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（由申请人证明）：饮酒障碍（AUD）和饮酒是严重的哭泣症的重要公共卫生问题，并有助于焦虑和其他精神疾病。通过酒精，恐惧和焦虑，对青少年的反应进行了表观遗传学的变化。青少年的大脑领导着青少年的成人精神病，XPOSERIGHT会增加焦虑症的行为，并减少杏仁核的触发型与可塑性相关的事件。在AIE之后，在成年杏仁核中与染色体塑料相关的基因的正面质量是MicroRNA-137（miR-137），可以调节LSD1+8a和The By Allotemone甲基甲基化机制和细胞异生在杏仁核中的miR-137表达持续，在关键的突触地位射血基因上降低了LSD1+8A的表达，并增加了H3K9me2，导致焦虑症在成年中，我们将在这种经验中进行挑战。挑战类似焦虑的行为，基因表达， 组蛋白甲基化和成年大鼠杏仁核中的树突状旋转。我们将确定MiR-137 CEA是否可以挽救类似焦虑的行为，嘶嘶声甲基化和AIE成年大鼠的树突状旋转，这一建议将增加您对染色质的理解。与GY相关的青少年饮酒的新型药理靶标。