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：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 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，长期接触乙醇对两者都有不同的调节作用 外侧/基底外侧杏仁核 (BLA) 中的谷氨酸和 GABA 能神经传递，是杏仁核内的一个“节点” 在情绪反应过程中，对于整合认知和感觉信息至关重要的电路，在输入中 具体的时尚。我们在本申请中提供了初步证据，表明长期乙醇有差异 促进谷氨酸能和 GABA 能神经传递到年轻的成年 BLA 神经元，投射到 伏隔核核心（BLANAc 细胞）和那些投射到终纹床核的细胞（BLABNST 细胞）。这些影响既与投入有关，也与性别有关。我们的研究结果强烈表明，慢性 乙醇对控制奖励样反应和厌恶样反应的 BLA 神经元有不同的影响。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 独特的神经生物学和分子反应赋予青少年对慢性乙醇的脆弱性 在不同的奖励/厌恶回路中。拟议的工作包括三个具体目标： 目标 1 将描述 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 了解青少年对慢性乙醇的特定回路和性别脆弱性的分子基础；并且， 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 BLA 内。这些目标共同意义重大，因为它们利用了弱势群体 （青少年）、创新的技术和概念方法以及我们研究的丰富专业知识 团队帮助确定控制乙醇暴露影响的特定细胞信号传导过程 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 用于中断从使用乙醇到滥用的转变的治疗方法。

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.