Biology subjects

Labonte, B.

Publications and source records attributed to Labonte, B..

14 recordsLinked to original sources

bioRxiv2026

Sex differences in epigenetic mechanisms of chronic pain-induced depression

Chronic pain is a major risk factor for depression, yet the molecular mechanisms underlying this comorbidity remain poorly understood, particularly in women. To address this gap, we systematically investigated sex differences in the epigenomic adaptations associated with chronic pain-induced depressive-like behaviors. Neuropathic pain was induced in the mouse using the sciatic nerve cuff model, and molecular analyses were performed in the anterior cingulate cortex (ACC), a key brain region implicated in both pain and affective processing. We profiled genome-wide DNA methylation, three histone modifications (H3K27ac, H3K4me1, and H3K27me3), and gene expression using EM-seq, Cut&Tag sequencing, and RNA-seq, respectively. Differential analyses were conducted for each molecular layer and integrated through gene co-expression network analysis. We found that chronic pain induced extensive remodeling of DNA methylation and histone modification landscapes in both sexes. Strikingly, these changes occurred at largely distinct genomic loci in males and females, revealing pronounced sex-specific epigenetic responses. Despite this divergence, the affected regions displayed similar regulatory organization, including enrichment at shared genic features, transcription factor binding sites, and chromatin profiles. Importantly, these adaptations converged on partly overlapping genes, biological pathways, and co-expression modules across sexes. The most affected gene modules were predominantly associated with synapse-related processes, consistent with previous knowledge, and were closely connected to modules enriched for epigenetic regulatory functions. Together, these findings indicate that chronic pain engages sex-specific epigenetic mechanisms that ultimately converge on common functional outcomes. Such convergence highlights the potential value of targeting sex-specific epigenetic substrates in future therapeutic strategies.

neuroscience↗

bioRxiv2026

Recurrent neuronal loops between medial prefrontal cortex and ventral tegmental area display sex-specific spatial reorganization in response to stress

The medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) form a highly interconnected circuit involved in emotional regulation, stress reactivity, and cognitive processing. While prior research has established the anatomical and functional interactions between these regions, the precise organization and molecular identity of VTA neurons involved in unidirectional and bidirectional mPFC connectivity remains poorly defined, particularly under stress. We combined dual anterograde and retrograde viral tracing in male and female mice to label VTA neurons according to their connectivity with the mPFC. This approach identified three distinct subpopulations including mPFC-projecting, mPFC-receiving, and bidirectionally-connected neurons which accounted for nearly half of the labelled VTA population. Each group displayed molecular heterogeneity, with most cells expressing dopaminergic (TH) and glutamatergic (VGLUT2) transcripts rather than single dopaminergic or GABAergic (GAD1) markers. Acute and chronic stress exposure revealed sex- and circuit-specific patterns of c-Fos activation. In males, acute and chronic stress generated opposing rostrocaudally organized activation profiles, whereas females showed a more uniform increase in activity. Spatial clustering analyses further revealed that stress induces distinct hotspot organization within the VTA, with chronic stress promoting cohesive hotspot organization and consistent local enrichment of bidirectionally connected neurons despite a limited global activation. Together, these findings uncover a molecularly diverse mPFC-VTA circuitry with bidirectional connectivity that undergoes sex-dependent spatial and functional rearrangement under stress, providing new insights on circuit-level mechanisms of stress-related disorders.

neuroscience↗

bioRxiv2026

Lateral hypothalamic input engages a disinhibitory microcircuit in the dorsal raphe to promote behavior activation

Behavioral activation involves coordination between hypothalamic and brainstem systems that regulate movement and internal state, but the circuit logic underlying this interaction remains poorly defined. The dorsal raphe nucleus (DRN), a major serotonergic hub, integrates diverse inputs to influence behavioral inhibition and activation, yet how hypothalamic signals shape its activity is unclear. Here, we identify a disinhibitory pathway through which the lateral hypothalamus (LHA) promotes behavioral activation via DRN. Using intersectional viral tracing, electrophysiology, and single-nucleus RNA sequencing, we show that LHA inputs preferentially target GABAergic DRN neurons that locally inhibit 5-HT neurons. Silencing these DRN neurons innervated by LHA increased locomotor and repetitive behaviors, decreased local inhibition, and enhanced cFos activity in serotonergic neurons, consistent with circuit-level disinhibition. Molecular profiling revealed distinct transmitter identities and transcriptional signatures of LHA-targeted versus LHA-projecting DRN populations. Together, these findings delineate a hypothalamic-raphe circuit that transforms hypothalamic drive into serotonergic activation, revealing a mechanism by which the lateral hypothalamus promotes behavioral activation through local inhibitory control. HIGHLIGHTSO_LILHA inputs preferentially target non-serotonergic, transcriptionally distinct DRN neurons C_LIO_LILHA-innervated DRN neurons form extensive local inhibition C_LIO_LISilencing LHA-innervated DRN neurons reduced local inhibitory tone and activate serotonin neurons C_LIO_LIDisrupting this circuit drives behavioral activation with repetitive motor pattern, not anxiety C_LI

neuroscience↗

bioRxiv2024

PrecisionTrack: Reliable Tracking of Large Groups of Animals Interacting in Complex Environments Over Extended Periods

Large-scale ethological behavioral studies can provide insights into the neuronal processes underlying complex and social behaviors, potentially opening new avenues for mental health research. However, studying socially interacting animals in naturalistic environments remains technically challenging, as current approaches struggle to simultaneously maintain subject identity, extract behavior, and characterize social interactions over prolonged periods. Here, we present PrecisionTrack, an open-source and fully integrated framework designed for real-time multi-animal tracking, behavioral analysis, and social interaction inference in large groups of interacting animals. PrecisionTrack achieves high spatiotemporal accuracy in crowded and highly occlusive environments while maintaining robust long-term identity tracking and low-latency processing. To extend behavioral inference beyond pose estimation, we developed the Multi-animal Action Recognition Transformer (MART), a transformer-based architecture enabling real-time subject-level action recognition, and Graph-MART (G-MART), a graph neural network module that infers directed social interactions and interaction partners within groups. In addition, PrecisionTrack supports quantitative analysis of evolving social networks across time, enabling investigation of the temporal organization and stability of social dynamics in naturalistic settings. The entire framework is open source and accompanied by standardized workflows and documentation, enabling users to train, evaluate, and deploy custom behavioral analysis pipelines across species and experimental contexts. PrecisionTrack provides a scalable platform for quantitative investigation of complex social behaviors at a resolution and duration not accessible with existing methods.

neuroscience↗

bioRxiv2024

The Tailtag System: Tracking Multiple Mice in a Complex Environment Over a Prolonged Period Using ArUco Markers.

Despite recent advancements, safely and reliably tracking individual movements over extended periods, particularly within complex social groups, remains challenging. Traditional methods like colour coding, tagging, and RFID tracking, while effective, have notable practical limitations. State-of-the-art neural network-based trackers often struggle to maintain individual identities in large groups for more than a few seconds. Fiducial tags like ArUco codes present a potential solution by enabling accurate tracking and identity management, yet their topical application on mammals has proven difficult without frequent human intervention. In this study, we introduce the Tailtag system: a non-invasive, ergonomic tail ring embedded with an ArUco marker. This system includes a comprehensive parameter optimization guide along with practical guidelines on marker selection. Our Tailtag system demonstrated the ability to automatically and reliably track individual mice in social colonies of up to 20 individuals over a period of seven days without performance degradation, facilitating a detailed analysis of social dynamics in naturalized environments.

animal behavior and cognition↗

bioRxiv2024

Transcriptional profiling of the cortico-accumbal pathway reveals sex-specific alterations underlying stress susceptibility

Anxiety and depressive disorders, including major depressive disorder (MDD), affect millions of people every year, imposing significant socio-economic burdens. In this scenario, current treatments for MDD show limited efficacy, highlighting the need to better understand its molecular mechanisms. The medial prefrontal cortex (mPFC) has been identified as a critical brain region in MDD pathology, displaying altered activity and morphology. This study targets the mPFC-to-nucleus accumbens (NAc) pathway, which is implicated in the regulation of emotional behavior. We used a pathway-specific approach to uncover transcriptional profiles in mPFC neurons projecting to the NAc in stressed male and female mice. Using the RiboTag technique and RNA sequencing, we identified sex-specific gene expression changes, revealing potential roles in stress susceptibility. Differential expression and weighted gene co-expression network analyses revealed distinct transcriptional responses to chronic stress in males and females. Key findings include the identification of the X-linked lymphocyte-regulated 4B (Xlr4b) gene, within a highly relevant gene module, as a stress susceptibility driver in males. By experimentally overexpressing the Xlr4b gene, we characterized its crucial role in regulating neuronal firing and influencing arborization patterns to promote anxiety-like behavior in a sex-specific fashion. These findings suggest that chronic stress induces unique and shared transcriptional alterations in mPFC neurons projecting to the NAc. Some of these alterations change the morphological and functional properties of neuronal pathways ultimately contributing to the differential manifestation of anxiety-like and depressive-like behaviors in male and female mice.

neuroscience↗

bioRxiv2023

Transcriptional dissection of symptomatic profiles across the brain of men and women with depression

Major depressive disorder (MDD) is one of the most important causes of disability worldwide. While recent work provides insights into the molecular alterations in the brain of patients with MDD, whether these molecular signatures can be associated with the expression of specific symptom domains in males and females remains unclear. Here, we identified sex-specific gene modules associated with the expression of MDD, combining differential gene expression and co-expression network analyses in six cortical and subcortical brain regions. Our results show varying levels of network homology between males and females across brain regions, although the association between these structures and the expression of MDD remains highly sex-specific. We refined these associations to several symptom domains and identified transcriptional signatures associated with distinct functional pathways, including GABAergic and glutamatergic neurotransmission, metabolic processes, and intracellular signal transduction, across brain regions associated with distinct symptomatic profiles in a sex-specific fashion. In most cases, these associations were specific to males or to females with MDD, although a subset of gene modules associated with common symptomatic features in both sexes was also identified. Together, our findings suggest that the expression of distinct MDD symptom domains is associated with sex-specific transcriptional structures across brain regions.

neuroscience↗

bioRxiv2021

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

neuroscience↗

bioRxiv2021

Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways

Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidences suggest that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical dopaminergic pathways. Yet, the molecular interactions underlying these changes are still poorly understood and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and cortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of the activity-dependent markers pERK and c-Fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We showed that social stress decreases the density of dopaminergic axonal projections to the mPFC but not to the NAc in susceptible and resilient mice. This was accompanied by sex-specific alterations of pERK and c-Fos expression in the VTA of susceptible but not resilient mice. Our results indicate that social defeat stress impacts the mesolimbic and mesocortical pathways by altering the molecular interactions regulating somatic and axonal plasticity differently in males and females.

neuroscience↗

bioRxiv2020

Sex-specific retinal anomalies induced by chronic social stress in mice

Major depressive disorder (MDD) is one of the most common consequences of chronic stress. Still, there is currently no reliable biomarker to detect individuals at risk to develop MDD. Recently, the retina emerged as an effective way to approach the brain and investigate psychiatric disorders with the use of the electroretinogram (ERG). In this study, cones and rods ERGs were performed in male and female mice before and after chronic social defeat stress (CSDS). Mice were then divided as susceptible or resilient to stress. Significant results were only observed in rods ERGs. In males, susceptible mice showed prolonged a-wave implicit times at baseline that were shortened after CSDS. The a-wave was also decreased in both susceptible and resilient male mice after CSDS. In females, rod a-waves were shorter in susceptible than in control mice after CSDS resulting from the latter demonstrating delayed a-waves. Baseline ERGs were able to predict - to some extent - the expression of susceptibility and resilience before stress exposition in male and female mice. Overall, our findings suggest that retinal activity is a presumptive biomarker of stress response and that the ERG could potentially serve as a predicting tool of the stress response in mice.

neuroscience↗

bioRxiv2020

Chronic stress induces sex-specific functional and morphological alterations in cortico-accumbal and cortico-tegmental pathways.

BackgroundThe medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown and the distinct contribution of these pathways to stress responses in males and females is unclear. MethodsBehavioral stress responses were induced by 21 days of chronic variable stress (CVS) in male and female C57BL6 mice. An inter-sectional viral approach was used to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes. ResultsCVS induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more severe in females in NAc-projecting mPFC neurons while males exhibited more drastic reductions in dendritic complexity in VTA-projecting mPFC neurons after CVS. Finally, chemogenetic overactivation of the cortico-accumbal pathway triggered anxiety and behavioral despair in both sexes while its inhibition rescued the phenotype only in females. ConclusionsOur results suggest that by changing the activity of transcriptional programs controlling neuronal plasticity, CVS interferes with the morphological and synaptic properties of the cortico-accumbal and tegmental pathways differently in males and females contributing to the expression of anxiety and depressive-like behaviors distinctly in a sex-specific fashion.

neuroscience↗

bioRxiv2019

Epigenetic signatures of chronic social stress in stress-susceptible animals

Exposure of mice to chronic social defeat stress (CSDS) produces depressive- and anxiety-like behaviors and widespread transcriptomic changes in several brain regions in susceptible animals. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to CSDS using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a critical region for CSDS effects on behavior. We found extensive evidence for differential methylation following exposure to CSDS in susceptible animals, with a greater proportion of CG hypermethylation than hypomethylation in CSDS-susceptible mice compared to non-stressed controls; non-CG methylation shows the opposite trend. Several genes previously implicated in the effects of CSDS are among those with the greatest number of differentially methylated sites, including estrogen receptor alpha (Esr1), the deleted in colorectal cancer (Dcc) gene and Cacna1c, which has been associated with a range of psychiatric conditions. Informatic analysis of DM sites revealed a gene network with {beta}-catenin as the hub gene of a network that included the {beta}-catenin-related WNT/frizzled signaling pathway as well as both Esr1 and Dcc. Finally, we found considerable overlap between DM genes associated with CSDS in susceptible animals and those associated with human neuroticism in a genome-wide association study. Analysis of these overlapping genes revealed WNT signaling as the top pathway, which features {beta}-catenin as the primary hub gene. These findings reveal a striking convergence between the molecular pathways identified through either transcriptional or epigenomic analyses of the mouse model of susceptibility to chronic stress and the genomic architecture of increased stress susceptibility reflected in neuroticism in humans.

neuroscience↗

bioRxiv2018

Biology and Bias in Cell Type-Specific RNAseq of Nucleus Accumbens Medium Spiny Neurons

Isolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.

neuroscience↗

bioRxiv2018

Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

neuroscience↗