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Here, we showed that disruption of secretin receptor (SCTR) signaling in dorsal raphe nucleus (DRN) astrocytes promotes depression\u2010like behaviors. We identified AMPK\u03b11 as a key downstream effector of astrocytic SCTR signaling and demonstrate its role in regulating astrocytic secretion of metallothionein\u20101 (Mt1) and downstream megalin\u2010mediated AMPK\u03b12 signaling in serotonergic neurons. We further identified the transcription factor Foxc2 as a downstream target of neuronal AMPK\u03b12 that modulates depressive\u2010like behaviors through suppression of serotonergic activity and reduced neuronal excitability. Mechanistically, AMPK\u03b12 regulates phosphorylation of the acetyltransferase KAT7, thereby modulating histone H4 acetylation and Foxc2 transcription. Together, these findings delineate an astrocyte\u2013neuron signaling axis linking SCTR\u2013AMPK\u03b11 signaling in astrocytes to epigenetic regulation of Foxc2 by AMPK\u03b12\u2013KAT7\/H4ac signaling in\u00a0serotonergic neurons, providing fundamental insight into circuit\u2010level mechanisms underlying depression.<\/jats:p>","DOI":"10.1002\/advs.77985","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SCTR\u2013Expressing Astrocyte\u2013Serotonergic Neuron Signaling Drives Sexual Dimorphism in Depression Through KAT7\/H4ac\u2013Foxc2 Epigenetic Axis in an AMPK\u2010Dependent Manner"],"prefix":"10.1002","author":[{"given":"Fantao","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine Binzhou Medical University Hospital  Binzhou Shandong 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