Cerebellar Contributions to Alcohol Use Disorders

项目摘要/摘要 酒精(乙醇；乙醇)滥用是导致死亡和残疾的主要原因，使我们对 影响从健康使用乙醇向酒精使用障碍(AUD)转变的机制a 高度重视生物医学。在这种情况下，对社会相关浓度的初始神经学反应 Etoh(5-20 mm)，以及这些反应的个体差异被认为在决定 对澳元发展的脆弱性或复原力。因此，识别分子靶点和神经回路是至关重要的。 对低浓度乙醇的反应，并确定这些反应在不同地区差异的机制 患AUD风险高或低的个人。在我们发表的和初步的研究中，我们有 确定了低浓度的乙醇(10 mM，在普通成年人的血液中会出现在 饮用1-2种标准酒精饮料)对小脑颗粒细胞GABAAR电流有强烈影响，但 在多个品系的啮齿动物中具有相反的极性，分别具有高和低乙醇消耗表型。 此外，我们还发现了一种以前未知的小脑和大脑的直接突触联系 腹侧被盖区(VTA)，一种已知影响乙醇奖赏的许多方面的大脑结构和相关的 行为。这些都是重要的发现，因为小脑结构、连接性和 已知的是，对乙醇的敏感性与人类发生AUD的风险有关，并与过量 在啮齿动物体内消耗乙醇，但其潜在机制尚不清楚。这项建议的目的是 加深我们对低浓度乙醇如何影响小脑时空加工的理解 行为，这些行为在具有不同乙醇相关行为表型的小鼠品系中如何变化，以及 描述将细胞水平的不同行为转化为不同行为的神经电路， 包括乙醇奖励和乙醇过度消费。这项努力的成功将增加我们的 了解小脑如何影响发生AUD的偏好，并将识别小说 操纵低浓度乙醇反应的分子靶标。总而言之，这些信息 应有助于指导制定心理和药理学方法来筛查和治疗 阻止澳元的发展和维护。我们将使用膜片钳记录的组合 小脑切片、图案化光刺激(以模拟体内的网络处理)，以及 结合行为技术和小脑加工的光遗传操作来确定有多低 乙醇浓度影响小脑的加工和输出，以及乙醇相关的行为。然后我们将使用 光遗传追踪技术，以充分表征小脑到VTA的电路和功能，这将 提供对神经回路的重要洞察，该神经回路将小脑中乙醇的不同动作翻译为 不同的乙醇相关行为表型。成功完成拟议的实验将改善 我们对影响AUD倾向的细胞机制和神经回路的理解。

Project Summary/Abstract Alcohol (ethanol; EtOH) abuse is a leading cause of death and disability, making our understanding of the mechanisms that affect transition from healthy use of EtOH to development of an alcohol use disorder (AUD) a high biomedical priority. In this context, the initial neurological responses to socially relevant concentrations of EtOH (5-20mM), and individual differences in those responses are thought to play a critical role in determining vulnerability or resilience to development of AUD. Thus, it is crucial to identify molecular targets and neural circuit responses to low concentrations of EtOH, and to identify the mechanisms by which such responses vary across individuals with high or low risk for developing AUD. In our published and preliminary studies, we have determined that low concentrations of EtOH (10mM, as would occur in the blood of an average adult human after consuming 1-2 standard alcoholic beverages) powerfully affect cerebellar granule cell GABAAR currents, but with opposite polarity in multiple strains of rodents with high and low EtOH consuming phenotypes respectively. Further, we have discovered a previously unknown direct synaptic connection between the cerebellum and the ventral tegmental area (VTA), a brain structure known to influence many aspects of EtOH reward and associated behaviors. These are important discoveries because genetic differences in cerebellar structure, connectivity and sensitivity to EtOH are known to be associated with risk for developing an AUD in humans and with excessive EtOH consumption in rodents, but the underlying mechanisms are unknown. The purpose of this proposal is to advance our understanding of how low concentrations of EtOH affect cerebellar spatiotemporal processing and behaviors, how such actions vary in strains of mice with divergent EtOH related behavioral phenotypes, and to characterize the neural circuitry that translates differential actions at a cellular level into differential behavior, including EtOH reward and excessive EtOH consumption. Success in this endeavor will increase our understanding of how the cerebellum influences predilection to developing an AUD, and will identify novel molecular targets for manipulating responses to low concentrations of EtOH. Collectively, such information should help guide the development of psychological and pharmacological approaches to screening for and deterring development and maintenance of AUD. We will use a combination of patch-clamp recording from cerebellar brain slices, patterned optical light stimulation (to simulate in vivo-like network processing), and behavioral techniques combined with optogenetic manipulations of cerebellar processing to determine how low concentrations of EtOH affect cerebellar processing and output, and EtOH related behaviors. We will then use optogenetic tract tracing techniques to fully characterize cerebellar to VTA circuitry and function, which will provide important insight into the neural circuitry that translates differential actions of EtOH in the cerebellum to divergent EtOH-related behavioral phenotypes. Successful completion of the proposed experiments will improve our understanding of the cellular mechanisms and neural circuitry that influences predilection to AUD.