Mesolimbic Circuit Function Underlying Individual Alcohol Drinking

项目总结 有害饮酒仍然是一个严重的公共卫生问题，每年导致全球300万人死亡， 造成了200多种疾病和受伤情况。在美国，风湿病的流行 酒精使用障碍(AUD)在过去10年中显著增加，从8.5%上升到12.7%，其 复杂的病因限制了目前可用的有效治疗方法的数量。一个有趣的故事 饮酒现象是指发生在人群中的消费变异性：一些 个人随意饮酒，而其他人则无节制地饮酒，这加剧了他们的消费和 最终形成对酒精的依赖。要了解其背后的电路特定功能 个体饮酒变异现象，我们利用同基因C57BL/6J小鼠，近交系小鼠 通常用于研究饮酒行为的菌株。这种鼠标模型提供了独特的机会 研究低度和高度饮酒行为的神经生理机制， 不受遗传因素影响。此外，众所周知，AUD进展的一个标志是功能障碍 多巴胺(DA)神经元从腹侧被盖区投射到伏核(VTA-NAC)， 对药物和自然刺激的显著程度进行编码的关键区域。利用活体纤维光度法 钙成像和活体电生理记录，我们现在能够确定神经 饮酒制度建立前后VTA-NAC DA环路的人群反应 表型，以说明向健康或不健康饮酒的过渡情况。我们的初步数据 结果表明，VTA-NAC DA对奖赏和显著刺激的初级强化反应的幅度 与今后确立的饮酒偏好相关(目标1)。此外，酒精诱导的神经适应 不同地影响小鼠的自然主义行为，包括探索和对奖励的反应，以及原因 对酒精反应增强或迟钝(目标2)。通过评估VTA-NAC DA神经元的活动轮廓 在接触酒精之前和之后的自然哺乳动物行为中，这个项目将提供新的 洞察未来的生理和实时预测因素、个人饮酒情况以及酒精如何活跃 并相互衰减或加剧VTA-NAC DA电路功能，导致随后的适应不良 行为。

PROJECT SUMMARY Harmful alcohol use remains a serious public health issue, resulting in 3 million global deaths per year and contributing to more than 200 disease and injury conditions. Within the United States, the prevalence of Alcohol-use Disorder (AUD) has increased significantly, from 8.5% to 12.7% over the last 10 years and whose complex etiology has limited the number of effective therapeutics currently available. An interesting phenomenon in alcohol drinking is the variability of consumption occurring within the human population: some individuals drink casually while others drink in an uncontrolled manner, escalating their consumption and eventually developing alcohol dependence. To understand the circuit-specific functions underlying this phenomenon of individual alcohol drinking variability, we utilized isogenic C57BL/6J mice, an inbred mouse strain typically used to study alcohol-drinking behaviors. This mouse model provides the unique opportunity to investigate the neurophysiological mechanisms underlying low and high alcohol drinking behaviors, independent of genetics. Furthermore, it is known that a hallmark of the progression of AUD is the dysfunction of dopamine (DA) neurons projecting from the ventral tegmental area to (VTA-NAc) the nucleus accumbens, an area critical to encoding the salience of both drug and naturalistic stimuli. Using in vivo fiber photometry calcium imaging and in vivo electrophysiological recordings, we are now able to determine the neural population response of the VTA-NAc DA circuit before and after the establishment of alcohol drinking phenotype, to illuminate the transition to healthy or unhealthy alcohol drinking profiles. Our preliminary data show that the magnitude of the primary reinforcing VTA-NAc DA response to rewarding and salient stimuli correlates with future establishment of alcohol preference (Aim 1). Further, alcohol-induced neuroadaptations differentially affect naturalistic behaviors in mice, including exploration and response to reward, and cause heightened or blunted responses to alcohol (Aim 2). By assessing the VTA-NAc DA neuronal profile of activity during naturalistic mammalian behaviors prior to and after alcohol exposure, this project will provide novel insight into physiological and real-time predictors of future, individual alcohol drinking and how alcohol actively and reciprocally attenuates or exacerbates VTA-NAc DA circuit function, leading to subsequent maladaptive behaviors.