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.

 描述（由适用提供）：几项临床和临床前研究表明，青少年饮酒是发展精神疾病的主要风险因素之一，包括后来生活中的酒精中毒。大脑边缘系统中的各种核，特别是杏仁核和海马，参与了情绪，认知，焦虑和酒精中毒的调节。基因表达受组蛋白或DNA化学修饰调节，组蛋白脱乙酰基酶（HDAC），组蛋白乙酰转移酶（HATS）和DNA甲基转移酶（DNMT）是这些过程中实现的关键酶。该研究成分将通过研究青少年间歇性乙醇（AIE）治疗期间的杏仁核和海马中突触可塑性的新型表观遗传学机制及其在焦虑和饮酒行为中的作用。 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与成年后AIE后杏仁核和海马中的合成可塑性（树突状刺和神经发生）有关的突触素）。我们还将确定突触可塑性表观遗传机制的持久变化是否与成年后的焦虑样和酒精饮用的行为有关。该提议的总体假设是，AIE诱导的表观遗传机制（组蛋白乙酰化或DNA甲基化）在杏仁核和海马群中恢复突触可塑性的基因网络中产生了定义，从而促进了掺假的动画和饮酒。具体目标1将检验以下假设：通过HDAC抑制[HDAC抑制剂或杏仁核的中央核（CEA）在成年期输注HDAC2 siRNA]将逆转AIE的表观遗传和行为效应。具体的目标2将检验以下假设：在青少年期间，使用慢病毒载体在CEA中敲低或过表达HDAC2基因，从而调节了AIE对成年期表观遗传机制以及动画和酒精摄入的影响。具体目标3将检验以下假设：成年期通过DNMT抑制剂或CEA输注DNMT3B siRNA的CEA降低染色质，这将逆转AIE对杏仁核和海马体以及焦虑和焦虑和酒精摄入的表观遗传机制的影响。具体目标4将检验以下假设：成年后通过HAT激活放松染色质会逆转AIE效应。我们将研究酪氨酸受体激酶B（TRKB）激动剂（7，8-二羟基氟氟氟氟此类）治疗或CEA的CBP基因过表达（慢病毒载体）对amygdala和Hippocampus及其焦虑症调节的表观遗传途径的调节。了解表观遗传机制，例如DNA甲基化和组蛋白乙酰化的动态相互作用在AIE期间杏仁核和海马的突触可塑性调节中，可能与成年中的焦虑和酒精摄入有关AIE引起的成年心理病理学。