Brain histone methylation mechanisms in adulthood after adolescent alcohol exposure

青少年酒精暴露后成年期的脑组蛋白甲基化机制

• 批准号: 9756249
• 负责人: Evan Kyzar
• 金额: $ 5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2020-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756249
• 关键词: Acute; Adolescence; Adolescent; Adult; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anxiety; Attenuated; Behavioral; Brain; Cell Nucleus; Chromatin; Comorbidity; Complex; Data; Dendritic Spines; Development; Dose; Emotions; Enzymes; Epigenetic Process; Ethanol; Event; Exons; Exposure to; Fright; Gene Expression; Gene Expression Profile; Genes; Histone Acetylation; Histones; Individual; Investigation; KDM1A gene; Lead; Lysine; Mediator of activation protein; Mental disorders; MicroRNAs; Neurites; Neuronal Differentiation; Neuronal Plasticity; Neurons; Pathology; Pharmacology; Phenotype; Process; Psychiatric Diagnosis; Psychopathology; Public Health; RNA Splicing; Rattus; Regulation; Research; Role; Saline; Series; Societies; Stains; Structure; Substrate Specificity; Synapses; Synaptic plasticity; Testing; Untranslated RNA; Variant; Work; adolescent alcohol exposure; adolescent binge drinking; alcohol effect; alcohol exposure; alcohol risk; alcohol use disorder; anxiety-like behavior; anxiety-related behavior; base; binge drinking; brain circuitry; chromatin remodeling; density; experimental study; histone demethylase; histone methylation; knock-down; methyl group; novel; promoter; public health relevance; response; small hairpin RNA; underage drinking

 DESCRIPTION (provided by applicant): Alcohol use disorder (AUD) and alcohol addiction are significant public health concerns with serious effects on society and individuals. Adolescent binge drinking is common and contributes to anxiety and other psychiatric disorders in adulthood. Recent research shows that epigenetic mechanisms are responsible for the development of brain structures and are modified by alcohol exposure. The amygdala, known as a regulator of emotion, fear, and anxiety, undergoes epigenetic changes in response to adolescent alcohol use that leads to increased anxiety-related behaviors and abnormal synaptic plasticity in adulthood. However, the crosstalk between epigenetic enzymes and chromatin is enormously complex, and many of the mechanisms of adolescent alcohol exposure have yet to be elucidated. The discovery of novel epigenetic effectors of alcohol in the adolescent brain may lead to new treatment targets for adolescent alcohol exposure-induced adult psychopathology. Our previous studies suggest that adolescent intermittent ethanol (AIE) exposure in rats increases anxiety-like behaviors and decreases synaptic plasticity associated events in the amygdala in adulthood. Lysine demethylase 1 (LSD1; also known as Kdm1a) and its neuron- specific splice variant Lsd1+8a are histone demethylases that may be responsible for altering chromatin around important synaptic plasticity-associated genes in the adult amygdala following AIE. Additionally, microRNA-137 (miR-137) may be responsible for regulating Lsd1+8a and thereby affecting downstream histone methylation mechanisms and spinogenesis. This proposal is based on the hypotheses that AIE produces a persistent increase in miR-137 expression in the amygdala, decreasing LSD1+8a expression and increasing H3K9me2 at crucial synaptic plasticity-related genes leading to anxiety-like behaviors in adulthood. We will perform a series of experiments to test these hypotheses. We will dose AIE adult rats with acute ethanol to determine if this challenge will rescue the alterations in anxiety-like behaviors, gene expression, histone methylation, and dendritic spines in the amygdala of AIE adult rats. We will inhibit Lsd1+8a in the central nucleus of the amygdala (CeA) using shRNA in control rats to determine if Lsd1+8a inhibition alone can recapitulate the behavioral and epigenetic deficits of AIE in adulthood. Finally, we will determine if miR-137 inhibition in the CeA can rescue the alterations in anxiety-like behaviors, gene expression, histone methylation, and dendritic spines in AIE adult rats. Taken together, this proposal will increase the understanding of chromatin remodeling by adolescent alcohol and may identify novel pharmacological targets for the treatment of adult psychopathology-related adolescent drinking.

 描述（由适用提供）：酒精使用障碍（AUD）和酒精成瘾是重要的公共卫生问题，对社会和个人产生了严重影响。青少年的饮料很普遍，并导致成年后的焦虑和其他精神疾病。最近的研究表明，表观遗传机制是导致大脑结构的发展，并通过酒精暴露来改变。杏仁核（被称为情绪，恐惧和焦虑的调节者）经历了表观遗传学的变化，以应对青少年的饮酒，从而导致焦虑相关的行为增加，并在成年期间引起异常的突触可塑性。但是，表观遗传酶和染色质之间的串扰非常复杂，许多青春期酒精暴露的机制尚未阐明。发现酒精在青少年大脑中的新表观遗传作用的发现可能会导致青少年酒精暴露诱导的成人精神病理学的新治疗靶标。我们先前的研究表明，大鼠的青少年间歇性乙醇（AIE）暴露会增加焦虑样行为，并减少成年杏仁核的突触可塑性相关事件。赖氨酸脱甲基酶1（LSD1；也称为KDM1A）及其神经元特异性剪接变体LSD1+8A是组蛋白脱甲基酶，可能导致在AIE之后成人杏仁核中重要的合成可塑性相关基因周围改变染色质。另外，MicroRNA-137（miR-137）可能负责控制LSD1+8A，从而影响下游组蛋白甲基化机制和旋转生成。该建议基于以下假设：AIE在杏仁核中产生miR-137表达的持续增加，从而降低了LSD1+8A表达并增加。关键的突触可塑性相关基因的H3K9Me2导致成年后的动画样行为。我们将执行一系列实验来检验这些假设。我们将用急性乙醇剂量成年大鼠，以确定这一挑战是否会挽救动画样行为的改变，基因表达， Heatone甲基化和成年大鼠杏仁核中的树突状刺。我们将使用对照大鼠中的shRNA抑制杏仁核（CEA）的中央核心中的LSD1+8a，以确定单独的LSD1+8A抑制是否可以概括AIE的行为和表观遗传缺陷。最后，我们将确定CEA中的miR-137抑制作用是否可以挽救AIE成年大鼠中焦虑样行为，基因表达，组蛋白甲基化和树突状棘的改变。综上所述，该提案将通过青少年酒精对染色质的重塑进行了解，并可能确定用于治疗与成人心理病理学相关的青少年饮酒的新型药理学靶标。