Integrating genetic and circuit variation to identify genes involved in behaviors related to substance use disorder

PROJECT SUMMARY The goal of this proposal is to identify genes that affect behaviors associated with substance use disorders (SUD) using a novel mechanism-to-gene strategy. Standard genome wide association strategies applied to behavior in humans or model organisms have not so far provided much mechanistic insight into the origins of psychiatric disease. In this project we address this problem by genetic mapping of circuit-driven behavioral output. We examine a circuit involved in anxiety-related behaviors that are comorbid with SUD. Optogenetic activation of this circuit, from the ventral hippocampus (vCA1) to lateral hypothalamus (LH), results in large quantitative differences in anxiety-related behaviors in different inbred mouse strains. These differences are highly heritable and amenable to genetic mapping. Since a circuit's function arises from a limited set of cellular and anatomic features, identifying the genes that are involved in circuit function will generate hypotheses on the mechanisms underlying the behavioral differences and hence of SUD. We will identify the genes and likely mechanisms through three aims: 1) determine heritability and behavioral variation of optogenetic activation of the vCA1-LH pathway in eight inbred strains 2) genetically map optogenetically-evoked behaviors of the vCA1-LH pathway using 800 diversity outbred mice derived from those eight strains, and 3) apply quantitative complementation tests to find which genes act through the vCA1-LH pathway to alter the behavioral function of this pathway. These experiments will allow us to identify where and how in the brain genetic variation gives rise to behavioral variation, and will demonstrate the importance of integrating systems neuroscience and genetic approaches.