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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2022

Improved production and expanded application of CVS-N2c-ΔG virus for retrograde tracing

Neurotropic virus tracers, particularly those with low toxicity and high efficient tracing, are powerful tools for structural and functional dissections of neural circuits. The retrograde trans-mono-synaptic technology based on rabies virus CVS-N2c strain has reduced cytotoxicity and enhanced efficiency, attains long-term gene manipulation for functional studies, but suffers from difficult preparation and low yield. To overcome these shortcomings, an improved production system was established for rapid rescue and preparation of CVS-N2c-{Delta}G virus, CVS-N2c-{Delta}G with the same titer as SAD-B19-{Delta}G can be prepared within a short time. Meanwhile, we found that N2cG coated CVS-N2c-{Delta}G allows efficient retrograde access to projection neurons, and further expand its application in VTA/SNc to DLS pathway that unaddressed by rAAV9-Retro, and the efficiency is 6 folds higher than that of rAAV9-Retro. Then the trans-synaptic efficiency of CVS-N2c-{Delta}G virus was evaluated. Results showed that the trans-mono-synaptic efficiency of oG-mediated CVS-N2c-{Delta}G was 2-3 folds higher than that of oG-mediated SAD-B19-{Delta}G, but there was no difference between oG-mediated and N2cG-mediated CVS-N2c-{Delta}G system. In addition, codon modified N2cG (optiG) did not increase the efficiency of CVS-N2c-{Delta}G tracing. Finally, we found that the CVS-N2c-{Delta}G produced by the improved method can be used for monitoring neural activity of projection neurons, and the time window can be maintained for 3 weeks, and it can also express sufficient recombinases for efficient transgene recombination. That is, the virus produced by the improved production system does not affect its own function, paving the way for its further optimization, popularization and application in structural and functional studies of neural circuits.

neuroscience↗
bioRxiv2024

Chronic intermittent alcohol yields sex-specific disruptions in cortical-striatal-limbic oscillations

BackgroundWhile the neurobiology of alcohol use disorder (AUD) has been extensively researched, the vast majority of these studies included only male organisms. However, there are significant sex differences in both the causes and consequences of alcohol misuse and dependence, suggesting sex-specific neurobiological mechanisms. The current study used a rodent model to determine whether chronic alcohol exposure impacts sex-specific neural circuits, and whether these changes contribute to the development of alcohol misuse. MethodsMale and female Sprague-Dawley rats were trained to self-administer 10% alcohol before implanting bilateral electrodes into the infralimbic medial prefrontal cortex (IL), nucleus accumbens shell (NAcSh), and central nucleus of the amygdala (CeA). Half of the rats were then exposed to four weeks of chronic intermittent alcohol (CIA) vapor (14 hours on/10 hours off). During acute withdrawal (6-8 after the vapor turns off), local field potentials (LFPs) were recorded from the IL, NAcSh, and CeA during 30-minute self-administration sessions. Using an unbiased machine learning approach, we built predictive models to determine whether/which LFP features could distinguish CIA-exposed from control rats in each sex, as well as if any of these LFP features correlated with rates of alcohol self-administration. ResultsFemale rats self-administered more alcohol in general compared to males, but only males exposed to CIA showed increased alcohol intake during acute withdrawal. LFPs predicted CIA exposure in both sexes better than chance estimates, but models built on IL and NAcSh oscillations performed the best in males, while models built on IL and CeA LFPs performed best in females. High {gamma} LFPs recorded in the NAcSh correlated with rates of alcohol self-administration in males exposed to CIA, while only left-right NAcSh {beta} coherence correlated with drinking in control females. ConclusionsThese data provide support for the hypothesis that the neural circuits driving alcohol dependence development are sex-specific, and that high frequency oscillations in the NAcSh may be related to the increased drinking observed in males exposed to CIA. Overall, these data add to our understanding of the neurobiological underpinnings behind the sex differences observed in AUD and offer promising biomarkers for future therapeutic research.

neuroscience↗
bioRxiv2022

Hemodynamic transient and functional connectivity follow structural connectivity and cell type over the brain hierarch

The neural circuit of the brain is organized as a hierarchy of functional units with wide-ranging connections that support information flow and functional connectivity. Studies using magnetic resonance imaging (MRI) indicate a moderate coupling between structural and functional connectivity at the system level. However, how do connections of different directions (feedforward and feedback) and regions with different excitatory and inhibitory (E/I) neurons shape the hemodynamic activity and functional connectivity over the hierarchy are unknown. Here, we used functional MRI to detect optogenetic-evoked and resting-state activities over a somatosensory pathway in the mouse brain in relation to axonal projection and E/I distribution. Using a highly sensitive ultrafast imaging, we identified extensive activation in regions up to the third order of axonal projections following optogenetic excitation of the ventral posteriomedial nucleus of the thalamus. The evoked response and functional connectivity correlated with feedforward projections more than feedback projections and weakened with the hierarchy. The hemodynamic response exhibited regional and hierarchical differences, with slower and more variable responses in high-order areas and bipolar response predominantly in the contralateral cortex. Importantly, the positive and negative parts of the hemodynamic response correlated with E/I neuronal densities, respectively. Furthermore, resting-state functional connectivity was more associated with E/I distribution whereas stimulus-evoked effective connectivity followed structural wiring. These findings indicate that the structure-function relationship is projection-, cell-type- and hierarchy-dependent. Hemodynamic transients could reflect E/I activity and the increased complexity of hierarchical processing. Significance StatementThe neural circuit of the brain is organized as a hierarchy of functional units with complicated feedforward and feedback connections to selectively enhance (excitation) or suppress (inhibit) information from massive sensory inputs. How brain activity is shaped by the structural wiring and excitatory and inhibitory neurons is still unclear. We characterize how brain-wide hemodynamic responses reflect these structural constituents over the hierarchy of a somatosensory pathway. We find that functional activation and connectivity correlate with feedforward connection strengths and neuronal distributions. This association subsides with hierarchy due to slower and more variable hemodynamic responses, reflecting increased complexity of processing and neuronal compositions in high-order areas. Our findings indicate that hemodynamics follow the hierarchy of structural wiring and neuronal distribution.

neuroscience↗
bioRxiv2025

Endothelial Adgrl2 expression and alternative splicing controls the cerebrovasculature

Central nervous system development requires parallel but interrelated processes of neural circuit assembly and vascularization. Intersecting between these two processes, the cell-adhesion G-protein coupled receptor Adgrl2 is expressed in select neuron populations where it has been found to localize and control the assembly of specific synaptic sites. Further, Adgrl2 is found to be expressed in select non-neuronal brain cells, where it is restricted to endothelial cells. Testing for Adgrl2 function in these cells, here we find that endothelial cell specific Adgrl2 deletion results in an impairment in cerebrovascular integrity. To understand how it might be possible for Adgrl2 to function independently in neuronal and endothelial contexts, we analyzed single-cell RNA sequencing datasets for differences in transcriptional identity between these cell classes. Doing so, we find that expression of Adgrl2 mRNA is subject to robust cell type-specific alternative splicing, resulting in distinct isoforms being produced in neurons compared to endothelial cells. Investigating the functional implication of this cell type-specific alternative splicing, we find that forced expression of the neuronal isoform of Adgrl2 in endothelial cells leads to alterations in cerebrovascular properties. Morphologically, endothelial cells with the non-native neuronal Adgrl2 isoform induce the formation of ectopic glutamatergic synaptic contacts onto endothelial cells, indicating alterations in the cell-cell recognition process. Functionally, in direct contrast to endothelial Adgrl2 deletion, this genetic expression switch instead enhances blood-brain barrier integrity. This overly restrictive cerebrovascular function results in dysregulation of blood to cerebrospinal fluid homeostasis, enlargement of brain ventricles, and a higher risk of hydrocephalus. As such, alternative splicing serves as a cell type specific mechanism that provides isoform specific Adgrl2 for discerning functions controlling neural circuit assembly and cerebrovascular homeostasis.

neuroscience↗
bioRxiv2026

Branch-specific axon pruning induced by Dpr4/DIP-{Theta} transneuronal interactions

Neuronal remodeling is a conserved, late developmental mechanism to refine neural circuits. Although remodeling typically occurs with remarkable spatiotemporal precision, its underlying molecular mechanisms remain poorly understood. In the Drosophila mushroom body (MB) circuit, {gamma}-Kenyon cells ({gamma}-KCs) undergo stereotyped remodeling during metamorphosis, in which they prune their larval vertical and medial axonal branches and subsequently regrow a medial, adult-specific branch. Our previous transcriptional profiling of developing {gamma}-KCs revealed dynamic expression of Defective proboscis extension response (Dpr) proteins and their binding partners, Dpr-interacting proteins (DIPs), members of the Immunoglobulin (Ig) superfamily. Despite their established roles in neurodevelopment, how Dpr/DIPs function - given their lack of intracellular domains - remains unclear. Here, we show that overexpression of Dpr4 in developing {gamma}-KCs cell-autonomously inhibits axon pruning. Strikingly, this effect is branch-specific: the vertical axonal branch fails to prune, while the medial branch prunes normally. To our knowledge, this represents the first demonstration of branch-specific control of pruning in this system. Moreover, the adult medial branch regrows normally, indicating that pruning and regrowth are independently regulated at the level of individual branches. We demonstrate that this unique branch-specificity arises from trans-neuronal interactions between Dpr4 in {gamma}-KCs and DIP-{theta} in dopaminergic neurons that selectively innervate the vertical larval MB lobe. Furthermore, our findings suggest that this phenotype relies on an Ig2 domain of a Dpr family member, implying the involvement of a third binding partner. Leveraging this robust overexpression phenotype to probe downstream mechanisms, we find that loss of the transmembrane adhesion protein N-Cadherin suppresses the Dpr4-induced pruning defect. Together, our findings highlight the local impact of Dpr/DIP-mediated trans-neuronal interactions on the spatial regulation of remodeling, and provide genetic evidence implicating N-Cadherin as a potential downstream mediator of Dpr/DIP function within a developing neural circuit.

neuroscience↗
bioRxiv2026

ConnectoFM: A Foundation Model for Learning the Language of the Connectome

Accurate reconstruction of neural circuits from electron microscopy (EM) data is central to connectomics, yet modern datasets are now so large and heterogeneous that manual annotation and dataset-specific model retraining have become major challenges. While recent EM foundation models provide general visual representations, they are not specifically tailored to the connectomics domain, where preserving fine membrane boundaries and synaptic structures is essential to mitigate topological and connectivity errors. Here, we present ConnectoFM, the first foundation model for connectomics, pretrained on a diverse corpus of 1.7 million unlabeled EM images drawn from six species and 25 subdomains. ConnectoFM combines masked image modeling with contrastive alignment to learn robust visual representations directly from large-scale connectomics data. These representations organize EM images into biologically meaningful clusters across species, brain regions, developmental cohorts, and acquisition domains. Using frozen pretrained features with lightweight decoder heads, we transfer ConnectoFM to three important downstream tasks: binary segmentation, multiclass cell typing, and instance segmentation. Across 29 diverse datasets, including established benchmarks, ConnectoFM consistently outperforms existing EM foundation models and state-of-the-art methods that require task-specific training from scratch. With only 10% labeled data, ConnectoFM surpasses the baselines trained on 100% annotation budget, showing the superiority of ConnectoFM in low-data regimes. Improvements of ConnectoFM are especially pronounced for challenging and biologically important targets, including membranes, mitochondria, vesicles, post-synaptic densities and synapses, and remain strong in low-label settings. Extension to 3D volumetric segmentation and qualitative comparisons further show that ConnectoFM enables more accurate and biologically faithful performance across downstream tasks. These results establish ConnectoFM as a generalizable and data-efficient foundation model for connectomics and provide a scalable route towards more reliable neural circuit reconstruction.

neuroscience↗
bioRxiv2024

Cholinergic interneurons of the dorsomedial striatum mediate winner-loser effects on social hierarchy dynamics in male mice.

Cholinergic interneurons of the dorsomedial striatum may play a role in social hierarchy dynamics. A social hierarchy is an organization of individuals by rank that occurs in social animals. Establishing a new social hierarchy involves flexible behavior in deciding whether to be a winner or loser, experience of winning or losing, and stabilization of rank. The neural circuits underlying such flexible behavior have yet to be fully understood, but previous research indicates that cholinergic interneurons in the dorsomedial striatum play a role in behavioral flexibility. We used the dominance tube test to measure ranking within group housed mice, before and after between-cage competitions using the same test. We found that the experience of winning or losing against mice from different cages not only contributes to new social hierarchies among the competitors, but also causally influences the subsequent social hierarchy among their cage mates in the home cage - supporting the hypothesis of winner-loser effects on later social ranking. To test the hypothesis that cholinergic interneurons contribute to social hierarchy dynamics, we made a selective lesion of cholinergic interneurons in the dorsomedial striatum. The lesion did not prevent social hierarchy formation among pairs of similarly ranked individuals from different cages. However, it reduced the loser effect of external competition on the subsequent home-cage rankings in dominant mice. In light of these results we suggest that cholinergic interneurons in dorsomedial striatum increase the flexibility of social hierarchy dynamics. Significance statementThe effect of winning or losing a competition on subsequent ranking in mouse home cage social hierarchies was examined using the dominance tube test. We found that losing, when dominant mice were defeated by equally ranked mice from another cage, led to decreased social rank in their home cage. Conversely, winning by initially subordinate mice led to increased rank in the home cage social hierarchy. The loser effect on subsequent behavior in dominant mice was reduced after selective lesions of the cholinergic interneurons of the dorsomedial striatum. We suggest that losing might produce these effects by altering the activity of cholinergic interneurons, and thus modulating synaptic plasticity in neural circuits involved in flexible decision making and positive reinforcement.

neuroscience↗
bioRxiv2023

HCN channels enhance robustness of patterned activity propagation in heterogeneous conductance-based ring networks

Continuous attractor network (CAN) models lend a powerful framework that has provided deep insights about several aspects of brain physiology. However, most CAN models employ homogeneous, rate-based or artificially spiking neurons with precisely structured synaptic connectivity, precluding detailed analyses of the impact of specific neural-circuit components and associated heterogeneities on CAN dynamics. To address this caveat, we built populations of tunable and scalable conductance-based, physiologically constrained, ring network models consisting of distinct rings of excitatory and inhibitory neurons. We assessed the network for its ability to sustain robust propagation of patterned activity across the rings. First, in homogeneous ring networks, we found that robust activity propagation could be sustained through several different combinations of synaptic weights, demonstrating synaptic degeneracy in the emergence of robust activity propagation. We incorporated intrinsic heterogeneity through randomized perturbations to ion channel parameters of all neurons and synaptic heterogeneity by adding jitter to the Mexican-hat connectivity between inhibitory neurons. We found the number of networks exhibiting robust propagation of patterned activity to reduce with increase in the degree of synaptic or intrinsic heterogeneities. Motivated by the ability of intrinsic neuronal resonance to stabilize heterogeneous rate-based CAN models, we hypothesized that increasing HCN-channel (a resonating conductance) density would stabilize activity propagation in heterogeneous ring networks. Strikingly, we observed that increases in HCN-channel density resulted in a pronounced increase in the proportion of heterogeneous networks that exhibited robust activity propagation, across multiple trials and across three degrees of either form of heterogeneity. Together, heterogeneous networks made of neurons with disparate intrinsic properties and variable HCN channel densities yielded robust activity propagation, demonstrating intrinsic degeneracy in the emergence of robust activity propagation. Finally, as HCN channels also contribute to changes in excitability, we performed excitability-matched controls with fast HCN channels that do not introduce resonance. We found that fast HCN channels did not stabilize heterogeneous network dynamics over a wide range of conductance values, suggesting that the slow negative feedback loop introduced by HCN channels is a critical requirement for network stabilization. Together, our results unveil a cascade of degeneracy in ring-network physiology, spanning the molecular-cellular-network scales. These results also demonstrate a critical role for the widely expressed HCN channels in enhancing the robustness of heterogeneous neural circuits by implementing a slow negative feedback loop at the cellular scale.

neuroscience↗
bioRxiv2019

Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study

BackgroundA variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking. Methods258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments. Outcomes79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls): the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait). InterpretationThe 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry. FundingThe Medical Research Council and the Medical Research Foundation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeveral copy number variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included "CNV", "genomics", "1q21.1", "2p16.3", "NRXN1", "9q34", "Kleefstra Syndrome", "15q11.2", "15q13.3", "16p11.2", "22q11.2", "psychiatry", and "cognition". Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains. Added value of this studyWe found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention) whereas for other traits there was evidence of genotype specific effects on severity (e.g., IQ, spatial planning, processing speed, subclinical psychotic experiences, ASD traits, motor coordination total psychiatric symptomatology, particularly anxiety, ADHD, and conduct related traits). However the proportion of variance explained by genotype was low, 5-20% depending on trait, indicating that overall ND-CNVs lead to similar neurodevelopmental outcomes. It is important that genotype-phenotype relationships are viewed through a developmental lens as some phenotypic outcomes were found to be associated with age. Implications of all the available evidenceChildren who carry a ND-CNV represent a patient group that warrants clinical and educational attention for a broad range of cognitive and behavioural impairments. Although qualitative and quantitative differences exist between ND-CNVs, our findings point to commonalities in clinical outcomes with neurodevelopmental impairments being present across all ND-CNVs. This group of young people could benefit from the development of a general intervention plan, to which genotype-specific recommendations can be added where needed. Our findings do not support a model whereby different ND-CNVs represent discrete forms of neuropsychiatric disorder and suggest that multiple processes and neural circuits are affected by ND-CNVs. The pleiotropic effects of ND-CNVs emphasises that research aiming to identify causal pathways between genetic variation and psychiatric outcomes via intermediary (or endo-)phenotypes needs to take a global perspective and not be narrowly focused on single phenotypes.

genomics↗
bioRxiv2021

Fast photoswitchable molecular prosthetics control neuronal activity in the cochlea

Artificial control of neuronal activity enables studies of neural circuits and restoration of neural function. Direct, rapid, and sustained photocontrol of intact neurons could overcome shortcomings of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors to establish such control in the auditory system. The new photoswitchable ligands produced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with visible light pulses of few milliseconds. As a proof of concept of these molecular prostheses, we apply them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method affords kilohertz rate stimulation of auditory neurons of adult gerbils without genetic manipulation that would be required for their optogenetic control. The new photoswitchable ligands are also broadly applicable to spatiotemporally control fast spiking interneurons in the brain.

neuroscience↗
bioRxiv2022

Specialized neuronal modules for economic and single-attribute choice in the orbitofrontal cortex

An important component of biological intelligence lies in the capacity to learn and execute various cognitive tasks. This ability may be facilitated by a neural system comprising functionally dissociable neuronal modules. Within the orbitofrontal cortex (OFC) lies a neural circuit that supports economic decision-making across diverse contexts. To investigate the functional specialization of this circuit, we compared the neural activity of OFC neurons in rhesus monkeys during multi-attribute choice (MC) and single-attribute choice (SC) tasks. In MC, the monkeys made subjective tradeoffs between competing attributes, whereas in SC, choices were deterministic based on a single attributes value. Neuronally, in MC, OFC neurons primarily encoded offer value, chosen value, and choice in goods space. Upon transitioning from MC to SC, a significant portion of MC-modulated neurons disengaged, while a separate set of neurons emerged to encode SC-related variables in a spatial reference frame. Notably, we observed the clustering of value-encoding neurons in MC but not SC. In essence, our findings suggest that choice tasks involving different mental processes are represented by dissociable neuronal modules within the OFC.

neuroscience↗
bioRxiv2022

Brain mechanism of foraging: reward-dependentsynaptic plasticity or neural integration of values?

During foraging behavior, action values are persistently encoded in neural activity and updated depending on the history of choice outcomes. What is the neural mechanism for action value maintenance and updating? Here we explore two contrasting network models: synaptic learning of action value versus neural integration. We show that both models can reproduce extant experimental data, but they yield distinct predictions about the underlying biological neural circuits. In particular, the neural integrator model but not the synaptic model requires that reward signals are mediated by neural pools selective for action alternatives and their projections are aligned with linear attractor axes in the valuation system. We demonstrate experimentally observable neural dynamical signatures and feasible perturbations to differentiate the two contrasting scenarios, suggesting that the synaptic model is a more robust candidate mechanism. Overall, this work provides a modeling framework to guide future experimental research on probabilistic foraging.

neuroscience↗
bioRxiv2022

Neuron secreted chemokine-like Orion is involved in the transformation of glial cells into phagocytes in different neuronal remodeling paradigms

During animal development, neurons often form exuberant or incorrect axons and dendrites at early stages, followed by the refinement of neuronal circuits at late stages. Neural circuit refinement leads to the production of large amounts of neuronal debris in the form of neuronal cell corpses, fragmented axons and dendrites, and pruned synapses requiring disposal. In particular, the predominant phagocytes acting during the neuronal remodeling and degeneration are glial cells and critical signaling pathways between neurons and glia leading to phagocytosis are required. Chemokine-like mushroom body neuron secreted Orion ligand was shown to be essential to the astrocyte infiltration into the {gamma} axon bundle leading to {gamma} axon pruning and clearance of debris left from axon fragmentation. Here we show a role of orion also in debris engulfment and phagocytosis. Interestingly, we show that orion is also involved in the overall transformation of astrocytes into phagocytes. In addition, analysis of several neuronal paradigms demonstrates the role of orion in the elimination of both peptidergic vCrz+ and PDF-Tri neurons via additional phagocytic glial cells as cortex and/or ensheathing glia. Our results suggest that Orion is essential for phagocytic activation of three different types of glial cells: astrocytes, cortex and ensheathing glia and point to Orion as a trigger not only of glial infiltration but also engulfment and phagocytosis.

neuroscience↗
bioRxiv2024

DIETARY REGULATION OF SILENT SYNAPSES IN THE DORSOLATERAL STRIATUM

Obesity and drugs of abuse share overlapping neural circuits and behaviors. Silent synapses are transient synapses that are important for remodeling brain circuits. They are prevalent during early development but largely disappear by adulthood. Drugs of abuse increase silent synapses during adulthood and may facilitate reorganizing brain circuits around drug-related experience, facilitating addiction and contributing to relapse during treatment and abstinence. Whether obesity causes alterations in the expression of silent synapses in a manner similar to drugs of abuse has not been examined. Using a dietary-induced obesity paradigm, mice that chronically consumed high fat diet (HFD) exhibited increased silent synapses in both direct and indirect pathway medium spiny neurons in the dorsolateral striatum. Both the time of onset of increased silent synapses and their normalization upon discontinuation of HFD occurs on an extended time scale compared to drugs of abuse. These data demonstrate that chronic consumption of HFD, like drugs of abuse, can alter mechanisms of circuit plasticity likely facilitating neural reorganization analogous to drugs of abuse.

neuroscience↗
bioRxiv2024

Bidirectional valence coding in amygdala intercalated clusters:A neural substrate for the opponent-process theory of motivation

Processing emotionally meaningful stimuli and eliciting appropriate valence-specific behavior in response is a critical brain function for survival. Thus, how positive and negative valence are represented in neural circuits and how corresponding neural substrates interact to cooperatively select appropriate behavioral output are fundamental questions. In previous work, we identified that two amygdala intercalated clusters show opposite response selectivity to fear- and anxiety-inducing stimuli - negative valence (Hagihara et al. 2021). Here, we further show that the two clusters also exhibit distinctly different representations of stimuli with positive valence, demonstrating a broader role of the amygdala intercalated system beyond fear and anxiety. Together with the mutually inhibitory connectivity between the two clusters, our findings suggest that they serve as an ideal neural substrate for the integrated processing of valence for the selection of behavioral output.

neuroscience↗
bioRxiv2019

Nitric Oxide Mediates Neuro-Glial Interaction that Shapes Drosophila Circadian Behavior

Drosophila circadian behavior relies on the network of heterogeneous groups of clock neurons. Short -and long-range signaling within the pacemaker circuit coordinates molecular and neural rhythms of clock neurons to generate coherent behavioral output. The neurochemistry of circadian behavior is complex and remains incompletely understood. Here we demonstrate that the gaseous messenger nitric oxide (NO) is a signaling molecule linking circadian pacemaker to rhythmic locomotor activity. We show that two independent mutants lacking nitric oxide synthase (NOS) have severely disturbed locomotor behavior both in light-dark cycles and constant darkness, although molecular clocks in the main pacemaker neurons are unaffected. Behavioral phenotypes are due in part to the malformation of neurites of the main pacemaker neurons, s-LNvs. Using cell-type selective and stage-specific gain -and loss-of-function of NOS, we demonstrate that NO secreted from diverse cellular clusters non-cell-autonomously affect molecular and behavioral rhythms. We further identify glia as a major source of NO that regulates circadian locomotor output. These results reveal for the first time the critical role of NO signaling in the Drosophila circadian system and highlight the importance of neuro-glial interaction in the neural circuit output.\n\nAuthor summaryCircadian rhythms are daily cycles of physiological and behavioral processes found in most plants and animals on our planet from cyanobacteria to humans. Circadian rhythms allow organisms to anticipate routine daily and annual changes of environmental conditions and efficiently adapt to them. Fruit fly Drosophila melanogaster is an excellent model to study this phenomenon, as its versatile toolkit enables the study of genetic, molecular and neuronal mechanisms of rhythm generation. Here we report for the first time that gasotransmitter nitric oxide (NO) has a broad, multi-faceted impact on Drosophila circadian rhythms, which takes place both during the development and the adulthood. We also show that one of the important contributors of NO to circadian rhythms are glial cells. The second finding highlights that circadian rhythms of higher organisms are not simply controlled by the small number of pacemaker neurons but are generated by the system that consists of many different players, including glia.

neuroscience↗
bioRxiv2023

The structure and function of neural connectomes are shaped by a small number of design principles

The map of synaptic connectivity among neurons in the brain shapes the computations that neural circuits may perform. Inferring the design principles of neural connectomes is, therefore, fundamental for understanding brain development and architecture, neural computations, learning, and behavior. Here, we learn probabilistic generative models for the connectomes of the olfactory bulb of zebrafish, part of the mouse visual cortex, and of C. elegans. We show that, in all cases, models that rely on a surprisingly small number of simple biological and physical features are highly accurate in replicating a wide range of properties of the measured circuits. Specifically, they accurately predict the existence of individual synapses and their strength, distributions of synaptic indegree and outdegree of the neurons, frequency of sub-network motifs, and more. Furthermore, we simulate synthetic circuits generated by our model for the olfactory bulb of zebrafish and show that they replicate the computation that the real circuit performs in response to olfactory cues. Finally, we show that specific failures of our models reflect missing design features that we uncover by adding latent features to the model. Thus, our results reflect surprisingly simple design principles of real connectomes in three different systems and species, and offer a novel general computational framework for analyzing connectomes and linking structure and function in neural circuits.

neuroscience↗
bioRxiv2021

A model of rapid homeostatic plasticity accounts for hidden, long-lasting changes in a neuronal circuit after exposure to high potassium.

Neural circuits must both function reliably and flexibly adapt to changes in their environment. We studied how both biological neurons and computational models respond to high potassium concentrations. Pyloric neurons of the crab stomatogastric ganglion (STG) initially become quiescent, then recover spiking activity in high potassium saline. The neurons retain this adaptation and recover more rapidly in subsequent high potassium applications, even after hours in control saline. We constructed a novel activity-dependent computational model that qualitatively captures these results. In this model, regulation of conductances is gated on and off depending on how far the neuron is from its target activity. This allows the model neuron to retain a trace of past perturbations even after it returns to its target activity in control conditions. Thus, perturbation, followed by recovery of normal activity, can hide cryptic changes in neuronal properties that are only revealed by subsequent perturbations.

neuroscience↗