Covalent Histone Modifications in Nucleus Accumbens and Amygdala of Mice: A Role in Alcoholism

Covalent histone modifications are important role in gene expression. C57BL/6J (C57) mice consume higher amounts of ethanol compared to DBA/2J (DBA) mice. Cyclic-AMP responsive element binding protein (CREB) is innately lower in the nucleus accumbens (NAc) shell of C57 compared to DBA mice. We found lower levels of CREB-binding protein (CBP) and acetylated histone H3 and higher methylated histone H3 in the shell, but not core of the NAc or amygdala of C57 compared to DBA mice. Acetylated H3 predominantly localized to NeuN-positive neurons in the NAc of C57 and DBA mice. Aberrant chromatin remodeling in the NAc shell may be operative in abnormal gene expression and excessive alcohol drinking behaviors of C57 mice. Voluntary ethanol exposure increased levels of CBP and acetylated H3 in the NAc shell, but not core or amygdala of C57 mice compared to controls; in addition to decreasing methylated H3 in the NAc shell and amygdala of C57 mice compared to controls. Acute ethanol exposure increased CBP, acetylated H3, and BDNF and decreased methylated H3 in the NAc shell of C57 mice compared to controls; with similar results occurring in both the NAc shell and core of DBA mice compared to controls. Baseline numbers of NeuN-positive neurons were similar in the NAc shell and core between C57 and DBA mice and acute ethanol had no effects of these numbers. Ethanol exposure elicits differential effects on chromatin remodeling in the NAc and amygdala of C57 and DBA mice. CREB deficient (+/-) mice exhibit higher anxiety-like behaviors and consume larger amounts of alcohol compared to wild-type (+/+) littermates. Partial deletion of CREB decreased levels of CBP and acetylation of H3 and H4 in the amygdala but not NAc of mice. The histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), corrected deficits in CBP and histone acetylation in CREB deficient (+/-) mice, while there were no observable effects of TSA in wild-type (+/+) mice. TSA also attenuated anxiety-like and alcohol-drinking behaviors of CREB deficient (+/-) mice. Partial deletion of the CREB gene produces aberrant chromatin remodeling in the amygdala, which may be operative in the processes of alcoholism.