Mechanisms of emergence from general anesthesia

全身麻醉苏醒机制

• 批准号: 10693281
• 负责人: Mitra Heshmati
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693281
• 关键词: Agitation; Anesthesia procedures; Anesthetics; Area; Arousal; Behavior; Behavioral; Behavioral Mechanisms; Brain; Caring; Cell Adhesion Molecules; Cells; Clinical; Dangerousness; Delirium; Development; Disease; Electrophysiology (science); Equilibrium; Foundations; General Anesthesia; Genes; Inhibitory Synapse; Intervention; Investigation; Light; Longevity; Machine Learning; Maps; Mediating; Microscopy; Mus; Neurons; Outcome; Patients; Persons; Pharmacologic Substance; Pre-Clinical Model; Research; Resolution; Rodent Model; Signal Transduction; Stress; Synapses; Synaptic plasticity; Therapeutic; Time; United States; Work; awake; cell type; design; experience; knock-down; mouse model; neuroligin 2; optical sensor; postsynaptic; pre-clinical; programs; scaffold; single cell sequencing; synaptic function; transcriptome sequencing

Project Summary Cellular mechanisms mediating the transition from a state of general anesthesia to an awake state are not understood. Patients emerge from anesthesia passively without the use of mechanistically targeted interventions, creating an unpredictable clinical outcome marked by behavioral phenomena like emergence agitation and delirium. Many anesthetics act either directly or indirectly to change excitatory/inhibitory balance in the brain, highlighting the importance of understanding inhibitory networks in emergence. My research program focuses on the effects of general anesthesia on inhibitory plasticity during the transition from anesthetized to awake state in mice. My prior work examines neuroligin-2, a central organizer of the inhibitory synapse, using cell-type and circuit specific manipulations. Neuroligin-2 is a cell adhesion protein that acts as a scaffold to regulate general inhibitory synaptic function and is recently implicated as an independent regulator of intracellular signaling and disease. I demonstrated that neuroligin-2 manipulation modulates agitation and related behaviors in mouse models. My established expertise in stress-induced inhibitory synaptic plasticity provides a strong foundation for the following three complementary research areas investigating general anesthesia emergence. (1) Inhibitory cell plasticity in emergence from anesthesia: Research area 1 will focus on effects of general anesthesia emergence on inhibitory cell plasticity, starting with an investigation of key inhibitory postsynaptic genes, like neuroligin-2, using targeted knockdown and electrophysiology studies. Single cell sequencing transcriptomic investigations will characterize all cell types and synaptic constituents modified by emergence. (2) Brain-wide cell type-specific circuit activity in emergence: Research area 2 will investigate whole brain circuit changes induced by general anesthesia emergence using activity mapping and light sheet microscopy at single cell resolution, along with recordings of neuronal activity using genetically encoded optical sensors expressed in anesthesia-regulated circuits. (3) Preclinical models for emergence delirium across the lifespan: Research area 3 will develop and validate preclinical rodent models of emergence delirium using machine learning approaches, in order to study vulnerability to anesthesia-induced delirium across the lifespan. Together, these three projects form an overarching research program to understand mechanisms of emergence from the inhibitory cellular to circuit to behavioral levels of analysis, providing a holistic view of emergence. We must understand the mechanisms of anesthetic emergence across all levels in order to design pharmaceutical interventions to bring about safer and predictable emergence.

项目摘要 介导从全身麻醉状态到清醒状态的转变的细胞机制不是 明白患者被动地从麻醉中苏醒，而不使用机械靶向药物。 干预，创造了一个不可预测的临床结果，其特征是行为现象，如出现 激动和精神错乱许多麻醉药直接或间接地改变兴奋/抑制平衡 在大脑中，强调了理解抑制网络在出现中的重要性。我的研究 该计划的重点是全身麻醉对抑制可塑性的影响，在过渡期间， 在小鼠中麻醉至清醒状态。我之前的工作研究了神经配素-2，一种抑制性的中枢组织者， 突触，使用细胞类型和电路特定的操作。神经连接素-2是一种细胞粘附蛋白， 支架调节一般抑制性突触功能，最近被认为是一种独立的调节剂 细胞内信号和疾病的联系。我证明了神经连接素-2操纵调节激动， 小鼠模型中的相关行为。我在压力诱导抑制性突触可塑性方面的专业知识 为以下三个互补的研究领域提供了坚实的基础， 麻醉苏醒(1)麻醉苏醒时抑制细胞可塑性：研究领域1将 关注全身麻醉苏醒对抑制性细胞可塑性的影响，从研究 关键抑制性突触后基因，如神经连接素-2，使用靶向敲除和电生理学研究。 单细胞测序转录组学研究将表征所有细胞类型和突触成分 因出现而改变。(2)出现时全脑细胞类型特异性回路活动：研究领域2 将使用活动映射研究全身麻醉苏醒引起的全脑回路变化 和单细胞分辨率的光片显微镜，沿着使用遗传学方法记录神经元活动， 在麻醉调节回路中表达的编码光学传感器。(3)临床前模型 研究领域3将开发和验证临床前啮齿动物模型， 使用机器学习的方法，以研究麻醉诱导的脆弱性 精神错乱。这三个项目共同构成了一个总体研究计划， 了解从抑制性细胞到电路再到行为层面的涌现机制分析， 提供了一个整体的观点。我们必须了解麻醉剂出现的机制， 在所有各级，以设计药物干预措施，实现更安全和可预测的紧急情况。