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The ventral tegmental area (VTA) dopaminergic (DA) neurons and the dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons are key components of the ascending arousal system. This study investigated the existence and functional role of VTA\n                    <jats:sup>DA<\/jats:sup>\n                    \u2192DRN\n                    <jats:sup>5-HT<\/jats:sup>\n                    circuit in regulating propofol anesthesia. Using virus-mediated neural circuit tracing in DAT-Cre and TPH2-CreER transgenic mice, we demonstrated an anatomically connected circuit appositions between VTA\n                    <jats:sup>DA<\/jats:sup>\n                    axon terminals and DRN\n                    <jats:sup>5-HT<\/jats:sup>\n                    neurons. In vivo fiber photometry revealed that the activity of both presynaptic VTA\n                    <jats:sup>DA<\/jats:sup>\n                    terminals in the DRN and postsynaptic DRN\n                    <jats:sup>5-HT<\/jats:sup>\n                    neurons was significantly suppressed under propofol anesthesia. Chemogenetic activation of either VTA\n                    <jats:sup>DA<\/jats:sup>\n                    or DRN\n                    <jats:sup>5-HT<\/jats:sup>\n                    neurons facilitated emergence from propofol anesthesia, whereas their inhibition prolonged the duration of anesthesia. Optogenetic activation of VTA\n                    <jats:sup>DA<\/jats:sup>\n                    terminals within the DRN rapidly induced behavioral and electroencephalographic (EEG) arousal from stable propofol anesthesia. Crucially, this pro-arousal effect was abolished by chemogenetic inhibition of DRN\n                    <jats:sup>5-HT<\/jats:sup>\n                    neurons, indicating a functional hierarchy. These findings identify a putative direct pathway VTA\n                    <jats:sup>DA<\/jats:sup>\n                    \u2192DRN\n                    <jats:sup>5-HT<\/jats:sup>\n                    circuit that bidirectionally regulates propofol anesthesia, providing a novel neural substrate for conscious state control and a potential target for therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1186\/s13062-026-00736-0","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T03:17:13Z","timestamp":1770607033000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A dopaminergic projection from the ventral tegmental area to the dorsal raphe nucleus critically regulates propofol anesthesia in mice"],"prefix":"10.1186","volume":"21","author":[{"given":"Junjie","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichuan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuangzhuang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ketao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangwen","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"736_CR1","doi-asserted-by":"publisher","unstructured":"Brown EN, Lydic R, Schiff ND. 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The experimental procedures were approved by the Animal Research Committee by Shihezi University (Approval No. A2024-367).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics declaration"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"28"}}