Arousal, orexins and anesthesia

唤醒、食欲素和麻醉

• 批准号: 7596180
• 负责人: Max Kelz
• 金额: $ 12.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596180
• 关键词: Acute; Affect; Agonist; Anesthesia procedures; Anesthetics; Arousal; Attenuated; Award; Awareness; Basic Science; Behavioral; Biological Assay; Brain; Brain region; Breathing; Cell Nucleus; Cells; Circadian Rhythms; Clinical; Commit; Complement; Conscious; Data; Discipline; Disease; Doctor of Philosophy; Dose; Drug Delivery Systems; Education; Electroencephalography; Exhibits; Exposure to; FOS Protein; FOS gene; Faculty; General Anesthesia; General anesthetic drugs; Genetic; Goals; Grant; Halothane; Human; Hypersensitivity; Hypothalamic structure; Immediate-Early Genes; Impairment; Individual; Intravenous Anesthetics; Isoflurane; Lateral; Maintenance; Maps; Measures; Mediating; Mentors; Messenger RNA; Methodology; Molecular Biology; Molecular Target; Mus; Narcolepsy; Neurobiology; Neurons; Neurosciences; Patient Care; Patients; Pattern; Peptides; Perioperative; Phenotype; Physicians; Play; Population; Preoptic Areas; Process; Proteins; Proto-Oncogene Proteins c-fos; REM Sleep; Records; Reflex action; Relative (related person); Research Personnel; Resistance; Role; Science; Scientist; Signal Transduction; Site; Sleep; Speed; Stimulus; Techniques; Time; Training; Transgenic Model; Unconscious State; Wakefulness; Work; behavior measurement; career; career development; cellular targeting; experience; hypnotic; hypocretin; improved; in vivo; insight; mRNA Expression; meetings; multidisciplinary; neural circuit; neuromechanism; neurophysiology; neurotransmission; non rapid eye movement; novel; orexin A; programs; protein expression; relating to nervous system; research study; response; sevoflurane; skills; tool

In the past two decades, genetic studies have revealed mechanisms that regulate circadian and sleep neurophysiology. They promise to unveil mechanisms of anesthetic-induced unconsciousness as well. Sensitivity to anesthetics varies across a population with some individuals requiring a higher dose to achieve a given depth of anesthesia. Anesthetic resistance may present in humans as awareness under anesthesia. One form of hypersensitivity may present as delayed emergence from anesthesia and js seen in a subset of narcoleptic patients with impaired orexin signaling. The central hypothesis of this grant is that inhaled anesthetics exert specific effects upon the endogenous neural circuitry regulating sleep and wakefulness. During induction and maintenance of anesthesia, we hypothesize that inhaled anesthetics produce their hypnotic effects through activation of the ventral lateral preoptic area (VLPO), the central sleep-active region of the brain. Emergence from anesthesia should depend upon re-activation of orexinergic (Ox) neurons, a wake-promoting and sustaining region of the brain. In aim 1 of this grant, we will map neural activation through c-Fos protein immunohistochemistry¿the same methodology used initially to find arousal state- dependent nuclei. We hypothesize that c-fos mRNA and protein levels will be induced in VLPO and repressed in Ox neurons during inhaled anesthesia; and that these changes must reverse during normal emergence from anesthesia. In aim 2, we will evaluate the contribution of Ox neurons to induction and emergence from inhaled anesthesia using behavioral (loss of righting reflex) as well as electroencephalographic (EEC) assays. We hypothesize that mice with genetically and pharmacologically impaired orexin signaling will show delayed emergence from anesthesia. Finally, in aim 3, we will demonstrate that administration of orexin agonists speeds emergence from anesthesia. We hypothesize that orexin agonists should also produce c-fos neuronal activation patterns that attenuate (or reverse) both inhaled anesthetic-induced activation of VLPO and inhibition of Ox neurons. As an anesthesiologist formally trained in neuroscience and mouse genetics, Dr. Kelz is firmly committed to a career in academic anesthesia. His ultimate career goal is to improve perioperative patient care through a better understanding of the mechanisms by which anesthetics suppress consciousness. This proposal will enhance his training toward that end by providing formal education in sleep neurobiology (including EEG and EMG acquisition and analysis), stereotactic surgerical techniques necessary for pharmacologic studies, and advanced molecular biology. His co-mentors have established records of nuturing junior faculty. Together with his current skill set, these new tools will help transition him towards becoming an independent physician-scientist by bridging the interface between sleep neurobiology and anesthetic action.

在过去的二十年中，遗传研究揭示了调节昼夜节律和睡眠的机制 神经生理学。他们承诺也可以揭示麻醉引起的无意识的机制。 对麻醉剂的敏感性范围在人群中，一些人需要更高剂量才能实现 给定的麻醉深度。在人类中可能存在麻醉性抗药性，因为在麻醉下的意识。 一种超敏反应的一种形式可能是从麻醉和JS的延迟出现中出现的 毒素患者患有OREXIN信号传导受损。这笔赠款的核心假设是继承 麻醉药对内源性神经回路发挥特定的影响，以减轻睡眠和清醒。 在诱导和维持麻醉期间，我们假设遗传麻醉药的产生 通过激活腹侧前侧面区域（VLPO），中央睡眠活性区域的催眠作用 麻醉的出现应取决于甲状腺素能（OX）神经元的重新激活，A 大脑的唤醒和维持区域。在这笔赠款的目标1中，我们将绘制神经激活 通过C-FOS蛋白免疫组织化学�最初使用的相同方法可以找到唤醒状态 依赖的核。我们假设C-FOS mRNA和蛋白质水平将在VLPO和 在遗传性麻醉期间反射在OX神经元中；而且这些变化必须在正常情况下逆转 麻醉的出现。在AIM 2中，我们将评估OX神经元对诱导和 使用行为（失去矫正反射）以及 脑电图（EEC）测定法。我们假设小鼠一般和药物 Orexin信号受损将显示麻醉的延迟出现。最后，在AIM 3中，我们将 证明施用Orexin激动剂会从麻醉中加快出现。我们假设 Orexin激动剂还应产生C-FOS神经元激活模式，以减弱（或反向） 吸入麻醉诱导的VLPO激活和OX神经元的抑制作用。 作为一名接受神经科学和小鼠遗传学正式训练的麻醉师，Kelz博士最初是为了 从事学术麻醉的职业。他的最终职业目标是通过 更好地理解麻醉药抑制意识的机制。该提议将 通过在睡眠神经生物学方面提供正规教育（包括脑电图和 EMG获取和分析），药物研究所需的立体定向手术技术以及 晚期分子生物学。他的副官员已经建立了营养初级教师的记录。一起 这些新工具以他目前的技能设置，将帮助他过渡成为独立的 医师科学家通过桥接睡眠神经生物学和麻醉作用之间的接口。