Mechanisms of emergence from general anesthesia

全身麻醉苏醒机制

• 批准号: 10795243
• 负责人: Mitra Heshmati
• 金额: $ 24.96万
• 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/10795243
• 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; Equipment; 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. The major equipment supplement application will support light sheet microscopy studies in Research area 2.

项目摘要 调节从全身麻醉状态向清醒状态转变的细胞机制不是 明白了。患者在没有使用机械靶向的情况下被动地从麻醉中苏醒过来 干预，造成以出现等行为现象为标志的不可预测的临床结果 情绪激动和精神错乱。许多麻醉剂直接或间接地改变兴奋/抑制平衡。 在大脑中，强调了了解抑制网络在涌现中的重要性。我的研究 项目的重点是全身麻醉对从儿童到青少年的过渡期间抑制可塑性的影响 麻醉至清醒状态的小鼠。我之前的工作是检测神经连接素-2，一种抑制作用的中心组织者 突触，使用细胞类型和电路特定的操作。神经连接蛋白-2是一种细胞黏附蛋白，它作为一种 调节一般抑制性突触功能的支架，最近被认为是一种独立的调节因子 细胞内信号和疾病。我证明了神经连接素-2的操作调节了焦虑和 小鼠模型中的相关行为。我在应激诱导的抑制性突触可塑性方面的专业知识 为以下三个相辅相成的研究领域提供了坚实的基础 麻醉出现了。(1)麻醉苏醒时抑制细胞可塑性：研究领域1将 全麻苏醒对抑制细胞可塑性的影响 关键的抑制性突触后基因，如神经连接素-2，使用定向敲除和电生理学研究。 单细胞测序转录研究将表征所有细胞类型和突触成分 被突现所改变的。(2)全脑细胞类型特定回路活动的浮现：研究领域2 将使用活动图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，以及使用遗传技术记录神经元活动 在麻醉调节电路中表示的编码光学传感器。(3)临床前急救模式 终生精神错乱：研究区域3将开发和验证临床前啮齿动物模型 利用机器学习的方法，研究麻木诱导的易感性 一生中的精神错乱。这三个项目一起构成了一个总体研究计划，以 理解从抑制细胞到电路再到行为分析层面的出现机制， 提供了对涌现的整体看法。我们必须了解麻药产生的机制。 为了设计药物干预措施，以实现更安全和可预测的出现，所有各级都将继续努力。这个 主要设备补充应用将支持研究区域2的光片显微镜研究。