Sunday, June 1, 2025
6/1/2025
Discovery of Addiction-Related Genes with Advanced Mouse Resources - PROJECT SUMMARY/ABSTRACT Our overarching goal is to discover the genetic and genomic mechanisms underlying behavioral predisposition and development of addiction. Addiction remains a substantial worldwide social and economic burden despite extensive efforts to curb drug availability and use. The high heritability of cocaine addiction, indicates that the propensity to develop a substance use disorder (SUD) after drug exposure is genetically influenced. Both human and animal studies indicate that behavioral traits such as novelty seeking are strongly correlated with the propensity to develop an SUD, but the biological basis of this relationship is unknown. We identify and characterize biological mechanisms of addiction and predisposing behavior by harnessing advances in mouse genetic resources, including the high-precision Diversity Outbred (DO) mouse population, validation in genetically modified mice, gene expression quantitation through RNA sequence analysis, and computational and statistical methods in systems genetics. In Aim 1 we will identify genetic mechanisms underlying predisposing novelty-related traits and drug self-administration through quantitative trait locus (QTL) analysis in a large set of DO mice. The most compelling and tractable of these will be validated in gene targeted mouse models. The intravenous drug-self administration (IVSA) paradigm, considered the gold standard for the assessment of addiction traits in rodent research, will enable quantification of the core features of addiction including initiation of drug use, poor extinction and enhanced reinstatement of reinforced drug taking. In Aim 2 we will quantify gene expression genetic variation in two connected addiction relevant tissues, the prefrontal cortex and striatum, map expression QTLs and identify genetic correlates of predisposing behavior using RNA- seq in a drug-naïve subset of DO mice, and disseminate these results through widely used informatics resources. Gene expression analysis in drug-naïve mice enables separation of the biological substrates of predisposition to addiction from the biological sequelae of drug exposure. In Aim 3, we will address the fundamental problem of evaluating coordinated gene expression across multiple components of the addiction circuitry to assess relative dysregulation toward the identification of global- vs brain region-specific factors in addiction vulnerability. This will be accomplished through the development of robust multivariate statistical methods for identification of relations across multiple high dimensional data sets. This strategy will make continued use of a common collection of phenotypes to relate disparate and incompatible measures across two independent sets of mice, while extending into multiple tissue co-expression networks. Development of this technique in the context of addiction research will extend a unifying data integration framework to multidimensional to human and mouse genetic and genomic studies for all disease areas. Synergy among the aims will reveal networks from polymorphism to addiction-related behavior.
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