Nucleus reuniens, chronic ethanol and cognitive deficits

核团聚、慢性乙醇和认知缺陷

• 批准号: 10825768
• 负责人: Kathy Lindquist
• 金额: $ 4.77万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-02 至 2026-09-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825768
• 关键词: Adult; Age; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Animal Model; Attention; Attenuated; Automobile Driving; Behavior; Behavioral; Brain region; Cells; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Dependence; Development; Drug usage; Electrophysiology (science); Ethanol; Exhibits; Female; Fetal Alcohol Syndrome; Fiber; Fright; Future; Goals; Health; Heavy Drinking; Hippocampus; Hyperactivity; Impaired cognition; Inhalation; Knowledge; Lead; Learning; Measures; Medial; Mediating; Memory; Midline Thalamic Nuclei; Modeling; Mus; Neurons; Pattern; Performance; Persons; Photometry; Physiology; Play; Predisposition; Prefrontal Cortex; Probability; Relapse; Research; Research Proposals; Reuniens Thalamic Nucleus; Role; Sex Differences; Short-Term Memory; Slice; Stress; Surveys; Synaptic Transmission; Testing; Thalamic structure; Tracer; Training; Withdrawal; alcohol abstinence; alcohol abuse therapy; alcohol consequences; alcohol exposure; alcohol use disorder; behavioral phenotyping; chronic alcohol ingestion; cognitive function; cognitive performance; cognitive process; cohort; drinking; executive function; experimental study; flexibility; functional adaptation; improved; in vivo; maladaptive behavior; male; mouse model; multimodality; negative affect; neurotransmission; new therapeutic target; optogenetics; patch clamp; sex; vapor

PROJECT SUMMARY Approximately 29.5 million people over the age of 12 in the US had alcohol use disorder (AUD) according to the 2021 National Survey on Drug Use and Health. Chronic alcohol use can lead to the emergence of cognitive deficits, particularly working memory, which persist during alcohol withdrawal and abstinence increasing the odds of relapse. Approved treatments for alcohol use disorder are not designed to treat alcohol-induced cognitive dysfunction, so understanding potential mechanisms is necessary to develop new treatments. The nucleus reuniens of the thalamus (RE) is a ventral midline thalamic nucleus that plays a key role in cognitive function, such as spatial working memory, attention, and behavioral flexibility. The RE is also bidirectionally connected to the medial prefrontal cortex (mPFC) and the hippocampus, which have been highly studied in AUD and cognition. Despite its interconnectedness, the RE is understudied in the alcohol field. In my preliminary studies, I induced alcohol dependence using chronic intermittent ethanol (CIE) vapor exposure (4 cycles) in male and female C57BL/6J mice. Following CIE, mice were either tested on a T-maze delayed alternation spatial working memory task or sacrificed for whole cell patch clamp electrophysiology to measure intrinsic excitability in the RE. Mice used in the T-maze task were trained prior to CIE and tested following 2 and 4 cycles, to track cognitive decline across the development of dependence. Both male and female mice exhibited significant deficits in performance after CIE. Despite this similar behavioral phenotype, CIE had divergent effects on intrinsic excitability, causing an increase in firing in females and a decrease in males. I also found that firing in the RE in the absence of alcohol exposure appeared to be sex-dependent, where males have significantly greater excitability than females. These results indicated that the RE could be an exciting new target for the study of chronic alcohol- induced cognitive deficits. The overall hypothesis of this research proposal is that chronic alcohol exposure causes sex-dependent functional adaptations to the RE and that regulating RE activation will improve cognitive performance. To achieve this, the proposal uses a multi-technical approach to study the RE in vivo and in slice physiology. Aim 1 of this proposal will determine if chronic alcohol exposure alters the function of the RE using fiber photometry during performance on a spatial working memory task and whether normalizing aberrant activity using optogenetics will improve cognitive performance in CIE-exposed mice. Aim 2 of this proposal will characterize the effect of CIE exposure on the physiology of RE neurons involved in mPFC and hippocampal circuitry by recording intrinsic excitability and synaptic transmission from neurons that project to the mPFC, the hippocampus, or both. The results of these experiments will serve as landmark studies for the role of the RE in alcohol-induced cognitive dysfunction and allow us to further understand the underlying mechanisms of cognitive deficits following chronic alcohol.

项目摘要 美国大约12岁以上的人大约有2950万人患有酒精使用障碍（AUD） 2021年全国毒品使用和健康调查。慢性饮酒会导致认知的出现 赤字，尤其是工作记忆，在戒酒和节制期间持续存在，增加了 复发的几率。批准的酒精使用障碍治疗并非旨在治疗酒精引起的认知 功能障碍，因此了解潜在的机制对于开发新治疗是必要的。核 丘脑的聚会（RE）是腹部中线丘脑核，在认知功能中起关键作用， 例如空间工作记忆，注意力和行为灵活性。 RE也在双向连接到 内侧前额叶皮层（MPFC）和海马，在AUD和认知方面进行了高度研究。 尽管它相互联系，但在酒精场中进行了研究。在我的初步研究中，我诱使 使用慢性间歇性乙醇（CIE）蒸气暴露（4个周期）的酒精依赖性 C57BL/6J小鼠。在CIE之后，对小鼠进行T迷宫延迟交替的空间工作记忆进行测试 全细胞贴片夹电生理学的任务或牺牲，以测量RE中的内在兴奋性。老鼠 在T-Maze任务中使用在CIE之前进行了训练，并在2和4周期后进行了测试，以跟踪认知能力下降 在整个依赖的发展中。男性和雌性小鼠均表现出严重的缺陷 在Cie之后。尽管采用了类似的行为表型，但CIE对内在兴奋性产生了不同的影响，导致 女性发射的增加和男性的减少。我还发现在没有 酒精暴露似乎是性别依赖性的，男性的兴奋性明显高于 女性。这些结果表明，RE可能是研究慢性酒精的一个令人兴奋的新目标。 诱发认知缺陷。该研究提案的总体假设是慢性酒精暴露 引起性别依赖性功能适应RE，并且调节重新激活将改善认知能力 表现。为了实现这一目标，该提案使用一种多技术方法来研究Re in Vivo和slice 生理。该提案的目标1将确定慢性酒精暴露是否改变了RE使用的功能 在空间工作记忆任务上性能期间的纤维光度法以及是否使异常活动正常化 使用光遗传学将改善CIE暴露的小鼠的认知性能。该提议的目标2将 表征CIE暴露对MPFC和海马涉及的RE神经元生理的影响 通过记录从投射到MPFC的神经元的内在兴奋性和突触传播来电路 海马或两者兼而有之。这些实验的结果将作为RE在RE中作用的里程碑研究 酒精引起的认知功能障碍，使我们能够进一步了解认知的潜在机制 慢性酒精后的缺陷。