Feature-specific threat coding in lateral septum guides defensive action

Feature-specific threat coding in lateral septum guides defensive action | 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 Biological Sciences - Article Feature-specific threat coding in lateral septum guides defensive action Gord Fishell, Dionnet Bhatti Mazo, Amanda Pasqualini, Sherry Wu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6831193/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 The ability to rapidly detect and evaluate potential threats is essential for survival and requires the integration of sensory information, with internal state and prior experience. The lateral septum (LS), an inhibitory structure in the limbic forebrain, is thought to integrate these higher-order ‘cognitive’ signals to regulate defensive responses. However, the cellular, circuit, and computational mechanisms fundamental to this process remain unknown. Here, we focus on the LS population expressing the type 2 CRH receptor (LS Crhr2 ), a neuronal subset shown to be critical for state-dependent behavioral changes and threat responsivity. We use a combination of single-cell calcium imaging, molecular sequencing, and circuit dissection to reveal the spatial and functional organization of the cell-types involved, the computations they perform, and the information relayed by their upstream activators. We determined that LS Crhr2 population activity is required for cue-driven defensive actions by rapidly and dynamically encoding threat representations that predict behavioral outcomes. We find that these threat representations are formed through the convergence of various signals differentially represented among distinct LS Crhr2 subclasses, which are defined by their molecular features, spatial location, and input architecture. Most importantly, their responses reflect specific afferents from the hippocampus and hypothalamus that preferentially impart cue- and action-related signals, respectively. These findings establish a multifeatured organizational principle that underlies how LS mediates motivated behaviors in response to environmental challenges. Biological sciences/Neuroscience/Cellular neuroscience Biological sciences/Neuroscience/Emotion/Limbic system Full Text Additional Declarations Yes there is potential Competing Interest. Gordon Fishell is a founder of Regel Therapeutics but it has no competing interest with the present manuscript. Supplementary Files LScrhr2manuscriptnatureDLBMextendeddata.pdf Extended data, Figures 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6831193","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":469505718,"identity":"d5c79d2c-f711-408e-84e0-9ad2392e6674","order_by":0,"name":"Gord Fishell","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-9640-9278","institution":"Harvard University","correspondingAuthor":true,"prefix":"","firstName":"Gord","middleName":"","lastName":"Fishell","suffix":""},{"id":469505719,"identity":"9e9b45c2-3388-474c-b9ea-b15c7286c1f2","order_by":1,"name":"Dionnet Bhatti Mazo","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Dionnet","middleName":"Bhatti","lastName":"Mazo","suffix":""},{"id":469505720,"identity":"51a5148b-b82d-4efe-9576-2ef97e7a9de3","order_by":2,"name":"Amanda Pasqualini","email":"","orcid":"https://orcid.org/0000-0002-0196-4827","institution":"University of Washington","correspondingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Pasqualini","suffix":""},{"id":469505721,"identity":"8ec1fac1-fe30-4772-a451-65547567c8e2","order_by":3,"name":"Sherry Wu","email":"","orcid":"https://orcid.org/0000-0001-9625-1661","institution":"Harvard Medical School And The Stanley Center At The Broad","correspondingAuthor":false,"prefix":"","firstName":"Sherry","middleName":"","lastName":"Wu","suffix":""},{"id":469505722,"identity":"06f5fc22-cf05-47d2-a43e-16e18be67b41","order_by":4,"name":"Marc Berger","email":"","orcid":"","institution":"Harvard Medical School And The Stanley Center At The Broad","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"","lastName":"Berger","suffix":""},{"id":469505723,"identity":"b1f7c2ed-c6ae-4c76-b9a8-8f13679d10e3","order_by":5,"name":"Christopher Reid","email":"","orcid":"","institution":"Whitehead Institute for Biomedical Research","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Reid","suffix":""},{"id":469505724,"identity":"ee4988f0-d88c-4f36-943b-7173201d7abf","order_by":6,"name":"Salvador Brito","email":"","orcid":"","institution":"F.M. 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The lateral septum (LS), an inhibitory structure in the limbic forebrain, is thought to integrate these higher-order ‘cognitive’ signals to regulate defensive responses. However, the cellular, circuit, and computational mechanisms fundamental to this process remain unknown. Here, we focus on the LS population expressing the type 2 CRH receptor (LS\u003csup\u003e\u003ci\u003eCrhr2\u003c/i\u003e\u003c/sup\u003e), a neuronal subset shown to be critical for state-dependent behavioral changes and threat responsivity. We use a combination of single-cell calcium imaging, molecular sequencing, and circuit dissection to reveal the spatial and functional organization of the cell-types involved, the computations they perform, and the information relayed by their upstream activators. We determined that LS\u003csup\u003e\u003ci\u003eCrhr2\u003c/i\u003e\u003c/sup\u003e population activity is required for cue-driven defensive actions by rapidly and dynamically encoding threat representations that predict behavioral outcomes. We find that these threat representations are formed through the convergence of various signals differentially represented among distinct LS\u003csup\u003e\u003ci\u003eCrhr2\u003c/i\u003e\u003c/sup\u003e subclasses, which are defined by their molecular features, spatial location, and input architecture. Most importantly, their responses reflect specific afferents from the hippocampus and hypothalamus that preferentially impart cue- and action-related signals, respectively. 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