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MDD is both a comorbidity and a risk factor for Alzheimer\u2019s disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5\/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5\/irisin expression is altered in depression remains elusive. Here, we investigate changes in<jats:italic>fndc5<\/jats:italic>expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased<jats:italic>fndc5<\/jats:italic>expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased<jats:italic>fndc5<\/jats:italic>expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased<jats:italic>fndc5<\/jats:italic>expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered<jats:italic>fndc5<\/jats:italic>expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased<jats:italic>fndc5<\/jats:italic>gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of<jats:italic>fndc5<\/jats:italic>in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex<jats:italic>fndc5<\/jats:italic>expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in<jats:italic>fndc5<\/jats:italic>mRNA suggests that decreased central FNDC5\/irisin could comprise a shared pathologic mechanism between MDD and AD.<\/jats:p>","DOI":"10.1523\/eneuro.0256-22.2023","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T18:50:18Z","timestamp":1674672618000},"page":"ENEURO.0256-22.2023","source":"Crossref","is-referenced-by-count":26,"title":["Brain FNDC5\/Irisin Expression in Patients and Mouse Models of Major Depression"],"prefix":"10.1523","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1168-149X","authenticated-orcid":false,"given":"Ricardo","family":"Lima-Filho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana 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