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

摘要 控制从饮酒到滥用的神经生物学机制还知之甚少。 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 参与了这一转变。例如，暴露在大量饮酒中的人类青少年更容易 成年后发展成酒精中毒的风险。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青少年慢性酒精暴露是不同的 调节外侧/基底外侧杏仁核(BLA)的谷氨酸和GABA能神经传递 在情绪反应过程中，对整合认知和感觉信息至关重要的回路中的“节点”， 以特定于输入的方式。我们的数据还表明，哺乳动物的雷帕霉素靶标(MTOR)- 依赖信号在突触强化中级联作用。此外，我们提供的初步数据表明， 在成年动物中，许多这种突触效应是不存在的，或者大大减弱了。这表明mTOR- 依赖信号直接调节青少年酒精暴露期间的突触调节。整体而言 因此，当前项目的目标是在青春期大鼠中使用公认的乙醇蒸气暴露来 通过整合细胞、分子和基因，了解这种接触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将描述影响 青少年酒精暴露对成人BLA谷氨酸和GABA能神经传递的影响 细胞膜片钳电生理学；目标2将描述青少年酒精暴露对mTOR的影响 BLA中突触后和突触前区的信号；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 青少年接触酒精的后果。这些目标加在一起很重要，因为它们利用 弱势群体(青少年)、创新的技术和概念方法以及实质性的 我们研究团队的专业知识，以帮助确定管理以下影响的特定细胞信号流程 在多个分析水平上接触乙醇。我们将直接测试这些信令过程是否代表 潜在的治疗目标，旨在中断从使用乙醇到滥用的转变。

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.