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Crf expression is responsive to arachidonic acid (AA), where CRF is released from the hypothalamic paraventricular nucleus (PVN) to initiate the hypothalamic-pituitary-adrenal axis, culminating in glucocorticoid stress hormone release. Despite this biological and clinical significance, Crf regulation is unclear. Here, we report that acyloxyacyl hydrolase, encoded by Aoah, is expressed in the PVN, and Aoah regulates Crf through the aryl hydrocarbon receptor (AhR). We previously showed that AOAH-deficient mice mimicked interstitial cystitis\/bladder pain syndrome, a condition frequently associated with comorbid anxiety and depression. With the use of novelty-suppressed feeding and sucrose preference assays to quantify rodent correlates of anxiety\/depression, AOAH-deficient mice exhibited depressive behaviors. AOAH-deficient mice also had increased CNS AA, increased Crf expression in the PVN, and elevated serum corticosterone, consistent with dysfunction of the hypothalamic-pituitary-adrenal axis. The human Crf promoter has putative binding sites for AhR and peroxisome proliferator-activated receptor (PPAR\u03b3). PPAR\u03b3 did not affect AA-dependent Crf expression in vitro, and conditional Ppar\u03b3 knockout did not alter the AOAH-deficient depressive phenotype, despite previous studies implicating PPAR\u03b3 as a therapeutic target for depression. In contrast, Crf induction was mediated by AhR binding sites in vitro and increased by AhR overexpression. Furthermore, conditional Ahr knockout rescued the depressive phenotype of AOAH-deficient mice. Finally, an AhR antagonist rescued the AOAH-deficient depressive phenotype. Together, our results demonstrate that Aoah is a novel genetic regulator of Crf mediated through AhR, and AhR is a therapeutic target for depression.<\/jats:p>","DOI":"10.1152\/ajpregu.00029.2019","type":"journal-article","created":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T19:05:29Z","timestamp":1556132729000},"page":"R289-R300","source":"Crossref","is-referenced-by-count":26,"title":["Acyloxyacyl hydrolase modulates depressive-like behaviors through aryl hydrocarbon receptor"],"prefix":"10.1152","volume":"317","author":[{"given":"Lizath M.","family":"Aguiniga","sequence":"first","affiliation":[{"name":"Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, 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