{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:10:12Z","timestamp":1792786212954,"version":"4.5.0"},"posted":{"date-parts":[[2025,9,17]]},"group-title":"Neuroscience","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["R01NS082046"],"award-info":[{"award-number":["R01NS082046"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["R01NS038572"],"award-info":[{"award-number":["R01NS038572"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"award":["K01MH121567"],"award-info":[{"award-number":["K01MH121567"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Temporal lobe epilepsy (TLE) is associated with cognitive, social, and emotional comorbidities that persist between seizures and remain poorly addressed by seizure-focused treatment. We examined whether these interictal deficits reflect altered ventral CA1\/subiculum (vCA1\/Sub) output and whether shifting principal-cell excitability can improve behavior despite persistent pathology. In pilocarpine-treated mice, vCA1\/Sub principal neurons were depolarized and showed altered recruitment, alveus\/oriens stimulation produced diminished hyperpolarizing responses, and parvalbumin- and somatostatin-immunopositive cell densities were reduced in stratum oriens. Epileptic mice did not demonstrate social discrimination above chance despite retained social approach and social-odor preference and showed increased open-field center avoidance. Multiplexed chemogenetic inhibition of vCA1\/Sub principal cells improved social discrimination and center exploration, whereas stronger inhibition did not reproduce the social-memory benefit. Within individual mice, discrimination was higher in predicted retuned than off-optimal states, and performance across inferred excitability states followed an inverted-U-like relationship. Anxiety-related and social improvements covaried across epileptic mice, consistent with shared dependence on vCA1\/Sub circuit state. In a separate EEG cohort, moderate inhibition suppressed local hippocampal activity during the behavior-aligned interval without detectably reducing spontaneous seizures or early interictal spikes. These findings identify excessive vCA1\/Sub output as a modifiable contributor to socio-affective dysfunction in TLE and show that retuning a disease-altered circuit can improve interictal behavior without acute seizure suppression.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"simple\">\n                    <jats:list-item>\n                      <jats:p>Chronic epilepsy shifts vCA1\/Sub toward a depolarized, disinhibited output state<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Moderate vCA1\/Sub inhibition improves social discrimination in epileptic mice<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Stronger inhibition does not reproduce the behavioral benefit<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>vCA1\/Sub inhibition improves behavior without acute seizure suppression<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.12.675815","type":"posted-content","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T20:05:21Z","timestamp":1758139521000},"source":"Crossref","is-referenced-by-count":1,"title":["Retuning ventral hippocampal output improves social memory and reduces anxiety-related behavior in temporal lobe epilepsy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5288-3667","authenticated-orcid":false,"given":"Anthoni","family":"Goodman","sequence":"first","affiliation":[{"name":"Univeristy of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8831-8826","authenticated-orcid":false,"given":"Emily","family":"Schellinger","sequence":"additional","affiliation":[{"name":"Univeristy of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5046-1003","authenticated-orcid":false,"given":"Julia","family":"Kahn","sequence":"additional","affiliation":[{"name":"Univeristy of Alabama at Birmingham"},{"name":"Division of Neurology and CHOP Research Institute, Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3033-2412","authenticated-orcid":false,"given":"Hajime","family":"Takano","sequence":"additional","affiliation":[{"name":"Univeristy of Alabama at Birmingham"},{"name":"Division of Neurology and CHOP Research Institute, Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1486-119X","authenticated-orcid":false,"given":"Douglas","family":"Coulter","sequence":"additional","affiliation":[{"name":"Univeristy of Alabama at Birmingham"},{"name":"Division of Neurology and CHOP Research Institute, Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3680-1358","authenticated-orcid":false,"given":"Srdjan","family":"Joksimovic","sequence":"additional","affiliation":[{"name":"Univeristy of Alabama at Birmingham"},{"name":"Division of Neurology and CHOP Research Institute, Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026102105500468000_2025.09.12.675815v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2013.11.010"},{"key":"2026102105500468000_2025.09.12.675815v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2014.05.021"},{"key":"2026102105500468000_2025.09.12.675815v2.3","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12186"},{"key":"2026102105500468000_2025.09.12.675815v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2020.04.028"},{"key":"2026102105500468000_2025.09.12.675815v2.5","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0270-21.2021"},{"key":"2026102105500468000_2025.09.12.675815v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06501-w"},{"key":"2026102105500468000_2025.09.12.675815v2.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf7003"},{"key":"2026102105500468000_2025.09.12.675815v2.8","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44182"},{"key":"2026102105500468000_2025.09.12.675815v2.9","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0429-22.2022"},{"key":"2026102105500468000_2025.09.12.675815v2.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1535-7511.2005.00049.x"},{"key":"2026102105500468000_2025.09.12.675815v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2015.05.009"},{"key":"2026102105500468000_2025.09.12.675815v2.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03215.x"},{"key":"2026102105500468000_2025.09.12.675815v2.13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03504.x"},{"key":"2026102105500468000_2025.09.12.675815v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.01.028"},{"key":"2026102105500468000_2025.09.12.675815v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2015.189"},{"key":"2026102105500468000_2025.09.12.675815v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/82900"},{"key":"2026102105500468000_2025.09.12.675815v2.17","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10622"},{"key":"2026102105500468000_2025.09.12.675815v2.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(96)00054-X"},{"key":"2026102105500468000_2025.09.12.675815v2.19","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn095"},{"key":"2026102105500468000_2025.09.12.675815v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/srep42090"},{"key":"2026102105500468000_2025.09.12.675815v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-52277-z"},{"key":"2026102105500468000_2025.09.12.675815v2.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2022.105859"},{"key":"2026102105500468000_2025.09.12.675815v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(83)90136-5"},{"key":"2026102105500468000_2025.09.12.675815v2.24","first-page":"255","article-title":"Experimental models of chronic focal epilepsy: a critical review of four models","volume":"60","year":"1987","journal-title":"Yale J. Biol. Med"},{"key":"2026102105500468000_2025.09.12.675815v2.25","doi-asserted-by":"publisher","DOI":"10.2174\/187152410793429746"},{"key":"2026102105500468000_2025.09.12.675815v2.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.0013-9580.2003.12004.x"},{"key":"2026102105500468000_2025.09.12.675815v2.27","doi-asserted-by":"publisher","DOI":"10.1113\/JP274565"},{"key":"2026102105500468000_2025.09.12.675815v2.28","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2000.84.5.2398"},{"key":"2026102105500468000_2025.09.12.675815v2.29","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.37701"},{"key":"2026102105500468000_2025.09.12.675815v2.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.031"},{"key":"2026102105500468000_2025.09.12.675815v2.31","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh004"},{"key":"2026102105500468000_2025.09.12.675815v2.32","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410290316"},{"key":"2026102105500468000_2025.09.12.675815v2.33","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv227"},{"key":"2026102105500468000_2025.09.12.675815v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(07)63014-3"},{"key":"2026102105500468000_2025.09.12.675815v2.35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.185bu.x"},{"key":"2026102105500468000_2025.09.12.675815v2.36","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2992-05.2005"},{"key":"2026102105500468000_2025.09.12.675815v2.37","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.450030309"},{"key":"2026102105500468000_2025.09.12.675815v2.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52466-4"},{"key":"2026102105500468000_2025.09.12.675815v2.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.05.035"},{"key":"2026102105500468000_2025.09.12.675815v2.40","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00167"},{"key":"2026102105500468000_2025.09.12.675815v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0559-0"},{"key":"2026102105500468000_2025.09.12.675815v2.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2025.107155"},{"key":"2026102105500468000_2025.09.12.675815v2.43","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz209"},{"key":"2026102105500468000_2025.09.12.675815v2.44","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318297ee50"},{"key":"2026102105500468000_2025.09.12.675815v2.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2014.02.013"},{"key":"2026102105500468000_2025.09.12.675815v2.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41536-022-00234-7"},{"key":"2026102105500468000_2025.09.12.675815v2.47","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00167"},{"key":"2026102105500468000_2025.09.12.675815v2.48","unstructured":"Study Details | FIH Study of NRTX-1001 Neural Cell Therapy in Drug-Resistant Unilateral Mesial Temporal Lobe Epilepsy | ClinicalTrials.gov https:\/\/clinicaltrials.gov\/study\/NCT05135091?term=NCT05135091&city=&rank=1."},{"key":"2026102105500468000_2025.09.12.675815v2.49","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12100"},{"key":"2026102105500468000_2025.09.12.675815v2.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2021.107868"},{"key":"2026102105500468000_2025.09.12.675815v2.51","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3392"},{"key":"2026102105500468000_2025.09.12.675815v2.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0103-x"},{"key":"2026102105500468000_2025.09.12.675815v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.08.013"},{"key":"2026102105500468000_2025.09.12.675815v2.54","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4847"},{"key":"2026102105500468000_2025.09.12.675815v2.55","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2376"},{"key":"2026102105500468000_2025.09.12.675815v2.56","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2020.00113"},{"key":"2026102105500468000_2025.09.12.675815v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.03.065"},{"key":"2026102105500468000_2025.09.12.675815v2.58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700293104"},{"key":"2026102105500468000_2025.09.12.675815v2.59","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214985"},{"key":"2026102105500468000_2025.09.12.675815v2.60","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(72)90177-0"},{"key":"2026102105500468000_2025.09.12.675815v2.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0209-y"},{"key":"2026102105500468000_2025.09.12.675815v2.62","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.19.049452"},{"key":"2026102105500468000_2025.09.12.675815v2.63","doi-asserted-by":"publisher","DOI":"10.1002\/0471140856.tx1118s63"},{"key":"2026102105500468000_2025.09.12.675815v2.64","doi-asserted-by":"publisher","DOI":"10.1111\/2041-210X.12584"},{"key":"2026102105500468000_2025.09.12.675815v2.65","doi-asserted-by":"publisher","DOI":"10.3389\/fcomp.2022.777728"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.12.675815","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T12:50:13Z","timestamp":1792587013000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.09.12.675815"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":65,"URL":"https:\/\/doi.org\/10.1101\/2025.09.12.675815","relation":{},"subject":[],"published":{"date-parts":[[2025,9,17]]},"subtype":"preprint"}}