The Role of Amygdaloid Chromatin and Synaptic Remodeling in Anxiety and Alcoholism

Alcoholism is a complex multifactorial disorder which involves genetic and environmental factors. Comorbid psychiatric disorders, including anxiety, appear to be robust factors in the promotion of alcohol intake and may be associated with aberrant regulation of synaptic plasticity and epigenetic mechanisms. Alcohol-preferring (P) and alcohol-nonpreferring (NP) rats, which show high and low levels of anxiety respectively, serve as a useful model to study the association between anxiety and the genetic predisposition to alcohol preference. Brain-derived neurotrophic factor (BDNF) and its downstream target, activity-regulated cytoskeleton-associated (Arc) protein, play a role in the regulation of synaptic plasticity and dendritic spine density (DSD). Histone deacetylases (HDAC) are involved in dynamic remodeling of chromatin structure and have been implicated in the regulation of specific BDNF exons involved the control of synaptic structure and function. In order to examine the role synaptic plasticity and epigenetic mechanisms in comorbid anxiety and alcohol preference, we investigated the effects of acute ethanol exposure on anxiety-like behaviors of P and NP rats and examined amygdaloid brain regions with regards to epigenetic regulation and synaptic plasticity. In comparison with NP rats, P rats had high anxiety-like behaviors associated with lower levels of BDNF, Arc and DSD that were related to increased HDAC2 levels resulting in hypoacetylation at BDNF exon IV in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA). Acute ethanol treatment had an anxiolytic effect in P, but not in NP rats, and corrected aberrant protein levels in the CeA and MeA. We then specifically knocked down HDAC2 in the CeA of P rats via stereotaxic cannulation and intracranial delivery of HDAC2 siRNA. Following HDAC2 knockdown, P rats were found to have reduced anxiety levels and alcohol consumption, which was associated with increased BDNF and Arc associated with elevated histone acetylation at BNDF exon IV and Arc. These results implicates elevated HDAC2 levels in the aberrant regulation of BDNF and Arc levels associated with changes DSD in the CeA and MeA, which may be responsible for anxiety-like and alcohol-drinking behaviors of P rats.