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.

项目概要 饮酒和相关行为可能是可预防死亡的第三大原因 美国。持续的 COVID-19 大流行改变了人们的饮酒方式，从而创造了 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 动物模型表明，运动有助于改善与以下行为相关的负面情感行为 戒酒。岛叶皮层 (IC) 是大脑回路的关键组成部分，有助于 禁欲期间扩展杏仁核的突触变化。我们已经证明 IC 对于 表达小鼠因强制戒酒而产生的负面情感行为。初级 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。自愿运动是一种依赖于 MOp 的行为，会导致小鼠 IC 活性的快速变化。 长期摄入酒精的小鼠表现出负面情感和厌恶行为 强制禁欲可以通过间歇性自愿轮跑来缓解。有一个 需要深入了解 MOp-IC 的互连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 与人类的负面影响有关。 GABA 能生长抑素中间神经元 (SST-IN) 富含 新皮质，对于调节啮齿动物药物使用模型中的负面情感行为至关重要 失调。我们的数据表明 IC 中的 GABA 在应激反应中发挥着重要作用。我的 初步数据表明 MOp 神经元投射支配 IC SST-IN。我们需要进一步调查 MOp-IC 微电路，以了解长期饮酒如何改变其内部活动。这 信息使我推测锻​​炼可以减少负面影响和厌恶 戒酒期间通过 MOp-岛微电路连接产生阻力。在此范围内 奖学金，我将首先确定小鼠大脑中的 MOp-mid-IC 微电路互连 电生理学方法。我通过调查酒精如何介导 IC 来跟踪这些结果 微电路。然后，我将通过测试酒精期间是否运动来观察该回路的行为影响 禁欲会促进 IC SST-IN 活性的改变。完成这项 F31 补助金将为我提供 新的技术和技能可以帮助我作为一名独立学术研究员在职业生涯中取得进步。