Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral mechanisms of adult AUD

项目 3：青少年对慢性乙醇的脆弱性：成人 AUD 的神经生理学、分子和行为机制

• 批准号: 10526645
• 负责人: BRIAN A MCCOOL
• 金额: $ 32.45万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526645
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Anatomy; Animals; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Brain; Brain region; Cells; Characteristics; Chronic; Classification; Cognitive; Data; Dependence; Development; Electrophysiology (science); Emotional; Ethanol; Exposure to; Glutamates; Goals; Heavy Drinking; Human; Individual; Interruption; Lateral; Messenger RNA; Metabolic; Molecular; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Pathway interactions; Persons; Phenotype; Population; Process; Property; Proteins; Publishing; Rattus; Research; Rewards; Ribosomal Proteins; Risk; Rodent; Sensory; Signal Transduction; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; Testing; Translating; Vulnerable Populations; Work; age related; aged; alcohol behavior; alcohol exposure; alcohol research; alcohol reward; alcohol use disorder; anxiety-like behavior; behavior measurement; behavioral outcome; designer receptors exclusively activated by designer drugs; differential expression; disability; experimental study; forest; gamma-Aminobutyric Acid; innovation; knock-down; neurobiological mechanism; neurophysiology; neurotransmission; overexpression; periadolescent; protein protein interaction; receptor; response; sex; therapeutic target; therapy design; transcriptome sequencing; underage drinking; vulnerable adolescent; young adult

Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral mechanisms of adult AUD Brian McCool, Kimberly Raab-Graham The neurobiological mechanisms controlling the transition from alcohol use to abuse are poorly understood. Our overall approach is to examine vulnerable populations to highlight specific cellular/molecular pathways involved in this transition. For example, human adolescents exposed to heavy alcohol use are at much greater risk for the development of alcoholism as adults. Recent studies suggest similar liabilities for adolescent animals including rodents. Our published work indicates chronic ethanol exposure differentially modulates both glutamatergic and GABAergic neurotransmission in the lateral/basolateral amygdala (BLA), a ‘node’ within circuits critical for the integration cognitive and sensory information during emotional responses, in an input- specific fashion. We provide preliminary evidence within this application that chronic ethanol differentially facilitates glutamatergic and GABAergic neurotransmission onto young adult BLA neurons projecting to the nucleus accumbens core (BLANAc cells) and those projecting to the bed nucleus of the stria terminalis (BLABNST cells). These effects are both input- and sex-specific. Together our findings strongly suggest that chronic ethanol differentially influences BLA neurons that control both reward- and aversion-like responses. The overall goal of the current project is to therefore to understand the neurobiological, molecular, and behavioral vulnerabilities of adolescent rats compared to mature adults. We will specifically test the central hypothesis that periadolescent vulnerability to chronic ethanol is conferred by unique neurobiological and molecular responses within distinct reward/aversion circuits. The proposed work includes three specific aims: Aim 1 will characterize age-dependent vulnerability of BLA neurophysiology within BLANAc and BLABNST neurons; Aim 2 will help us understand the molecular basis for adolescent circuit- and sex-specific vulnerability to chronic ethanol; and, Aim 3 will define the behavioral consequences of circuit- and sex-specific functional/molecular adaptations within the BLA. Together these aims are significant because they leverage a vulnerable population (adolescents), innovative technical and conceptual approaches, and the substantial expertise of our research team to help identify specific cellular signaling processes governing the impact of ethanol exposure across multiple levels of analysis. We will also directly test if these processes represent potential therapeutic targets for treatments designed to interrupt the transition from ethanol use to abuse.

项目3：青少年对慢性乙醇的脆弱性：神经生理学，分子和行为 成人AUD的机制 布莱恩·麦库尔，金伯利·拉布-格雷厄姆 控制从酒精使用过渡到滥用的神经生物学机制知之甚少。 我们的总体方法是检查脆弱人群，以突出特定的细胞/分子途径 参与到这一转变中。例如，暴露于大量饮酒的人类青少年的死亡率要高得多。 成年后酗酒的风险。最近的研究表明，青少年也有类似的责任。 包括啮齿动物在内的动物。我们发表的研究表明，慢性乙醇暴露差异调节这两个 外侧/基底外侧杏仁核（BLA）中的多巴胺能和GABA能神经传递，BLA是杏仁核内的“节点”， 在情绪反应过程中，在输入中，对整合认知和感觉信息至关重要的电路， 具体的时尚。我们在本申请中提供了初步证据，表明慢性乙醇差异 促进多巴胺能和γ-氨基丁酸能神经传递到年轻的成年BLA神经元投射到 终纹床核（BLANST）和终纹床核（BLANAc 细胞）。这些影响既有输入方面的，也有性别方面的。我们的研究结果强烈表明， 乙醇差异影响BLA神经元，控制奖励和厌恶样反应。整体 因此，当前项目的目标是了解神经生物学，分子和行为 与成年大鼠相比，青春期大鼠的脆弱性。我们将具体检验中心假设， 青少年对慢性乙醇的脆弱性是由独特的神经生物学和分子反应所赋予的 在不同的奖赏/厌恶回路中。拟议的工作包括三个具体目标： BLANAc和BLABNST神经元内BLA神经生理学的年龄依赖性脆弱性;目标2将帮助我们 了解青少年回路和性别对慢性乙醇的特定脆弱性的分子基础;以及， 目标3将定义电路和性别特异性功能/分子适应的行为后果 在BLA。这些目标合在一起意义重大，因为它们影响到弱势群体 （青少年），创新的技术和概念方法，以及我们研究的大量专业知识 团队，以帮助确定特定的细胞信号传导过程，控制乙醇暴露的影响， 多层次分析。我们还将直接测试这些过程是否代表潜在的治疗靶点 旨在中断从使用乙醇到滥用的过渡的治疗方法。