The Genetic Basis of Opioid Dependence Vulnerablility in a Rodent Model

Opioid use disorder (OUD) is a complex and devastating condition resulting from the interplay of genet neurobiological, and environmental factors. Our previous work has made significant strides in understanding ti genetic and neurobiological basis of OUD by identifying distinct behavioral profiles and sexually dimorph neurobiological circuitry associated with vulnerability and resilience in heterogeneous stock (HS) rats. Throug a genome-wide association study (GWAS, we revealed several genes, including Phb112, involved mitochondrial function and oxidative phosphorylation, as potential contributors to OUD-like behaviors. In this renewal application, we propose to build upon these findings and further elucidate the complex interaction: between genetic and neurobiological factors contributing to OUD vulnerability and resilience. Our approac involves a multimodal investigation that integrates advanced genetic, transcriptomic, and circuitry studies, anc establishes a comprehensive data and tissue repository. Our research strategy will focus on expanding the genetic determinants of OUD vulnerability and resilience by phenotyping additional HS rats at UCSD and integrating new data with existing datasets from prior-cycle laboratories. This UCSD consolidation enhances efficiency while preserving multi-site heterogenization benefits, increasing sample size, exploring sex differences, improving reproducibility and environmental variability accounting, and strengthening gene-OUD associations for deeper mechanistic investigation. In parallel, we will conduct a comprehensive assessment of the neurobiological differences between vulnerable and resilient rats using whole-brain imaging and single-nucleus RNA sequencing. This approach will enhance our understanding of the circuit and transcriptomic bases of OUD vulnerability and resilience. To facilitate interdisciplinary OUD research and maximize compatibility across research methods, we will establish a tissue repository from behaviorally and genetically characterized rats. This resource will enable researchers without access to chronic intravenous self-administration or next-generation genome sequencing resources to perform molecular, cellular, or neuroanatomical testing on tissue samples from well-characterized animals. By achieving these objectives, we anticipate significantly advancing our understanding of OUD and informing the development of more effective prevention and treatment strategies. Our multidisciplinary investigative team, comprising leaders in OUD research, is uniquely positioned to address these critical questions and drive innovation in the field.