NEURONAL BASIS UNDERLYING VOLATILE ANESTHETIC INDUCED HYPNOSIS

挥发性麻醉剂诱导催眠的神经基础

• 批准号: 7887096
• 负责人: Max Kelz
• 金额: $ 30.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887096
• 关键词: Adenoviruses; Affect; Anesthesia procedures; Anesthetic Hypnosis; Anesthetics; Animals; Arousal; Awareness; Behavioral; Biological Assay; Breathing; Cell Nucleus; Cells; Clinical; Dose; Electroencephalography; Electrophysiology (science); Entropy; Exhibits; Exposure to; FOS gene; Galanin; General Anesthesia; General anesthetic drugs; Histologic; Hypersensitivity; Hypnosis; Hypothalamic structure; Ibotenic Acid; Immunohistochemistry; Impaired cognition; Individual; Ion Channel; Label; Lesion; Light; Maintenance; Measures; Microinjections; Mus; Neurons; Neurosciences; Neurotransmitters; Patient Care; Patients; Pharmaceutical Preparations; Physiologic pulse; Physiological; Postoperative Period; Process; Recruitment Activity; Reflex action; Relative (related person); Reporting; Research; Resistance; Sleep; Sleeplessness; Slice; Stimulus; Synaptic Transmission; Testing; Tetrodotoxin; Tracer; Unconscious State; United States; Viral; Wakefulness; base; cell type; experience; hypnotic; improved; indexing; mammilloinfundibular nucleus structure; mortality; neuromechanism; neuronal cell body; piriform cortex; preoptic nucleus; public health relevance; relating to nervous system; response; sleep onset

DESCRIPTION (provided by applicant): Although much progress has been made deciphering the effects of anesthetics upon individual ion channels, identification of the neural substrates upon which anesthetics act to produce their behavioral effects remains as a challenge. Of the key components that characterize the anesthetized state, we focus on volatile anesthetic-induced hypnosis, defined as a lack of awareness to non-noxious stimuli. Understanding how anesthetics produce hypnosis has become more than a central question for neuroscience, as multiple reports over the past decade suggest that existing general anesthetics may annually harm a subset of the 40 million US patients who require anesthesia. One hypothetical alternative to anesthetic-induced unconsciousness is to generate a state of reversible physiological unconsciousness, such as sleep, in which the patient is locked out of access to the state of wakefulness. To determine whether existing volatile anesthetics cause their desirable hypnotic effects through interactions with endogenous sleep-promoting neural substrates, this proposal focuses on two emerging hypothalamic targets with proven ability to affect arousal state: the median preoptic nucleus, MnPO, and ventrolateral preoptic nucleus, VLPO. Depolarization of these two regions is respectively thought to underlie onset and maintenance of natural sleep. Our global hypothesis is that volatile anesthetics cause hypnosis by affecting VLPO and MnPO function. In Aim 1, we will show that exposure to hypnotic doses of volatile anesthetics activates VLPO and MnPO using c-Fos immunohistochemistry and slice electrophysiology. We will establish that exposure to a non-immobilizer fails to activate VLPO and MnPO in mice and in hypothalamic slices exposed ex vivo. In Aim 2, we will determine if the subset of neurons activated during natural sleep is the same subset activated by anesthetic exposure. In Aim 3, we will determine whether local destruction of VLPO and MnPO, microinjection of drugs that impair firing of VLPO and MnPO, or light-induced hyperpolarization of VLPO cause resistance to anesthetic hypnosis as determined by righting reflex assays and processed EEG entropy. Finally, we will determine if light-induced depolarization of VLPO causes hypersensitivity to anesthetic hypnosis. Cumulatively, these aims will determine whether or not volatile anesthetic-induced hypnosis is caused by recruitment of VLPO and/or MnPO. PUBLIC HEALTH RELEVANCE: Inhaled volatile anesthetics are safely used in the vast majority of the nation's 40 million patients who annually require general anesthesia; however, these drugs may harm a subset of vulnerable patients. Surprisingly, mechanisms of anesthetic-induced unconsciousness remain poorly understood. This research will evaluate the effects of volatile anesthetics upon hypothalamic sleep-promoting neurons to test the hypothesis that volatile anesthetic-induced unconsciousness is caused by recruitment of endogenous sleep- promoting substrates.

描述（由申请人提供）：尽管在破译麻醉剂对个体离子通道的影响方面已经取得了很大进展，但识别麻醉剂作用以产生其行为效应的神经基质仍然是一个挑战。在表征麻醉状态的关键组成部分中，我们关注挥发性麻醉剂引起的催眠，定义为对无害刺激缺乏意识。了解麻醉剂如何产生催眠作用已不仅仅是神经科学的一个核心问题，因为过去十年的多项报告表明，现有的全身麻醉剂每年可能会伤害美国 4000 万需要麻醉的患者中的一部分。麻醉引起的无意识的一种假设替代方案是产生一种可逆的生理无意识状态，例如睡眠，在这种状态下，患者无法进入清醒状态。为了确定现有的挥发性麻醉剂是否通过与内源性促进睡眠的神经底物相互作用而产生理想的催眠效果，该提案重点关注两个已被证明能够影响觉醒状态的下丘脑靶点：正中视前核（MnPO）和腹外侧视前核（VLPO）。这两个区域的去极化分别被认为是自然睡眠的开始和维持的基础。我们的总体假设是挥发性麻醉剂通过影响 VLPO 和 MnPO 功能引起催眠。在目标 1 中，我们将使用 c-Fos 免疫组织化学和切片电生理学证明暴露于催眠剂量的挥发性麻醉剂会激活 VLPO 和 MnPO。我们将确定，暴露于非固定剂无法激活小鼠和离体暴露的下丘脑切片中的 VLPO 和 MnPO。在目标 2 中，我们将确定自然睡眠期间激活的神经元子集是否与麻醉暴露激活的神经元子集相同。在目标 3 中，我们将确定 VLPO 和 MnPO 的局部破坏、损害 VLPO 和 MnPO 放电的药物的显微注射或光诱导的 VLPO 超极化是否会导致对麻醉催眠的抵抗，如通过翻正反射测定和处理的 EEG 熵确定的。最后，我们将确定光诱导的 VLPO 去极化是否会导致对麻醉催眠的过敏。总的来说，这些目标将确定挥发性麻醉药诱导的催眠是否是由 VLPO 和/或 MnPO 的募集引起的。 公共卫生相关性：全国每年需要全身麻醉的 4000 万患者中，绝大多数患者可以安全地使用吸入挥发性麻醉剂；然而，这些药物可能会伤害一部分弱势患者。令人惊讶的是，麻醉引起的意识丧失的机制仍然知之甚少。本研究将评估挥发性麻醉剂对下丘脑促进睡眠神经元的影响，以检验挥发性麻醉剂诱发的意识丧失是由内源性睡眠促进底物的募集引起的假设。