Arousal, orexins and anesthesia

唤醒、食欲素和麻醉

• 批准号: 7081741
• 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/7081741
• 关键词: arousal; brain mapping; electroencephalography; electromyography; fos protein; hormone regulation /control mechanism; inhalation anesthesia; laboratory mouse; messenger RNA; neural information processing; neurogenetics; neurotransmitter antagonist; neurotransmitter transport; orexin; pharmacogenetics; pharmacokinetics; preoptic areas; psychic activity level; unconsciousness

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：在过去的二十年中，遗传学研究揭示了调节昼夜节律和睡眠神经生理学的机制。他们承诺也可以揭示麻醉引起的无意识的机制。对麻醉剂的敏感性在人群中有所不同，一些人需要更高剂量才能达到给定的麻醉深度。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在麻醉症患者中延迟出现的麻醉和JS的延迟出现。这项赠款的中心假设是吸入麻醉药对调节睡眠和清醒的内源性神经回路发挥特定影响。在麻醉诱导和维持期间，我们假设吸入麻醉药通过激活腹侧前侧面区域（VLPO）（脑的中央睡眠活性区域）通过激活而产生催眠作用。麻醉的出现应取决于对脑力（OX）神经元的重新激活，这是大脑的唤醒和持续区域。在该赠款的目标1中，我们将通过C-FOS蛋白免疫组织化学绘制神经激活？最初用于查找唤醒状态依赖性核的方法。我们假设C-FOS mRNA和蛋白质水平将在VLPO中诱导，并在吸入麻醉期间抑制OX神经元。并且这些变化必须在麻醉正常出现期间逆转。在AIM 2中，我们将使用行为（失去矫正反射）以及脑电图（EEC）测定法评估OX神经元对吸入麻醉的诱导和出现的贡献。我们假设患有遗传和药理障碍的小鼠OREXIN信号传导将显示麻醉的延迟出现。最后，在AIM 3中，我们将证明Orexin Amonists的给药速度从麻醉中加快出现。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）吸入麻醉剂诱导的VLPO激活和OX神经元的抑制。作为接受神经科学和老鼠遗传学的正式培训的麻醉师，Kelz博士坚定地致力于学术麻醉的职业。他的最终职业目标是通过更好地理解麻醉剂抑制意识的机制来改善围手术期患者护理。该提案将通过提供睡眠神经生物学（包括脑电图和EMG获取和分析），药理研究所需的立体定向手术技术以及高级分子生物学来提高他对此的训练。他的副官员已经建立了营养初级教师的记录。这些新工具将与他当前的技能组合一起，通过弥合睡眠神经生物学和麻醉作用之间的界面来帮助他成为独立的医师科学家。