Exercised-induced modulation of insular cortex microcircuitry during alcohol abstinence

戒酒期间运动诱导的岛叶皮质微电路调节

• 批准号: 10748763
• 负责人: Danielle Nicole Adank
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748763
• 关键词: Abstinence; Acute; Affective; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Anxiety; Automobile Driving; Behavior; Behavioral; Brain; Brain region; COVID-19 pandemic; Cells; Chronic; Communication; Data; Dose; Electrophysiology (science); Ethanol; Etiology; Exercise; Exercise Test; Exposure to; Feeling; Fellowship; Fiber; Genetic; Grant; Health protection; Human; Individual; Insula of Reil; Interneurons; Interoception; Investigation; Maps; Mediating; Methods; Motor Activity; Motor Cortex; Mus; Neocortex; Neurons; Neuropeptides; Neurotransmitters; Pattern; Persons; Photometry; Play; Property; Public Health; Quinine; Regulation; Relapse; Reporter; Research Personnel; Resistance; Rodent Model; Role; Running; Self Administration; Signal Transduction; Somatostatin; Stress; Structure; Study models; Substance Use Disorder; Synapses; Techniques; Testing; United States; Withdrawal; alcohol abstinence; alcohol behavior; alcohol effect; alcohol exposure; alcohol sensitivity; alcohol use disorder; alcohol-related death; brain circuitry; career; cell cortex; drinking; feeding; follow-up; gamma-Aminobutyric Acid; improved; in vivo; insight; negative affect; neocortical; optogenetics; prevent; preventable death; rabies viral tracing; recruit; relapse prevention; sensor; skills; transmission process

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.

项目摘要 酒精消费和相关行为可以占可预防死亡的第三大原因， 美国的持续的COVID-19大流行改变了人们饮酒的方式， 需要新的策略来帮助和保护酒精使用障碍（AUD）患者的健康。研究 在动物模型中表明，运动可以帮助改善与以下相关的消极情感行为： 戒酒岛叶皮层（IC）是大脑回路的关键组成部分，有助于 戒断期间杏仁核的突触变化。我们已经证明，IC对于 表达了老鼠在强制戒酒后出现的消极情感行为。主 运动皮层（MOp）在情感过程中调节IC和扩展杏仁核之间的重要信息 行为。自主运动是一种依赖于MOp的行为，可引起小鼠IC活性的快速变化。 长期摄入酒精的小鼠表现出消极的情感和厌恶行为， 强迫禁欲，通过暴露于间歇性自愿轮运行访问来减轻。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 饮酒后的禁欲相关行为。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）富含于 在啮齿动物物质使用模型中， 紊乱我们的数据表明，GABA在IC中起着重要的作用，在应激反应。我 初步数据表明MOp神经元投射支配IC SST-IN，我们需要进一步研究 MOP-IC微电路的研究，以了解慢性酒精摄入如何改变其活动。这 信息使我假设锻炼可以减少消极情绪和厌恶 通过MOp-MEMS微电路连接，在戒酒期间产生电阻。在这 为了获得奖学金，我将首先通过以下方式确定小鼠大脑中的Mop-中间-IC微电路互连性： 电生理学方法。我通过研究酒精如何介导IC来跟进这些结果 微电路然后，我将通过测试饮酒期间的运动是否会影响大脑的行为， 禁欲促进IC SST-IN活性的改变。完成F31补助金将为我提供 新的技术和技能，以帮助我在我的职业生涯作为一个独立的学术研究人员前进。