Project 2: Non-Human Primate Studies of Anesthetic Action

项目 2：非人类灵长类动物麻醉作用研究

• 批准号: 10093074
• 负责人: EMERY N BROWN
• 金额: $ 34.36万
• 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/10093074
• 关键词: Absence of pain sensation; Address; Adrenergic Agonists; Amnesia; Anesthesia procedures; Anesthetics; Animals; Anterior; Area; Arousal; Behavior; Behavioral; Brain; Brain region; Cerebral cortex; Coma; Conscious; Data Analyses; Dexmedetomidine; Dose; Electrodes; Electroencephalogram; GABA Agents; General Anesthesia; Hallucinations; Human; Implanted Electrodes; Ketamine; Knowledge; Lead; Macrophage-1 Antigen; Maintenance; Measures; Mental Depression; Modeling; Molecular; Molecular Target; N-Methylaspartate; NMDA receptor antagonist; Nature; Neurosciences; Operative Surgical Procedures; Pain; Parietal; Parietal Lobe; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Play; Primates; Propofol; Research; Rodent; Rodent Model; Role; Scalp structure; Sedation procedure; Site; Sleep Disorders; Statistical Methods; Stimulus; Structure; Study models; System; Testing; Thalamic structure; Training; Unconscious State; United States; behavior test; design; drug action; drug induced behavior; experimental study; fascinate; frontal lobe; man; mathematical model; molecular site; multi-electrode arrays; neural circuit; neurophysiology; nonhuman primate; programs; relating to nervous system; sedative; sevoflurane; somatosensory; spatiotemporal

PROJECT 2: NON-HUMAN PRIMATE 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). In our primate studies we will record brain activity using multi-electrode arrays designed to target at least two brain regions simultaneously and record multiple single unit activity and local field potentials. We will record from paired sites in the, frontal cortex, thalamus, and parietal cortex while unconsciousness is induced by systematically controlling the anesthetic dosing. The dosing of the anesthetic will be systematically decreased to allow the animal to recover consciousness. The animals will be trained to execute a continually administered behavioral task so we track the changes in the animal's arousal state. We will characterize the altered states of arousal induced by each anesthetic by relating the dynamics of the neurophysiological changes to the changes in behavior. The primate studies will play a particularly crucial role in the research to be conducted in the program project. They will allow us to relate for each anesthetic neural activity in relevant brain regions to the concomitant changes in behavior the drug induces. These studies will also provide fundamental new knowledge about the neurophysiology of the brain's arousal circuits that will be relevant to problems such as coma, sleep disorders, pain and depression.

项目2：麻醉作用的非人灵长类动物研究 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）。在我们的灵长类动物研究中，我们将使用多电极阵列记录大脑活动， 同时靶向至少两个脑区并记录多个单个单位活动和局部场电位。 我们将从额叶皮层、丘脑和顶叶皮层的成对部位记录， 通过系统地控制麻醉剂剂量诱导。麻醉剂的剂量将系统地 让动物恢复意识。这些动物将被训练来执行一个持续的 管理的行为任务，所以我们跟踪动物的唤醒状态的变化。我们将描述 通过将神经生理学的动力学与每种麻醉剂诱导的唤醒状态的改变相关联， 行为的改变。灵长类动物的研究将在研究中发挥特别重要的作用， 在计划项目中进行。它们将使我们能够将每一种麻醉神经活动与相关的 大脑区域对药物引起的行为变化的反应。这些研究还将提供 关于大脑唤醒回路的神经生理学的基本新知识， 昏迷、睡眠障碍、疼痛和抑郁等问题。