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 人们对控制从饮酒到滥用的转变的神经生物学机制知之甚少。 我们的总体方法是检查弱势群体以突出特定的细胞/分子途径 参与这一转变。例如，暴露于大量饮酒的人类青少年的风险要大得多。 成人酗酒的风险。最近的研究表明青少年也有类似的责任 动物，包括啮齿类动物。我们发表的研究表明青少年慢性乙醇暴露存在差异 调节外侧/基底外侧杏仁核 (BLA) 的谷氨酸能和 GABA 能神经传递， 电路中的“节点”对于情绪反应期间认知和感觉信息的整合至关重要， 以特定于输入的方式。我们的数据还表明哺乳动物雷帕霉素靶点 (mTOR) 的关键作用 - 突触强化中的依赖性信号级联。此外，我们提供的初步数据表明 许多这些突触效应在成年动物中不存在或大大减弱。这表明 mTOR- 依赖性信号传导直接调节青少年乙醇暴露期间的突触调节。整体 因此，当前项目的目标是利用青春期大鼠中成熟的乙醇蒸气暴露来 通过整合细胞、分子和功能，了解这种暴露对成年动物的长期影响 行为方法论。拟议的工作包括三个具体目标： 目标 1 将描述效果 青少年乙醇暴露对成人 BLA 谷氨酸能和 GABA 能神经传递的影响 细胞膜片钳电生理学；目标 2 将描述青少年乙醇暴露对 mTOR 的影响 BLA 突触后和突触前区室的信号传导；并且，目标 3 将检查 mTOR 信号通路的药物干预及其对长期行为的影响 青少年接触乙醇的后果。这些目标结合起来意义重大，因为它们利用了 弱势群体（青少年）、创新技术和概念方法以及实质性 我们研究团队的专业知识可帮助确定控制影响的特定细胞信号传导过程 跨多个分析水平的乙醇暴露。我们将直接测试这些信令进程是否代表 旨在中断从使用乙醇到滥用的转变的治疗的潜在治疗目标。