatial Pattern (CSP) algorithm to optimize the signal-to-noise ratio, namely MC2CMI and MC2SMI approaches. We recorded EEG signals from seven healthy subjects during an 8-class EEG experiment including the rest condition and all possible combinations using the left hand, right hand, and feet. The proposed multilabel approaches convert the original 8-class problem into a set of three binary problems to facilitate the use of the CSP algorithm. In the case of the MC2CMI method, each binary problem groups together in one class all the MIs engaging one of the three selected body parts, while the rest of MIs that do not engage the same body part are grouped together in the second class. In this way, for each binary problem, the CSP algorithm produces features to determine if the specific body part is engaged in the task or not. Finally, three sets of features are merged together to predict the user intention by applying an 8-class linear discriminant analysis. The MC2SMI method is quite similar, the only difference is that any of the combined MIs is considered during the training phase, which drastically accelerates the calibration time. For all subjects, both the MC2CMI and the MC2SMI approaches reached a higher accuracy than the classic pair-wise (PW) and one-vs.-all (OVA) methods. Our results show that, when brain activity is properly modulated, multilabel approaches represent a very interesting solution to increase the number of commands, and thus to provide a better interaction.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 19, 2020 12:00 AM.

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    Prospects of Directly Reprogrammed Adult Human Neurons for Neurodegenerative Disease Modeling and Drug Discovery: iN vs. iPSCs Models

    A reliable disease model is critical to the study of specific disease mechanisms as well as for the discovery and development of new drugs. Despite providing crucial insights into the mechanisms of neurodegenerative diseases, translation of this information to develop therapeutics in clinical trials have been unsuccessful. Reprogramming technology to convert adult somatic cells to induced Pluripotent Stem Cells (iPSCs) or directly reprogramming adult somatic cells to induced Neurons (iN), has allowed for the creation of better models to understand the molecular mechanisms and design of new drugs. In recent times, iPSC technology has been commonly used for modeling neurodegenerative diseases and drug discovery. However, several technological challenges have limited the application of iN. As evidence suggests, iN for the modeling of neurodegenerative disorders is advantageous compared to those derived from iPSCs. In this review, we will compare iPSCs and iN models for neurodegenerative diseases and their potential applications in the future.

    in Frontiers in Neuroscience: Neurodegeneration on November 19, 2020 12:00 AM.

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    Dynamic Modeling of Common Brain Neural Activity in Motor Imagery Tasks

    Evaluation of brain dynamics elicited by motor imagery (MI) tasks can contribute to clinical and learning applications. The multi-subject analysis is to make inferences on the group/population level about the properties of MI brain activity. However, intrinsic neurophysiological variability of neural dynamics poses a challenge for devising efficient MI systems. Here, we develop a time-frequency model for estimating the spatial relevance of common neural activity across subjects employing an introduced statistical thresholding rule. In deriving multi-subject spatial maps, we present a comparative analysis of three feature extraction methods: Common Spatial Patterns, Functional Connectivity, and Event-Related De/Synchronization. In terms of interpretability, we evaluate the effectiveness in gathering MI data from collective populations by introducing two assumptions: (i) Non-linear assessment of the similarity between multi-subject data originating the subject-level dynamics; (ii) Assessment of time-varying brain network responses according to the ranking of individual accuracy performed in distinguishing distinct motor imagery tasks (left-hand vs. right-hand). The obtained validation results indicate that the estimated collective dynamics differently reflect the flow of sensorimotor cortex activation, providing new insights into the evolution of MI responses.

    in Frontiers in Neuroscience: Brain Imaging Methods on November 19, 2020 12:00 AM.

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    Editorial: Neurologic Correlates of Motor Function in Cerebral Palsy: Opportunities for Targeted Treatment

    in Frontiers in Human Neuroscience on November 19, 2020 12:00 AM.

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    Abnormal Connectivity and Brain Structure in Patients With Visual Snow

    Objective

    Visual snow (VS) is a distressing, life-impacting condition with persistent visual phenomena. VS patients show cerebral hypermetabolism within the visual cortex, resulting in altered neuronal excitability. We hypothesized to see disease-dependent alterations in functional connectivity and gray matter volume (GMV) in regions associated with visual perception.

    Methods

    Nineteen patients with VS and 16 sex- and age-matched controls were recruited. Functional magnetic resonance imaging (fMRI) was applied to examine resting-state functional connectivity (rsFC). Volume changes were assessed by means of voxel-based morphometry (VBM). Finally, we assessed associations between MRI indices and clinical parameters.

    Results

    Patients with VS showed hyperconnectivity between extrastriate visual and inferior temporal brain regions and also between prefrontal and parietal (angular cortex) brain regions (p < 0.05, corrected for age and migraine occurrence). In addition, patients showed increased GMV in the right lingual gyrus (p < 0.05 corrected). Symptom duration positively correlated with GMV in both lingual gyri (p < 0.01 corrected).

    Conclusion

    This study found VS to be associated with both functional and structural changes in the early and higher visual cortex, as well as the temporal cortex. These brain regions are involved in visual processing, memory, spatial attention, and cognitive control. We conclude that VS is not just confined to the visual system and that both functional and structural changes arise in VS patients, be it as an epiphenomenon or a direct contributor to the pathomechanism of VS. These in vivo neuroimaging biomarkers may hold potential as objective outcome measures of this so far purely subjective condition.

    in Frontiers in Human Neuroscience on November 19, 2020 12:00 AM.

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    Individualized Responses to Ipsilesional High-Frequency and Contralesional Low-Frequency rTMS in Chronic Stroke: A Pilot Study to Support the Individualization of Neuromodulation for Rehabilitation

    Background: In this pilot study, we examined the effects of ipsilesional high-frequency rTMS (iHF-rTMS) and contralesional low-frequency rTMS (cLF-rTMS) applied via a double-cone coil on neurophysiological and gait variables in patients with chronic stroke.

    Objective/Hypothesis: To determine the group and individual level effects of two types of stimulation to better individualize neuromodulation for rehabilitation.

    Methods: Using a randomized, within-subject, double-blind, sham-controlled trial with 14 chronic stroke participants iHF-rTMS and cLF-rTMS were applied via a double-cone coil to the tibialis anterior cortical representation. Neurophysiological and gait variables were compared pre-post rTMS.

    Results: A small effect of cLF-rTMS indicated increased MEP amplitudes (Cohen’s D; cLF-rTMS, d = −0.30). Group-level analysis via RMANOVA showed no significant group effects of stimulation (P > 0.099). However, secondary analyses of individual data showed a high degree of response variability to rTMS. Individual percent changes in resting motor threshold and normalized MEP latency correlated with changes in gait propulsive forces and walking speed (iHF-rTMS, nLAT:Pp, R = 0.632 P = 0.015; cLF-rTMS, rMT:SSWS, R = −0.557, P = 0.039; rMT:Pp, R = 0.718, P = 0.004).

    Conclusions: Changes in propulsive forces and walking speed were seen in some individuals that showed neurophysiological changes in response to rTMS. The neurological consequences of stroke are heterogeneous making a “one type fits all” approach to neuromodulation for rehabilitation unlikely. This pilot study suggests that an individual’s unique response to rTMS should be considered before the application/selection of neuromodulatory therapies. Before neuromodulatory therapies can be incorporated into standard clinical practice, additional work is needed to identify biomarkers of response and how best to prescribe neuromodulation for rehabilitation for post-stroke gait.

    in Frontiers in Human Neuroscience on November 19, 2020 12:00 AM.

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    Single-Cell Visualization Deep in Brain Structures by Gene Transfer

    A projection neuron targets multiple regions beyond the functional brain area. In order to map neuronal connectivity in a massive neural network, a means for visualizing the entire morphology of a single neuron is needed. Progress has facilitated single-neuron analysis in the cerebral cortex, but individual neurons in deep brain structures remain difficult to visualize. To this end, we developed an in vivo single-cell electroporation method for juvenile and adult brains that can be performed under a standard stereomicroscope. This technique involves rapid gene transfection and allows the visualization of dendritic and axonal morphologies of individual neurons located deep in brain structures. The transfection efficiency was enhanced by directly injecting the expression vector encoding green fluorescent protein instead of monitoring cell attachment to the electrode tip. We obtained similar transfection efficiencies in both young adult (≥P40) and juvenile mice (P21–30). By tracing the axons of thalamocortical neurons, we identified a specific subtype of neuron distinguished by its projection pattern. Additionally, transfected mOrange-tagged vesicle-associated membrane protein 2–a presynaptic protein—was strongly localized in terminal boutons of thalamocortical neurons. Thus, our in vivo single-cell gene transfer system offers rapid single-neuron analysis deep in brain. Our approach combines observation of neuronal morphology with functional analysis of genes of interest, which can be useful for monitoring changes in neuronal activity corresponding to specific behaviors in living animals.

    in Frontiers in Neural Circuits on November 19, 2020 12:00 AM.

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    Astrocyte–Oligodendrocyte–Microglia Crosstalk in Astrocytopathies

    Defective astrocyte function due to a genetic mutation can have major consequences for microglia and oligodendrocyte physiology, which in turn affects the white matter integrity of the brain. This review addresses the current knowledge on shared and unique pathophysiological mechanisms of astrocytopathies, including vanishing white matter, Alexander disease, megalencephalic leukoencephalopathy with subcortical cysts, Aicardi–Goutières syndrome, and oculodentodigital dysplasia. The mechanisms of disease include protein accumulation, unbalanced secretion of extracellular matrix proteins, pro- and anti-inflammatory molecules, cytokines and chemokines by astrocytes, as well as an altered gap junctional network and a changed ionic and nutrient homeostasis. Interestingly, the extent to which astrogliosis and microgliosis are present in these astrocytopathies is highly variable. An improved understanding of astrocyte–microglia–oligodendrocyte crosstalk might ultimately lead to the identification of druggable targets for these, currently untreatable, severe conditions.

    in Frontiers in Cellular Neuroscience on November 19, 2020 12:00 AM.

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    Human Motor Neurons With SOD1-G93A Mutation Generated From CRISPR/Cas9 Gene-Edited iPSCs Develop Pathological Features of Amyotrophic Lateral Sclerosis

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by gradual degeneration and elimination of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord. Some familial forms of ALS are caused by genetic mutations in superoxide dismutase 1 (SOD1) but the mechanisms driving MN disease are unclear. Identifying the naturally occurring pathology and understanding how this mutant SOD1 can affect MNs in translationally meaningful ways in a valid and reliable human cell model remains to be established. Here, using CRISPR/Cas9 genome editing system and human induced pluripotent stem cells (iPSCs), we generated highly pure, iPSC-derived MNs with a SOD1-G93A missense mutation. With the wild-type cell line serving as an isogenic control and MNs from a patient-derived iPSC line with an SOD1-A4V mutation as a comparator, we identified pathological phenotypes relevant to ALS. The mutant MNs accumulated misfolded and aggregated forms of SOD1 in cell bodies and processes, including axons. They also developed distinctive axonal pathologies. Mutants had axonal swellings with shorter axon length and less numbers of branch points. Moreover, structural and molecular abnormalities in presynaptic and postsynaptic size and density were found in the mutants. Finally, functional studies with microelectrode array demonstrated that the individual mutant MNs exhibited decreased number of spikes and diminished network bursting, but increased burst duration. Taken together, we identified spontaneous disease phenotypes relevant to ALS in mutant SOD1 MNs from genome-edited and patient-derived iPSCs. Our findings demonstrate that SOD1 mutations in human MNs cause cell-autonomous proteinopathy, axonopathy, synaptic pathology, and aberrant neurotransmission.

    in Frontiers in Cellular Neuroscience on November 19, 2020 12:00 AM.

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    Distinct Microtubule Organizing Center Mechanisms Combine to Generate Neuron Polarity and Arbor Complexity

    Dendrite and axon arbor wiring patterns determine the connectivity and computational characteristics of a neuron. The identities of these dendrite and axon arbors are created by differential polarization of their microtubule arrays, and their complexity and pattern are generated by the extension and organization of these arrays. We describe how several molecularly distinct microtubule organizing center (MTOC) mechanisms function during neuron differentiation to generate and arrange dendrite and axon microtubules. The temporal and spatial organization of these MTOCs generates, patterns, and diversifies arbor wiring.

    in Frontiers in Cellular Neuroscience on November 19, 2020 12:00 AM.

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    Interphotoreceptor Retinoid-Binding Protein (IRBP) in Retinal Health and Disease

    Interphotoreceptor retinoid-binding protein (IRBP), also known as retinol binding protein 3 (RBP3), is a lipophilic glycoprotein specifically secreted by photoreceptors. Enriched in the interphotoreceptor matrix (IPM) and recycled by the retinal pigment epithelium (RPE), IRBP is essential for the vision of all vertebrates as it facilitates the transfer of retinoids in the visual cycle. It also helps to transport lipids between the RPE and photoreceptors. The thiol-dependent antioxidant activity of IRBP maintains the delicate redox balance in the normal retina. Thus, its dysfunction is suspected to play a role in many retinal diseases. We have reviewed here the latest research on IRBP in both retinal health and disease, including the function and regulation of IRBP under retinal stress in both animal models and the human retina. We have also explored the therapeutic potential of targeting IRBP in retinal diseases. Although some technical barriers remain, it is possible that manipulating the expression of IRBP in the retina will rescue or prevent photoreceptor degeneration in many retinal diseases.

    in Frontiers in Cellular Neuroscience on November 19, 2020 12:00 AM.

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    HERC1 Ubiquitin Ligase Is Required for Hippocampal Learning and Memory

    Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.

    in Frontiers in Neuroanatomy on November 19, 2020 12:00 AM.

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    Which Parameters of Beat-to-Beat Blood Pressure Best Predict Poor In-Hospital Outcome in Spontaneous Intracerebral Hemorrhage?

    Objective: There is increasing evidence that high blood pressure (BP) levels and BP variability (BPV) over 24 h or longer are associated with poor clinical outcomes in patients with intracerebral hemorrhage (ICH). The objective of this study was to examine the association between different beat-to-beat BP parameters and in-hospital outcomes.

    Methods: Patients with a diagnosis of acute spontaneous ICH were recruited consecutively and prospectively between September 2018 and January 2019. Beat-to-beat recordings were measured non-invasively for 5 min within the first 72 h after the onset of symptoms. BPV was analyzed by standard deviation (SD), coefficient of variation (CV), average real variability (ARV), and variation independent of mean (VIM). Outcome was assessed at discharge using the modified Rankin Scale (mRS) score. Multivariate logistic regression analysis was used to assess the association between BP levels, BPV, and clinical outcomes.

    Results: A total of 66 patients were included, of whom 34 had poor outcomes (mRS score, 3–6). Patients with poor outcomes had significantly higher National Institute of Health Stroke Scale scores (4.5 vs. 9, p < 0.001), a larger ICH volume (8 vs. 14.5 mL, p = 0.004), and an increased systolic BP (SBP) -CV (3.2 vs. 4.8, p < 0.001) and diastolic BP (DBP) -CV (3.7 vs. 4.9, p = 0.015). After adjustment for major covariates, multivariate logistic regression analysis revealed that SBP-CV was independently associated with an increased risk of poor in-hospital outcomes [odds ratio (OR) 2.535; 95% confidence interval (CI), 1.211–5.305; p = 0.014]. The receiver operating characteristic area for SBP-CV in predicting poor in-hospital outcome was 0.827 (95% CI, 0.730–0.925; p < 0.001), and the best cutoff point was 3.551 (sensitivity, 82.35%; specificity, 68.75%).

    Conclusion: A higher beat-to-beat BPV in the first 72 h of admission was associated with unfavorable in-hospital outcomes in patients with ICH. The stabilization of BPV during the acute phase may be a therapeutic target; this could be tested in future clinical trials.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    Anisotropy of Anomalous Diffusion Improves the Accuracy of Differentiating and Grading Alzheimer's Disease Using Novel Fractional Motion Model

    Background and Purpose: Recent evidence shows that the fractional motion (FM) model may be a more appropriate model for describing the complex diffusion process of water in brain tissue and has shown to be beneficial in clinical applications of Alzheimer's disease (AD). However, the FM model averaged the anomalous diffusion parameter values, which omitted the impacts of anisotropy. This study aimed to investigate the potential feasibility of anisotropy of anomalous diffusion using the FM model for distinguishing and grading AD patients.

    Methods: Twenty-four patients with AD and 11 matched healthy controls were recruited, diffusion MRI was obtained from all participants and analyzed using the FM model. Generalized fractional anisotropy (gFA), an anisotropy metric, was introduced and the gFA values of FM-related parameters, Noah exponent (α) and the Hurst exponent (H), were calculated and compared between the healthy group and AD group and between the mild AD group and moderate AD group. The receiver-operating characteristic (ROC) analysis and the multivariate logistic regression analysis were used to assess the diagnostic performances of the anisotropy values and the directionally averaged values.

    Results: The gFA(α) and gFA(H) values of the moderate AD group were higher than those of the mild AD group in left hippocampus. The gFA(α) value of the moderate AD group was significantly higher than that of the healthy control group in both the left and right hippocampus. The gFA(ADC) values of the moderate AD group were significantly lower than those of the mild AD group and healthy control group in the right hippocampus. Compared with the gFA(α), gFA(H), α, and H, the ROC analysis showed larger areas under the curves for combination of α + gFA(α) and the combination of H + gFA(H) in differentiating the mild AD and moderate AD groups, and larger area under the curves for combination of α + gFA(α) in differentiating the healthy controls and AD groups.

    Conclusion: The anisotropy of anomalous diffusion could significantly differentiate and grade patients with AD, and the diagnostic performance was improved when the anisotropy metric was combined with commonly used directionally averaged values. The utility of anisotropic anomalous diffusion may provide novel insights to profoundly understand the neuropathology of AD.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    Effects of Chronic Tinnitus on Metabolic and Structural Changes in Subjects With Mild Cognitive Impairment

    Tinnitus is a conscious auditory perception in the absence of an external stimulus. Despite previous reports of a recognized association between tinnitus and cognitive deficits, the effects of tinnitus on functional and structural brain changes associated with cognitive deficits remain unknown. We aimed to investigate the changes in glucose metabolism and gray matter (GM) volume in subjects diagnosed with mild cognitive impairment (MCI) depending on tinnitus. Twenty-three subjects were subclassified into MCI with the chronic tinnitus (MCI_T) and MCI without tinnitus (MCI_NT) groups. Encouraged by the identification of neural substrates associated with tinnitus and cognitive deficits, we correlated the extent of tinnitus severity with the changes in glucose metabolism and GM volume and conducted a glucose metabolic connectivity study. Compared to the MCI_NT group, the MCI_T group showed significantly lower metabolism in the right superior temporal pole and left fusiform gyrus. Additionally, the GM volume in the right insula was markedly lower in the MCI_T group compared to the MCI_NT group. Moreover, correlation analyses in metabolism or GM volumes revealed specific brain regions associated with the cognitive decline with increasing tinnitus severity. Metabolic connectivity analysis revealed that MCI_NT had markedly strengthened intra-hemispheric connectivity in the frontal, parietal, and occipital regions than did MCI_T. Furthermore, MCI_NT showed a strong negative association between the parietal and temporal and parietal and limbic regions, but the association was not observed in MCI_T. These findings indicate that tinnitus may cause metabolic and structural changes in the brain and alters complex inter- or intra-hemispheric networks in MCI. Considering the impact of MCI on accelerating dementia, these results provide a valuable basis on which yet-to-be-identified neurodegenerative markers of tinnitus can be refined.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease

    In the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    Disrupted Regional Cerebral Blood Flow and Functional Connectivity in Pontine Infarction: A Longitudinal MRI Study

    Abnormal cerebral blood flow (CBF) and resting-state functional connectivity (rs-FC) are sensitive biomarkers of disease progression and prognosis. This study investigated neural underpinnings of motor and cognitive recovery by longitudinally studying the changes of CBF and FC in pontine infarction (PI). Twenty patients underwent three-dimensional pseudo-continuous arterial spin labeling (3D-pcASL), resting-state functional magnetic resonance imaging (rs-fMRI) scans, and behavioral assessments at 1 week, 1, 3, and 6 months after stroke. Twenty normal control (NC) subjects underwent the same examination once. First, we investigated CBF changes in the acute stage, and longitudinal changes from 1 week to 6 months after PI. Brain regions with longitudinal CBF changes were then used as seeds to investigate longitudinal FC alterations during the follow-up period. Compared with NC, patients in the left PI (LPI) and right PI (RPI) groups showed significant CBF alterations in the bilateral cerebellum and some supratentorial brain regions at the baseline stage. Longitudinal analysis revealed that altered CBF values in the right supramarginal (SMG_R) for the LPI group, while the RPI group showed significantly dynamic changes of CBF in the left calcarine sulcus (CAL_L), middle occipital gyrus (MOG_L), and right supplementary motor area (SMA_R). Using the SMG_R as the seed in the LPI group, FC changes were found in the MOG_L, middle temporal gyrus (MTG_L), and prefrontal lobe (IFG_L). Correlation analysis showed that longitudinal CBF changes in the SMG_R and FC values between the SMG_R and MOG_L were associated with motor and memory scores in the LPI group, and longitudinal CBF changes in the CAL_L and SMA_R were related to memory and motor recovery in the RPI group. These longitudinal CBF and accompany FC alterations may provide insights into the neural mechanism underlying functional recovery after PI, including that of motor and cognitive functions.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    Perceptual Priming Can Increase or Decrease With Aging

    A decline in declarative or explicit memory has been extensively characterized in cognitive aging and is a hallmark of cognitive impairments. However, whether and how implicit perceptual memory varies with aging or cognitive impairment is unclear. Here, we compared implicit perceptual memory and explicit memory measures in three groups of participants: (1) 59 healthy young volunteers (20–30 years); (2) 269 healthy old volunteers (50–90 years) and (3) 21 patients with mild cognitive impairment, i.e., MCI (50–90 years). To measure explicit memory, participants were tested on standard recognition and recall tasks. To measure implicit perceptual memory, we used a classic perceptual priming paradigm. Participants had to report the shape of a visual search pop-out target whose color or position was varied randomly across trials. Perceptual priming was measured as the speedup in response time for targets that repeated in color or position. Our main findings are as follows: (1) Explicit memory was weaker in old compared to young participants, and in MCI patients compared to age- and education-matched controls; (2) Surprisingly, perceptual priming did not always decline with age: color priming was smaller in older participants but position priming was larger; (3) Position priming was less frequent in the MCI group compared to matched controls; (4) Perceptual priming and explicit memory were uncorrelated across participants. Thus, perceptual priming can increase or decrease with age or cognitive impairment, but these changes do not covary with explicit memory.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    Cognitive and Psychosocial Outcomes of Self-Guided Executive Function Training and Low-Intensity Aerobic Exercise in Healthy Older Adults

    Objectives

    Prior work has demonstrated that executive function training or physical exercise can improve older adults’ cognition. The current study takes an exploratory approach to compare the feasibility and efficacy of online executive function training and low-intensity aerobic exercise for improving cognitive and psychosocial functioning in healthy older adults.

    Method

    Following a standard pretest-training-posttest protocol, 40 older adults (aged 65 and above) were randomly assigned to an executive function or a physical training group. A battery of cognitive and psychosocial outcome measures were administered before and after training. During the 10 weeks of self-guided training at home (25–30 min/day, 4 days/week), the executive function training group practiced a set of adaptive online executive function tasks designed by Lumos Labs, whereas the physical training group completed an adaptive Digital Video Disc (DVD)-based low-intensity aerobic exercise program.

    Results

    Training transfer effects were limited. Relative to low-intensity aerobic exercise, executive function training yielded cognitive improvement on the 64-card Wisconsin Card Sorting Task (WCST-64), a general executive function measure. Depression and stress levels dropped following both training programs, but this could be driven by decreased stress or excitement in performing the tasks over time.

    Discussion

    The results revealed limited cognitive benefits of the online executive function training program, specifically to a near transfer test of general executive control. Importantly, the current study supports the feasibility of home-based self-guided executive function and low-intensity physical training with healthy older adults.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    Effects of Smoking on Regional Homogeneity in Mild Cognitive Impairment: A Resting-State Functional MRI Study

    Background

    Smoking is a modifiable risk factor for Alzheimer’s disease (AD). However, smoking-related effects on intrinsic brain activity in high-risk AD population are still unclear.

    Objective

    We aimed to explore differences in smoking effects on brain function between healthy elderly and amnestic mild cognitive impairment (aMCI) patients using ReHo mapping.

    Methods

    We identified 64 healthy elderly controls and 116 aMCI patients, including 98 non-smoking and 18 smoking aMCI. Each subject underwent structural and resting-state functional MRI scanning and neuropsychological evaluations. Regional homogeneity (ReHo) mapping was used to assess regional brain synchronization. After correction for age, gender, education, and gray matter volume, we explored the difference of ReHo among groups in a voxel-wise way based on analysis of covariance (ANCOVA), followed by post hoc two-sample analyses (p < 0.05, corrected). Further, we correlated the mean ReHo with neuropsychological scales.

    Results

    Three groups were well-matched in age, gender, and education. Significant ReHo differences were found among three groups, located in the left supramarginal gyrus (SMG) and left angular gyrus (AG). Specifically, non-smoking aMCI had lower ReHo in SMG and AG than smoking aMCI and controls. By contrast, smoking aMCI had greater AG ReHo than healthy controls (p < 0.05). Across groups, correlation analyses showed that left AG ReHo correlated with MMSE (r = 0.18, p = 0.015), clock drawing test (r = 0.20, p = 0.007), immediate recall (r = 0.36, p < 0.001), delayed recall (r = 0.34, p < 0.001), and auditory verbal learning test (r = 0.20, p = 0.007).

    Conclusion

    Smoking might pose compensatory or protective effects on intrinsic brain activity in aMCI patients.

    in Frontiers in Ageing Neuroscience on November 19, 2020 12:00 AM.

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    DeepPheno: Predicting single gene loss-of-function phenotypes using an ontology-aware hierarchical classifier

    by Maxat Kulmanov, Robert Hoehndorf

    Predicting the phenotypes resulting from molecular perturbations is one of the key challenges in genetics. Both forward and reverse genetic screen are employed to identify the molecular mechanisms underlying phenotypes and disease, and these resulted in a large number of genotype–phenotype association being available for humans and model organisms. Combined with recent advances in machine learning, it may now be possible to predict human phenotypes resulting from particular molecular aberrations. We developed DeepPheno, a neural network based hierarchical multi-class multi-label classification method for predicting the phenotypes resulting from loss-of-function in single genes. DeepPheno uses the functional annotations with gene products to predict the phenotypes resulting from a loss-of-function; additionally, we employ a two-step procedure in which we predict these functions first and then predict phenotypes. Prediction of phenotypes is ontology-based and we propose a novel ontology-based classifier suitable for very large hierarchical classification tasks. These methods allow us to predict phenotypes associated with any known protein-coding gene. We evaluate our approach using evaluation metrics established by the CAFA challenge and compare with top performing CAFA2 methods as well as several state of the art phenotype prediction approaches, demonstrating the improvement of DeepPheno over established methods. Furthermore, we show that predictions generated by DeepPheno are applicable to predicting gene–disease associations based on comparing phenotypes, and that a large number of new predictions made by DeepPheno have recently been added as phenotype databases.

    in PLoS Computational Biology on November 18, 2020 10:00 PM.

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    BioAFMviewer: An interactive interface for simulated AFM scanning of biomolecular structures and dynamics

    by Romain Amyot, Holger Flechsig

    We provide a stand-alone software, the BioAFMviewer, which transforms biomolecular structures into the graphical representation corresponding to the outcome of atomic force microscopy (AFM) experiments. The AFM graphics is obtained by performing simulated scanning over the molecular structure encoded in the corresponding PDB file. A versatile molecular viewer integrates the visualization of PDB structures and control over their orientation, while synchronized simulated scanning with variable spatial resolution and tip-shape geometry produces the corresponding AFM graphics. We demonstrate the applicability of the BioAFMviewer by comparing simulated AFM graphics to high-speed AFM observations of proteins. The software can furthermore process molecular movies of conformational motions, e.g. those obtained from servers which model functional transitions within a protein, and produce the corresponding simulated AFM movie. The BioAFMviewer software provides the platform to employ the plethora of structural and dynamical data of proteins in order to help in the interpretation of biomolecular AFM experiments.

    in PLoS Computational Biology on November 18, 2020 10:00 PM.

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    Systems biology informed deep learning for inferring parameters and hidden dynamics

    by Alireza Yazdani, Lu Lu, Maziar Raissi, George Em Karniadakis

    Mathematical models of biological reactions at the system-level lead to a set of ordinary differential equations with many unknown parameters that need to be inferred using relatively few experimental measurements. Having a reliable and robust algorithm for parameter inference and prediction of the hidden dynamics has been one of the core subjects in systems biology, and is the focus of this study. We have developed a new systems-biology-informed deep learning algorithm that incorporates the system of ordinary differential equations into the neural networks. Enforcing these equations effectively adds constraints to the optimization procedure that manifests itself as an imposed structure on the observational data. Using few scattered and noisy measurements, we are able to infer the dynamics of unobserved species, external forcing, and the unknown model parameters. We have successfully tested the algorithm for three different benchmark problems.

    in PLoS Computational Biology on November 18, 2020 10:00 PM.

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    Hippocampal cells integrate past memory and present perception for the future

    by Cen Yang, Yuji Naya

    The ability to use stored information in a highly flexible manner is a defining feature of the declarative memory system. However, the neuronal mechanisms underlying this flexibility are poorly understood. To address this question, we recorded single-unit activity from the hippocampus of 2 nonhuman primates performing a newly devised task requiring the monkeys to retrieve long-term item-location association memory and then use it flexibly in different circumstances. We found that hippocampal neurons signaled both mnemonic information representing the retrieved location and perceptual information representing the external circumstance. The 2 signals were combined at a single-neuron level to construct goal-directed information by 3 sequentially occurring neuronal operations (e.g., convergence, transference, and targeting) in the hippocampus. Thus, flexible use of knowledge may be supported by the hippocampal constructive process linking memory and perception, which may fit the mnemonic information into the current situation to present manageable information for a subsequent action.

    in PLoS Biology on November 18, 2020 10:00 PM.

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    A Transcriptome‐Based Drug Discovery Paradigm for Neurodevelopmental Disorders

    Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin‐associated proteins, transcription factors, and RNA‐binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called “transcriptome reversal” for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene‐expression signatures associated with disease states. ANN NEUROL 2020

    in Annals of Neurology on November 18, 2020 05:35 PM.

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    Functional connectivity with the anterior and posterior hippocampus during spatial memory

    Abstract

    Evidence of differential connectivity and activity patterns across the long‐axis of the hippocampus has led to many hypotheses about functional specialization of the anterior and posterior hippocampus, including a hypothesis linking the anterior hippocampus to memory encoding and the posterior hippocampus to memory retrieval. The hippocampal encoding/retrieval and network (HERNET) model of memory predicts that encoding should engage the anterior hippocampus and the attention network, whereas retrieval should engage the posterior hippocampus and the default network. In a previous fMRI study that employed multivoxel pattern analysis, we found that the patterns of activity in the anterior hippocampus predicted the quadrant of spatial memory encoding. In the current fMRI study, we investigated whether the spatial memory encoding activity in the anterior hippocampus and retrieval activity in the posterior hippocampus had a higher degree of connectivity to the attention network or the default network. During the study phase, abstract shapes were presented in each quadrant of the visual field and participants were instructed to remember each shape's location while maintaining central fixation. During the test phase, the same shapes were presented in the center of the screen and participants identified the previous location of each shape. Generalized psychophysiological interaction analyses were conducted between the anatomically defined anterior and posterior hippocampus and the rest of the brain. This revealed preferential connectivity between the anterior hippocampus and regions of the attention network during encoding and between the posterior hippocampus and regions of the default network during retrieval. In addition, there were location‐specific patterns of connectivity with the anterior hippocampus and posterior hippocampus during encoding and retrieval of right visual field items. These results suggest that the anterior and posterior hippocampus interact with regions of the attention network and default network during spatial memory encoding and retrieval, respectively, and support the HERNET model of memory.

    in Hippocampus on November 18, 2020 05:25 PM.

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    Distribution and morphology of P2X3‐immunoreactive subserosal afferent nerve endings in the rat gastric antrum

    Distribution and morphology of P2X3‐immunoreactive subserosal afferent nerve endings in the rat gastric antrum

    P2X3‐immunoreactive subserosal afferent nerve endings in the rat antral lesser curvature were revealed by immunohistochemistry of whole‐mount preparations with confocal scanning laser microscopy. The immunoreactive nerve endings consisted of web‐like complex terminal structures and peripheral variform axon terminals. The nerve endings may have morphological characteristics of mechanoreceptors for detecting a mechanical deformation of the antral wall associated with antral peristalsis.


    Abstract

    The present study investigated the morphological characteristics of subserosal afferent nerve endings with immunoreactivity for the P2X3 purinoceptor (P2X3) in the rat stomach by immunohistochemistry of whole‐mount preparations using confocal scanning laser microscopy. P2X3 immunoreactivity was observed in subserosal nerve endings proximal and lateral to the gastric sling muscles in the distal antrum of the lesser curvature. Parent axons ramified into several lamellar processes to form net‐like complex structures that extended two‐dimensionally in every direction on the surface of the longitudinal smooth muscle layer. The axon terminals in the periphery of P2X3‐immunoreactive net‐like structures were flat and looped or leaf‐like in shape. Some net‐like lamellar structures and their axon terminals with P2X3 immunoreactivity were also immunoreactive for P2X2. P2X3‐immunoreactive nerve fibers forming net‐like terminal structures were closely surrounded by S100B‐immunoreactive terminal Schwann cells, whereas axon terminals twined around these cells and extended club‐, knob‐, or thread‐like protrusions in the surrounding tissues. Furthermore, a retrograde tracing method using fast blue dye indicated that most of these nerve endings originated from the nodose ganglia of the vagus nerve. These results suggest that P2X3‐immunoreactive subserosal nerve endings have morphological characteristics of mechanoreceptors and contribute to sensation of a mechanical deformation of the distal antral wall associated with antral peristalsis.

    in Journal of Comparative Neurology on November 18, 2020 03:36 PM.

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    Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options

    Abstract

    Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia‐ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long‐term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti‐inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.

    in Journal of Neuroscience Research on November 18, 2020 10:38 AM.

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    Henry Colecraft

    Nature Methods, Published online: 18 November 2020; doi:10.1038/s41592-020-01012-3

    A soccer striker and his ion channel rescue tools.

    in Nature Methods on November 18, 2020 12:00 AM.

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    Astaxanthin protects cognitive function of vascular dementia

    The purpose of this study was to evaluate the effect of astaxanthin (AST) on cognition function, inflammatory response and oxidative stress in vascular dementia (VD) mice.

    in Behavioural and Brain Functions on November 18, 2020 12:00 AM.

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    Budgerigars have complex sleep structure similar to that of mammals

    by Sofija V. Canavan, Daniel Margoliash

    Birds and mammals share specialized forms of sleep including slow wave sleep (SWS) and rapid eye movement sleep (REM), raising the question of why and how specialized sleep evolved. Extensive prior studies concluded that avian sleep lacked many features characteristic of mammalian sleep, and therefore that specialized sleep must have evolved independently in birds and mammals. This has been challenged by evidence of more complex sleep in multiple songbird species. To extend this analysis beyond songbirds, we examined a species of parrot, the sister taxon to songbirds. We implanted adult budgerigars (Melopsittacus undulatus) with electroencephalogram (EEG) and electrooculogram (EOG) electrodes to evaluate sleep architecture, and video monitored birds during sleep. Sleep was scored with manual and automated techniques, including automated detection of slow waves and ey