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A glutamatergic projection from the ventral CA1 (vCA1) to the dorsomedial prefrontal cortex (dmPFC) is identified as a critical pathway for morphine reward memory retrieval. In vivo monitoring and ex vivo electrophysiology show that vCA1 inputs engage distinct dmPFC neuronal populations and differentially regulate local parvalbumin (PV+) and somatostatin (SST+) interneurons, thereby reshaping cortical output during memory retrieval. Pathway\u2010specific inhibition abolishes cue\u2010induced memory retrieval, which is restored by local NMDA administration, whereas blockade of NMDA receptors in the dmPFC impairs retrieval during pathway activation, supporting a critical role for NMDA receptor signaling in memory retrieval driven by vCA1 input. Beyond reward memory, chronic inhibition of the vCA1\u2013dmPFC pathway attenuates somatic withdrawal and the development of analgesic tolerance without affecting the acute analgesic effect of morphine. Together, these findings reveal a cell\u2010type\u2010specific hippocampal\u2013prefrontal mechanism regulating opioid\u2010associated maladaptive behaviors and provide a potential circuit\u2010level strategy to reduce addiction\u2010related consequences while preserving morphine analgesia.<\/jats:p>","DOI":"10.1002\/advs.77735","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:29:12Z","timestamp":1789619352000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the Neural Circuit Underlying Context\u2010Cue Association in Retrieval of Morphine Reward Memory"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1553-6434","authenticated-orcid":false,"given":"Zhifeng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology First Affiliated Hospital of Soochow University  Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"},{"name":"Institute of Anesthesiology Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangying","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9734-3241","authenticated-orcid":false,"given":"Qian","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rusun","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghan","family":"Gu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingmei","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Biology &amp; Food Sciences Suzhou University of Technology  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3755-3373","authenticated-orcid":false,"given":"John L.","family":"Waddington","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"},{"name":"School of Pharmacy and Biomolecular Sciences RCSI University of Medicine and Health Sciences  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3269-3417","authenticated-orcid":false,"given":"Fuhai","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology First Affiliated Hospital of Soochow University  Suzhou Jiangsu China"},{"name":"Institute of Anesthesiology Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7458-2566","authenticated-orcid":false,"given":"Xuechu","family":"Zhen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology First Affiliated Hospital of Soochow University  Suzhou Jiangsu China"},{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research For Brain Diseases College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu China"},{"name":"Institute of Anesthesiology Soochow University  Suzhou Jiangsu China"},{"name":"College of Biology &amp; Food Sciences Suzhou University of Technology  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586\u2010018\u201000045\u20101"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)33078\u20102"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20174302"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.3390\/ph14111091","article-title":"Opioid Analgesia and Opioid\u2010Induced Adverse Effects: A Review","volume":"14","author":"Paul A. 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