In silico genome scan with high-throughput addiction related phenotypes in mice

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DESCRIPTION (provided by applicant): The progression towards addictive behavior has been described as a process involving several stages beginning with the initial contact with the drug, followed by its regular use, and finally substance dependence or addiction. Addiction research has traditionally concentrated on the final stages. Recently yeas has shown more interest in initial drug use as a determinant of future developmental trajectories. Variables labeled with terms as dysregulation, lack of persistence, dysinhibition, sensation seeking, inattention, and reward dependence have been postulated as a key factor underlying heightened vulnerability during the initial stages. The less than perfect intercorrelations suggest that this cluster may lack a single biological basis. It is therefore important to identify the specific dimension that constitutes the most important risk. Among the most promising candidates is impulsive choice of which the core feature is a preference for small immediate rewards rather than larger delayed rewards. A better understanding of its role in the initial stages of drug use will be important from a scientific perspective and may eventually contribute to prevention and treatment. Furthermore, as a construct mediating between genes and addiction, impulsive choice could be a relevant endophenotype that may result in more straightforward and successful genetic analyses. We propose a mouse study. Mice offer the possibility to collect data enabling a micro-analysis of initial episodes of drug use that, due to ethical and practical constraints, would be extremely difficult to obtain in human subjects. Furthermore, new high quality public resources will make it possible to perform an "in silico" whole-genome scan for causal genetic variants without the need for any genotyping. Finally, phenotypic and genetic correspondence suggests that results from such a mouse study will be relevant for humans. To study pathways, animal experiments usually involve a small number of subjects that need to be observed intensively over long periods of time. Genetic studies, on the other hand, focus on how variation between subjects affects the outcomes of interest requiring large samples. To link these two paradigms we propose a) "high-throughput" phenotyping procedures that can collect data from many animals while still capturing meaningful process information, and b) analytical tools that can extract indices from the within-subject data that have a theoretical interpretation and can be analyzed in a between-subject fashion.