Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses

Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses Bénédicte Amilhon, Suzanne van der Veldt, Fiona Henderson, Lucia Pizzoccaro, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7859016/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Mood and anxiety disorders display robust sex differences in prevalence, symptom profile, and treatment outcomes, yet the circuit mechanisms underlying this sex bias remain unclear. Here, we identify a serotonergic (5-HT) pathway from the median raphe region (MRR) to the ventral hippocampus (vHP) that drives sex-specific anxiety regulation in mice. Using a multimodal approach combining electrophysiology, fiber photometry, and optogenetics, we show that vHP-projecting 5-HT neurons (5-HTvHP) in females are intrinsically hyperexcitable and exhibit delayed adaptation during exposure to aversive environments. Optogenetic activation of this pathway selectively enhanced anxiety-like behavior and stress-related grooming in females, while leaving locomotion unaffected. Fiber photometry revealed that grooming episodes coincide with transient suppression of 5-HTvHP activity, suggesting an adaptive feedback mechanism to downregulate serotonergic tone under elevated anxiety. Moreover, activation of this pathway disrupted hippocampal theta dynamics during habituation to a novel arena exclusively in females, revealing serotonergic modulation of anxiety and novelty processing. Collectively, our findings uncover a hyperexcitable MRR-vHP serotonergic circuit that drives female-specific anxiety states, providing a mechanistic framework for understanding sex-specific vulnerability to mood and anxiety disorders. Biological sciences/Neuroscience/Emotion Biological sciences/Neuroscience/Stress and resilience Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7859016","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":533542016,"identity":"d88063bc-d934-4aa7-9f35-4b6fc67ffab6","order_by":0,"name":"Bénédicte 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