{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:02:14Z","timestamp":1782280934063,"version":"3.54.5"},"posted":{"date-parts":[[2025,3,24]]},"group-title":"Neuroscience","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not fully understood. Here we show that the intrinsic membrane excitability of IL layer 5 pyramidal neurons projecting to the NAc shell (IL-NAcSh neurons) suppresses cocaine-associated memories. Following repeated cocaine exposures in a conditioned place preference paradigm, IL-NAcSh neurons anatomically traced by fluorescent retrobeads undergo prolonged decrease of membrane excitability, lasting for at least 15 days after cocaine withdrawal. This persistent IL-NAcSh neuron hypoexcitability was accompanied by an increase in the rheobase, an increase in the afterhyperpolarization potential, and a decrease in the membrane input resistance. This cocaine induced neuroadapation in intrinsic excitability was not observed in prelimibic cortex neurons projecting to the NAc core (PL-NAcCo neurons), a separate descending circuit thought to promote cue-triggered drug seeking. Chemogenetic restoration of IL-NAcSh neuron activity extinguishes both the acquisition and retention of cocaine conditioned place preference memories. Our results provide direct support for the notion that the IL-NAcSh circuit serves to extinct drug associated memories and restoring the drug impaired excitability of IL-NAcSh neurons has the potential to mitigate drug-cue association memories and drug seeking.<\/jats:p>","DOI":"10.1101\/2025.03.21.644656","type":"posted-content","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T04:11:41Z","timestamp":1742875901000},"source":"Crossref","is-referenced-by-count":2,"title":["A Prefrontal Cortex-Nucleus Accumbens Circuit Attenuates Cocaine-conditioned Place Preference Memories"],"prefix":"10.64898","author":[{"given":"Xiaobo","family":"Wu","sequence":"first","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY 13210"},{"name":"Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Jiangsu, China, 226019"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya M.","family":"Kobeissi","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihui","family":"Dai","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5124-1486","authenticated-orcid":false,"given":"Wei-Dong","family":"Yao","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY 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