{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T18:43:56Z","timestamp":1786214636060,"version":"build-2736575974"},"posted":{"date-parts":[[2025,12,26]]},"group-title":"Neuroscience","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["ZIA NS009415"],"award-info":[{"award-number":["ZIA NS009415"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The cognitive map in the medial entorhinal cortex (MEC) is essential for spatial memory and exhibits experience-dependent changes. Yet, it remains unclear whether MEC activation is sufficient to bias the network toward memory-guided navigation, precluding a causal link between the MEC and spatial memory. To address this gap, we examined and optogenetically manipulated MEC activity as mice navigated a virtual track for a water reward based on memory. During learning, spatial activity in the pre-reward region showed the highest consistency along the track and closely paralleled improvements in reward-predictive behaviors. This elevated pre-reward consistency was widespread across MEC neurons, rather than confined to a particular cell type, indicating a network-level representation supporting reward prediction. Strikingly, optogenetic activation of MEC at non-reward locations biased reward-predictive behaviors toward stimulation sites, but only when stimulation patterns were spatially consistent. Consistent stimulation also induced anticipatory reward-seeking before stimulation onset and this behavior gradually developed with repeated stimulation, reflecting memory formation for stimulation locations. Moreover, in animals that failed to learn the track well, consistent pre-reward activation, alone or combined with landmark activation, significantly enhanced their reward prediction. Thus, spatially consistent MEC activation underlies memory-guided reward prediction, supporting a causal role for the MEC in spatial memory.<\/jats:p>","DOI":"10.64898\/2025.12.24.696388","type":"posted-content","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T17:40:21Z","timestamp":1766770821000},"source":"Crossref","is-referenced-by-count":0,"title":["Activation of the medial entorhinal cortex drives memory-guided navigation behavior"],"prefix":"10.64898","author":[{"given":"Yan","family":"Ma","sequence":"first","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor J.","family":"Malone","sequence":"additional","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Wen","family":"Tien","sequence":"additional","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"June Hoan","family":"Kim","sequence":"additional","affiliation":[{"name":"Section on Cellular and Synaptic Physiology, Eunice Kennedy Shriver National Institute of Child and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxym V.","family":"Myroshnychenko","sequence":"additional","affiliation":[{"name":"Integrative Neuroscience Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Tyan","sequence":"additional","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Yusufi","sequence":"additional","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Shahid","sequence":"additional","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kupferschmidt","sequence":"additional","affiliation":[{"name":"Integrative Neuroscience Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA"},{"name":"Section on Functional Neural Circuits, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Gu","sequence":"additional","affiliation":[{"name":"Spatial Navigation and Memory Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080811400735000_2025.12.24.696388v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1932"},{"key":"2026080811400735000_2025.12.24.696388v2.2","unstructured":"O\u2019Keefe, J. , and Nadel, L . 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