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Its activity is highly inducible by pro\u2010inflammatory cytokines and correlates with the severity of major depressive disorder (MDD). MicroRNAs (miRNAs) are involved in gene regulation and the development of neuropsychiatric disorders including MDD. However, the role of miRNAs in targeting IDO1 in the pathophysiology of MDD is still unknown. In this study, we investigated the role of novel miRNAs in the regulation of IDO1 activity and its effect on lipopolysaccharide (LPS)\u2010induced depression\u2010like behavior in mice. LPS up\u2010regulated miR\u2010874\u20103p concomitantly with increase in IDO1 expression in the prefrontal cortex (PFC), increase in immobility in the forced swimming test as depression\u2010like behavior and decrease in locomotor activity as sickness behavior without motor dysfunction. The miR\u2010874\u20103p increased in both neuron and microglia after LPS. Its mimic significantly suppressed LPS\u2010induced IDO1 expression in the PFC. Infusion of IDO1 inhibitor (1\u2010methyl\u2010<jats:italic>l<\/jats:italic>\u2010tryptophan) and miR\u2010874\u20103p into PFC prevented an increase in immobility in the forced swimming test, but did not decrease in locomotor activity induced by LPS. These results suggest that miR\u2010874\u20103p may play an important role in preventing the LPS\u2010induced depression\u2010like behavior through inhibition of IDO1 expression. This may also serve as a novel potential target molecule for the treatment of MDD.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15222-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15222","type":"journal-article","created":{"date-parts":[[2020,10,23]],"date-time":"2020-10-23T19:08:25Z","timestamp":1603480105000},"page":"1963-1978","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Prefrontal cortex miR\u2010874\u20103p prevents lipopolysaccharide\u2010induced depression\u2010like behavior through inhibition of indoleamine 2,3\u2010dioxygenase 1 expression in mice"],"prefix":"10.1111","volume":"157","author":[{"given":"Willy Jaya","family":"Suento","sequence":"first","affiliation":[{"name":"Department of Disease Control and Prevention Fujita Health University Graduate School of Health Science Aichi Japan"},{"name":"Department of Psychiatry Hasanuddin University Faculty of Medicine South Sulawesi Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4786-9681","authenticated-orcid":false,"given":"Kazuo","family":"Kunisawa","sequence":"additional","affiliation":[{"name":"Department of Regulatory Science for Evaluation &amp; 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