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 据统计，美国约有2950万12岁以上的人患有酒精使用障碍（AUD）。 2021年全国药物使用和健康调查。长期饮酒会导致认知障碍的出现 缺陷，特别是工作记忆，在戒酒和戒酒期间持续存在， 复发的几率批准的酒精使用障碍治疗方法并不是为了治疗酒精引起的认知障碍。 因此，了解潜在的机制对于开发新的治疗方法是必要的。细胞核 丘脑连合（RE）是在认知功能中起关键作用的腹侧中线丘脑核， 例如空间工作记忆、注意力和行为灵活性。RE还双向连接到 内侧前额叶皮层（mPFC）和海马，这在AUD和认知中得到了高度研究。 尽管其相互关联，RE在酒精领域的研究不足。在我的初步研究中， 在男性和女性中使用慢性间歇性乙醇（CIE）蒸汽暴露（4个周期）的酒精依赖 C57 BL/6 J小鼠。在CIE之后，在T-迷宫延迟交替空间工作记忆上测试小鼠， 任务或牺牲用于全细胞膜片钳电生理学以测量RE中的内在兴奋性。小鼠 在CIE之前训练用于T-迷宫任务的人，并在2和4个周期后测试，以跟踪认知下降 跨越依赖性的发展。雄性和雌性小鼠在表现上都表现出明显的缺陷 在CIE之后。尽管这种行为表型相似，CIE对内在兴奋性有不同的影响， 女性的放电次数增加，而男性的放电次数减少。我还发现，在没有 酒精暴露似乎是性别依赖的，男性的兴奋性明显高于男性。 女性这些结果表明，RE可能是一个令人兴奋的新靶点，用于慢性酒精中毒的研究。 导致认知缺陷。这项研究建议的总体假设是， 导致对RE的性别依赖性功能适应，调节RE激活将改善认知功能。 性能为了实现这一目标，该提案使用多技术方法来研究体内和切片中的RE physiology.本提案的目标1将确定慢性酒精暴露是否会改变RE的功能， 在空间工作记忆任务的执行过程中的纤维光度测定以及是否使异常活动正常化 使用光遗传学将改善CIE暴露小鼠的认知表现。本提案的目标2将 表征CIE暴露对涉及mPFC和海马的RE神经元的生理学的影响 通过记录投射到mPFC的神经元的内在兴奋性和突触传递， 海马体或两者。这些实验的结果将作为对可再生能源在以下方面作用的里程碑式研究： 酒精引起的认知功能障碍，并使我们能够进一步了解认知功能障碍的潜在机制。 慢性酒精中毒后的症状