A role of repressive modified histone in an animal model of differential vulnerability to anxiety and addiction

Chaudhury S, Watson SJ, Akil H
Society for Neuroscience. 2011.


Post-translational modifications of the histone tails in the chromatin template can influence phenomena such as drug addiction, memory formation and stress responses. Studies have shown that acute or chronic stress, social defeat stress as well as cocaine exposure alters the levels of acetylated and methylated Histone H3 and H4 at lysine residue in the hippocampus, amygdala and nucleus accumbens. These epigenetic changes are stable and long lasting which makes it important to understand its role in conditions including stress, anxiety and addiction. Here we report on differences in the levels of modified histone proteins and their association with various target genes in an animal model of differential vulnerability to anxiety and substance abuse. Our laboratory has produced selectively bred lines of high responder (bHR) and low responder (bLR) rats, segregated on the basis of their locomotor exploration of a novel environment. These animals show profound and stable differences in both anxiety behavior and vulnerability to drug abuse, with bLRs being prone to anxiety-like and depression-like behavior and bHRs prone to addictive behavior. Thus, in the present study we compared the basal protein levels of repressive acetylated and methylated histone H3 and H4 at lysine and arginine residue in the hippocampus, amygdala and nucleus accumbens of bLR- bHR rats. Moreover, using CHIP assays in these same regions, we have also evaluated the levels of association of these modified histone proteins at the target genes implicated in anxiety behavior and addiction. Our results to date reveal significant differences in the basal levels of repressive modified histone proteins in all brain regions examined and differential alteration in the association of various modified histones around the genes, indicating their potential role in the vulnerability to affective and addictive behaviors. The impact of these altered protein levels and their interactions with selected target genes in relation to the functional and physiological modifications will be described.