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Acute sleep deprivation (SD) produces rapid but transient antidepressant effects, yet the underlying mechanisms remain poorly understood. Using a mouse model of stress-induced depression, we found altered sleep architecture, impaired sleep homeostasis, and disrupted day-night oscillations of the markers of glutamatergic plasticity - Homer1a and synaptic AMPAR expression in the medial prefrontal cortex (mPFC). These changes were accompanied by a blunted homeostatic response to SD. We further show that SD and ketamine, both rapid-acting antidepressants, exert opposing effects on mPFC circadian gene expression: SD enhances the expression of negative clock loop genes (e.g.,\n                    <jats:italic>Per<\/jats:italic>\n                    ,\n                    <jats:italic>Cry<\/jats:italic>\n                    ), mirroring stress effects, while ketamine downregulates these same genes. Targeted deletion of the core clock gene\n                    <jats:italic>Bmal1<\/jats:italic>\n                    in CaMK2a-expressing excitatory neurons of the mPFC disrupted sleep-wake architecture, elevated slow-wave activity, and abolished the behavioral and molecular (Homer1a) response to SD. Additionally, pharmacological activation of the clock repressor REV-ERB suppressed the antidepressant effects of SD. Our results demonstrate that the mPFC molecular clock is essential for the regulation of sleep consolidation and homeostasis, and mediates the effects of SD on behavior.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03276-7","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T14:22:09Z","timestamp":1759155729000},"page":"1530-1545","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The mPFC molecular clock mediates the effects of sleep deprivation on depression-like behavior and regulates sleep consolidation and homeostasis"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-9873","authenticated-orcid":false,"given":"Wilf","family":"Gardner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1326-3232","authenticated-orcid":false,"given":"David H.","family":"Sarrazin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Balzinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Marchese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axelle","family":"Ragno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3668-4478","authenticated-orcid":false,"given":"Chockalingam","family":"Ramanathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6760-3488","authenticated-orcid":false,"given":"Maxime","family":"Veleanu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9150-8712","authenticated-orcid":false,"given":"Stefan","family":"Vestring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5693-8936","authenticated-orcid":false,"given":"Claus","family":"Normann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Bourgin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2234-2875","authenticated-orcid":false,"given":"Tsvetan","family":"Serchov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"3276_CR1","unstructured":"World mental health report: transforming mental health for all. 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All other authors declare that they have no competing interests to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The Chronobiotron animal facility (Strasbourg) is registered for animal experimentation (Agreement A67-2018-38). All procedures were performed in accordance with the German animal protection law (TierSchG), FELASA (\n                      \n                      ), the guide for care and use of laboratory animals of the national animal welfare body GV-SOLAS\n                      \n                      ) and the EU Directive 2010\/63\/EU for animal experiments and were approved by the local animal welfare committee of the University of Freiburg (X-20\/06R, 35-9185.81\/G-19\/44 and G-15\/117) and University of Strasbourg (CREMEAS, APAFIS n\u00b02020042818477700).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}