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：青少年脆弱性慢性乙醇：神经生理，分子和行为 成人aud的机制 Brian McCool，Kimberly Raab-Graham 对控制从酒精使用到滥用的过渡的神经生物学机制知之甚少。 我们的总体方法是检查脆弱的人群，以突出特定的细胞/分子途径 参与了这一过渡。例如，暴露于大量酒精的人的青少年要大得多 成年人酗酒发展的风险。最近的研究表明青少年的责任类似 包括啮齿动物在内的动物。我们发表的工作表明慢性乙醇暴露对两者的调节都不同 外侧/基底外侧杏仁核（BLA）中的谷氨酸能和GABA能神经传递，其中一个“节点” 在情感反应期间，在输入中的情感反应期间的认知和感官信息至关重要的电路 - 特定的时尚。我们在此应用中提供了慢性乙醇差异性的初步证据 促进谷氨酸能和GABA能神经传递，向投射到该的年轻成人BLA神经元投射到 伏隔核（Blanac细胞）和那些投射到质子末端的床核的核心（Blabnst 细胞）。这些效果既输入又是性别的。我们的发现共同表明了慢性 乙醇差异影响控制奖励和厌恶式反应的BLA神经元。总体 因此，当前项目的目标是理解神经生物学，分子和行为 与成年人相比，青少年大鼠的脆弱性。我们将专门检验中心假设 独特的神经生物学和分子反应赋予了周围慢性乙醇的脆弱性 在独特的奖励/厌恶电路中。拟议的工作包括三个具体目标：AIM 1将表征 Blanac和Blabnst神经元内BLA神经生理学的年龄依赖性脆弱性； AIM 2将帮助我们 了解青少年电路和性别特异性慢性乙醇的分子基础；和， AIM 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内。这些目标在一起很重要，因为它们利用了脆弱的人群 （青少年），创新的技术和概念方法以及我们研究的实质专业知识 团队有助于确定有关乙醇暴露在整个范围的影响的特定蜂窝信号传导过程 多个分析级别。我们还将直接测试这些过程是否代表潜在的治疗靶标 用于打断从乙醇使用到滥用的过渡的治疗方法。