PROJECT SUMMARY IMPULSIVITY (PROJECT 1) Impulsivity describes a heightened propensity to engage in excessive reward pursuit or consumption, perhaps resulting from unusually strong motivational urges to obtain the reward and/or difficulty with reasoning about the consequences of, or suppressing, reward-related behaviors. High levels of impulsivity segregate with recreational and clinically impairing drug use in humans, including the initiation of misuse, escalation into repetitive and habitual use and attempts to achieve and maintain abstinence. Impulsive behaviors can both predict susceptibility for relatively greater drug self-administration in both humans and animal models and result from experience with stimulant drugs of abuse. The overall objective of Project 1 is to identify genetic, genomic and neurobiological mechanisms contributing to individual differences in impulsive behaviors that may be relevant to addiction. The scientific synergy made possible through collaboration with investigators, projects and cores within the CSNA is designed to generate insights into the genetic correlations between impulsivity and other biobehavioral risk factors for addiction, novel genetic variations and gene expression mechanisms associated with reinforcement learning and impulsivity, and neural mechanisms by which the identified variants act to influence behavior. Using the high diversity Collaborative Cross (CC) and Diversity Outbred (DO) lines that represent powerful polygenic models of trait variation, we will: 1) assess shared mechanisms among measures of impulsivity and novelty-related behaviors, psychomotor and incentive sensitization to cocaine and cocaine IVSA and 2) identify molecular mechanisms underlying variation in impulsive behavior using gene expression correlations and genetic mapping. We will also design, create and phenotype engineered CC strains reliably exhibiting variable behavioral phenotypes to test the role for candidate genes in regulating impulsive behaviors and underlying neurobiology. These analyses represent one of the deepest phenotypic and genomic analysis of impulsivity yet conducted and will expose new biological influences on inter-individual differences in addiction liability.