Cortical GABAergic inhibition dynamics around hippocampal sharp-wave ripples

Cortical GABAergic inhibition dynamics around hippocampal sharp-wave ripples | 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 Cortical GABAergic inhibition dynamics around hippocampal sharp-wave ripples Edris Rezaei, Setare Tohidi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7391041/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 Cortical inhibition, mediated by GABA, is essential in balancing excitation and modulating neural processing, but it is unclear to what extent inhibitory dynamics are responsive to internally generated hippocampal activity, such as sharp-wave ripples (SWRs). Employing widefield imaging of extracellular GABA with iGABASnFR2 and hippocampal recordings, we characterized cortical inhibition during sleep–awake states and in the neighborhood of SWRs. Sleep–awake transitions drastically reorganized cortical levels of GABA, with increased inhibition in wakefulness and decreased upon entering NREM sleep. In the neighborhood of SWRs, inhibition was state- and region-specific: during NREM, medial cortices (e.g., retrosplenial) increased GABA before SWRs, whereas sensory areas in the lateral cortices decreased it; during wake, GABA increased in lateral cortices after SWRs. These findings reveal that cortical inhibition is not static and ubiquitous but instead is dynamically characterized by brain state, orchestrating the flow of hippocampal outputs to the rest of the cortex. Inhibitory modulation, as our data reveal, forms a mechanism allowing selective gating of memory-related activity during wakefulness and sleep. Biological sciences/Neuroscience/Neural circuits Biological sciences/Neuroscience/Sensory processing Cortical inhibition GABA dynamics Sharp-wave ripples Brain state transitions Hippocampal–cortical communication Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementarydata.pdf Supplementary_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-7391041","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":502124137,"identity":"925fd582-50a3-46a3-991f-995a0a23ce58","order_by":0,"name":"Edris Rezaei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIie3OsQrCMBCA4QsFXQJdTxT7ChEXBcVXuSJ00kkQNwUhLgHXPk5DVnF2EkTQRbBuHRyMoIJL1M0h/3SBfNwB+Hx/GUH2HLMcWgD4C9Gp/c+/Ia8C/g0Jy8OdLmBbjxZGm67Eeq86Y3nhIBV1FIbDqMlUQmYosclrWVBRDiI2CRh7XTyHgbiTWCGVgDtIzxJ7GE1leM5NW+L0TtjVtQUTyDgQcRyAYRLtQKXAtQVXBzBcUCPFg9BqjQ21iefVmoOEiyS4FBOKomV/nxfjTlRO+/pycpDHeW8vNvsIfD6fz+fuBmAFR1yvhvbVAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2832-5803","institution":"University of Lethbridge","correspondingAuthor":true,"prefix":"","firstName":"Edris","middleName":"","lastName":"Rezaei","suffix":""},{"id":502124138,"identity":"9ba5a2cc-45d4-409b-afd1-95d1e56bd65b","order_by":1,"name":"Setare Tohidi","email":"","orcid":"","institution":"University of Lethbridge","correspondingAuthor":false,"prefix":"","firstName":"Setare","middleName":"","lastName":"Tohidi","suffix":""}],"badges":[],"createdAt":"2025-08-17 07:40:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7391041/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7391041/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90537949,"identity":"f4642bbe-2e99-476d-8b86-e3cea1be8b2b","added_by":"auto","created_at":"2025-09-03 21:08:23","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1720509,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Manuscriptsecond.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7391041/v1_covered_90e4fe01-04fc-461f-893d-bff8508f51b5.pdf"},{"id":89877717,"identity":"8a842b7e-aaea-499f-b199-78eb57023eea","added_by":"auto","created_at":"2025-08-26 04:52:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1103797,"visible":true,"origin":"","legend":"Supplementary_data","description":"","filename":"Supplementarydata.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7391041/v1/8224cc72487ac0928af7fd10.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Cortical GABAergic inhibition dynamics around hippocampal sharp-wave ripples","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":"Cortical inhibition, GABA dynamics, Sharp-wave ripples, Brain state transitions, Hippocampal–cortical communication","lastPublishedDoi":"10.21203/rs.3.rs-7391041/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7391041/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCortical inhibition, mediated by GABA, is essential in balancing excitation and modulating neural \u0026nbsp;processing, but it is unclear to what extent inhibitory dynamics are responsive to internally \u0026nbsp;generated hippocampal activity, such as sharp-wave ripples (SWRs). Employing widefield \u0026nbsp;imaging of extracellular GABA with iGABASnFR2 and hippocampal recordings, we \u0026nbsp;characterized cortical inhibition during sleep–awake states and in the neighborhood of SWRs. \u0026nbsp;Sleep–awake transitions drastically reorganized cortical levels of GABA, with increased inhibition \u0026nbsp;in wakefulness and decreased upon entering NREM sleep. In the neighborhood of SWRs, \u0026nbsp;inhibition was state- and region-specific: during NREM, medial cortices (e.g., retrosplenial) \u0026nbsp;increased GABA before SWRs, whereas sensory areas in the lateral cortices decreased it; during \u0026nbsp;wake, GABA increased in lateral cortices after SWRs. These findings reveal that cortical inhibition \u0026nbsp;is not static and ubiquitous but instead is dynamically characterized by brain state, orchestrating \u0026nbsp;the flow of hippocampal outputs to the rest of the cortex. 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