Project 3: Rodent Studies of Anesthetic Action

项目 3：啮齿动物麻醉作用研究

• 批准号: 10093076
• 负责人: Ken Solt
• 金额: $ 35.74万
• 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/10093076
• 关键词: Absence of pain sensation; Address; Adrenergic Agonists; Amnesia; Anesthesia procedures; Anesthetics; Animals; Anterior; Area; Arousal; Behavior; Behavioral; Brain; Brain Stem; Cognitive; Coma; Conscious; Data Analyses; Dexmedetomidine; Dose; Electroencephalogram; GABA Agents; General Anesthesia; Glutamates; Hallucinations; Human; Hyperactivity; Implanted Electrodes; Injections; Interneurons; Intralaminar Nuclear Group; Ketamine; Knowledge; Lead; Maintenance; Medial; Mental Depression; Midbrain structure; Modeling; Molecular; Molecular Target; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurosciences; Operative Surgical Procedures; Pain; Parietal; Parietal Lobe; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Physiological; Pontine structure; Prefrontal Cortex; Preoptic Areas; Production; Propofol; Research; Reticular Formation; Rodent; Rodent Model; Sedation procedure; Site; Sleep Disorders; Statistical Methods; Structure; Study models; System; Testing; Thalamic structure; Training; Unconscious State; United States; Visual; behavior test; drug action; experimental study; fascinate; frontal lobe; hippocampal pyramidal neuron; locus ceruleus structure; man; mathematical model; molecular site; multi-electrode arrays; neural circuit; neurophysiology; nonhuman primate; noradrenergic; optogenetics; parabrachial nucleus; programs; receptor; relating to nervous system; sevoflurane

PROJECT 3: RODENT 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 rodent studies we will use multi-electrode arrays to record multiple single unit activity and local field potentials from two or more sites in the frontal cortex, thalamus, parietal cortex, while unconsciousness is induced by systematically controlling anesthetic dosing. The dosing will be systematically decreased to allow the animal to recover consciousness. The animals will be trained to execute a continually administered cognitive visual task so we track the changes in its 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 rodent studies will allow simultaneous recording from multiple brain areas to gain a detailed description of how anesthetics alter brain circuit dynamics to produce a specific behavioral state. We will also conduct neural modulation experiments using optogenetics and local pharmacology to understand how changes in specific circuits alter network dynamic and lead to changes in arousal state. 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3：麻醉作用的啮齿动物研究 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）。在我们的啮齿动物研究中，我们将使用多电极阵列记录多个单个单位的活动 以及来自额叶皮层、丘脑、顶叶皮层中的两个或更多个部位的局部场电位，而 通过系统地控制麻醉剂剂量来诱导无意识。给药将系统地 让动物恢复意识。这些动物将被训练来执行一个持续的 因此我们可以追踪其唤醒状态的变化。我们将描述 通过将神经生理学变化的动力学与麻醉剂引起的唤醒状态相关联， 行为上的改变啮齿动物的研究将允许同时记录多个大脑区域，以获得一个 麻醉剂如何改变脑回路动力学以产生特定行为状态的详细描述。我们 还将利用光遗传学和局部药理学进行神经调制实验，以了解 特定回路的变化如何改变网络动态并导致唤醒状态的变化。这些研究将 还提供了关于大脑唤醒回路神经生理学的基本新知识， 与昏迷、睡眠障碍、疼痛和抑郁等问题有关。