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

Cocaine self-administration induces neurobiological adaptations in brain circuits involved in encoding reward-associated context. The dorsal hippocampus, particularly the dorsal dentate gyrus, plays a critical role in the precise encoding of spatial and contextual information. We hypothesized that the dentate gyrus is uniquely positioned to undergo epigenomic and transcriptomic changes because of the convergence of the contextual features of reward and cocaine-enhanced dopamine and norepinephrine signals during volitional drug-taking. We report that cocaine self-administration produces significant DNA methylation changes at an unusually large number of ~30,000 genomic regions (>10%, q<0.01) in dentate granule cells (DGCs) of male mice. Cocaine preferentially hypomethylated regions with heterogenous methylation, switching the methylation state in ~16% of DGCs on average. The cocaine-sensitive/responsive epigenomic regions were overrepresented in enhancers and were associated with 9,833 genes, many of which were involved in diverse functions relevant to neuronal functioning. However, among the differentially methylated genes only two regulatory genes,