OVERALL COMPONENT The Center for Systems Neurogenetics of Addiction (CSNA) synergizes the expertise and effort of behavioral neuroscientists, computational biologists and geneticists, who each bring state-of-the-art approaches to an integrated research program that will identify and model the common underlying biological mechanisms of biobehavioral risks for stimulant self-administration. Drug addiction is a devastating and highly complex neurobehavioral phenomenon, characterized by multiple etiological factors, stages and behaviors that have proven difficult to study in combination. Advanced mouse genetic populations provide a platform for evaluating the relationships among these behaviors, finding genetic variants responsible for their variation and identifying their associated biological mechanisms and pathways. We will make use of the new Collaborative Cross genetic reference population and Diversity Outbred mapping population to identify the biological mechanisms by which predisposing traits predict the tendency to self-administer the psychostimulant drug cocaine. Each predisposing trait, including impulsivity, acute and sensitized drug responses, reward-seeking, adolescent nicotine exposure and circadian variation, is studied in one of the Center's five scientific projects. Our approach is unprecedented in that we will evaluate these traits simultaneously in a mouse population exhibiting extreme genetic and phenotypic variation, enabling a holistic and extensible assessment of the common and distinct biological mechanisms of addiction vulnerability. We will definitively and directly identify sources of trait correlation in the population. We will produce functional genomics and phenomics datasets, which will be deposited in widely accessed and highly functional informatics resources, where they may be expanded upon by the global research community. Our Center will also generate novel, validated mouse mutants and complex models for mechanistic studies of addiction-related phenomena. In addition to aiding the scientific mission of our five scientific projects, our three research support cores will provide proven, state-of-the-art and innovative technologies to the broader field, including: 1) a sophisticated, large-capacity Behavioral Phenotyping Core, 2) an Integrative Genetics and Genomics Core for statistical genetics, molecular profiling, biobanking and data dissemination, and 3) a Mouse Resource and Validation Core for delivering novel mouse resources for systems genetics, in vitro and in vivo mutation induction and validation. The Administrative Core will oversee the effective coordination, integration and dissemination of the Center's research activities and deliver our findings through The Jackson Laboratory (JAX)'s well-established educational programs. The Pilot Core will offer additional investigators the opportunity to initiate collaborative work with the Center. Through its combined efforts, the CSNA will enable discovery of the mechanisms linking multiple susceptibility phenotypes to the propensity to seek and take drugs, opening up new opportunities for both prevention in those at risk for addiction and intervention in those already afflicted.
OVERALL COMPONENT Illicit drug use costs the US economy over $190 billion annually. The Center for Systems Neurogenetics of Addiction (CSNA) takes on the pervasive challenge of identifying the biological relationships between the stages and patterns of cocaine addiction and behaviors that predict drug abuse, including impulsivity, reward seeking, adolescent nicotine exposure, acute drug response and circadian dysregulation. To uncover these relationships, we will make use of advanced mouse genetic tools that allow us to sample unprecedented genetic and behavioral diversity. These populations enable us to precisely and efficiently identify the genes related to addiction, and with more biological depth and less cost than human genetic studies. We will also make use of advances in a strategy called systems genetics that enables holistic study of genes, biological molecules and behaviors with advanced computational methods. We are working as a complementary team of investigators from several laboratories and institutions, each bringing deep experience and knowledge in the genetic studies of specific aspects of addiction in the laboratory mouse. Together we will test the hypothesis that each addiction risk factor involves a biological mechanism that is shared with drug taking and drug response, and that genetic variation in these biological pathways influences addiction. We will discover addiction-related genes and generate novel mouse models of addiction, data resources, educational offerings and research services that will enable other researchers to readily adopt our advanced tools, techniques and results. By doing this, our team and future investigators will be able to discover and develop new approaches for addiction prevention, early intervention and treatment that take into account the complexity of addiction risk and individual differences in genes, environment and behavior.
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