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）：焦虑是乙醇戒断的常见早期症状，被认为是继续使用酒精饮料的重要因素。众所周知，酒精会产生抗焦虑作用。不同的表观遗传机制如何导致与酒精成瘾有关的神经可塑性的变化。研究表明，由于组蛋白共价修饰，通过乙酰化和脱乙酰化在基因表达调节中，染色质结构的变化作用。组蛋白乙酰化由两组称为组蛋白乙酰基转移酶（HATS）和组蛋白脱乙酰基酶（HDACS）的酶控制。已经描述了三个不同的HDAC家族，而Trichostatin A（ISA）是I和II类HDAC的有效抑制剂，但不是III级HDAC [静音信息调节剂2（SIR2）蛋白质家族]，需要辅助因子，烟酰胺 - 辅助辅助辅助二甲核苷酸（NAD），以进行Enzymatic Activation。已经表明，磷酸化的cAMP响应元件结合（P-CREB）通过募集与CREB结合蛋白（CBP）相关的HAT来调节神经元可塑性以激活基因转录。神经肽Y（NPY）是与CREB相关的基因之一，它是一种有效的内源性抗焦虑化合物，并在酒精中毒中起作用。我们的建议基于以下假设：由于杏仁核中乙酰化状态的改变，组蛋白的修饰参与酒精依赖性的分子机制。我们提出了几种方法，通过检查a）急性乙醇对中心（CEA），内侧（MEA）和基底外侧杏仁核（CEA）和基底外侧杏仁核（BLA）在中心（CEA）中的各种组成部分以及NPY表达的影响，以检验a）急性乙醇对大鼠的大鼠和焦点的焦点对CRA的焦点和cier2 in 2 in 2 in和siriol的焦点的影响。乙醇。 b）HDACS抑制剂（trichostatin a）挑战或杏仁核内siR 2抑制剂输注对焦虑样行为以及在慢性乙醇后戒断期间在戒断期间的组蛋白乙酰化和NPY表达的各种成分的影响。我们还将检查H3乙酰化对乙醇处理期间杏仁核NPY mRNA水平的影响及其戒断。拟议的研究将提供有关杏仁核神经记录中表观遗传机制的新信息，这些信息可能与酒精依赖过程有关。