Discovery of genetic and genomic mechanisms driving the relationship between social reward and cocaine addiction

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PROJECT ABSTRACT Drug addiction is a critical public health crisis that is strongly genetically driven. A fundamental driver of human addiction is the repeated choice to pursue a drug reward at the expense of a social reward, a strong reinforcer of human behavior in non-addicted individuals. Despite the importance of this phenomenon in human addiction, the genetic mechanisms underlying variation in the preference for a social reward over a drug reward (henceforth social reward preference) have been totally unexplored because of the absence of a relevant mouse model. Establishing a mouse model of social reward preference would enable leveraging the vast mouse genetics toolkit for discovery and characterization of the mechanisms driving this trait, which, at its extremes, represents vulnerability to and resistance to a key addiction vector. To this end, we propose to harness the unprecedented genetic diversity of advanced mouse populations and the exceptional construct- validity of the intravenous cocaine self-administration paradigm to discover genetic and genomic mechanisms driving social reward preference. To quantify social reward preference in the mouse, we will use a recently introduced paradigm for the rat in which the subject makes a binary choice to (1) intravenously self-administer an addictive drug or (2) briefly interact with a conspecific. To capture maximum phenotypic variation and enable discovery of genetic mechanisms driving social reward preference, we will use mice from the Collaborative Cross (CC) mouse panel which contains 90% of the genetic diversity in the mouse species and enables the integration of genomic and phenomic datasets across studies. In Aim 1 we will quantify the preference for social reward relative to cocaine reward in male and female mice from eight CC strains. We will quantify heritability of these phenotypes and identify strains exhibiting vulnerability and resistance to social reward preference phenotypes (e.g., strong preference for a cocaine reward relative to a social reward, and vice versa). In Aim 2 we will quantify gene expression in the nucleus accumbens following operant self- administration of a social reward, yoked exposure to a social reward, and sham exposure to a social reward in mice from the same eight CC strains used in Aim 1. We will perform RNA-seq in eight CC strains and scRNA- seq in two extreme CC strains. We will integrate gene expression data (Aim 2) with behavioral data (Aim 1) to identify cell-type specific gene expression signatures predictive of social reward preference. The successful completion of these aims will provide (1) a foundation for future deep characterization of identified mechanisms underlying social reward preference in mice; (2) a lasting community resource enabling genetic correlational analysis among a subset of the CC strains across phenotypes, experiments, and laboratories; and (3) a refined and robust pipeline for future characterization of social reward preference in the full panel of 60 CC strains. Ultimately, this work will contribute to the development of novel, more effective addiction treatments.