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.

项目摘要/摘要 长期的研究目标是通过开发新工具和技术来进行麻醉 更好的麻醉管理和疼痛控制，候选人将研究重点放在阐明 麻醉尤其是下丘脑奥列海（OX）回路在麻醉和 镇痛。麻醉剂与大脑神经网络的相互作用仍然很少了解。 ox电路是 被认为是睡眠/清醒的主调节器。候选人最近的工作表明激活 具有化学作用方法的OX神经元促进了异氟烷麻醉的出现并诱导 镇痛。在这些发现的基础上，他提议应用光遗传学专门激活OX的子集 预测以解决潜在机制。候选人始于映射基本的神经解剖学 小鼠大脑中的牛突约。在他的初步工作中，他绘制了三维牛 使用共聚焦和灯光片显微镜的预测，并确定了他将集中精力的三个有趣的区域 在此提案中。在AIM 1中，他将检验以下假设：OX神经元在麻醉期间调节唤醒状态 通过他们对基础前脑（BF）和外侧Habenula（LHB）的预测。在AIM 2中，他计划检验假设 对灰灰色（PAG）的OX投影有助于镇痛。在操纵神经元活动的同时 使用光遗传学工具，候选人将记录脑电图（EEG），体内神经钙的图像 活动，并测试动物的行为与唤醒状态或疼痛有关。拟议的工作将导致 鉴定出与麻醉相关的唤醒和疼痛控制中不同子集的新作用的新作用。 该候选人目前是麻醉和围手术期护理系的助理教授 加利福尼亚大学旧金山大学（UCSF）。他的职业目标是成为一名独立医师科学家 致力于了解管理麻醉的机制，并将患者护理带入一个新的水平 更安全，更有效的麻醉。该候选人拥有未受杰出的机构支持，并受到75％的保护 研究时间，实验室和办公空间，行政支持以及技术人员的部门资助 设备。 UCSF是一家世界一流的研究所，候选人有一个多学科指导团队来指导 他的职业发展。此外，他还有一个广泛的教学计划，可以在接下来的几个中接受高级培训 多年以进一步为他在神经回路在麻醉中作用的研究方面的专业知识建立坚实的基础 和镇痛。