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 全身麻醉是一种引人入胜的人造神经生理现象，已经开发 从经验上讲，多年来，可以实现手术和非手术程序的安全和人道的表现。 具体而言，它是一种药物引起的疾病，包括无意识，健忘症，镇痛和不动， 以及生理稳定性。每天对联合的60,000名患者进行全身麻醉 国家，麻醉药在大脑中如何创建麻醉状态的机制不好 理解。最近在表征麻醉的分子位点方面取得了重大进展 目标。但是，特定分子靶标的行动如何导致行为状态的理解较少。 解决此问题需要采用系统神经科学方法来定义药物在特定方面的作用 分子靶标和神经回路导致全身麻醉的行为状态。在这个程序项目中 我们将开发一个集成系统的题为“综合系统神经科学研究” 神经科学计划由人类，非人类灵长类动物，啮齿动物和建模研究组成 麻醉药：Gabaa特工，丙泊酚和七氟烷； Alpha-2肾上腺素激动剂，右美托咪定； NMDA受体拮抗剂氯胺酮。程序项目还将包括数据分析核心， 这将为助手提供数据分析并进行统计方法研究。具体目标 要了解麻醉药在特定分子靶标和神经回路上的作用如何产生 振荡动力学（EEG节奏，LFP的变化和神经尖峰活动）可能是主要的 麻醉剂会产生改变唤醒状态的常见机制（镇静，幻觉， 无意识）。在啮齿动物研究中，我们将使用多电极阵列记录多个单位活动 以及来自额叶皮质，丘脑，顶叶皮质的两个或多个地点的本地田间潜力，而 潜意识是通过系统地控制麻醉剂量引起的。剂量将是系统的 减少以使动物恢复意识。这些动物将经过训练以连续执行 管理认知视觉任务，因此我们跟踪其唤醒状态的变化。我们将描述更改的 每种麻醉剂引起的唤醒状态通过将神经生理学变化的动力学与 行为变化。啮齿动物研究将允许从多个大脑区域进行同时记录 麻醉药如何改变脑电路动力学以产生特定行为状态的详细描述。我们 还将使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。这些研究会 还提供有关大脑唤醒电路神经生理学的基本知识 与昏迷，睡眠障碍，疼痛和抑郁症等问题有关。