VIP interneurons control hippocampal place cell remapping through transient disinhibition in novel environments

VIP interneurons control hippocampal place cell remapping through transient disinhibition in novel environments | 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 VIP interneurons control hippocampal place cell remapping through transient disinhibition in novel environments Máté Neubrandt, Nora Lenkey, Koen Vervaeke This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5974632/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 Hippocampal place cells dynamically reorganize their activity, or "remap", to encode novel spatial environments, a process tightly regulated by inhibitory networks. Here, we identify vasoactive intestinal peptide (VIP)-expressing interneurons as key regulators of this plasticity. Using all-optical methods in mice navigating virtual reality, we show that novel environments trigger a transient increase in VIP interneuron activity, which facilitates rapid place field formation and stable spatial map construction. Bidirectional optogenetic manipulation —suppressing or upregulating VIP interneuron activity— modulates the speed of spatial map formation and alters signatures of behavioral timescale plasticity (BTSP), a mechanism critical for place field induction. Both insufficient and excessive VIP interneuron activity impair reward-seeking behavior specifically in novel environments, revealing that a precise balance of VIP activity is essential for spatial learning. Our findings demonstrate that VIP interneurons gate a temporal window for place cell plasticity, mediating the impact of environmental novelty on hippocampal remapping and spatial memory. Biological sciences/Neuroscience/Neural circuits Biological sciences/Neuroscience/Synaptic plasticity Cognitive maps spatial memory and navigation place cells hippocampus inhibitory interneurons VIP interneurons disinhibition two-photon microscopy optogenetics virtual reality 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. 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-5974632","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":439111493,"identity":"b6c47b49-ba0a-4c4a-b5c1-07aa3fc7cbbd","order_by":0,"name":"Máté Neubrandt","email":"","orcid":"","institution":"Institute of Basic Medical Sciences, Section of Physiology, University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Máté","middleName":"","lastName":"Neubrandt","suffix":""},{"id":439111619,"identity":"66e3d805-6c5a-469f-9603-ebc6354adae3","order_by":1,"name":"Nora Lenkey","email":"","orcid":"","institution":"Institute of Basic Medical Sciences, Section of Physiology, University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Nora","middleName":"","lastName":"Lenkey","suffix":""},{"id":423569655,"identity":"0be4e7e1-f5da-46c0-a1d9-f0d1998554a4","order_by":2,"name":"Koen Vervaeke","email":"data:image/png;base64,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","orcid":"","institution":"Institute of Basic Medical Sciences, Section of Physiology, University of Oslo","correspondingAuthor":true,"prefix":"","firstName":"Koen","middleName":"","lastName":"Vervaeke","suffix":""}],"badges":[],"createdAt":"2025-02-06 15:05:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5974632/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5974632/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80005091,"identity":"ba5b8bba-f7c1-4a41-a16c-dc346142f186","added_by":"auto","created_at":"2025-04-06 19:30:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3906578,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Neubrandtetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5974632/v1_covered_10728d7b-f1f0-40be-b1d1-26763a071149.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"\u003cp\u003eVIP interneurons control hippocampal place cell remapping through transient disinhibition in novel environments\u003c/p\u003e","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":"Cognitive maps, spatial memory and navigation, place cells, hippocampus, inhibitory interneurons, VIP interneurons, disinhibition, two-photon microscopy, optogenetics, virtual reality","lastPublishedDoi":"10.21203/rs.3.rs-5974632/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5974632/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHippocampal place cells dynamically reorganize their activity, or \"remap\", to encode novel spatial environments, a process tightly regulated by inhibitory networks. Here, we identify vasoactive intestinal peptide (VIP)-expressing interneurons as key regulators of this plasticity. Using all-optical methods in mice navigating virtual reality, we show that novel environments trigger a transient increase in VIP interneuron activity, which facilitates rapid place field formation and stable spatial map construction. Bidirectional optogenetic manipulation —suppressing or upregulating VIP interneuron activity— modulates the speed of spatial map formation and alters signatures of behavioral timescale plasticity (BTSP), a mechanism critical for place field induction. Both insufficient and excessive VIP interneuron activity impair reward-seeking behavior specifically in novel environments, revealing that a precise balance of VIP activity is essential for spatial learning. 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