This component will examine novel epigenetic mechanisms (HDAC-induced chromatin remodeling) that may be involved in changes in the putative DA neurons’ response to γ-aminobutyric acid (GABA) after chronic ethanol exposure and its withdrawal.
Alcohol dependence involves alterations in the allostatic state driven by negative emotional adaptations within the amygdaloid circuitry. This research component will investigate the role of specific isoforms of HDAC- and DNMT mediated epigenetic mechanisms in regulating the gene expression in the negative affective states of ethanol dependence.
This research component will evaluate epigenetic modifications, such as histone acetylation, methylation, and DNA methylation, due to ethanol exposure in astrocytes that may be involved in ethanol-induced hippocampal neural plasticity and depression-like symptoms during withdrawal after chronic ethanol exposure.
The objectives of this research project are to investigate the expression and promoter binding of components of the DNA-methylation and DNA-demethylation networks in cortico-limbic structures [prefrontal cortex (PFC), hippocampus, and amygdala] of post-mortem brains of alcoholics (compared with age/sex matched control subjects).
This proposal will test the hypothesis that sex differences in alcohol consumption in adulthood may be related to prenatal stress-induced lasting changes in epigenetic (histone code-acetylation and methylation) control on transcriptional regulation of genes related to synaptic plasticity in the cortico- limbic reward system using animal model.
The overarching aims of this project is to test the behavioral and structural abnormalities during alcohol use disorder (AUD) using structural and functional MRI with simultaneous startle collection in young adults with current and remitted AUD, and a sample of matched healthy controls (HC). The study will examine whether compared with controls, individuals with AUD display exaggerated behavioral reactivity, structural anticipatory anxiety network (ANN) abnormalities, and aberrant AAN circuit functioning during U-threat. This proposal will also examine if individuals with current AUD display altered epigenetic modifications and whether this relates to exaggerated reactivity to U-threat.
The proposed studies will establish the effect of chronic ethanol on the mitochondrial epigenome, and determine if these interactions produce ethanol withdrawal-induced pain.
Alcohol induced epigenetic modifications in microglia and its role in the regulation of innate immune gene expression will be investigated in this pilot project. Several future pilot projects are planned to be included.