We will use quantitative genetic techniques to identify genes and alleles that influence a constellation of psychologically complex behavioral phenotypes that are associated with drug abuse. Our center capitalizes on a number of recent advances in study design, next-generation sequencing and statistical methods that together create an exceptional opportunity. Whereas the past two decades have seen enormous advances in both forward (phenotype to genotype) and reverse (genotype to phenotype) genetic studies in mice, there has been much less progress developing and applying the same techniques in rats. Although both forward and reverse genetic studies in mice have been extremely fruitful, many important but complex psychological processes are difficult or impossible to study in mice. For this reason we are proposing to adapt a variety of genetic techniques that we have already used successfully in mice, for behavioral studies in rats. In the current application, we propose to employ state-of-the-art tools to elucidate the genetic basis of a variety of behaviors that are relevant to drug abuse in 4,800 rats. A key strength of our center is that we utilize a unique rat heterogeneous stock (HS). These rats, sometimes referred to as N/NIH, are an HS that was created in 1984 by intercrossing 8 inbred rat strains and have been maintained as an outbred population for 65 generations. This has given rise to numerous accumulated recombinations that make them an ideal resource for performing studies that are analogous to human genome wide association studies (GWAS). Significantly, all 8 inbred founder strains have recently been re-sequenced, identifying 7.2 million SNPs. We will genotype these rats using an innovative next-generation sequencing-based method that provides ~100K SNPs at an extremely low cost. We will use these data to infer haplotypes, which will allow us to impute all 7.2 million SNPs in each rat. In addition to identifying associations between these SNPs and the behavioral traits, we will also examine gene expression in 72 behaviorally naive rats focusing on 4 key brain regions. We will use these data to identify expression quantitative trait loci (eQTLs). We will then integrate all of these data to identify specific genes that influece behavior. Many of the behavioral domains being studied are known to be sexually dimorphic; our study will use both male and female rats, which will allow us to identify sex differences and sex by genotype interactions. We will also identify co-heritability among these traits, as well as pleiotropic effects of individual loci on multiple putatively related behavioral domains. Finally, the proposed center includes numerous educational, career development and public outreach activities. We will implement a program to train high school and undergraduate students. In addition, technicians, graduate students, postdocs and junior faculty will receive career development advice in the form of individual development plans and research performance progress reports. Finally, we will engage in public outreach programs that will draw on diverse communities in Chicago, Buffalo and Memphis.
(Overall) The proposed studies are designed to exploit recent advances in rat genetics. Using powerful molecular and statistical techniques, we will examine the genetic basis of traits that have well-established relevance to drug abuse. We expect that by discovering new genes that can influence these behaviors, we will improve our understanding of genetic susceptibility to drug abuse in humans and may identify new opportunities to treat psychiatric disorders including addiction.
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