Epigenetic Mechanisms of Negative Affective State of Alcoholism

$211,266P50FY2018AANIH

University Of Illinois At Chicago, Chicago IL

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Abstract

One major hypothesis of drug and alcohol dependence involves alterations in allosteric state driven by negative emotional adaptations within the circuitry of the extended amygdala (EA). Histone modifications via lysine acetylation and DNA methylation have been shown to play a role in the regulation of gene expression. Histone deacetylases (HDACs) remove acetyl groups from histones and DNA methyl transferases (DNMTs) cause DNA methylation, leading to a condensed chromatin state, which blocks transcriptional activator access to DNA and decreases gene transcription. Several genes, such as brain-derived neurotropic factor (BDNF), activity regulated cytoskeleton-associated (Arc) protein, and protein kinase Limki are involved in regulating dendritic spine density (DSD) in the brain and may be epigenetically controlled by histone acetylation and DNA methylation. The association between HDACs, DNMTs, gene expression, and DSD in the amygdala during chronic ethanol exposure and its withdrawal is currently unknown. Our proposal is based on the hypothesis that HDAC and DNMT-induced epigenetic modifications during ethanol withdrawal will cause changes in DSD due to changes in the expression of BDNF, Arc, and Limki in the amygdala and this mechanism may be operative in the synaptic plasticity related to alcohol dependence. This will be tested by examining the effects of the HDAC inhibitor on i) anxiety-like behaviors; ii) HDAC activity, HDAC isoform expression (mRNA and protein), histone acetylation and expression (mRNA and protein) of BDNF, Arc, Limki, as well as DSD in the amygdala of rats during ethanol withdrawal after chronic ethanol exposure; and iii) fold changes in histone acetylafion and methylafion at the promoter of BDNF, Arc, and Limki genes and also genome-wide changes in gene expression and histone acetylation patterns in the amygdala of rats during ethanol withdrawal after chronic ethanol exposure. Furthermore, the effects of central and medial amygdaloid infusion of DNMT inhibitor will be examined on i) anxiety-like behaviors; and ii) DNMT activity, DNMT isoform expression, and DNA methylation-induced changes in the expression of BDNF, Arc, Limki, as well as DSD in the amygdala of rats during ethanol withdrawal after chronic ethanol exposure.

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