ABSTRACT: Cocaine addiction is characterized by compulsive drug use and relapse triggered by drug-related cues and contexts. Though previous research on substance use disorders has primarily focused on the mesolimbic reward pathway, the hippocampus plays an important role in encoding the spatial and contextual features of reward-associated learning. The dorsal dentate gyrus of the hippocampus receives contextual information from the entorhinal cortex and forms the memories of drug-associated contexts in sparse ensembles of dentate granule cells. Since dentate granule cells, unlike other principal hippocampal neurons, express dopamine D1 receptors; they uniquely respond to the extracellular increase of dopamine during cocaine use. Given these inputs, we hypothesized that repeated experience with cocaine during self-administration would produce substantial epigenetic and transcriptional changes in dentate granule cells that, via circuit maladaptation, contributes to the strong and lasting memories of drug experience and to the high incidence of relapse. Here we report DNA methylation changes, biased toward hypomethylation, in dentate granule cells at the unusually high number of ~30,000 small, 100-200 bp genomic regions, while the purely environmental challenge of chronic unpredictable stress produced 10 times fewer differentially methylated regions. Cocaine-sensitive epigenomic regions, in contrast to the rest of the genome, had heterogenous methylation in the otherwise largely homogenous population of mature dentate granule cells, suggesting that their cocaine-induced epigenetic malleability is due to relatively unhindered switching between the methylated and unmethylated states. Further, these regions were overrepresented in enhancers and associated with about half of the expressed genes (~8,000) of diverse gene ontology functions that, however, were not random and had relevance to neuronal plasticity. In contrast, only ~400 genes were upregulated in cocaine self-administration that included a significant number of differentially methylated genes. These genes included many collage genes and were enriched in the functional category of Organization of extracellular matrix (ECM), an extra-neuronal structure involved in neuronal connectivity and plasticity. The DNA methylation and gene expression structure of dentate granule cells suggests a poly/omni-epigenic model of context-driven cocaine seeking, similar to the proposed genetic architecture of omnigenic complex traits with the contribution of large effect variants to extreme trait values. This model involves interaction between a large number of epigenetically modified neuronal genes that have small effect size and a small group of differentially methylated and expressed core genes that have large effect size and direct connection to the neuroplasticity phenotype, driving hippocampal plasticity and acquisition of cocaine self-administration. Overall, our data suggest cocaine-induced epigenetic and transcriptional changes that, via maladaptive hippocampal plasticity, may contribute to reward-related contextual learning in the dentate gyrus of cocaine self-administration in mice.
