Spatiotemporal remodeling in the habenula marks the onset of depression

Spatiotemporal remodeling in the habenula marks the onset of depression | 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 Spatiotemporal remodeling in the habenula marks the onset of depression Manuel Mameli, Patricia Molina, Denys Osypenko, Josep Garnica Caparrós, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7773881/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 Chronic stress has lasting adverse consequences that can lead, over time, to depressive disorders1‑4 yet identifying the optimal timeframe for effective therapies remains an unmet challenge. Enhanced neuronal activity and disrupted aversion-encoding in lateral habenula (LHb) are important mediators of stress-related behavioral repercussions5‑10, although the precise timing of its contribution is not understood. Here, we identified an antidepressant-sensitive onset of stress consequences in mice, observable across multiple levels of biological complexity – behavioral, functional, and molecular. Using spatial transcriptomics11,12, we generated a spatially-resolved molecular atlas of the LHb, revealing a topographically-organized and temporally-defined remodeling of gene expression in chronic stress. Longitudinal in vivo two-photon calcium imaging to survey the encoding properties of individual LHb neurons revealed progressively heightened excitatory responses to aversive stimuli. These neuronal adaptations were reversed by the antidepressant ketamine and mirrored both the progression of transcriptional changes as well as the emergence of depression-related behavioral phenotypes. Finally, both chemogenetically limiting LHb neuronal activity and administering ketamine at the onset of the remodeling processes exerted antidepressant effects. Together, these findings associate shared spatiotemporal signatures of LHb neuronal ensembles and genetic landscape with the onset of stress-induced depression-related states. This has implications for temporally tailoring therapeutical interventions in clinical practice. Biological sciences/Neuroscience/Stress and resilience Biological sciences/Neuroscience/Motivation Biological sciences/Neuroscience/Neural circuits Full Text Additional Declarations There is NO Competing Interest. Supplementary Files ExtendedDataTable1.csv Dataset1 ExtendedDataTable2.xlsx Dataset2 MolinaetalExtendedData.pdf Extended Data 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-7773881","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":541707792,"identity":"50bb7492-4c0b-4e7e-9ae6-9fbf87a5363b","order_by":0,"name":"Manuel Mameli","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYNCCAjDJeCChgoGBjZ2BgZmwFgMIdSDhDFALM0laGNsYwOrxatFtP3tM4oMBQzT/tMMHDjycdziPj5mB8XMBHi1mZ/LSJGcYMOTOuJ2WcCBx2+FioMOYpWfg03Igx0yaB6il4XaOAUhLYhsz0Ds8+LScf2Mm/QeoZf7t/A8HEucQo+UG0Bag93M33M5hOJDYQJSWN8aWPQYSuRtvpxkcSDiWDtTC2CyN32E5hjd+VNjkzrud/PDhjxrrxPntzQc/49MCBRLIHMYGwhpGwSgYBaNgFOAFAOCwS546gNToAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-0570-6964","institution":"The University of Lausanne","correspondingAuthor":true,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Mameli","suffix":""},{"id":541707793,"identity":"8b3e0516-5789-4020-952a-fcffc1aa17e5","order_by":1,"name":"Patricia Molina","email":"","orcid":"","institution":"The University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Molina","suffix":""},{"id":541707794,"identity":"c6ce9369-386d-49ea-accc-55a7895bea95","order_by":2,"name":"Denys Osypenko","email":"","orcid":"","institution":"The University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Denys","middleName":"","lastName":"Osypenko","suffix":""},{"id":541707795,"identity":"de993ddd-d7cf-4d18-b317-c52d3a401b86","order_by":3,"name":"Josep Garnica Caparrós","email":"","orcid":"https://orcid.org/0000-0001-9493-1321","institution":"University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Josep","middleName":"Garnica","lastName":"Caparrós","suffix":""},{"id":541707796,"identity":"b7e991fc-2c11-4f98-b712-09132ed14fb8","order_by":4,"name":"Quentin Amossé","email":"","orcid":"https://orcid.org/0000-0002-5553-9594","institution":"The University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Quentin","middleName":"","lastName":"Amossé","suffix":""},{"id":541707797,"identity":"5c65e230-73d7-4cc6-8e7b-fdb7ba2a9180","order_by":5,"name":"Sarah Mondoloni","email":"","orcid":"","institution":"The University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Mondoloni","suffix":""},{"id":541707798,"identity":"2186689d-7148-4d54-a9fc-eefa74d2a1bf","order_by":6,"name":"Mauro Congiu","email":"","orcid":"","institution":"The University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Mauro","middleName":"","lastName":"Congiu","suffix":""},{"id":541707799,"identity":"93f95b83-a147-4dca-af5c-7fee9aa39155","order_by":7,"name":"Claudia Kathe","email":"","orcid":"https://orcid.org/0000-0001-6441-1755","institution":"University of Lausanne","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Kathe","suffix":""}],"badges":[],"createdAt":"2025-10-03 13:35:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7773881/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7773881/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96363627,"identity":"8175755a-b9e8-48ac-94cb-3e4aa8fe2189","added_by":"auto","created_at":"2025-11-20 10:07:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9373204,"visible":true,"origin":"","legend":"Article File","description":"","filename":"MolinaetalMS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7773881/v1_covered_f8ebd482-b457-44f8-a5cd-ca229ca65d31.pdf"},{"id":96262830,"identity":"8aacee5c-5ff8-4d5d-b70e-a6d16593d4fc","added_by":"auto","created_at":"2025-11-19 08:10:48","extension":"csv","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":88494,"visible":true,"origin":"","legend":"Dataset1","description":"","filename":"ExtendedDataTable1.csv","url":"https://assets-eu.researchsquare.com/files/rs-7773881/v1/f48e4b323508c3324a214f36.csv"},{"id":96262829,"identity":"b4167f59-46f2-4ec9-a4bc-c0c2e4ff1818","added_by":"auto","created_at":"2025-11-19 08:10:48","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":29370,"visible":true,"origin":"","legend":"Dataset2","description":"","filename":"ExtendedDataTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7773881/v1/66c71508c76459a10e69a87c.xlsx"},{"id":96262831,"identity":"cf862ab4-c82b-4876-8f2f-a1b85b26eb6a","added_by":"auto","created_at":"2025-11-19 08:10:48","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":23709644,"visible":true,"origin":"","legend":"Extended Data","description":"","filename":"MolinaetalExtendedData.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7773881/v1/48d7c129501defa1f585d81e.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Spatiotemporal remodeling in the habenula marks the onset of depression","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7773881/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7773881/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Chronic stress has lasting adverse consequences that can lead, over time, to depressive disorders1‑4 yet identifying the optimal timeframe for effective therapies remains an unmet challenge. Enhanced neuronal activity and disrupted aversion-encoding in lateral habenula (LHb) are important mediators of stress-related behavioral repercussions5‑10, although the precise timing of its contribution is not understood. Here, we identified an antidepressant-sensitive onset of stress consequences in mice, observable across multiple levels of biological complexity – behavioral, functional, and molecular. Using spatial transcriptomics11,12, we generated a spatially-resolved molecular atlas of the LHb, revealing a topographically-organized and temporally-defined remodeling of gene expression in chronic stress. Longitudinal in vivo two-photon calcium imaging to survey the encoding properties of individual LHb neurons revealed progressively heightened excitatory responses to aversive stimuli. These neuronal adaptations were reversed by the antidepressant ketamine and mirrored both the progression of transcriptional changes as well as the emergence of depression-related behavioral phenotypes. Finally, both chemogenetically limiting LHb neuronal activity and administering ketamine at the onset of the remodeling processes exerted antidepressant effects. Together, these findings associate shared spatiotemporal signatures of LHb neuronal ensembles and genetic landscape with the onset of stress-induced depression-related states. This has implications for temporally tailoring therapeutical interventions in clinical practice.","manuscriptTitle":"Spatiotemporal remodeling in the habenula marks the onset of depression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-19 08:10:43","doi":"10.21203/rs.3.rs-7773881/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-neuroscience","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"neuro","sideBox":"Learn more about [Nature Neuroscience](http://www.nature.com/neuro/)","snPcode":"","submissionUrl":"","title":"Nature Neuroscience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"23ff3df0-6667-4c7e-a6b0-fea844a41c60","owner":[],"postedDate":"November 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":57636276,"name":"Biological sciences/Neuroscience/Stress and resilience"},{"id":57636277,"name":"Biological sciences/Neuroscience/Motivation"},{"id":57636278,"name":"Biological sciences/Neuroscience/Neural circuits"}],"tags":[],"updatedAt":"2025-11-19T08:10:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-19 08:10:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7773881","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7773881","identity":"rs-7773881","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}