Neurophysiological Mechanisms of Variable Alcohol Drinking Behaviors

描述（由申请人提供）：酒精使用障碍造成了巨大的全球卫生保健负担，在精神，神经和物质使用障碍中排名第二，表明迫切需要更有效的治疗方法。众所周知，酒精的使用在多个方面与可卡因等其他滥用药物有很大的不同：有些人以可控的方式饮酒数十年而不产生依赖性，而另一些人则有无法控制的饮酒欲望并发展严重的酒精成瘾。为了了解不同饮酒行为背后的神经生理机制，我们假设即使在遗传相同的近交系小鼠中也存在饮酒变异性。这一假设很重要，因为以前在动物模型中理解饮酒变化的努力遇到了巨大的挑战，这在一定程度上是由可变的基因背景和基因与环境之间未知的复杂相互作用引起的。在我们对这一假设进行测试的初步研究中，我们观察到，在C57 BL/6 J小鼠中，由于其自由饮酒量高，通常用于酒精研究的近交系小鼠中，大约10%的小鼠具有较低的饮酒行为（偏好和消费）。这为我们提供了一个特殊的实验模型来探索饮酒行为的个体差异。为了研究变量饮酒行为背后的神经生理学基础，我们专注于大脑的奖励回路，这是一个众所周知的神经系统，主要参与介导自然奖励和药物强化。我们建议：（1）研究低浓度和高浓度饮酒小鼠腹侧被盖区（VTA）多巴胺神经元放电活动的差异，更具体地说，研究投射到丘脑核（NAc）、内侧前额叶皮质（mPFC）和杏仁核（BLA）的VTA神经元亚群的差异;（2）光遗传学研究腹侧被盖区多巴胺神经元及其向NAc、mPFC和BLA的特异性投射在调节饮酒行为中的功能作用;（3）深入研究腹侧被盖区多巴胺神经元和投射特异性神经元放电特性差异的离子通道和受体机制，以确定可能的新型药物靶点。在这个项目中，我们将通过在自由行为的小鼠中结合使用最先进的电生理学和复杂的光遗传学方法，提供饮酒行为与放电模式，细胞类型和神经回路的特定作用之间的直接因果关系。这些拟议的分子，细胞和神经回路研究将提供非常有用和高度新颖的信息，既可以提高我们对可变饮酒行为的认识，也可以确定新的药物靶点，以开发更有效的，个性化的酒精使用障碍治疗方法。

DESCRIPTION (provided by applicant): Alcohol-use disorders create a huge global health care burden, which ranks number two in the mental, neurological and substance-use disorders, indicating an urgent need for more effective treatments. It is well known that alcohol-use is very different from other drugs of abuse such as cocaine in multiple aspects: whereas some individuals drink alcohol for decades in a controlled manner and without developing dependence, others have an uncontrollable desire to drink and develop severe alcohol addiction. To understand the neurophysiological mechanisms that underlie the evidently different drinking behaviors, we hypothesize that there is alcohol drinking variability even in genetically identical inbred mice. This hypothesis is important because previous efforts to understand the drinking variations in animal models have encountered huge challenges, which is in part induced by the variable gene backgrounds and the unknown complex interactions between genes and the environment. In our preliminary studies toward testing this hypothesis, we observed that in C57BL/6J mice, an inbred strain typically used in alcohol research because of its high ad libitum consumption of alcohol, roughly 10% had lower alcohol drinking behaviors (preference and consumption). This provides us with an exceptional experimental model to explore the individual variations in alcohol drinking behaviors. To investigate the neurophysiological basis underlying variable alcohol drinking behaviors, we focus on the brain's reward circuit, a well-known neural system that is critically involved in mediating natural reward and drug reinforcement. We propose to: (1) characterize the differences in the firing activity of ventral tegmental area (VTA) dopamine neurons in low and high alcohol drinking mice, and, more specifically, of the subpopulations of VTA neurons projecting to the nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and amygdala (BLA); (2) optogenetically dissect the functional roles of VTA dopamine neurons and their specific projections to NAc, mPFC and BLA in mediating the variable alcohol drinking behaviors; (3) intensively explore the ion channel and receptor mechanisms underlying the differences in the firing properties of VTA dopamine neurons and projection-specific neurons in the VTA to identify possible novel drug targets. In this project, we will provide the direct causal links between alcohol drinking behaviors and the specific roles of firing patterns, cell types and neural circuits via the combined use of state-of-the-art electrophysiological and sophisticated optogenetic approaches in freely behaving mice. These proposed molecular, cellular and neural circuit studies will provide very useful and highly novel information, both for improving our knowledge of variable alcohol drinking behaviors and for identifying new drug targets to develop more effective, individualized treatments for alcohol-use disorders.