Systems approach for discovery of genetic and genomic mechanisms driving drug use and addiction-like behavior in experimental mouse populations. The overarching goal driving my research is to identify the genetic, genomic, and environmental mechanisms underlying drug addiction, a heritable disease with devastating effects on individuals and society. To this end, I use a multidisciplinary approach which includes systems genetics, cutting-edge mouse populations, and gold-standard behavioral techniques for addiction phenotyping, most notably intravenous drug self-administration.
Systems genetics using experimental mouse populations is a powerful approach that enables discovery of novel genetic and genomic mechanisms influencing disease by associating natural genotypic and phenotypic variation. The systems approach requires no a priori hypotheses about the genetic mechanisms driving a disease; the only requirement is a well-defined, construct-valid assay through which to index a disease phenotype. Using complementary methodology that includes disease phenotyping in mice, quantitative trait locus (QTL) mapping, expression QTL mapping, and gene expression to phenotype correlation, systems genetics enables identification of novel and possibly unexpected disease-associated genes. These candidates can then be validated using a CRISPR-Cas9 knockout approach. Once the effect of these genes on the disease phenotype is established, knockout mice and a range of in vivo and other neuroscience techniques can be used to uncover the mechanisms through which these genes influence the disease..
To apply a systems genetics approach, I use recombinant inbred (RI) mouse panels which are sets of isogenic strains derived from a cross of inbred founder strains. RI mouse panels are particularly suited for systems genetics studies because individual animals within an RI strain are genetically identical and, consequently, reproducible. Therefore, data from multiple experiments and laboratories can be integrated over time enabling discovery of novel genetic relationships among behavioral phenotypes, molecular phenotypes, or their combination.
Drug addiction is a critical public health issue with genetic and environmental causes for which the underlying biological mechanisms remain largely unknown. To uncover these mechanisms, I use construct-valid behavioral techniques within the context of a systems genetics approach. The intravenous drug self-administration paradigm is the gold-standard of volitional drug use assessment in rodents due to its ability to index drug taking and seeking at many stages of drug use including initiation, maintenance, and relapse. Variation in several behavioral phenotypes such as sensation seeking and incentive salience attribution are genetically associated with variation in rodent drug self-administration indicating shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Through integration of a systems genetics approach and construct-valid behavioral techniques such as intravenous drug self-administration, novel and unexpected genetic mechanisms underlying the complex psychological phenotype of drug addiction and behaviors that predict drug use and addiction can be discovered.