––– PROJECT SUMMARY/ABSTRACT ––––––––––––––––– The Genetics of Impulsivity and Motivation ––– One way to isolate novel genes contributing to addiction is to focus on endophenotypes, more circumscribed biological and behavioral markers well-correlated with the substance use disorder (SUD). Impulsivity, making rash decisions and ‘bad’/costly choices, and motivation, the impetus for goal-directed behavior and the willingness to incur effort or cost to reach said goal, are key behavioral domains that are common to all SUDs, but their genetic underpinnings are poorly understood. The vinegar fly, Drosophila melanogaster, has been a genetic model organism for more than a hundred years. Major strides have been made in the last 15 years studying the behavioral responses to alcohol and other drugs of abuse in flies, both in characterizing novel conserved genes and pathways, but also in the development of new assays that resemble endophenotypes of addiction more closely. The goal of this proposal is to isolate, validate, and functionally characterize genes that affect a novel model of impulsivity and motivation. In our newly developed Fly Liquid-food Electroshock Assay (FLEA), Drosophila choose between two wells of liquid food that are paired with two distinct electroshocks, allowing us to ask whether flies prefer high shock/high sucrose, or low shock/low sucrose. Importantly, when flies are food deprived, they change their relative valuation of shock/sucrose and prefer the high shock/high sucrose. Commonly used animal models for impulsivity, e.g. the delay discounting task, are insensitive to deprivation. Conversely, humans do act more impulsively when deprived, e.g. shifting towards a smaller drug dose now, rather than a larger ‘hit’ later. Therefore, our novel FLEA assay models some important aspects of human impulsivity that are highly relevant for SUD. We will combine the economy of scale of Drosophila with the unique face validity of our innovative FLEA assay to illuminate the genes and variants that underlie impulsivity and motivation to 1) determine the role M6 plays in impulsivity and motivation. M6 is the fly ortholog of the human candidate impulsivity gene GPM6B. 2) We will perform a GWAS with ~200 fully sequenced Drosophila lines, giving us unprecedented insight into variants and genes that affect impulsivity and motivation. This will serve to seed new avenues of research to investigate the function and circuitry regulating impulsivity and motivation. We will also test candidate genes from these Aims in our just developed assays measuring experience-dependent amphetamine or cocaine preference. Our proposal is therefore fully compatible with the Cutting-Edge Basic Research Award (CEBRA) which is “not intended for incremental research or research extending ongoing programs”, but rather “this announcement encourages applications from investigators with experience in SUD- relevant research who wish to explore and develop new methods, techniques or c...