Large-scale reorganization of DNA methylation and upregulation of extracellular matrix genes in the dorsal dentate gyrus following cocaine taking

Repeated cocaine induces neuroplasticity in brain circuits that encode reward-associated context. The dorsal hippocampus, particularly the dorsal dentate gyrus, plays a critical role in the initial encoding and early consolidation of contextual memories, thus, is uniquely positioned to undergo cocaine-induced neuroplasticity and associated epigenomic and transcriptomic changes during volitional drug-taking. We report that cocaine self-administration in male mice produces significant DNA methylation changes (> 10%, q < 0.01) at an unusually large number of ~30,000 small genomic regions in dentate granule cells (DGCs) of male mice. Cocaine preferentially hypomethylated regions, switching the methylation state in ~16% of DGCs on average. The cocaine-sensitive/responsive epigenomic regions were overrepresented in enhancers and were associated with 9833 genes, many of which involved in diverse functions relevant to neuronal functioning. Among the differentially methylated genes two regulatory genes, c-fos and cartpt (known to be activated by cocaine), and a cluster of genes encoding components of the extracellular matrix (implicated in neuroplasticity) were differentially expressed (mostly upregulated) following cocaine self-administration, suggesting a gene regulatory network that is transcriptionally robust to perturbations but still allows the upregulation of a specific group of neuroplasticity related genes. Overall, our data demonstrates that cocaine self-administration induces epigenomic and transcriptomic changes in the dorsal dentate gyrus that may contribute to dorsal hippocampal plasticity and contextual memory associated with cocaine self-administration. These findings support continued investigation of dorsal hippocampus in contributing to cocaine-related behaviors.