Nucleus reuniens, chronic ethanol and cognitive deficits

项目总结 美国大约有2950万12岁以上的人患有酒精使用障碍(AUD) 2021年全国药物使用与健康调查。长期饮酒会导致认知障碍的出现 缺乏，特别是工作记忆，在戒酒和戒酒期间持续存在，增加了 复发的几率。已批准的酒精使用障碍治疗方法并不是用来治疗酒精引起的认知障碍的 因此，了解潜在的机制对于开发新的治疗方法是必要的。原子核 丘脑节(RE)是丘脑腹侧中线核，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还双向连接到 内侧前额叶皮质(MPFC)和海马体，已被高度研究的AUD和认知。 尽管RE相互关联，但在酒精领域还没有得到充分的研究。在我的初步研究中，我诱导 慢性间歇性酒精(CIE)蒸气暴露(4个周期)对男性和女性的酒精依赖 C57BL/6J小鼠。在CIE后，对小鼠进行T迷宫延迟交替空间工作记忆测试 任务或牺牲的全细胞膜片钳电生理学，以测量固有的兴奋性在RE。老鼠 在CIE之前进行训练，并在2次和4次循环后进行测试，以跟踪认知能力下降 跨越了依赖的发展。雄性和雌性小鼠都表现出显著的性能缺陷。 在CIE之后。尽管有相似的行为表型，CIE在内在兴奋性上有不同的影响，导致 女性的射击增加，而男性的射击减少。我还发现在RE的情况下解雇 酒精暴露似乎与性别有关，男性的兴奋性明显高于男性 女性。这些结果表明，RE可能成为慢性酒精研究的一个新的靶点。 诱导性认知缺陷。这项研究建议的总体假设是，长期接触酒精 导致对RE的性别依赖性功能适应，调节RE的激活将改善认知 性能。为了实现这一点，该方案使用多技术方法来研究活体和切片中的RE 生理学。这项提案的目标1将确定长期酒精暴露是否会改变RE的功能 空间工作记忆任务执行过程中的纤维光度测量以及是否使异常活动正常化 利用光遗传学将改善暴露于CIE的小鼠的认知能力。本提案的目标2将 CIE暴露对参与mPFC和海马RE神经元生理的影响 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，或者两者都有。这些实验的结果将成为对RE在 酒精引起的认知功能障碍，使我们进一步了解认知功能障碍的潜在机制 长期饮酒导致的身体缺陷。

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.