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.
