The Anesthetic Circuitry of the Midbrain

中脑的麻醉回路

• 批准号: 10059249
• 负责人: Ken Solt
• 金额: $ 36.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059249
• 关键词: Age; Amygdaloid structure; Anesthesia procedures; Anesthetics; Arousal; Brain; Brain Stem; Cell Nucleus; Cells; Cognition; Conscious; Data; Delirium; Development; Discrimination; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Electroencephalogram; General Anesthesia; Genetic; Goals; Hippocampus (Brain); Hospitals; Hypersensitivity; Hypnosis; Hypothalamic structure; Impaired cognition; Knock-in Mouse; Light; Medial; Mediating; Methods; Midbrain structure; Mus; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Pain; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Play; Population; Postoperative Complications; Prefrontal Cortex; Process; Rattus; Recovery; Reporting; Rodent; Role; Site; System; Techniques; Unconscious State; United States; Ventral Tegmental Area; Visual; Work; base; clinical practice; cognitive recovery; cognitive testing; common treatment; design; dopaminergic neuron; drug inhalation; experience; gamma-Aminobutyric Acid; improved; intravenous administration; neural circuit; neurophysiology; novel; optogenetics; patient safety; rapid technique; side effect; touchscreen

PROJECT SUMMARY/ABSTRACT Every day approximately 100,000 people undergo general anesthesia in the United States, and by the age of 70, almost all of us will experience general anesthesia. Yet it remains unknown how anesthetics produce unconsciousness, and how consciousness is restored after general anesthesia. The broad, long- term objectives of this project are to: (1) make general anesthesia safer by developing new ways to restore consciousness and cognition in anesthetized patients, and (2) aid the development of safer anesthetics by elucidating the mechanisms of anesthetic-induced unconsciousness. In our application we show that midbrain GABA neurons in the rostromedial tegmental nucleus (RMTg) are involved in anesthetic-induced unconsciousness, while midbrain dopamine neurons in the ventral tegmental area (VTA) are involved in emergence and cognitive recovery from general anesthesia. The Specific Aims are to: (1) characterize the role of the RMTg-VTA circuit in anesthetic-induced unconsciousness, (2) characterize the role of VTA dopamine neurons and their projections in anesthetic emergence, and (3) identify the VTA dopaminergic projections that promote cognitive recovery from the anesthetized state, using a touchscreen-based visual discrimination task. Using genetically modified rodents that allow for selective targeting of dopamine and GABA neurons, we will employ a combination of optogenetics, chemogenetics, neurophysiological recordings, and touchscreen cognitive testing to elucidate the anesthetic circuitry of the midbrain. This project will shed light on fundamental mechanisms of anesthesia and consciousness, which will allow us to improve patient care by developing new techniques to help the brain recover from general anesthesia. In addition, this work will facilitate the development of new anesthetics with fewer side effects.

项目概要/摘要 在美国，每天约有 10 万人接受全身麻醉， 70岁时，几乎我们所有人都会经历全身麻醉。但目前尚不清楚麻醉剂如何 产生意识丧失，以及全身麻醉后意识如何恢复。又宽又长—— 该项目的长期目标是：(1) 通过开发新的恢复方法使全身麻醉更加安全 麻醉患者的意识和认知，以及（2）通过以下方式帮助开发更安全的麻醉剂： 阐明麻醉引起的意识丧失的机制。在我们的应用中，我们表明中脑 喙内侧被盖核 (RMTg) 中的 GABA 神经元参与麻醉诱导的 意识不清，而腹侧被盖区（VTA）的中脑多巴胺神经元参与 全身麻醉的苏醒和认知恢复。具体目标是： (1) 描述 RMTg-VTA 回路在麻醉引起的无意识中的作用，(2) 表征 VTA 的作用 多巴胺神经元及其在麻醉苏醒时的投射，以及 (3) 识别 VTA 多巴胺能神经元 使用基于触摸屏的视觉进行预测，促进麻醉状态下的认知恢复 歧视任务。使用允许选择性靶向多巴胺和 GABA 的转基因啮齿动物 神经元，我们将结合光遗传学、化学遗传学、神经生理学记录和 触摸屏认知测试可阐明中脑的麻醉回路。该项目将揭示 麻醉和意识的基本机制，这将使我们能够通过以下方式改善患者护理 开发新技术帮助大脑从全身麻醉中恢复。此外，这项工作将 促进副作用更少的新型麻醉剂的开发。