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: 8061958
• 负责人: Max Kelz
• 金额: $ 30.89万
• 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/8061958
• 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; Slice; Stimulus; Synaptic Transmission; Testing; Tetrodotoxin; Tracer; Unconscious State; 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）：尽管已经取得了很大的进展，使麻醉剂对单个离子通道的影响取得了成功，但对麻醉剂产生其行为影响的神经底物的鉴定仍然是挑战。在表征麻醉状态的关键成分中，我们专注于挥发性麻醉诱导的催眠，定义为缺乏对非毒性刺激的认识。了解麻醉剂如何产生催眠剂已成为神经科学的核心问题，因为在过去的十年中，多个报告表明，现有的一般麻醉药可能每年损害需要麻醉的4000万美国患者中的一部分。麻醉引起的无意识的一种假设替代方法是产生一种可逆的生理无意识状态，例如睡眠，其中患者被锁定在进入觉醒状态的情况下。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神经底物的相互作用引起其理想的催眠作用，该提议着重于两个新兴的下丘脑靶标具有可证明影响唤醒状态的能力：中间核心核，MNPO，MNPO，MNPO和腹侧外同外侧核核，vlpo，vlpo。这两个区域的去极化分别被认为是自然睡眠的发作和维持。我们的全球假设是，挥发性麻醉药通过影响VLPO和MNPO功能引起催眠。在AIM 1中，我们将表明，使用C-FOS免疫组织化学和切片电生理学，接触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Immobilizer不会激活小鼠和下丘脑切片中暴露于体内的VLPO和MNPO。在AIM 2中，我们将确定在自然睡眠期间激活的神经元的子集是否是通过麻醉暴露激活的子集。在AIM 3中，我们将确定VLPO和MNPO的局部破坏，损害VLPO和MNPO发射的药物的显微注射是否是通过右反射分析和处理过的EEG熵确定的光引起VLPO的光诱导的VLPO导致对麻醉性催眠的抗性。最后，我们将确定VLPO的光诱导的去极化是否导致麻醉性催眠的超敏反应。累积地，这些目标将决定挥发性麻醉诱导的催眠是否是由VLPO和/或MNPO募集引起的。 公共卫生相关性：吸入的挥发性麻醉剂是在全国大多数4000万患者中都安全地使用的，这些患者每年都需要全身麻醉；但是，这些药物可能会损害一部分脆弱的患者。令人惊讶的是，麻醉诱发的无意识的机制仍然很少理解。这项研究将评估挥发性麻醉药对下丘脑促进睡眠神经元的影响，以检验以下假设：挥发性麻醉性诱发的潜意识是由募集内源性睡眠促进底物引起的。