Exercised-induced modulation of insular cortex microcircuitry during alcohol abstinence

项目总结 饮酒和相关行为可能是可预防死亡的第三大原因 美国。正在进行的新冠肺炎大流行已经改变了个人饮酒的方式，这产生了 需要新的战略来帮助和保护酒精使用障碍(AUD)患者的健康。研究 动物模型表明，锻炼可以帮助改善与以下方面相关的负面情感行为 戒酒戒酒。岛叶皮质(IC)是大脑回路的关键组成部分，有助于 戒断期间杏仁核延长区的突触变化。我们已经证明，IC对于 表达因强制戒酒而产生的消极情感行为。初级阶段 运动皮质(MOP)在情绪化过程中调节IC和延伸杏仁核之间的基本信息 行为。自愿运动是一种依赖于拖把的行为，它会导致小鼠IC活动的快速变化。 长期饮酒的小鼠表现出消极的情感和抗厌恶行为 强制禁欲，可通过接触间歇性自愿车轮跑道来缓解。有一个 需要深入了解MOP-IC的相互联系，以确定运动如何调节强迫 饮酒后与禁欲相关的行为。抑制性神经递质GABA是 与人类的负面情绪有关。GABA能生长抑素中间神经元(SST-INS)富含 在物质使用的啮齿动物模型中，新皮质在调节消极情感行为方面起到了关键作用 精神错乱。我们的数据表明，IC中的GABA在应激反应中起着重要作用。我的 初步数据表明，MOP神经元投射支配IC SST-INS。我们需要进一步的调查 MOP-IC微电路的研究，以了解长期饮酒可能会如何改变其中的活动。这 信息使我假设锻炼可以减少负面情绪和厌恶情绪 戒酒期间通过脑岛微电路连通性产生抵抗。在这个范围内 团契，我将首先确定MOP-MID-IC微电路在小鼠大脑中的互连 电生理学方法。我通过调查酒精是如何调节IC的来跟进这些结果的 微电路。然后，我将通过测试是否在饮酒期间锻炼来观察这一回路的行为暗示 禁欲促进IC SST-IN活性的改变。完成这笔F31拨款将为我提供 新的技术和技能，帮助我在作为一名独立学术研究人员的职业生涯中取得进步。

PROJECT SUMMARY Alcohol consumption and related behaviors can account for the third-highest cause of preventable death in the United States. The ongoing COVID-19 pandemic has altered how individuals consume alcohol, which creates a need for new strategies to help and protect the health of individuals with alcohol use disorder (AUD). Studies in animal models suggest that exercise can help improve negative affective behaviors associated with abstinence from alcohol exposure. The insular cortex (IC) is a key component in brain circuitry, contributing to synaptic changes in the extended amygdala during abstinence. We have demonstrated that the IC is critical for expressing negative affective behaviors that emerge from forced alcohol abstinence in mice. The primary motor cortex (MOp) regulates essential information between the IC and extended amygdala during affective behaviors. Voluntary exercise, a behavior dependent on the MOp, causes rapid changes in IC activity in mice. Mice exposed to chronic alcohol intake display negative affective and aversion-resistant behaviors following forced abstinence which is mitigated by exposure to intermittent voluntary wheel running access. There is a need to gain insight into the interconnection of the MOp-IC to determine how exercise modulates forced abstinence-associated behavior following alcohol consumption. The inhibitory neurotransmitter GABA is associated with negative affect in humans. GABAergic somatostatin interneurons (SST-INs) are rich in the neocortex and have been critical in regulating negative affective behaviors in rodent models of substance use disorders. Our data suggest that GABA in the IC plays an important role in stress responsiveness. My preliminary data indicates that MOp neuronal projections innervate IC SST-INs. We need further investigation of MOp-IC microcircuitry to understand how activity within it might be altered by chronic alcohol intake. This information has led me to hypothesize that exercise can decrease negative affect and aversion resistance during abstinence from alcohol via the MOp-insula microcircuit connectivity. Within this fellowship, I will first determine the MOp-mid-IC microcircuit inter-connectivity in the mouse brain via electrophysiological methods. I follow up on these results by investigating how alcohol mediates IC microcircuitry. I will then observe the behavioral implications of this circuit by testing if exercise during alcohol abstinence promotes alterations in the IC SST-IN activity. Completion of this F31 grant will provide me with new techniques and skills to help me advance in my career as an independent academic researcher.