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

项目摘要 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手术患者中非常普遍 睡眠障碍是PND发生的重要因素。但有 缺乏关于睡眠中断与认知能力之间确切关系的机制研究或数据， 手术和麻醉后的损伤。下丘脑的视前区是一个关键的节点， 控制睡眠开始和睡眠稳态。此外，我们小组最近的工作确定了一个子集， 内侧和外侧视前区（MLPO）中促进觉醒的多巴胺能神经元。重要的是， 该应用获得的初步数据显示，脑中神经元亚群的化学发生激活 正中视前核（MnPO）可改善（GABA能刺激）或损害（GABA能刺激 刺激）麻醉后的记忆表现。我们的长期目标是通过 哪些睡眠和觉醒相关网络影响手术和麻醉后的认知功能。的目标 本研究拟探讨视前神经元在手术后睡眠依赖性认知中的作用。 这项研究将验证一个中心假设，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。目的1将使用化学刺激 以及抑制MnPO和MLPO中的GABA能和谷氨酸能神经元，以研究这些神经元的作用。 神经元在小鼠手术模型中的急性和长期术后认知功能。目标2将使用 钙成像技术，以评估GABA能和多巴胺能神经元的活动模式， MnPO和MLPO与术后睡眠-觉醒状态的关系。其他实验将 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 并改变了小鼠手术模型的皮质动力学。目标3将测试咖啡因给药的效果 对术后认知功能、MnPO和MLPO神经元活性、睡眠-觉醒结构和皮质 振动和动力学。在一组单独的实验中，我们将测试是否化学遗传学调节， 视前GABA能和多巴胺能活动减轻咖啡因对术后认知功能的影响 性能拟议的实验将通过提供系统级的 对手术后睡眠和认知功能之间关系的机械理解， 麻醉此外，拟议的研究将测试一种药理学方法， 认知功能可以转化为外科病人。

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.