Brain epigenetic mechanisms in alcohol dependence

酒精依赖的大脑表观遗传机制

• 批准号: 7217066
• 负责人: SUBHASH C. PANDEY
• 金额: $ 25.37万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217066
• 关键词: acetylation; acyltransferase; alcoholism /alcohol abuse; amidohydrolases; amygdala; antisense nucleic acid; anxiety; behavioral genetics; cAMP response element binding protein; drug withdrawal; enzyme activity; enzyme inhibitors; epigenetics; laboratory rat; messenger RNA; molecular psychobiology; neural plasticity; neurochemistry; neurogenetics; neuropeptide Y; oligonucleotides; polymerase chain reaction; psychopharmacology

DESCRIPTION (provided by applicant): Anxiety is a common early symptom of ethanol withdrawal and is considered an important factor in the continued use of alcohol by alcoholics. It is also well known that alcohol produces anxiolytic effects. How different epigenetic mechanisms are contributing to changes in neural plasticity associated with alcohol addiction is unknown. Studies have shown the role of changes in chromatin structure due to histone covalent modifications via acetylation and deacetylation in the regulation of gene expression. Histone acetylation is controlled by two groups of enzymes known as histone acetyl-transferases (HATs) and histone deacetylases (HDACs). Three distinct families of HDACs have been described and trichostatin A (ISA) is a potent inhibitor of class I and II HDACs, but not the class III HDACs [silent information regulator 2(Sir2) protein family] which requires a cofactor, nicotinamide-adenine dinucleotide (NAD), for enzymatic activity. It has been shown that phosphorylated cAMP-responsive element binding (p-CREB) regulates neuronal plasticity via recruitment of the HAT associated with CREB binding protein (CBP) to activate gene transcription. Neuropeptide Y (NPY) is one of the CREB-related genes and acts as a potent endogenous anxiolytic compound ,and plays a role in alcoholism. Our proposal is based on the hypothesis that histone modifications, due to an altered acetylation state in the amygdala, are involved in the molecular mechanisms of alcohol dependence. We have proposed several approaches to test this hypothesis specifically by examining a) the effects of acute ethanol on various components of histone acetylation mechanisms as well as NPY expression in the central (CeA), medial (MeA) and basolateral amygdala(BLA) of rats and manipulations of activities of HATs activity and Sir2 in the CeA, MeA, and BLA will also be examined on the anxiolytic properties of ethanol. b) Effects of HDACs inhibitor (Trichostatin A) challenge or intra-amygdaloid Sir 2 inhibitor infusion on anxiety-like behaviors and also on various components of histone acetylation and on NPY expression in amygdala during withdrawal after chronic ethanol exposure. We will also examine the effects of H3 acetylation on NPY mRNA levels in the amygdala during ethanol treatment and its withdrawal. The proposed studies will provide new information on epigenetic mechanisms in the neurocircuitry of the amygdala that may be involved in the process of alcohol dependence.

描述（由申请人提供）：焦虑是酒精戒断的常见早期症状，被认为是酗酒者继续使用酒精的重要因素。众所周知，酒精具有抗焦虑作用。不同的表观遗传机制如何影响与酒精成瘾相关的神经可塑性变化尚不清楚。研究表明，由于组蛋白通过乙酰化和去乙酰化进行共价修饰而引起的染色质结构变化在基因表达调控中的作用。组蛋白乙酰化由两组酶控制，称为组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）。已经描述了HDAC的三个不同家族，并且阿司他汀A（伊萨）是I类和II类HDAC的有效抑制剂，但不是III类HDAC [沉默信息调节因子2（Sir 2）蛋白家族]的有效抑制剂，其需要辅因子烟酰胺腺嘌呤二核苷酸（NAD）用于酶活性。磷酸化cAMP反应元件结合（p-CREB）通过募集与CREB结合蛋白（CBP）相关的HAT激活基因转录来调节神经元可塑性。神经肽Y（NPY）是CREB相关基因之一，作为一种有效的内源性抗焦虑化合物，并在酒精中毒中发挥作用。我们的建议是基于这样的假设，即组蛋白修饰，由于改变乙酰化状态的杏仁核，参与酒精依赖的分子机制。我们已经提出了几种方法来测试这一假设，特别是通过检查a）急性乙醇对组蛋白乙酰化机制的各种组分以及大鼠中央（CeA），内侧（MeA）和基底外侧杏仁核（BLA）中NPY表达的影响，以及对CeA，MeA和BLA中HATs活性和Sir 2活性的操纵也将对乙醇的抗焦虑特性进行检查。B）HDAC抑制剂（曲古抑菌素A）激发或杏仁核内Sir 2抑制剂输注对焦虑样行为以及对组蛋白乙酰化的各种组分和对慢性乙醇暴露后戒断期间杏仁核中NPY表达的影响。我们还将研究在乙醇处理和戒断过程中，H3乙酰化对杏仁核中NPY mRNA水平的影响。拟议的研究将提供有关杏仁核神经回路中可能参与酒精依赖过程的表观遗传机制的新信息。