A circuit-driven evaluation of the use of physical activity interventions to improve binge-like ethanol drinking

项目摘要 身体活动（PA）是人类健康和福祉的基石;然而，将其作为一种可行的 酒精使用障碍（AUDs）的治疗和预防选择仍然研究不足。这是强调 在社会层面上，大约26%的成年美国公民报告酗酒，只有3%的公民报告酗酒。 符合美国PA的日常指南。NIAAA认识到理解的重要性， 促进PA用于治疗AUDs。自愿性PA对临床前过度测量的影响 酒精摄入量是混合的。我们力求通过探讨巴勒斯坦权力机构在以下方面的作用，更好地评估这种关系： 在饮酒致中毒的独特遗传风险模型中，减少酗酒式的乙醇饮酒， 在黑暗中（HDID-1）小鼠系（Aim 1）。理解和界定PA发展的关键阶段， 强化对于确定其作为AUD治疗选择的潜力可能是重要的。慢性PA和 酒精的使用会在属于中皮质边缘的相互连接的大脑区域中产生神经重塑 系统这个神经网络由内感受性大脑区域组成，这些区域负责处理 并翻译内部身体状态[如大脑皮层（IC）] -厌恶相关的大脑区域[如 基底外侧杏仁核（BLA）]和对于强化重要的脑区域[即，腹侧被盖区 （VTA）]。在这里，我们计划逆行追踪的核心nucleus lapbens（NAc）-的中心点的收敛， 这个系统-并确定哪些神经输入在2周和4周的车轮运行。先前的车轮- Running工作已经使用基于切片的免疫组织化学表征了cFos，但仅在雄性啮齿动物中。 考虑到人类和啮齿动物中PA的明显性别差异，本申请解决了人类和啮齿动物中PA的主要差距。 文学cFos免疫反应性（IR）将与逆行示踪剂（rAAV 2-retro-GFP）联合使用， 可靠地表征和跟踪NAc的神经输入。我们假设，不同的厌恶相关的NAc 在急性车轮运行期间，投射（例如，扩展杏仁核）将参与，并且重要区域 内感受和强化（如IC和NAc）将在慢性PA后进行。的IC 中继相关的内感受信息的边缘区域，如NAc，并影响动机 行为（如PA和酒精使用）。化学遗传学沉默IC β NAc回路已被证明， 增加酒精对大鼠内感受性的影响。为了确定IC在增强 PA，我们将测试是否在化学遗传学上沉默或激活IC的NAc回路[使用设计者 受体专门激活的设计师药物（DREADDs）]将调节自愿PA在急性和慢性 时间点。我们假设，化学基因沉默IC β NAc投射将增加急性PA （与厌恶相关）和减少慢性PA（与奖励相关）。相反，我们假设， 化学发生学激活IC-NAc投射将减少急性PA并增加慢性PA。到 恭维以前的酒精工作，我们将确定这一电路在PA的重要性。

Project Summary Physical activity (PA) is a cornerstone of human health and well-being; however, its implementation as a viable treatment and preventative option for alcohol use disorders (AUDs) remains understudied. This is underscored at the social level by the ~26% of adult U.S. citizens that report binge drinking and the mere 3% of citizens who manage to meet daily U.S. PA guidelines. The NIAAA recognizes the importance of understanding and promoting the use of PA for treating AUDs. The effects of voluntary PA on preclinical measures of excessive alcohol intake are mixed. We seek to better evaluate this relationship by addressing the role of voluntary PA in reducing binge-like ethanol drinking in a unique genetic risk model of drinking to intoxication, the High Drinking in the Dark (HDID-1) mouse line (Aim 1). Understanding and defining key stages of PA development and reinforcement may be important for determining its potential as an AUD treatment option. Chronic PA and alcohol use create neural remodeling across interconnected brain regions belonging to the mesocorticolimbic system. This neural network comprises of interoceptive brain regions – those responsible for the processing and translating the internal body state [such as the insula cortex (IC)] - aversion-related brain regions [such as the basolateral amygdala (BLA)] and brain regions important for reinforcement [i.e., the ventral tegmental area (VTA)]. Here, we plan to retrogradely trace the nucleus accumbens (NAc) - the central point of convergence for this system – and determine which neural inputs are engaged at 2- and 4-weeks of wheel-running. Prior wheel- running work has characterized cFos using slice-based immunohistochemistry, but only in male rodents. Considering stark sex differences in PA in humans and rodents, this application addresses a major gap in the literature. cFos immunoreactivity (IR) will be used in combination with a retrograde tracer (rAAV2-retro-GFP) to reliably characterize and trace the neural inputs to the NAc. We hypothesize that distinct aversion-related NAc projections (e.g. extended amygdala) will be engaged during acute wheel-running and that regions important for interoception and reinforcement (such as the IC and NAc) will be engaged following chronic PA. The IC relays relevant interoceptive information to limbic regions, such as the NAc, and influences motivated behaviors (like PA and alcohol use). Chemogenetically silencing the IC  NAc circuit has been shown to increase interoceptive effects of alcohol in rats. To determine the importance of the IC in the reinforcement of PA, we will test whether chemogenetically silencing or activating the IC  NAc circuit [using designer receptors exclusively activated by designer drugs (DREADDs)] will modulate voluntary PA at acute and chronic timepoints. We hypothesize that chemogenetically silencing the IC  NAc projection will increase acute PA (associated with aversion) and reduce chronic PA (associated with reward). In contrast, we hypothesize that chemogenetically activating the IC  NAc projection will decrease acute PA and increase chronic PA. To compliment prior alcohol work, we will to determine the importance of this circuit in PA.