Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Episodic Memory Circuits

Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Episodic Memory Circuits | 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 Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Episodic Memory Circuits Hui Zhang, Zorica Petrovic, Elizabeth Wood, Ana Cicvaric, Maayan Krispil-Alon, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6864379/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Impairments of episodic memory, the capacity to remember and re-live details from one’s past, are common across mental illnesses, but are particularly severe in those with late adolescent onset, such as schizophrenia and major depression. Using mice, we demonstrate that during late adolescence, the retrosplenial cortex (RSP), an established hub of episodic memory and default mode networks, undergoes extensive reorganization, interfering with memory functions and potentially increasing vulnerability to these illnesses. Specifically, we demonstrated that the levels of perineuronal nets (PNN), key PNN constituents, and parvalbumin-positive (PVALB) interneurons established during early adolescence (p30), significantly declined by late adolescence(p60-75). Using context fear conditioning (CFC), we found that these structural, molecular, and cellular changes facilitated the formation of long-lasting and context-specific memories, but at the expense of memories acquired during early adolescence. Interestingly, early adolescent memories spontaneously recovered by middle adulthood but lost context specificity. The observed neurobiological and behavioral changes were attenuated by stabilizing PNN, and exacerbated by disrupting PNN, suggesting that PVALB neuron loss and memory expression deficits were secondary to PNN degradation. These findings showed that despite its superior performance during early adolescence relative to early life, the RSP memory circuit does not show full cortical maturity until late adolescence. In susceptible individuals, the observed dynamics of the extracellular matrix and PVALB neurons could interact with genetic factors, increasing risk for the development of late adolescent psychopathologies. Biological sciences/Neuroscience/Molecular neuroscience Biological sciences/Neuroscience/Learning and memory Full Text Additional Declarations The authors declare no competing interests. Supplementary Files Supplementaryinformation.docx Supplementary Information Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-6864379","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":512859544,"identity":"307e468c-546f-4999-91f1-fdb032e27055","order_by":0,"name":"Hui Zhang","email":"","orcid":"https://orcid.org/0000-0002-1755-4494","institution":"Dominick P. 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