Project 4: Mathematical Modeling Studies of Anesthetic Action

项目4：麻醉作用的数学模型研究

• 批准号: 10093080
• 负责人: NANCY KOPELL
• 金额: $ 26.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093080
• 关键词: Absence of pain sensation; Address; Adrenergic Agonists; Affect; Amnesia; Anesthesia procedures; Anesthetics; Arousal; Behavioral; Brain; Brain Stem; Brain region; Cell Nucleus; Coma; Data Analyses; Dexmedetomidine; Dose; Electroencephalography; Frequencies; General Anesthesia; Glutamates; Goals; Hallucinations; Human; Interneurons; Investigation; Ketamine; Kinetics; Knowledge; Lead; Mediating; Mental Depression; Modeling; Molecular; Molecular Target; NMDA receptor antagonist; Neurons; Neuropsychology; Neurosciences; Operative Surgical Procedures; Pain; Parietal; Parietal Lobe; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Propofol; Research; Rodent Model; Sedation procedure; Sleep; Statistical Methods; Study models; System; Testing; Thalamic structure; Unconscious State; United States; drug action; experimental study; fascinate; frontal lobe; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; inhibitory neuron; insight; locus ceruleus structure; man; mathematical model; molecular site; neural circuit; neurophysiology; nonhuman primate; noradrenergic; parabrachial nucleus; predictive modeling; programs; relating to nervous system; sevoflurane

PROJECT 4: MODELING STUDIES OF ANESTHETIC ACTION 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 assistant 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 goal of the modeling research will be to develop detailed, circuit-level descriptions of the neurophysiological mechanisms underlying each brain state of each anesthetic. The modeling will provide a systematic way to organize and integrate information across all of the three experimental projects and thereby, allow us to develop precise statements about anesthetic mechanisms of action. As the research proceeds, the modeling will enable us to make predictions that can be tested with experiments. In addition to providing new insights into the systems neuroscience of anesthetic states, these studies will also provide fundamental new quantitative knowledge about the neurophysiology of the brain's arousal circuits that will be relevant to studies of other neuropsychological problems such as coma, pain, sleep and depression.

项目4：麻醉作用的模拟研究 全身麻醉是一个迷人的人造，神经生理学现象，已开发 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，它是一种药物引起的疾病，包括意识丧失、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， 协助进行数据分析和统计方法研究。具体目标 是为了了解麻醉剂在特定分子靶点和神经回路中的作用， 振荡动力学（EEG节律，LFP和神经尖峰活动的变化）可能是主要的 麻醉剂通过其产生改变的唤醒状态（镇静，幻觉， 无意识）。建模研究的目标是开发详细的电路级描述， 每种麻醉剂的每种大脑状态下的神经生理学机制。建模将提供 一种系统的方式来组织和整合所有三个实验项目的信息， 从而使我们能够对麻醉剂的作用机制进行精确的描述。为研究 如果继续下去，建模将使我们能够做出可以用实验来检验的预测。除了 这些研究为麻醉状态的系统神经科学提供了新的见解， 关于大脑唤醒回路的神经生理学的基本新定量知识， 与其他神经心理学问题的研究有关，如昏迷、疼痛、睡眠和抑郁。