Brain Reward and Stress System Interactions in Alcohol Dependence

项目Summary_________________________________________________________________________ 酒精使用障碍(AUD)影响着约1700万美国人，每年导致超过250万人死亡 仅在美国，每年就要花费美国2490亿美元。过量饮酒由 AUD患者是与酒精相关的伤害和死亡的主要原因，目前是可预防的第四大原因 美国的死亡。个体对酒精反应的神经生物学机制，以及他/她 患上澳门氏症的倾向，目前还不完全了解。众所周知，酒精会改变脑内的神经传递 中皮质边缘环路，包括腹侧被盖区(VTA)，以及慢性酒精改变 中央杏仁核(CEA)的神经传递，这是一个与酒精饮酒升级有关的区域。近期 研究表明，VTA多巴胺(DA)神经元之间存在着相当大的异质性，并且 根据投射靶点对这些神经元进行分类，揭示了神经元亚群对 奖赏和厌恶的刺激。对于这里提出的工作来说，在以下各项之间存在功能上的联系 VTA和CEA，虽然这些区域中的每一个对成瘾行为都很重要，但 它们在成瘾行为中的联系尚不清楚。这项提议的首要假设是 投射到CEA的VTA DA神经元在介导酒精依赖所致的兴奋性兴奋中起关键作用 酗酒。为了验证这一假设，该提案将利用解剖学、细胞学和 行为技术。这项提议将为一位有前途的年轻科学家提供重要的研究培训和 通过实验促进职业发展机会，使用综合方法测试 预测：1)投射到CEA的VTA DA神经元在重复循环后表现出更高的活动 酒精暴露和戒断的关系，以及2)VTA DA向CEA的投射调节饮酒的升级 依赖酒精的动物。这些研究的结果将为神经科学研究开辟新的途径。 探索成瘾中大脑奖励和大脑压力系统之间的串扰。这项工作也可能会让人们 制定治疗策略以减少AUD患者不断升级的饮酒行为，导致 改善受影响个人的生活质量和健康，降低与这些疾病相关的发病率 疾病，并可能为美国节省数百万美元的医疗保健成本。

Project Summary_________________________________________________________________________ Alcohol use disorder (AUD) affects ~17 million Americans, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $249 billion annually. Excessive alcohol drinking by individuals with AUD contributes to alcohol-related injury and death, currently the 4th leading cause of preventable death in the U.S. The neurobiological mechanisms underlying an individual’s response to alcohol, and his/her propensity to develop AUD, are not entirely understood. It is known that alcohol alters neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA), and that chronic alcohol alters neurotransmission in the central amygdala (CeA), an area involved in escalated alcohol drinking. Recent research showed that there is considerable heterogeneity among VTA dopamine (DA) neurons, and that classification of these neurons based on projection targets reveals different responses of neuronal subsets to rewarding and aversive stimuli. Important for the work proposed here, there is a functional connection between the VTA and CeA, and although each of these regions is important for addictive behavior, the role of the connection between them in addictive behaviors is unknown. The overarching hypothesis of this proposal is that VTA DA neurons projecting to the CeA are critical for mediating alcohol dependence-induced escalation of alcohol drinking. To test this hypothesis, the proposal will utilize a combination of anatomical, cellular, and behavioral techniques. This proposal will provide a promising young scientist with vital research training and professional development opportunities facilitated by experiments that use an integrative approach to test the predictions that: 1) VTA DA neurons projecting to the CeA display increased activity following repeated cycles of alcohol exposure and withdrawal, and 2) VTA DA projections to CeA mediate escalation of alcohol drinking in alcohol-dependent animals. The results of these studies will open new avenues of neuroscientific investigation exploring the crosstalk between brain reward and brain stress systems in addiction. This work may also inform development of treatment strategies for reducing escalated alcohol drinking in individuals with AUD, leading to improvements in quality of life and health of affected individuals, decreasing morbidity associated with these disorders, and potentially saving the U.S. millions of dollars in health care costs.