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Establishing the mechanisms underpinning declining physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HT\n                  <jats:sup>DR<\/jats:sup>\n                  tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT\n                  <jats:sub>2C<\/jats:sub>\n                  receptors (5-HT\n                  <jats:sub>2C<\/jats:sub>\n                  Rs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT\n                  <jats:sub>2C<\/jats:sub>\n                  Rs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.\n                <\/jats:p>","DOI":"10.64898\/2025.12.27.695444","type":"posted-content","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:15:11Z","timestamp":1767179711000},"source":"Crossref","is-referenced-by-count":0,"title":["Brain serotonin circuit reverses decline in physical activity with age"],"prefix":"10.64898","author":[{"given":"Pablo B.","family":"Martinez de Morentin","sequence":"first","affiliation":[{"name":"The Rowett Institute, Aberdeen UK"},{"name":"School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair","family":"Leeson-Payne","sequence":"additional","affiliation":[{"name":"The Rowett Institute, Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Mu","sequence":"additional","affiliation":[{"name":"The Rowett Institute, Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliia","family":"Martynova","sequence":"additional","affiliation":[{"name":"The Rowett Institute, Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Mohammadkhani","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary Calgary, Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew M.","family":"Neyens","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary Calgary, Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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