AUTHOR=De Clerck Mael , Manguin Martin , Henkous Nadia , d’Almeida Marion N. , Beracochea Daniel , Mons Nicole 

TITLE=Chronic alcohol-induced long-lasting working memory deficits are associated with altered histone H3K9 dimethylation in the prefrontal cortex

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=Volume 18 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2024.1354390

DOI=10.3389/fnbeh.2024.1354390

ISSN=1662-5153

ABSTRACT=Epigenetic modifications have emerged as key contributors to the enduring behavioral, molecular and epigenetic neuroadaptations during withdrawal from chronic alcohol exposure.In the present study, we investigated long-term effects of a 3-week abstinence period after 5 months of ethanol consumption on working memory (WM) on a T-maze and transcriptionally repressive histone H3 lysine 9 dimethylation (H3K9me 2 ) in the prefrontal cortex (PFC) of male C57BL/6 mice. Withdrawal mice displayed WM impairments along with reduced prefrontal H3K9me 2 levels, compared to water-drinking mice. The withdrawal-induced decrease of H3K9me 2 occurred concomitantly with increased level of permissive H3K9 acetylation (H3K9ac) in the PFC. Treatment with the GABA B agonist baclofen during alcohol fading and early withdrawal rescued withdrawal-related WM deficits and fully restored prefrontal H3K9me 2 and H3K9ac. Alcohol withdrawal induced brain region-specific changes of H3K9me 2 and H3K9ac after testing, with significant decreases of both histone marks in the dorsal hippocampus and no changes in the amygdala and dorsal striatum. Furthermore, the magnitude of H3K9me 2 in the PFC, but not the hippocampus, significantly and positively correlated with individual WM performances. No correlation was observed between H3K9ac and behavioral performance. Results also indicate that pre-testing intraperitoneal injection of UNC0642, a selective inhibitor of histone methyltransferase G9a responsible for H3K9me 2 , led to WM impairments in water-drinking and withdrawal-baclofen mice. Collectively, our results demonstrate that alcohol withdrawal induced brain-region specific alterations of H3K9me 2 and H3K9ac, an effect that persisted for at least three weeks after cessation of chronic alcohol intake. The findings suggest a role for long-lasting decreased H3K9me 2 specifically in the PFC in the persistent WM impairments related to alcohol withdrawal.