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学现象 多年来根据经验，确保外科和非外科手术的安全和人道执行。 具体来说，它是一种由药物引起的病症，包括意识不清、健忘、痛觉缺失和不动， 以及生理稳定性。美国每天有 60,000 名患者接受全身麻醉 状态，麻醉剂如何在大脑中作用以产生麻醉状态的机制尚不清楚 明白了。最近在表征麻醉剂的分子位点方面取得了重大进展 目标。然而，对特定分子靶标的作用如何导致行为状态尚不清楚。 解决这个问题需要一种系统神经科学方法来定义药物在特定情况下的作用 分子靶标和神经回路导致全身麻醉的行为状态。在本次计划项目中 题为“麻醉的综合系统神经科学研究”，我们将开发一个综合系统 神经科学项目，包括人类、非人类灵长类动物、啮齿动物和四种动物的建模研究 麻醉剂：GABAA剂、丙泊酚和七氟醚； α-2肾上腺素能激动剂，右美托咪定； 以及 NMDA 受体拮抗剂氯胺酮。该计划项目还将包括数据分析核心， 它将提供数据分析方面的帮助并进行统计方法的研究。具体 目的是了解麻醉剂如何作用于特定的分子靶点和神经回路 产生振荡动力学（脑电图节律、LFP 的变化和神经尖峰活动），这可能是 麻醉剂改变唤醒状态的主要共同机制（镇静、 幻觉、意识不清）。该研究将开发有关以下方面的新的基础知识： 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 提供了一种实时监测和控制接受一般治疗的患者大脑状态的新方法 麻醉和镇静。麻醉护理人员将能够将突出的振荡动力学联系起来 麻醉剂通过对特定分子靶点的作用而改变其唤醒状态， 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输送策略提供 有望减少不良麻醉副作用，如恶心、呕吐、神经毒性和 术后认知功能障碍。这项研究将为以下问题提供新的、基本的定量见解： 大脑的唤醒和认知系统的运作可能转化为创造新的方法 全身麻醉的状态以及治疗觉醒障碍的方法，例如睡眠、抑郁、昏迷和 疼痛。

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.