Aging-related vulnerability in dopamine–glutamate neurons weakens entorhinal dopamine signaling and underlies novelty discrimination deficits

Aging-related vulnerability in dopamine–glutamate neurons weakens entorhinal dopamine signaling and underlies novelty discrimination deficits | 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 Aging-related vulnerability in dopamine–glutamate neurons weakens entorhinal dopamine signaling and underlies novelty discrimination deficits Susana Mingote, Jacquelyn Tomaio, Yifei Li, Omar Ghazy, Gillian Pavia, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9321992/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 lateral entorhinal cortex supports novelty detection and episodic memory and is highly vulnerable to aging. Dopamine conveys novelty signals in this region, but how aging alters this input is unknown. Using viral strategies to distinguish ventral tegmental area dopamine neurons with or without glutamate co-release, we show that co-releasing neurons comprise about 30% of dopamine neurons yet provide nearly all dopaminergic input to the lateral entorhinal cortex. In aged mice, these axons show reduced markers of dopamine synthesis and diminished dopamine release during high-frequency activity, whereas glutamate-related markers are reduced to a lesser extent. Stimulation of lateral entorhinal dopaminergic axons during novelty exploration restores novelty discrimination in aged mice. Together, these findings identify the age-related vulnerability of dopamine-glutamate neurons as a circuit-specific mechanism that impairs entorhinal dopamine signaling and underlies to deficits in novelty discrimination. Biological sciences/Neuroscience/Cognitive ageing Biological sciences/Neuroscience/Neural ageing Biological sciences/Neuroscience/Learning and memory/Hippocampus Biological sciences/Neuroscience/Neural circuits Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryVideo1YoungMouse.mov Supplementary Video 1 | Tyrosine hydroxylase and EYFP expression in dopaminergic axons in the LEC of a young mouse SupplementaryVideo2AgedMouse.mov Supplementary Video 2 | Tyrosine hydroxylase and EYFP expression in dopaminergic axons in the LEC of an aged mouse 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. 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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-9321992","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":628202822,"identity":"28425146-e398-4e42-a97f-f8329ab97269","order_by":0,"name":"Susana 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