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

项目摘要 体力活动(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未得到充分研究。这一点被强调了。 在社会层面上，约26%的美国成年公民报告酗酒，仅3%的公民报告酗酒 设法满足美国每日PA的指导方针。NIAAA认识到了解和 推广PA在AUDS治疗中的应用。自愿性PA对过度行为临床前措施的影响 酒精摄入量是混合的。我们寻求更好地评估这种关系，通过解决自愿PA在 减少酗酒样酒精饮酒的独特遗传风险模型饮酒到醉酒，高饮酒 在黑暗(HDID-1)小鼠品系中(目标1)。了解和定义PA开发和管理的关键阶段 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 酒精使用在属于中皮质边缘的相互连接的脑区造成神经重塑 系统。这个神经网络由负责加工的大脑内感觉区组成。 以及翻译身体内部状态[如岛叶皮质(IC)]-厌恶相关的脑区[如 杏仁基底外侧核(BLA)和对强化很重要的大脑区域[即腹侧被盖区 (VTA)]。在这里，我们计划逆行追踪伏隔核(NAC)- 这个系统--并确定在车轮运行2周和4周时，哪些神经输入被激活。前轮- 运行工作使用基于切片的免疫组织化学来表征CFO，但仅在雄性啮齿类动物中。 考虑到人类和啮齿动物PA的明显性别差异，这项应用解决了 文学。CFOS免疫反应性(IR)将与逆行示踪剂(rAAV2-retro-GFP)相结合用于 可靠地表征和跟踪NAC的神经输入。我们假设与厌恶相关的明显的NAC 投射(如杏仁核扩大)将在急转轮运行时被激活，该区域很重要 对于内感和强化(如IC和NAC)，将在慢性PA后进行。集成电路 将相关的感觉间信息传递到边缘区域，如NAC，并影响被激发的 行为(如PA和饮酒)。用化学方法使ICNAC电路静音已被证明 增强酒精对大鼠的内感作用。确定IC在加固中的重要性 PA，我们将测试是否通过化学方法静默或激活ICNAC电路[使用Designer 由特制药物(DREADD)专属激活的受体]将在急性和慢性调节自发性PA 时间点。我们假设化学上沉默ICNAC投射会增加急性PA (与厌恶相关)和减少慢性PA(与奖励相关)。相反，我们假设 化学激活ICNAC投射可降低急性PA，增加慢性PA。至 赞扬之前的酒精工作，我们将确定这一巡回在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.