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：啮齿动物麻醉作用研究 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， 它将提供数据分析的协助并进行统计方法的研究。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如何产生 振荡动力学（EEG 节律、LFP 的变化和神经尖峰活动）可能是主要的 麻醉剂产生改变的唤醒状态的常见机制（镇静、幻觉、 失去知觉）。在我们的啮齿动物研究中，我们将使用多电极阵列来记录多个单个单元的活动 以及来自额叶皮层、丘脑、顶叶皮层两个或多个部位的局部场电位，同时 意识不清是通过系统地控制麻醉剂量来诱导的。剂量将系统化 减少以使动物恢复意识。这些动物将被训练来连续执行 执行认知视觉任务，以便我们跟踪其唤醒状态的变化。我们将描述改变后的 通过将神经生理学变化的动态与 行为的改变。啮齿动物研究将允许同时记录多个大脑区域以获得 详细描述麻醉剂如何改变大脑回路动力学以产生特定的行为状态。我们 还将利用光遗传学和局部药理学进行神经调节实验，以了解 特定电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 还提供有关大脑唤醒回路的神经生理学的基本新知识 与昏迷、睡眠障碍、疼痛和抑郁等问题相关。