The nuclear receptor superfamily (NR) and ligand regulated transcription factors that have proven to be a rich source of targets for development of drugs that target myriad human diseases. The retinoic acid receptor- related orphan receptors (RORs) are members of this superfamily and regulate several physiological processes including the circadian rhythm, neural development, metabolism and the immune response. Our data suggests that activation of ROR? by synthetic ligands reduces autistic-behavior in mouse models while increasing the expression of key genes that are known to be downregulated in individuals with this disorder. ROR? inverse agonists that we discovered have been characterized for their ability to reduce proinflammatory TH17 cell differentiation, which has been shown to be associated with depression. In fact, treatment of mice with SR1001 (a ROR? inverse agonist) reduces depression-like behavior. We hypothesize that optimized ROR? agonists may hold utility in treatment of autism and that optimized ROR? inverse agonists may hold utility in the treatment of depression. In order to address these hypotheses we propose the following 2 specific aims: Aim 1: Develop and optimize ROR? agonists for treatment of autism and Aim 2: Develop and optimize ROR? inverse agonists for treatment of depression. The studies described in this application are highly innovative given that we have developed a range of novel, first-in-class ROR ligands and we have demonstrated that these compounds have efficacy in mouse models of autism as well as TH17 cell mediated diseases. If successful, this work would have significant impact given the potential translation of this work into drugs in the clinic.