Corticotropin-releasing factor (CRF) regulates stress responses, and aberrant CRF signals are associated with depressive disorders. 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, regulation is unclear. Here, we report that acyloxyacyl hydrolase, encoded by , is expressed in the PVN, and regulates 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 expression in the PVN, and elevated serum corticosterone, consistent with dysfunction of the hypothalamic-pituitary-adrenal axis. The human promoter has putative binding sites for AhR and peroxisome proliferator-activated receptor (PPARγ). PPARγ did not affect AA-dependent expression in vitro, and conditional γ knockout did not alter the AOAH-deficient depressive phenotype, despite previous studies implicating PPARγ as a therapeutic target for depression. In contrast, induction was mediated by AhR binding sites in vitro and increased by AhR overexpression. Furthermore, conditional knockout rescued the depressive phenotype of AOAH-deficient mice. Finally, an AhR antagonist rescued the AOAH-deficient depressive phenotype. Together, our results demonstrate that is a novel genetic regulator of mediated through AhR, and AhR is a therapeutic target for depression.