Integrated Systems Neuroscience Studies of Anaesthesia

总体摘要 全身麻醉是一种令人着迷的人造神经生理现象，已经被开发出来 多年来的经验，以实现安全和人道的手术和非手术程序的性能。 具体来说，它是一种药物诱导的疾病，包括无意识、健忘、镇痛和不动， 沿着生理稳定性。在美国，每天有60，000名患者接受全身麻醉 关于麻醉剂在大脑中如何作用以产生麻醉状态的机制， 明白近年来，在麻醉剂作用的分子位点的表征方面取得了重大进展， 目标然而，在特定的分子靶点上的作用如何导致行为状态还不太清楚。 解决这个问题需要一个系统神经科学的方法来定义药物的作用，在特定的 分子靶点和神经回路导致全身麻醉的行为状态。在这个项目中， 名为“麻醉的集成系统神经科学研究”，我们将开发一个集成系统， 神经科学计划，包括人类，非人类灵长类动物，啮齿动物和建模研究的四个 麻醉剂：GABAA药物，丙泊酚和七氟烷; α-2肾上腺素能激动剂，右美托咪定; 和NMDA受体拮抗剂氯胺酮该计划项目还将包括一个数据分析核心， 该小组将协助进行数据分析，并对统计方法进行研究。具体 目的是了解麻醉剂如何作用于特定分子靶点和神经回路 产生振荡动力学（EEG节律，LFP和神经尖峰活动的变化），这可能是一个 麻醉剂通过其产生改变的唤醒状态（镇静， 幻觉、无意识）。这项研究将开发新的，关于 麻醉作用的神经生理机制，将产生广泛的影响。这些新知识将 提供了一种新的方法来实时监测和控制接受一般治疗的患者的大脑状态， 麻醉和镇静。麻醉护理人员将能够将突出的振荡动力学 通过麻醉剂对特定分子靶点的作用， 在特定的神经回路中。改进的基于神经生理学的监测和药物递送策略提供了 减少不希望的麻醉副作用如恶心、呕吐、神经毒性和 术后认知功能障碍这项研究将提供新的，基本的定量见解， 大脑的唤醒和认知系统的工作，可能转化为新的方法来创造 全身麻醉状态沿着治疗觉醒障碍的方法，如睡眠、抑郁、昏迷和 痛苦

OVERALL ABSTRACT General anesthesia is a fascinating man-made, neurophysiological phenomenon that has been developed empirically over many years to enable safe and humane performance of surgical and non-surgical procedures. Specifically it is a drug-induced condition consisting of unconsciousness, amnesia, analgesia and immobility, along with physiological stability. General anesthesia is administered daily to 60,000 patients in the United States, the mechanisms for how anesthetics act in the brain to create the states of anesthesia are not well understood. Significant progress has been made recently in characterizing the molecular sites that anesthetics target. However, how actions at specific molecular targets lead to the behavioral states is less well understood. Addressing this issue requires a systems neuroscience approach to define how actions of the drugs at specific molecular targets and neural circuits lead to a behavioral state of general anesthesia. In this program project entitled, Integrated Systems Neuroscience Studies of Anesthesia, we will develop an integrated systems neuroscience program consisting of human, non-human primate, rodent and modeling studies of four anesthetics: the GABAA agents, propofol and sevoflurane; the alpha-2 adrenergic agonist, dexmedetomidine; and the NMDA receptor antagonist, ketamine. The program project will also include a DATA ANALYSIS CORE, which will provide assistance with data analysis and conduct research on statistical methods. The Specific Aims are to understand how the actions of the anesthetics at specific molecular targets and neural circuits produce the oscillatory dynamics (EEG rhythms, changes in LFPs and neural spiking activity) that are likely a primary common mechanism through which anesthetics create altered states of arousal (sedation, hallucination, unconsciousness). The research will develop new, fundamental knowledge about the neurophysiological mechanisms of anesthetic actions that will have broad impact. This new knowledge will offer a new approach to real-time monitoring and control of brain states of patients receiving general anesthesia and sedation. Anesthesia caregivers will be able to relate the prominent oscillatory dynamics induced by anesthetics to their altered states of arousal through their actions at specific molecular targets and in specific neural circuits. Improved neurophysiologically-based monitoring and drug delivery strategies offer the promise of reducing the undesirable anesthetic side effects such as nausea, vomiting, neurotoxicity and post-operative cognitive dysfunction. This research will provide new, fundamental quantitative insights into the workings of the brain's arousal and cognitive systems that may translate into new approaches to creating the states of general anesthesia along with ways to treat disorders of arousal such as sleep, depression, coma and pain.