The Genetic and Epigenetic Interplay of Cocaine Addiction: A Cell-Type, Circuitry, and Functional Dissection

PROJECT SUMMARY The intricate orchestration of genetic and epigenetic dynamics in neurobiological systems plays a central role in substance use disorders (SUDs), with cocaine use constituting a significant public health concern. This project employs a cutting-edge, interdisciplinary approach to elucidate the epigenetic landscapes and gene regulatory

networks activated following cocaine self-administration in a mouse model, as well as to understand how epigenetic variations influence these processes. The project comprises three core objectives at the intersection of genomics, epigenomics, neuroscience, and computational biology. First, we will conduct high-resolution

chromatin accessibility and DNA methylation profiling to delineate cell-type and circuit-specific epigenetic configurations post-cocaine self-administration in mice. This analysis aims to uncover granular alterations in the epigenome, illuminating the regulatory pathways implicated in cocaine-induced neural plasticity and behavioral

adaptations. Second, we will leverage the Hybrid Mouse Diversity Panel (HMDP), comprising approximately 100 different strains of mice, to investigate variances in epigenetic regulation. Utilizing the HMDP as a mechanistic intermediary, we aim to identify epigenetic variations underlying strain-specific susceptibilities and resistances

to cocaine exposure, thus deepening our understanding of the genetic and epigenetic factors associated with cocaine self-administration. Lastly, we will construct cell-type and circuit-specific gene regulatory networks that encapsulate the interplay of genetic and epigenetic factors. These networks will be established through rigorous

computational analyses that integrate genomic, epigenomic, and transcriptomic data. In summary, this project aims not only to detail regulatory dynamics but also to identify key nodes and pathways for potential therapeutic intervention, representing a significant stride towards alleviating the global burden of cocaine use disorder. The

work pushes the boundaries of current epigenetic studies in SUDs by employing a multidimensional approach to unravel the complex genetic and epigenetic landscapes governing cocaine response. The outcomes are expected to fundamentally enhance our understanding and present unprecedented avenues for therapeutic

innovation.