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Despite ketamine exhibiting rapid relief of the core symptoms of PTSD, its clinical efficacy varies considerably depending on the timing of drug delivery. However, the underlying mechanism remains unclear. In this study, the therapeutic effects of early (day 1) and late (day 7) administration of\n                    <jats:italic>S<\/jats:italic>\n                    \u2010Ketamine on behavioral phenotypes in rodent's models of PTSD are compared. It is observed that early rather than late administration of\n                    <jats:italic>S<\/jats:italic>\n                    \u2010Ketamine significantly ameliorates PTSD symptoms, especially impaired fear extinction. The firing and burst rates of VTA\n                    <jats:sup>DA<\/jats:sup>\n                    neurons consecutively decrease following PTSD modeling and are restored by early\n                    <jats:italic>S<\/jats:italic>\n                    \u2010Ketamine intervention. In particular, VTA\n                    <jats:sup>DA<\/jats:sup>\n                    neurons respond to the conditioned stimuli, mediating the replacement of aversive memory encoding during fear extinction. The inhibition of VTA\n                    <jats:sup>DA<\/jats:sup>\n                    \u2010OFC interrupts the PTSD treatment induced by\n                    <jats:italic>S<\/jats:italic>\n                    \u2010Ketamine. A non\u2010invasive temporally interfering brain stimulation targeting the OFC is further developed, sensitizing cortical dopaminergic transmission and extending the effective time window of\n                    <jats:italic>S<\/jats:italic>\n                    \u2010Ketamine for anti\u2010PTSD. Overall, a neural mechanism for the heterogeneous VTA\n                    <jats:sup>DA<\/jats:sup>\n                    \u2010OFC neurocircuit\u2010mediated time\u2010dependent therapeutic effect of\n                    <jats:italic>S<\/jats:italic>\n                    \u2010Ketamine is illustrated. In addition, a novel technique is developed to optimize the strategy of ketamine\u2010assisted psychotherapy for PTSD treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202500805","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T09:23:57Z","timestamp":1758792237000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Time\u2010Dependent Therapeutic Effect of\n                    <i>S<\/i>\n                    \u2010Ketamine on PTSD Mediated by VTA\u2010OFC Dopaminergic Neurocircuit"],"prefix":"10.1002","volume":"12","author":[{"given":"Ye","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine Xijing Hospital The Fourth Military Medical University  Xi'an 710032 China"},{"name":"Department of Pharmacology School of Pharmacy The Fourth Military Medical University  Xi'an 710032 China"},{"name":"Key Laboratory of 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