Combinatorial modifications of acetylated H3 and histone H3 lysine 4 trimethylation (H3K4me3) have been implicated in long-term adaptive changes in the HPC resulting from prolonged alcohol intake (126, 153). Using a 3-week mouse model of chronic ethanol consumption, Stragier and colleagues (154) recently reported that ethanol-induced BDNF-mediated neuroplastic changes in the HPC are controlled by combinatorial modifications of acetylated H3 and H3K4me3 around individual Bdnf gene promoters in dorsal CA3 region and the dentate gyrus and by decreased Bdnf DNA methylation in CA1–CA3 regions of the HPC. These ethanol-induced changes were associated with a deficit in HPC-dependent (contextual fear and novel recognition object) memory while sparing AMG-based cued fear memory. Chronic intermittent ethanol vapor exposure followed by 2–5 days of abstinence robustly and selectively increased histone H3K9 acetylation and DNA demethylation in PFC neurons with a parallel decrease of H3K9 methylation repressive mark as well as a downregulation of a set of histone methyltransferases (HMT) (155, 156). These changes mostly occurred after ethanol removal and contributed to the development of physical dependence on alcohol through an adaptive long-lasting upregulation of
