Role of orexin/hypocretin circuit in anesthesia and analgesia

食欲素/下丘脑分泌素回路在麻醉和镇痛中的作用

• 批准号: 10186780
• 负责人: Wei Zhou
• 金额: $ 19.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186780
• 关键词: 3-Dimensional; Absence of pain sensation; Acute; Address; Affect; Agitation; Alzheimer' s Disease; Anesthesia and Analgesia; Anesthesia procedures; Anesthetics; Animal Behavior; Animal Testing; Animals; Arousal; Biological Assay; Brain; Brain region; Calcium; California; Cardiovascular system; Cataplexy; Chemicals; Delirium; Development; Electric Stimulation; Electroencephalogram; Emotions; Equipment; Exhibits; Formalin Tests; Foundations; Funding; Future; Goals; Habenula; Hypothalamic structure; Institutes; Isoflurane; Knowledge; Lateral; Link; Maps; Mental Depression; Mentors; Microscopy; Midbrain structure; Modern Medicine; Monitor; Mus; Muscle Tonus; Muscular Atrophy; Narcolepsy; Neuroanatomy; Neurons; Nociception; Operative Surgical Procedures; Opioid; Pain; Pain Threshold; Pain management; Pathogenesis; Patient Care; Patients; Pattern; Perioperative Care; Physicians; Recovery; Regulation; Reporting; Research; Rewards; Risk; Rodent; Role; San Francisco; Scientist; Site; Sleep; Sleep Fragmentations; Solid; Speed; Spinal Cord; Spinal cord posterior horn; Stress; Structure; Suggestion; Surface; System; Techniques; Technology; Testing; Time; Training; Transgenic Mice; Universities; Wakefulness; Work; aging brain; basal forebrain; base; career; career development; clinical practice; experience; hypocretin; in vivo calcium imaging; in vivo imaging; midbrain central gray substance; multidisciplinary; nerve supply; neural circuit; neural network; neuropsychiatry; neurotoxicity; novel; optogenetics; pain behavior; pain relief; professor; relating to nervous system; respiratory; tool; voltage

Project Summary/Abstract With the long-term research goal of advancing anesthesia through developing new tools and techniques for better anesthetic management and pain control, the candidate focuses his research on elucidating the mechanisms underlying anesthesia, in particular, the role of hypothalamic orexin (Ox) circuit in anesthesia and analgesia. How anesthetics interact with brain neural network is still poorly understood. The Ox circuit is considered to be a master regulator in sleep/wakefulness. The candidate's recent work showed that activation of Ox neurons with chemogenetic approach facilitates emergence from isoflurane anesthesia and induces analgesia. Building upon these findings, he proposes to apply optogenetics to specifically activate subsets of Ox projections to address the underlying mechanisms. The candidate started with mapping the basic neuroanatomy of the Ox projections in the mouse brain. In his preliminary work, he mapped out three-dimensional Ox projections using both confocal and lightsheet microscopy and identified three interesting regions he will focus on in this proposal. In aim 1, he will test the hypothesis that Ox neurons regulate arousal state during anesthesia via their projections to basal forebrain (BF) and lateral habenula (LHb). In aim 2, he plans to test the hypothesis that Ox projections to periaqueductal gray (PAG) contributes to analgesia. While manipulating neuronal activities with optogenetic tools, the candidate will record electroencephalogram (EEG), image in vivo neural calcium activities, and test the animal's behavior related to arousal state or pain. The proposed work will lead to the identification of novel roles of different subsets of Ox projections in anesthesia-related arousal and pain control. The candidate is currently an Assistant Professor in the Department of Anesthesia and Perioperative Care at the University of California San Francisco (UCSF). His career goal is to become an independent physician scientist dedicated to understanding the mechanisms governing anesthesia and bring patient care to the next level with safer and more efficient anesthesia. The candidate has outstanding institutional support with 75% protected research time, lab and office space, administrative support, and department funding for a technician and selected equipment. UCSF is a world-class institute and the candidate has a multidisciplinary mentoring team to guide his career development. Additionally, he has an extensive didactic plan to take advanced training in the next few years to further build a solid foundation for his expertise in the research on the role of neural circuits in anesthesia and analgesia.

项目总结/摘要 随着通过开发新的工具和技术来推进麻醉的长期研究目标， 更好的麻醉管理和疼痛控制，候选人的研究重点是阐明 麻醉机制，特别是下丘脑食欲素（Ox）回路在麻醉中的作用， analgesia.麻醉剂如何与大脑神经网络相互作用仍然知之甚少。Ox电路是 被认为是睡眠/觉醒的主要调节器。这位候选人最近的工作表明， 用化学发生方法对Ox神经元进行处理有助于从异氟烷麻醉中苏醒并诱导 analgesia.基于这些发现，他建议应用光遗传学来特异性激活Ox亚群。 预测，以解决潜在的机制。候选人从绘制基本的神经解剖图开始 老鼠大脑中的Ox投射。在他的初步工作中，他绘制了三维牛 投影使用共聚焦和光片显微镜，并确定了三个有趣的区域，他将重点 在这个提案中。在aim 1中，他将测试Ox神经元在麻醉期间调节唤醒状态的假设 通过它们向基底前脑（BF）和外侧缰核（LHb）的投射。在aim 2中，他计划验证这一假设 Ox投射到中脑导水管周围灰质（PAG）有助于镇痛。在操纵神经元活动的同时 利用光遗传学工具，候选人将记录脑电图（EEG），体内神经钙成像 活动，并测试动物的行为有关的唤醒状态或疼痛。拟议的工作将导致 确定Ox投射的不同子集在麻醉相关唤醒和疼痛控制中的新作用。 候选人目前是麻醉和围手术期护理系的助理教授， 加州旧金山弗朗西斯科大学（UCSF）。他的职业目标是成为一名独立的医生科学家 致力于了解麻醉的机制，并将患者护理提升到一个新的水平， 更安全、更有效的麻醉。候选人拥有出色的机构支持，75%的人受到保护 研究时间，实验室和办公空间，行政支持和部门资金的技术人员和选定的 设备.加州大学旧金山分校是一个世界级的研究所和候选人有一个多学科的指导团队，以指导 他的职业发展。此外，他有一个广泛的教学计划，在未来几年内进行高级培训， 多年来，他在麻醉中神经回路作用的研究方面的专业知识进一步奠定了坚实的基础 和镇痛。