Neurochemical mechanisms of sedative effects on sleep homeostasis

镇静作用对睡眠稳态的神经化学机制

• 批准号: 10381005
• 负责人: Dinesh Pal
• 金额: $ 5.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381005
• 关键词: Adenosine; Biological Markers; Brain; Data; Delirium; Dexmedetomidine; Dissociation; Drug Design; Electroencephalography; Eye; Goals; Homeostasis; Incidence; Intensive Care Units; Knowledge; Laboratories; Mediating; Medicine; Midazolam; Mission; National Institute of General Medical Sciences; Neurobiology; Nitric Oxide; Nitric Oxide Synthase; Patient Care; Patients; Perioperative Care; Pharmaceutical Preparations; Phase; Plant Roots; Process; Propofol; Protein Isoforms; Public Health; REM Sleep; Rattus; Recovery; Regimen; Research; Research Proposals; Role; Sedation procedure; Signaling Molecule; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Slow-Wave Sleep; Testing; adverse outcome; basal forebrain; behavioral phenotyping; biomarker development; care providers; clinically relevant; density; functional outcomes; hypnotic; indexing; innovation; mortality; neural circuit; neurobiological mechanism; neurochemistry; public health relevance; sedative; sevoflurane

Project Title: Neurochemical mechanisms of sedative effects on sleep homeostasis PROJECT SUMMARY/ABSTRACT Sedative-hypnotics are administered to about two-third of the patients admitted to the intensive care unit (ICU). Although patients might appear to be “sleeping,” there are varying effects of sedatives on sleep architecture. The dissociation between the behavioral phenotype of sleep (quiescence, eyes closed) and the restorative effects of sleep can mislead care providers and cause adverse consequences for patients. For example, it is known that certain sedative strategies are associated with a higher incidence of delirium, which is associated with increased mortality. The lack of rational sedation strategies is rooted in a profound gap in our knowledge at the neurobiological level. Two main questions persist and have not been explored: (1) do sedative-hypnotics accomplish the beneficial effects of sleep? and if so, (2) what is the mechanism? The long-term goal of the proposed studies is to identify sedative regimens that can be used more effectively in ICU and perioperative care to achieve homeostatic sleep recovery, and the neurochemical mechanisms through which sedative- hypnotics could provide a sleep-like state with positive functional outcomes. The overall objective of the proposed studies is to examine the effect of sedatives on sleep homeostatic neural circuitry, and to identify the mechanisms of differential effects on slow-wave sleep and rapid eye movement sleep. The central hypothesis, supported by our preliminary data, is that sedatives modulate levels of nitric oxide (NO) and adenosine, the signaling molecules that serve as the “currency” of sleep debt, in basal forebrain to provide recovery from sleep loss. The rationale for the proposed research is that it will provide the fundamental mechanistic understanding of the interaction between sedatives and sleep homeostasis, which is currently unknown. The study will use four clinically relevant sedative-hypnotics (propofol, dexmedetomidine, midazolam, sevoflurane) and test the hypothesis by pursuing three specific aims that investigate 1) the relationship between sedative- induced changes in sleep homeostasis and the changes in NO and adenosine levels in basal forebrain, 2) the causal influence of NO and adenosine in basal forebrain on sedative-mediated recovery sleep, and 3) the role of NO synthase isoforms in sedative-mediated recovery of distinct sleep phases, i.e., slow-wave sleep vs. rapid eye movement sleep. The approach is innovative because this will be the first study to develop a mechanistic understanding of the processes mediating homeostatic sleep recovery during sedation. In addition, two technical innovations from our laboratory – high density EEG recordings and mass spectrometric analysis of simultaneous changes in >55 brain analytes in rats – will be used for mapping changes in rat brain cortical networks as an index of sedative-mediated sleep recovery, and comparison of basal forebrain neurochemistry between sedation and non-sedation states. The proposed research is significant because it is expected to help establish an EEG biomarker for sedation-induced sleep recovery, a framework for rational sedation strategies and, ultimately, facilitate drug design that could be used for sedation and sleep disorders.

项目名称：镇静作用于睡眠稳态的神经化学机制 项目摘要/摘要 大约三分之二住进重症监护病房(ICU)的患者服用镇静催眠药。 虽然病人可能看起来在“睡觉”，但镇静剂对睡眠结构有不同的影响。 睡眠行为表型(安静、闭眼)与恢复期的分离 睡眠的影响可能会误导护理人员，并给患者造成不良后果。例如，它是 已知某些镇静策略与较高的精神错乱发生率有关，这与 随着死亡率的增加。缺乏合理的镇静策略植根于我们知识上的巨大鸿沟 在神经生物学层面上。有两个主要问题仍然存在，而且还没有得到探索：(1)镇静催眠药 实现睡眠的有益效果？如果是这样的话，(2)机制是什么？中国的长期目标是 建议的研究是确定可以在ICU和围手术期更有效地使用的镇静方案 护理以实现稳态睡眠恢复，以及镇静剂通过的神经化学机制- 催眠药可以提供一种类似睡眠的状态，具有积极的功能结果。《公约》的总体目标 建议的研究是检查镇静剂对睡眠稳态神经回路的影响，并确定 慢波睡眠和快速眼动睡眠的不同作用机制。核心假设是， 我们的初步数据支持的是，镇静剂调节一氧化氮(NO)和腺苷的水平， 信号分子充当睡眠债务的“货币”，在基底前脑中提供恢复 失眠。拟议研究的基本原理是，它将提供基本的机制 了解镇静剂和睡眠稳态之间的相互作用，目前尚不清楚。这个 研究将使用四种临床相关的镇静催眠药(异丙酚、右美托咪定、咪达唑仑、七氟醚) 并通过追求三个具体目标来检验这一假设，这三个目标调查1)镇静剂- 诱导睡眠动态平衡的改变及基底前脑NO和腺苷水平的变化 基底前脑NO和腺苷对镇静恢复睡眠的因果影响及3)作用 一氧化氮合酶同工酶在镇静剂介导的不同睡眠阶段的恢复中的作用，即慢波睡眠与快速睡眠 动眼睡眠。这种方法是创新的，因为这将是第一次研究开发一种机械 了解镇静期间调节稳态睡眠恢复的过程。此外，还有两个 我们实验室的技术创新-高密度脑电记录和质谱分析 大鼠脑&gt；55分析物的同步变化-将用于绘制大鼠大脑皮层的变化 网络作为镇静剂介导的睡眠恢复的指标，以及基底前脑神经化学的比较 在镇静和非镇静状态之间。这项拟议的研究意义重大，因为预计它将有所帮助 建立镇静诱导睡眠恢复的脑电生物标志物，为合理的镇静策略提供框架 最终，有助于设计可用于镇静和睡眠障碍的药物。