3/8 NADIA UO1 Adolescent Alcohol, Epigenetics and Behavioral Changes in Adulthood

3/8 NADIA UO1 青少年酒精、表观遗传学和成年期行为变化

• 批准号: 9326097
• 负责人: SUBHASH C. PANDEY
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326097
• 关键词: Acetylation; Adolescence; Adolescent; Adult; Agonist; Alcohol consumption; Alcoholism; Amygdaloid structure; Anxiety; Attenuated; Azacitidine; Behavioral; Brain; Brain-Derived Neurotrophic Factor; CREBBP gene; Cell Nucleus; Chemicals; Chromatin; Clinical Research; Cognition; Cytoskeleton; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Modification Methylases; DNA methyltransferase inhibition; DNMT3B gene; Data; Dendritic Spines; Development; Enzymes; Epigenetic Process; Ethanol; Event; Exons; Future; Gene Expression; Genes; HDAC2 gene; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Homer 1; Infusion procedures; Lead; Lentivirus Vector; Life; Limbic System; Mental disorders; Methylation; Modification; Molecular; Neurobiology; Pathway interactions; Pharmacotherapy; Process; Protein Isoforms; Proteins; Psychopathology; Rattus; Receptor Protein-Tyrosine Kinases; Regulation; Regulator Genes; Research; Risk Factors; Role; Small Interfering RNA; Synaptic plasticity; Synaptophysin; Testing; Therapeutic Agents; Trichostatin A; Vorinostat; adolescent alcohol; adolescent binge drinking; alcohol effect; alcohol exposure; alcohol use disorder; anxiety-like behavior; brain circuitry; drinking behavior; emotion regulation; epigenetic regulation; epigenome; histone acetyltransferase; histone modification; inhibitor/antagonist; knock-down; neurogenesis; neurogranin; novel; novel therapeutics; overexpression; preclinical study; prevent; promoter; public health relevance; underage drinking

 DESCRIPTION (provided by applicant): 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.

 Description (Provied by Application): Several Clinical and Preclinical Studies Suggest That Adolescent Binging IDORESCENGE OF THE MAJOR RISK FORS FORS FORS FORS FORS FORS FORS FORS FORS FORS FORS FORS He Development of Psychiatric Disorder, Various Nuclei within the Braine Limbic System La and Hippocampus ,参与了情绪，认知，焦虑和酗酒的调节，并且组蛋白脱乙酸（HDACS），组蛋白乙酰助剂（HATS）和DNA甲基转移酶（DNMTS）是这些研究组成部分的关键酶。在青少年间歇性以太酚（AIE）中，杏仁核和海马的新型表观遗传机制在焦虑和饮酒行为中的作用 - 我们将采用多向方法来检查HDAC2 3B的直接作用）和HATONE（CBP）的直接作用修饰和DNA甲基化，以及与突触的塑料卵子有关的（BDNF和相关基因，弧形，homer1，homer1，神经素蛋白和突触素））突触。 hDAC2 siRNA]在成年中，AIE特定目标的表观遗传和行为效应将测试TIAC2中HDAC2基因的敲低或过表达，这会影响表观遗传的Mecohanism和DNMT抑制剂的表观遗传遗传性Mecohanism和焦虑。校园以及焦虑和酒精摄入量。 （慢病毒载体）在杏仁核和海马，杏仁核和海马及其对焦虑和酒精摄入的调节。成年后新的药物心理病理学。