Deep Analysis of Transcriptome to Understand the Genetics of Substance Use Disorders in Rats - Project Summary Substance Use Disorders (SUDs) are a major public health problem for which new therapies are urgently needed. A significant impediment to developing new treatments is our extremely limited understanding of the biological basis of SUDs. Although animal models cannot recapitulate all aspects of human SUDs, drugs of abuse produce several key behavioral phenomena in rodents, including hedonically motivated drug self-administration, escalation of drug intake, tolerance, withdrawal, and reinstatement of drug-seeking behavior. Rats are the preferred model system for such studies, and Heterogeneous Stock (HS) rats are especially useful because they exhibit highly variable behaviors such that some rats escalate drug intake and show compulsivity whereas others do not. These behaviors are heritable and have already been extensively studied using genome-wide association studies (GWAS). GWAS in both humans and animals have identified heritable differences in gene expression as the primary source of behavioral differences. Thus, there is an urgent need to understand heritable differences in gene regulation in order to make sense of GWAS of behaviors like iv self- administration of opioids. Many techniques have already been introduced to examine transcriptome variation as a potential molecular mediator of GWAS signals. While these methods have provided numerous mechanistic insights and testable hypotheses, they consider gene expression changes as the only source of regulatory variation a. However, there is growing evidence that other complex regulatory phenomena can contribute to heritable differences across individuals. Here, we are proposing to improve molecular interpretation of GWAS results from SUD-related phenotypes by expanding integrative genome and transcriptome analysis in rats to a wide range of transcriptional phenotypes, including but not limited to transcript isoform usage, lncRNA expression, alternative transcription start, and polyA sites, exon skipping, intron retention, and RNA stability. Upon completing this project, we will have produced an unprecedented atlas of variation in rat transcriptome as a mediator of SUD-relevant traits. We will integrate these findings with SUD-related GWAS data to facilitate the identification of specific genes and provide a molecular understanding of SUD that will identify new novel drug targets.
