Center for Systems Neurogenetics of Addiction

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PROJECT SUMMARY OVERALL The Center for Systems Neurogenetics of Addiction (CSNA) leverages approaches and expertise in behavioral neuroscience, computational science, genome biology, mouse and human genetics, and genetic engineering to identify, contextualize and model shared and distinct biological mechanisms of biobehavioral risk for cocaine self-administration. Drug addiction is a devastating and complex disorder influenced by multiple etiological factors. Extensive evidence demonstrates the role of genetic variation on a range of addiction behaviors, from experimentation and initiation of drug use to compulsive drug-taking behavior. Yet discovery of predisposing genes and variants in human populations is limited by high sample size requirements, phenotyping capacity, and variability in drug exposure and other environmental factors. Advanced mouse genetic populations exhibit variation in addiction-relevant behaviors and offer an experimental platform to discover the neurobiological mechanisms by which predisposing traits predict the tendency to self-administer cocaine. The CSNA employs the Collaborative Cross genetic reference population and Diversity Outbred mapping population across three integrated research projects focused on three interrelated aspects of addiction susceptibility: impulsivity, cocaine sensitization and self-administration. These traits are evaluated using a multidimensional phenotyping platform in a mouse population exhibiting extreme genetic and phenotypic variation, enabling a replicable and extensible assessment of the shared and distinct biological mechanisms of addiction vulnerability. These complementary populations are derived from the same founder strains, allowing for extensive data integration across studies within and outside the CSNA. The CSNA develops data integration methods and produces multiple functional genomics and phenomics datasets, deposited in widely accessed and highly functional informatics resources for the global research community. The Center also extends its results into basic neurobiological and preclinical therapeutic research by integrating findings with human genetic and genomic studies, generating novel, validated mouse mutants and identifying vulnerable and resistant strains for mechanistic studies. Three research support cores provide state-of-the-art approaches to the CSNA research projects and the larger research community, including a sophisticated, large-capacity Behavioral Phenotyping Core, an Integrative Genetics and Genomics Core for statistical genetics, molecular profiling, biobanking, data integration and data dissemination, and a Mouse Resource and Validation Core for creating and delivering novel mouse resources for systems genetics, validation, and disease modeling. The Administrative Core coordinates, integrates, and disseminates research, education and outreach activities. Finally, a Pilot Core enables collaborative work to promote innovation and diversity in addiction science. Through its combined efforts, the CSNA will have a lasting impact on the study of addiction genetics through the holistic examination of biobehavioral risk, the generation of community data resources that we and others will expand and exploit in future studies, and through education and training.