Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, biochemical, 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、生化和行为机制

• 批准号: 10310702
• 负责人: BRIAN A MCCOOL
• 金额: $ 32.63万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310702
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Animals; Behavioral; Behavioral Mechanisms; Biochemical; Biochemical Pathway; Biological Assay; Brain; Cells; Chronic; Cognitive; Complex; Data; Dependence; Development; Electrophysiology (science); Emotional; Ethanol; Exposure to; FRAP1 gene; Glutamates; Goals; Heavy Drinking; Human; Hyperactivity; Individual; Inhalation; Interruption; Intervention; Lateral; Learning; Mediating; Memory; Methodology; Modeling; Molecular; Neurobiology; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Pre-Clinical Model; Process; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteins; Publishing; Rattus; Regulation; Research; Resistance; Rewards; Risk; Rodent; Rodent Model; Role; Sensory; Signal Pathway; Signal Transduction; Sirolimus; Slice; Structure; Synapses; Synaptic plasticity; Testing; Vulnerable Populations; Work; addiction; adolescent alcohol exposure; age related; aged; alcohol effect; alcohol exposure; alcohol research; alcohol use disorder; antagonist; anxiety-like behavior; behavioral outcome; cognitive control; differential expression; disability; experimental study; forest; gabapentin; innovation; insight; mature animal; motivated behavior; negative affect; neurobiological mechanism; neuronal circuitry; neurophysiology; neurotransmission; nonhuman primate; patch clamp; postsynaptic; presynaptic; prevent; response; therapeutic target; therapy design; therapy development; underage drinking; vapor; vulnerable adolescent

SUMMARY 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 adolescent 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. Our data also suggest a critical role for mammalian target of rapamycin (mTOR)- dependent signaling cascades in synaptic strengthening. Further, we provide preliminary data suggesting that many of these synaptic effects are absent or greatly diminished in adult animals. This suggests that mTOR- dependent signaling directly regulates synaptic modulation during adolescent ethanol exposure. The overall goal of the current project is to therefore use a well-established ethanol vapor exposure in adolescent rats to understand the long-term impact of this exposure in adult animals by integrating cellular, molecular, and behavioral methodologies. The proposed work includes three specific aims: Aim 1 will characterize the effects of adolescent ethanol exposure on adult BLA glutamatergic and GABAergic neurotransmission using whole- cell patch clamp electrophysiology; Aim 2 will describe the effect of adolescent ethanol exposure on mTOR signaling in both postsynaptic and presynaptic compartments in the BLA; and, Aim 3 will examine pharmacological intervention along the mTOR-signaling pathway and its impact on the long-term behavioral consequences of adolescent ethanol exposure. 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 directly test if these signaling processes represent potential therapeutic targets for treatments designed to interrupt the transition from ethanol use to abuse.

概括 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青少年慢性乙醇暴露差异 在外侧/基底外侧杏仁核（BLA）中调节谷氨酸能和GABA能神经传递 电路中的“节点”对于情感反应期间的认知和感官信息至关重要， 以特定于投入的方式。我们的数据还表明，雷帕霉素的哺乳动物靶标（MTOR）至关重要 - 依赖的信号传导级联反应。此外，我们提供了初步数据，表明 成年动物中的许多突触作用中的许多是不存在或大大减少的。这表明mtor- 依赖信号传导直接调节青少年乙醇暴露期间的突触调节。总体 因此，当前项目的目标是在青少年大鼠中使用良好的乙醇蒸气暴露于 通过整合细胞，分子和 行为方法。拟议的工作包括三个具体目标：AIM 1将表征效果 青少年乙醇对成人BLA谷氨酸能和GABA能神经传递的暴露 细胞贴片夹电生理学； AIM 2将描述青少年乙醇暴露对MTOR的影响 BLA中突触后和突触前室的信号传导；而且，AIM 3将检查 沿MTOR信号途径及其对长期行为的影响 青少年乙醇暴露的后果。这些目标在一起很重要，因为它们利用了 脆弱的人口（青少年），创新的技术和概念方法以及实质性的 我们的研究团队的专业知识，以帮助确定有关影响的特定蜂窝信号传导过程 乙醇跨多个分析。我们将直接测试这些信号过程是否代表 旨在中断从乙醇使用到滥用的过渡的治疗的潜在治疗靶标。