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Results for “neuroscience”

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bioRxiv2026

Dendritic hotspots support switching between competing rules without expanding the cortical engram

Adaptive behavior requires updating responses when contingencies change while preserving prior associations and the capacity to learn a new. How this trade-off is resolved remains unknown. Here, we combined in vivo imaging of apical tuft spines in the secondary motor cortex (M2) with biologically constrained network modeling in mice performing a cross-modal rule-switch task. M2 inactivation impaired rule-switching but not learning or maintenance, identifying it as a conflict resolution substrate. Adaptation was accompanied by elevated spine turnover concentrated within stable dendritic hotspots, in which the formation, elimination and clustering of new spines were coupled and pre-existing spines were lost early. A network model reproduces these dynamics and predicts that dendritic hotspots are critical for resource-efficient adaptation. Within these reusable domains, spines encoding the prior rule are replaced by newly-relevant ones via sharing of plasticity-related resources. Preventing reuse increases both the plasticity and the engram size requirements to encode the two rules. We propose that dendritic hotspots provide a mechanistic substrate for efficient adaptive learning.

neuroscience↗

bioRxiv2026

An egocentric map prioritizing peri-personal space in the mouse rostro-lateral visual area

All physical interactions between an organism and its environment occur within the space immediately adjacent to and surrounding its body, its peripersonal space (PPS). This space has been extensively studied behaviorally in humans, and through sparse single-neuron recordings in primates. However, how PPS is represented and organized at cellular and circuit scales remains poorly understood. Here, using dense extracellular recordings in the mouse rostro-lateral visual cortex (VISrl; >19,000 single units), we reveal the cellular and circuit organization of PPS in mice. Visuo-tactile neurons prioritize near-body space while also representing farther space in a direction-selective manner, tracking approaching but not receding objects across the environment. VISrl PPS neurons integrate vision and touch nonlinearly, and their tactile responses are progressively facilitated as visual objects near the body. PPS neurons are embedded in structured networks characterized by "like-to-like" functional connectivity and remap according to recent visuo-tactile statistics. Together, these findings establish VISrl as a circuit-accessible substrate for PPS, and reveal how near-body space is represented by a dynamic, plastic, multisensory cortical network.

neuroscience↗

bioRxiv2026

Spacing theta-burst stimulation enhances synaptic potentiation in the vulnerable prefrontal cortex

Neuromodulation with intermittent theta-burst stimulation (iTBS) is a clinical treatment for major depression. One postulated mechanism of iTBS is to strengthen the synaptic connections which activate the prefrontal cortex to regulate mood. With ex vivo electrical stimulation and neuronal calcium imaging, we demonstrate that a common, clinical iTBS pattern (600-stimuli, ~3-min) reliably strengthens the synaptic recruitment of the adult mouse prefrontal cortex. This synaptic potentiation, however, becomes less reliable in the depressive-like mouse model of prolonged social isolation. Examining the complex calcium elevations during clinical iTBS reveals that the induction peaks rise higher in social isolation but no longer predict the synaptic potentiation outcome. To better regulate calcium dynamics during induction, we test a paradigm with fewer iTBS episodes, separated by longer intervals. This spaced iTBS (90-stimuli, ~10-min) in the adult prefrontal cortex limits calcium elevation during induction and yields greater long-term potentiation (LTP) following either juvenile- or adult-onset social isolation. This research illustrates new strategies to interrogate and to enhance synaptic plasticity in the vulnerable prefrontal cortex.

neuroscience↗

bioRxiv2026

Stronger brain responses to acute stress reflect greater everyday stress variability

Laboratory stress tasks are widely used to assess individual differences in acute stress reactivity, yet it remains unclear how these responses correspond to stress experienced in everyday life. Here, we combined the Montreal imaging stress task (MIST) with ecological momentary assessment (EMA) over three months to assess acute and everyday stress in 67 healthy women. Greater within-person variability in everyday stress, but not average stress levels, were associated with stronger overall stress-related brain responses (b = 0.73, p = .039), with a whole-brain association particularly evident in the bilateral caudate (rROI = .32, pcluster.FWE < .001). Greater everyday stress variability was also associated with stronger stress-related functional connectivity between the ventromedial prefrontal cortex (vmPFC) and parietal and posterior medial regions (pcluster.FWE < .001). We conclude that acute neural stress responses relate more closely to fluctuations in perceived stress than to how stressed an individual feels on average. This suggests that laboratory stress tasks capture acute stress responsivity that is distinct from average stress exposure, highlighting the importance of considering what these tasks measure when interpreting individual differences in acute stress responses.

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bioRxiv2026

VDAC1 regulates stress-associated matrix localization of DJ-1 to support mitochondrial homeostasis and neuronal survival

DJ-1 is a redox-sensitive protein implicated in early-onset Parkinson's disease, and its mitochondrial localization protects against oxidative stress, but the mechanisms regulating its submitochondrial targeting and functional impact on mitochondrial integrity remain poorly understood. We identify voltage-dependent anion channel 1 (VDAC1) as a regulator of the submitochondrial distribution of DJ-1 during stress. Endogenous DJ-1 interacted with VDAC1, and loss of VDAC1 reduced stress-induced DJ-1 accumulation within the mitochondrial matrix. VDAC1-deficient neurons exhibited mitochondrial fragmentation, impaired oxidative phosphorylation, reduced ATP levels, altered reactive oxygen species (ROS) responses, and increased sensitivity to MPP+;. Matrix-targeted, but not outer-membrane-targeted, DJ-1 rescued basal, ATP-linked, and maximal respiration, improved mitochondrial morphology, and enhanced neuronal survival. ATP synthase inhibition also rapidly increased mitochondrial DJ-1, suggesting bioenergetic stress promotes its mitochondrial accumulation. Our findings identify compartment-specific localization as a key determinant of DJ-1 function and establish VDAC1-dependent matrix targeting as a critical mechanism supporting mitochondrial integrity during stress.

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bioRxiv2026

Synaptic adhesion molecule signaling is activated and organized by tyrosine phosphorylation-induced biomolecular condensate formation

The precise formation of synapses ensures the proper wiring and function of nervous systems. Specific synapse formation is controlled by synaptic adhesion molecules, which link pre- and post-synaptic cells. Despite this central role, details of how adhesion molecules organize and signal intracellularly to build core synaptic structures are limited. Here, we identify multiple tyrosine phosphorylation sites on the cytoplasmic tail of the C. elegans SYG-1 synaptic adhesion molecule that are critical to initiate presynapse formation. We determine that SRC-1 and SRC-2 tyrosine kinases are redundantly responsible for SYG-1 phosphorylation and are consequently critical for presynapse assembly. The phosphorylated population of SYG-1 localizes in clusters within a larger SYG-1 pool and these clusters mark sites of presynaptic active zone assembly. Reconstitution of SYG-1 clusters in vitro with SH2-domain adapters and WSP-1 reveals a dynamic biomolecular condensate-forming system. Blocking phosphotyrosine adapters and condensate formation in vivo results in the loss of SYG-1 clusters, defective presynapse formation, and compromised neurotransmission. We conclude that phosphorylation of a subpopulation of synaptic adhesion molecules activates and organizes them into condensate-based clusters to initiate presynapse formation.

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bioRxiv2026

MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia

Tauopathies are characterized by the accumulation and spread of pathogenic tau aggregates throughout the brain, a process that is increasingly recognized to involve not only neurons but also microglia. However, whether pathogenic MAPT directly alters microglial degradative capacity remains poorly understood. Here, using isogenic human induced pluripotent stem cell-derived microglia carrying the pathogenic MAPT IVS10+16 mutation, we identify tau as a regulator of microglial lysosomal function. MAPT IVS10+16 microglia exhibited coordinated suppression of lysosomal and autophagic pathways, reduced lysosomal protease abundance and activity, and impaired autophagosome-lysosome fusion. Mutant microglia also showed reduced uptake of extracellular tau aggregates, reduced tau accumulation in acidic compartments, and a blunted lysosomal response to proteopathic stress. Conversely, genetic loss of MAPT increased lysosomal degradative capacity and accumulation of extracellular tau aggregates within acidic compartments, supporting a cell-intrinsic role for endogenous tau in regulating microglial degradative function. Pharmacologic enhancement of the autophagy lysosome pathway in MAPT IVS10+16 microglia increased proteolytic activity and improved tau handling. Together, these findings reveal a reciprocal relationship between tau and microglial lysosome function and identify degradative capacity as a modifiable component of the microglial response to tau pathology.

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bioRxiv2026

GABAB Receptors Gate Sex-Specific Synaptic Plasticity in the Nucleus Accumbens

Excitatory synaptic plasticity within the nucleus accumbens (NAc) drives motivated behaviors, and dysregulation is implicated in several psychiatric disorders marked by impaired reward processing. The NAc integrates glutamatergic input, which conveys information about reward, context, and behavioral goals, with local GABAergic signaling that regulates excitatory transmission and medium spiny neuron (MSNs) output. However, little is known regarding GABA-dependent modulation of activity-dependent excitatory synaptic plasticity. Here, we investigated GABAB receptor (GABABR) regulation of plasticity at hippocampus (Hipp)-NAc synapses, at which plasticity is a key mediator of reward-related behaviors. Using whole-cell electrophysiological recordings in mouse brain slices, we found that pharmacological inhibition of GABABRs converts long-term potentiation (LTP) into long-term depression (LTD) selectively in females, identifying a sex-specific role for GABABRs in modulating long-term plasticity of Hipp-MSN synapses. This LTD required mGluR5 activation and estrogen receptor alpha (ER) in both D1- and D2-expressing MSN subtypes, while only D1-MSNs suggested that LTD was expressed presynaptically through a CB1 receptor-dependent mechanism. Notably, GABABR inhibition did not alter basal synaptic transmission, indicating a specific role for these receptors in gating plasticity beyond regulation of basal excitatory drive. Together, these findings identify a novel, sex-specific mechanism by which GABABRs control the direction of synaptic plasticity.

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bioRxiv2026

Structure-Constrained Intrinsic Timescales Across Tasks

Intrinsic neural timescale (INT) quantifies the persistence of spontaneous neural dynamics and offers a principled metric for characterizing brain-wide temporal organization. Although a hierarchy of INTs has been established during rest, how task engagement reconfigures this organization and how it is constrained by the structural connectome (SC) remain poorly understood. Here, we systematically mapped whole-brain INT using high-resolution fMRI data from the Human Connectome Project during rest and seven tasks spanning working memory, gambling, motor, language, social, relational, and emotion domains. Task engagement induced robust, regionally heterogeneous changes in INT while largely preserving the brain-wide temporal hierarchy across cognitive states. SC-INT coupling remained strong but consistently decreased during tasks, indicating that anatomical architecture continues to constrain INT, although its influence is attenuated under task demands. To investigate these findings mechanistically, we employed a multiscale, whole-brain neuronal-network model, which revealed that INT increase and peak within a broad critical-like regime. Strong SC-INT coupling, as observed empirically, emerged in the subcritical regime, weakened progressively with increasing network excitability, and reversed in the supercritical regime. These results demonstrate that task engagement reconfigures INTs while maintaining their hierarchical organization, suggesting that both resting and task states operate largely within a common subcritical dynamical regime.

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bioRxiv2026

Neural spiketrains and population vectors entangle neural representations

Neural recordings are usually analyzed by comparing neural spiketrains or comparing time bins (population vectors). If multiple variables drive the neural activity these comparisons will be affected by all of them. Our aim is to disentangle these different latent variables or covariates that drive neural activity and reveal their structure and geometry. The central idea of the paper is that a matrix is disentangled when its rows and columns are local on each other, a condition we call bidirectional locality. In such a matrix, rows and columns encode the same geometry and they respond to only one localized part of it. This suggests finding bidirectional local matrices in a given data matrix, from which we can recover the geometry of the covariates driving it in a straightforward way. We present two ways of doing just this. The first method, coherent projections, works by finding non-negative projections of the neural data matrix (neurons by time bins) that are bidirectionally local. The second method, clumps, works by finding dense submatrices of the neural data matrix, that each identify a local region of one covariate. We apply these methods to two neural datasets, showing that they can separate grid cell modules and reveal a movement-driven low-dimensional structure in the motor cortex.

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bioRxiv2026

Excessive cholesterol accumulation in microglia increases neuronal synaptic vulnerability to amyloid-beta

Cholesterol efflux is an important determinant of cellular lipid homeostasis. However, how microglial excessive cholesterol accumulation affects neuronal synaptic integrity remains poorly understood, particularly in the context of Alzheimer's disease. Here, we utilized a conditional knockout mouse model targeting the cholesterol transporters ABCA1 and ABCG1 in microglia. The microglia-specific ABCA1/ABCG1 deficiency triggered marked cholesterol accumulation, microglial hypertrophy, downregulation of the homeostatic marker P2ry12, and upregulation of the reactivity-associated marker CD11b, indicating shift toward a reactive phenotype. This phenotype was accompanied by increased reactive oxygen species, consistent with enhanced oxidative stress in ABCA1/ABCG1-deficient microglia compared with control. Using organotypic hippocampal slice cultures, we investigated the downstream neuronal outcomes of microglial ABCA1/ABCG1 deficiency. Under basal conditions, microglial ABCA1/ABCG1 knockdown did not significantly alter dendritic spine density in CA1 pyramidal neurons. However, upon exposure to amyloid-beta (A{beta}) stress, microglial ABCA1/ABCG1 deficiency markedly exacerbated dendritic spine loss in CA1 pyramidal neurons. Taken together, our findings highlight an important role for ABCA1/ABCG1-dependent cholesterol efflux in maintaining microglial homeostasis and limiting neuronal synaptic vulnerability to A{beta}-associated stress. These results support further investigation of microglial cholesterol transport as a potential target for preserving synaptic resilience in Alzheimer's disease.

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bioRxiv2026

Redundant information across functionally coupled cortical networks supports rapid perceptual decisions in the ferret

Coordinated activity across cortical areas transforms sensory inputs into perceptual decisions, yet how task-relevant information is distributed across sites and linked to functional interactions and behavior remains unclear. Conventional functional connectivity measures reveal statistical dependencies between neural signals but cannot distinguish information encoded uniquely at individual sites, shared redundantly across sites, or available only from their joint activity. Here, we used Partial Information Decomposition (PID) to characterize stimulus information during fast and slow correct decisions. We analyzed local field potentials (LFPs) extracted from mesoscale electrocorticographic recordings from auditory, visual, and parietal cortices in ferrets performing a visual and audiovisual spatial-detection task. Time- and frequency-resolved analyses of local field potential power and phase showed that stimulus-side information was strongest in the theta and alpha bands and greater during fast than slow responses. PID applied to pairs of recording sites revealed that fast responses were associated with earlier and stronger unique information and a greater relative contribution of redundancy, whereas synergistic contributions were smaller. During fast responses, redundancy was selectively associated with stronger LFP power-envelope coupling. These findings indicate that faster perceptual decisions involve a frequency-specific reorganization of cortical information, characterized by early local encoding and enhanced redundant information across functionally interacting sites.

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bioRxiv2026

Anxiety-Related Traits Are Associated with Subjective Biases but not Altered Threat-Safety Discrimination

Anxiety-related traits (ARTs) have been linked to altered fear learning, but previous studies have typically examined different experimental phases and response systems, limiting the comparability of findings and the accumulation of consistent evidence. Here, we comprehensively examined associations between ARTs and fear conditioning across acquisition, extinction and renewal and across subjective, physiological and neural response systems in a well-powered sample (N = 267) using a two-day differential conditioning paradigm. ARTs were operationalized as a composite of trait anxiety, neuroticism, and intolerance of uncertainty and conditioned responding was assessed using skin conductance responses, fear-potentiated startle, US expectancy ratings, fear ratings, and functional magnetic resonance imaging. Higher ARTs were consistently associated with elevated subjective fear and US expectancy to both threat and safety cues during extinction and renewal, without corresponding elevations in physiological responding. At the same time, ARTs were not associated with threat-safety discrimination in subjective or physiological measures across phases, while neural associations were limited to reduced dorsal anterior cingulate cortex discrimination during early renewal. These findings suggest that ARTs are characterized by a CS unspecific cognitive bias toward heightened threat expectancy and evaluation rather than altered associative fear learning, highlighting the importance of distinguishing conditioned discrimination from general levels of responding across response systems.

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bioRxiv2026

Ancient Somatosensory Circuit Architectures Employ Flexible Molecular Strategies

The extent to which conserved neural circuit architectures depend on shared molecular specification programs remains unclear. Here, we address this question by examining the somatosensory system of the little skate, Leucoraja erinacea, an early-diverging vertebrate that retains ancestral features of both finned and limb-based body plans. We show that core features of somatosensory circuit organization, including laminar organization of the spinal cord and dorsally restricted targeting of sensory afferents, are deeply conserved. Unexpectedly, the molecular programs specifying dorsal root ganglion (DRG) sensory subtypes diverge extensively from those of mammals. Although DRG neuron subtype specification and spinal connectivity rely on target-derived cues, skates employ distinct neurotrophin receptor and transcription factor identity codes. These findings support a model in which conserved spinal circuit architectures provide a stable scaffold that leverages flexible sensory neuron specification programs, enabling the evolutionary diversification of vertebrate somatosensory systems. HighlightsO_LIIntegrated analysis of spinal cord and DRG neuronal diversity in Leucoraja erinacea C_LIO_LILaminar organization of the dorsal spinal cord is an ancestral vertebrate feature C_LIO_LIDivergent neurotrophin receptor and transcription factor codes in sensory neurons C_LIO_LIConserved target-dependent regulation of sensory identity and connectivity C_LI

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bioRxiv2026

Increased activity in the somatosensory and insular cortex during the transition from acute to chronic neuropathic pain

Pathophysiological mechanisms underlying the transition from acute to chronic neuropathic pain remain incompletely understood. The somatosensory and insular cortices are key cortical components of the pain matrix. We examined changes in activation of these cortical regions during the transition from acute to chronic neuropathic pain. The right sciatic nerve was ligated in activity reporter TRAP mice using standard procedures. Mechanical allodynia was confirmed after CCI or sham surgery using von Frey monofilaments applied to the hind paws. To label active neurons, 4-hydroxytamoxifen was administered to separate cohorts at 1, 3, and 6 weeks following nerve ligation. Passive tissue clearing of brain sections and confocal imaging was used to assess active neurons. Progressive reduction of ipsilateral hind paw in CCI mice indicated mechanical allodynia development. CCI mice showed robust neuronal activation in the bilateral somatosensory and insular cortices. The somatosensory cortical activation peaked at 3 weeks post-CCI, whereas insular cortical activity increased during the transition from acute to chronic neuropathic pain. These studies revealed that CCI induced progressive mechanical allodynia and distinct temporal patterns of cortical neuronal activation, with transient peak neuronal activity in the somatosensory cortex and sustained, increasing activation in the insular cortex during acute-to-chronic pain transformation.

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bioRxiv2026

Microglia drive demyelination via multiple sclerosis antibodies and BTK signaling

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge its debris is unknown. Here, we explore whether pathogenic autoantibodies found in MS may induce the phagocytic destruction of myelin by microglia. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and Fc gamma receptor and complement binding. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Brutons tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.

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bioRxiv2026

A reproducibility-audit framework for generalizable versus dataset-specific molecular transition boundaries in Alzheimer's disease

Molecular staging of Alzheimer's disease (AD) increasingly defines transition boundaries along single-cell pseudo-progression trajectories, yet whether such boundaries reproduce across brain regions, cohorts and molecular modalities is rarely tested. We present a permutation-controlled audit that combines nine boundary-detection algorithms with a fixed marker panel and four orthogonal reproducibility axes-algorithmic consensus, region, cohort and modality. On synthetic data with planted ground-truth boundaries the audit reaches 100% sensitivity and 94% specificity, rejecting four distinct artefact classes each by a different axis. Applied to the Seattle Alzheimer's Disease Brain Cell Atlas middle temporal gyrus, it localizes a transition that is robust across algorithms and recovered in most cell types but does not generalize: its leading marker is attenuated or absent in prefrontal cortex, entorhinal cortex and cerebrospinal fluid, and an apparent cross-region conservation of glial metabolic genes proves to be a global-expression offset rather than a shared program. The same audit nonetheless certifies an externally validated marker (astrocytic PTGDS) as reproducible across regions and modalities, showing that it separates generalizable anchors from dataset-specific ones rather than rejecting all signals. We provide this four-axis audit as a transferable, code-available standard to apply before a trajectory boundary is read as a biological stage, in AD and other progressive proteinopathies.

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bioRxiv2026

A transcriptomic and spatial map of serotonin autoreceptor expression in Drosophila

Serotonin is an evolutionarily ancient neurotransmitter that modulates an array of behaviors such as mood, sleep, and appetite across species. Serotonin acts primarily by binding to serotonin receptors, which are expressed in post-synaptic neurons (heteroreceptors) and serotonergic neurons themselves (autoreceptors). Serotonin autoreceptors modulate serotonergic tone, the foundational principles of which have been excellently demonstrated in vertebrate and invertebrate models. However, many aspects of the mechanisms and contexts in which this modulation occurs are still unclear. Drosophila melanogaster is a powerful model organism that can provide unique insights into autoreceptor function by the ability to perform precise spatial and temporal genetic manipulation with structural and functional readouts / behaviors of serotonin systems. However, a systematic characterization of serotonin autoreceptor expression in Drosophila has not been conducted. Here we use single-cell sequencing and genetic labeling to show that all five serotonin receptors are expressed in serotonergic neurons and map their expression at both the larval and adult stages of development. This is the first evidence of 5-HT2A and 5-HT7 expression in serotonergic neurons in any organism. Moreover, the unique combinations of autoreceptor expression in specific neuronal clusters will aid in the development of novel hypotheses for autoreceptor function, and demonstrates the utility of Drosophila as a model organism to study the function of serotonin autoreceptors.

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