{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:19:51Z","timestamp":1791569991405,"version":"4.3.4"},"reference-count":56,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation (ISF)","doi-asserted-by":"publisher","award":["993\/20"],"award-info":[{"award-number":["993\/20"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Early life stress (ELS) increases predisposition to major depressive disorder (MDD), with neuroinflammation playing a crucial role. This study investigated the long-term effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on ELS-induced depressive-like behavior and messenger RNA (mRNA) of pro-inflammatory cytokines in the medial prefrontal cortex (mPFC) and CA1 regions. We also assessed whether these gene expression alterations were present at the onset of URB597 treatment during late adolescence. ELS induced a depressive-like phenotype in adult male and female rats, which was reversed by URB597. In the mPFC, ELS downregulated nuclear factor kappa B1 (nf\u03bab1) in both sexes, while URB597 normalized this expression exclusively in males. In females, ELS downregulated interleukin (il) 6 and tumor necrosis factor alpha (tnf\u03b1) but upregulated il1\u03b2 and corticotropin-releasing factor (crf); URB597 normalized il6, il1\u03b2, and crf. In the CA1, ELS downregulated il1\u03b2 and tnf\u03b1 in males and upregulated il1\u03b2 expression in females, which was reversed by URB597. Some of these effects began in late adolescence, including mPFC-nf\u03bab1 expression in both sexes, mPFC-il6 and mPFC-il1\u03b2 in females, CA1-il1\u03b2 and CA1-tnf\u03b1 in males, and CA1-il1\u03b2 in females. These findings highlight URB597 as a therapeutic approach for reversing ELS-induced depressive-like behavior by associating with changes in the gene expression of neuroinflammatory cytokines, with notable sex differences.<\/jats:p>","DOI":"10.3390\/cells13221881","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T08:06:32Z","timestamp":1731571592000},"page":"1881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["FAAH Inhibition Reverses Depressive-like Behavior and Sex-Specific Neuroinflammatory Alterations Induced by Early Life Stress"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8848-7139","authenticated-orcid":false,"given":"Anna","family":"Portugalov","sequence":"first","affiliation":[{"name":"School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa 3498838, Israel"},{"name":"The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7633-5953","authenticated-orcid":false,"given":"Irit","family":"Akirav","sequence":"additional","affiliation":[{"name":"School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa 3498838, Israel"},{"name":"The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s12264-021-00638-3","article-title":"Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications","volume":"37","author":"Li","year":"2021","journal-title":"Neurosci. 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