Genetic Analyses of Pavlovian Conditioning in Outbred Models

Addiction is a heritable trait. There is substantial inter-individual variability in the susceptibility to the development of addiction. Environmental cues that have been repeatedly paired with rewards are believed to be major contributors to the progression to and maintenance of addiction. These reward-associated cues are attributed with incentive salience, which makes them attractive, desirable, and capable of prompting motivated, reward-seeking behaviors. It is thought that the variability in individuals' susceptibilities to addiction is due in part to differences in the degree to which individuals attribute incentive salience to reward cues. In my dissertation, I performed the first mapping studies aimed at identifying genetic loci influencing the propensity to attribute incentive salience, estimating the heritability of this trait in the process. These genome-wide association studies (GWAS) were carried out in independent, outbred rat populations to provide replication, and the results of the studies were meta-analyzed. To successfully accomplish the GWAS, I optimized a reduced-representation sequencing approach called genotyping-by-sequencing (GBS) for use in rats and designed a variant calling workflow to obtain dense, high-quality genotypes from the GBS data. In the process of performing the mapping studies, I discovered substantial divergence between different vendor populations (FST > 0.4) of a commonly used laboratory rat strain, the Sprague Dawley (SD). Ultimately, I uncovered 21 genome-wide significant loci in the SD and 22 in the heterogeneous stock associated with various quantitative metrics that capture different aspects of this complex behavior in rats. Within these loci were a handful of candidate genes that warrant in vivo follow up experiments to test their effects on this important addiction-related behavior. Notably, the candidate gene TAAR1 has significant evidence linking it to addiction and potential therapeutic uses.