Role of preoptic hypothalamus in sleep-dependent cognition after surgery and general anesthesia

项目总结 围手术期神经认知障碍(PND)是外科手术中常见的、使人衰弱和痛苦的并发症。 65岁以上的患者。睡眠障碍或睡眠不足在外科病人中非常普遍。 睡眠障碍是PND发生发展的重要因素。然而，有一些 关于睡眠中断和认知之间的确切关系的机械性研究或数据很少 手术和麻醉后的损害。下丘脑的视前区是一个关键的结节 控制睡眠开始和睡眠动态平衡。此外，我们小组最近的工作确定了以下内容的子集 内侧和外侧视前区(MLPO)中促进觉醒的谷氨酸能神经元。重要的是 为这一应用而获得的初步数据表明，脑内神经元亚群的化学生成激活 正中视前核(MnPO)可增强(GABA能刺激)或损害(谷氨酸能 刺激)麻醉后的记忆表现。我们的长期目标是通过 哪些睡眠和清醒相关的网络会影响手术和麻醉后的认知功能。的目标是 这项拟议的研究旨在调查手术后视前神经元在睡眠依赖认知中的作用。 拟议中的研究将检验中枢假说，即下丘脑中的视前神经元调节 睡眠-觉醒状态也调节手术后的认知障碍。目标1将使用化学生成刺激 以及对MnPO和MLPO中GABA能和谷氨酸能神经元的抑制作用 神经细胞对手术后急性和长期认知功能影响的小鼠模型。AIM 2将使用 钙离子成像技术评价大鼠脑内GABA能和谷氨酸能神经元的活动模式 MnPO和MLPO与术后睡眠-觉醒状态的关系更多的实验将 使用化学发生抑制来证明这些神经元在术后睡眠障碍中的因果作用 并在手术的小鼠模型中改变了皮质动力学。目标3将测试咖啡因的使用效果 术后认知功能、MnPO和MLPO神经元活动、睡眠-觉醒结构和皮质 振荡和动力学。在另一组实验中，我们将测试化学发生调节是否 视前GABA能和谷氨酸能活动减轻咖啡因对术后认知的影响 性能。拟议的实验将通过提供系统级别的 手术后睡眠与认知功能关系的机械性认识 麻醉。此外，拟议的研究将测试改善术后疗效的药理学方法。 可以转化为外科病人的认知功能。

PROJECT SUMMARY Perioperative neurocognitive disorder (PND) is a common, debilitating, and distressing complication in surgical patients over the age of 65. Sleep disorders or insufficient sleep are highly prevalent among surgical patients and sleep disturbances are an important factor associated with the development of PND. However, there are scarce mechanistic studies or data on the precise relationship between disrupted sleep and cognitive impairment after surgery and anesthesia. The preoptic region of the hypothalamus is a critical node for the control of sleep onset and sleep homeostasis. Additionally, recent work from our group identified a subset of glutamatergic neurons in the medial and lateral preoptic (MLPO) region that promote wakefulness. Importantly, preliminary data obtained for this application show that chemogenetic activation of neuronal subpopulations in the median preoptic nucleus (MnPO) can improve (GABAergic stimulation) or impair (glutamatergic stimulation) memory performance after anesthesia. Our long-term goal is to understand the mechanisms by which sleep- and wake-related networks influence cognitive function after surgery and anesthesia. The goal of the proposed research is to investigate the role of preoptic neurons in sleep-dependent cognition after surgery. The proposed studies will test the central hypothesis that preoptic neurons in the hypothalamus that regulate sleep-wake states also regulate cognitive disturbances after surgery. Aim 1 will use chemogenetic stimulation and inhibition of GABAergic and glutamatergic neurons in the MnPO and MLPO to investigate the role of these neurons in acute and long-term postoperative cognitive function in a mouse model of surgery. Aim 2 will use calcium imaging technology to assess the activity patterns of GABAergic and glutamatergic neurons in the MnPO and MLPO in relation to sleep-wake states during the postoperative period. Additional experiments will use chemogenetic inhibition to demonstrate a causal role of these neurons in postoperative sleep disturbances and altered cortical dynamics in a mouse model of surgery. Aim 3 will test the effect of caffeine administration on postoperative cognitive function, MnPO and MLPO neuronal activity, sleep-wake architecture, and cortical oscillations and dynamics. In a separate set of experiments, we will test whether chemogenetic modulation of preoptic GABAergic and glutamatergic activity mitigates the effect of caffeine on postoperative cognitive performance. The proposed experiments will significantly advance the field by providing a systems-level mechanistic understanding of the relationship between sleep and cognitive function after surgery and anesthesia. Furthermore, the proposed studies will test a pharmacological approach to improve postoperative cognitive function that can be translated to surgical patients.