Several clinical and preclinical studies suggest that adolescent binge drinking is one of the major risk factors for the development of psychiatric disorders, including alcoholism later in life. Various nuclei within the brain limbic system, specifically the amygdala and hippocampus, are involved in the regulation of emotion, cognition, anxiety, and alcoholism. Gene expression is regulated by histone or DNA chemical modifications, and histone deacetylases (HDACs), histone acetyltransferases (HATs), and DNA methyltransferases (DNMTs) are the key enzymes implicated in these processes. This research component will contribute to NADIA (Neurobiology of Adolescent Drinking in Adulthood) by investigating the novel epigenetic mechanisms of synaptic plasticity in the amygdala and hippocampus during adolescent intermittent ethanol (AIE) treatment and its role in anxiety and alcohol-drinking behaviors in adulthood. We will take a multidirectional approach to examine the direct roles of specific isoforms of HDAC (HDAC2), DNMT (DNMT3b) and HAT (CBP) in histone modifications and DNA methylation, and their functions as epigenetic regulators of gene networks (BDNF and associated genes, Arc, Homer1, NeuroD1, NeuroD2, Neurogranin and Synaptophysin) related to synaptic plasticity (dendritic spines and neurogenesis) in the amygdala and hippocampus after AIE in adulthood. We will also determine whether enduring changes in epigenetic mechanisms of synaptic plasticity are involved in anxiety-like and alcohol-drinking behaviors in adulthood. The overarching hypothesis of this proposal is that AIE-induced perturbation of epigenetic mechanisms (histone acetylation or DNA methylation) produce deficits in gene networks regulating synaptic plasticity in the amygdala and hippocampus, thereby promoting anxiety and alcohol drinking in adulthood.
Specific aim 1 will test the hypothesis that relaxing chromatin by HDAC inhibition [HDAC inhibitors or central nucleus of amygdaloid (CeA) infusion of HDAC2 siRNA] in adulthood will reverse the epigenetic and behavioral effects of AIE.
Specific aim 2 will test the hypothesis that knockdown or overexpression of the HDAC2 gene in the CeA using lentiviral vectors during adolescence regulates AIE effects on epigenetic mechanisms and anxiety and alcohol intake in adulthood.
Specific aim 3 will test the hypothesis that relaxing the chromatin by DNMT inhibition (DNMT inhibitors or CeA infusion of DNMT3b siRNA) in adulthood will reverse AIE effects on epigenetic mechanisms in amygdala and hippocampus as well as on anxiety and alcohol intake.
Specific aim 4 will test the hypothesis that relaxing the chromatin by HAT activation in adulthood will reverse AIE effects. We will examine the effects of the tyrosine receptor kinase B (TrkB) agonist (7, 8-dihydroxyflavone) treatment or CeA overexpression of the CBP gene (lentiviral vectors) on regulation of epigenetic pathways in the amygdala and hippocampus and their modulation of anxiety and alcohol intake. Understanding epigenetic mechanisms, such as the dynamic interaction of DNA methylation and histone acetylation in the regulation of synaptic plasticity in the amygdala and hippocampus during AIE, that may be involved in anxiety and alcohol intake in adulthood are of high significance and may lead to the development of new pharmacotherapy (HDAC, DNMT isoform specific inhibitors, and TrkB agonists) for AIE-induced psychopathology in adulthood.
Adolescent binge drinking is one of the major risk factors for development of substance and alcohol-use disorders later in life. This proposal will enhance our understanding of the brain epigenetic mechanisms associated with the development of anxiety and alcoholism in adulthood after adolescent intermittent ethanol (AIE) exposure and will identify novel targets within epigenome that can be used to develop future therapeutic agents in treating these psychiatric disorders.
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