Mesolimbic Circuit Function Underlying Individual Alcohol Drinking

项目摘要 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， 导致200多种疾病和伤害。在美国境内， 酒精使用障碍（AUD）在过去10年中从8.5%大幅增加到12.7%， 复杂的病因限制了目前可用的有效治疗剂的数量。一个有趣 饮酒的一种现象是在人群中发生的消费变化：一些 个人随意饮酒，而其他人则以不受控制的方式饮酒，从而增加他们的消费量， 最终形成酒精依赖。为了理解在此基础上的特定于电路的功能， 个体饮酒变异现象，我们利用同基因C57 BL/6 J小鼠，一种近交系小鼠， 通常用于研究饮酒行为的菌株。这种小鼠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， 与基因无关。此外，已知AUD进展的标志是功能障碍， 从腹侧被盖区投射到腹侧被盖核的多巴胺（DA）神经元， 这是一个对药物和自然刺激的显著性进行编码的关键区域。使用体内纤维光度法 钙成像和体内电生理记录，我们现在能够确定神经 饮酒建立前后VTA-NAc DA回路的群体反应 表型，以阐明健康或不健康的饮酒概况的转变。我们的初步数据 表明初级强化VTA-NAc DA反应对奖励和显著刺激的幅度 与未来酒精偏好的建立相关（目标1）。此外，酒精诱导的神经适应 差异影响小鼠的自然行为，包括探索和对奖励的反应，并导致 对酒精的反应增强或减弱（目标2）。通过评估VTA-NAc DA神经元的活动特征， 在酒精暴露前后的自然哺乳动物行为中，该项目将提供新的 深入了解未来的生理和实时预测，个人饮酒以及酒精如何积极地 并且VTA-NAc DA回路功能减弱或恶化，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.