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: 9209578
• 负责人: Emad N Eskandar
• 金额: $ 34.97万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9209578
• 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; Drug effect disorder; 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 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：麻醉作用的非人类灵长类动物研究 全麻是一种令人着迷的人造神经生理现象，已经发展起来。 多年来的经验证明，能够安全和人性化地执行手术和非手术程序。 具体地说，它是一种由药物引起的状态，包括意识丧失、健忘、止痛和静止， 以及生理稳定性。在美国，每天有6万名患者接受全身麻醉 麻醉剂如何在大脑中产生麻醉状态的机制还不是很好。 明白了。最近在表征麻醉药的分子位置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还不太清楚。 解决这一问题需要系统神经科学方法来定义药物在特定情况下的作用 分子靶点和神经回路导致全身麻醉的行为状态。在该计划项目中 题为《麻醉的集成系统神经科学研究》，我们将开发一个集成系统 神经科学项目包括人类、非人灵长类、啮齿动物和四个模型研究 麻醉药：GABAA类药物异丙酚和七氟醚，α-2肾上腺素能激动剂右旋美托咪定； 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， 它将为数据分析提供辅助，并对统计方法进行研究。具体目标 是为了了解麻醉剂对特定分子靶点和神经回路的作用是如何产生的 振荡动力学(脑电节律、LFP的变化和神经放电活动)可能是主要的 麻醉剂产生不同的唤醒状态(镇静、幻觉、 无意识)。在我们的灵长类研究中，我们将使用多电极阵列来记录大脑活动 同时瞄准至少两个脑区，并记录多个单单位活动和局部场电位。 我们将在无意识的情况下从额叶皮质、丘脑和顶叶皮质的配对位置进行记录 通过系统地控制麻醉剂的剂量而诱发。麻醉剂的剂量将是系统的 减少，以使动物恢复意识。这些动物将接受训练，以连续地执行 执行行为任务，这样我们就可以跟踪动物唤醒状态的变化。我们将描述 每种麻醉剂引起的觉醒状态改变与神经生理学动力学的关系 对行为的更改。灵长类研究将在以下研究中发挥特别关键的作用 将在项目项目中进行。它们将使我们能够联系到每一种麻醉剂的神经活动 大脑区域对药物诱导的行为的伴随变化。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，将与 昏迷、睡眠障碍、疼痛和抑郁等问题。