Mechanisms of emergence from general anesthesia

全身麻醉苏醒机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要细胞机制介导了从一般麻醉状态到清醒状态的过渡不是理解。患者从麻醉中被动地出现，而无需使用机械靶向干预措施，创造出一个不可预测的临床结果，并以行为现象（如出现）标记搅动和del妄。许多麻醉药直接或间接以改变兴奋性/抑制平衡在大脑中，强调理解抑制网络在出现中的重要性。我的研究程序侧重于全身麻醉对从麻醉以在小鼠中清醒状态。我先前的工作检查Neuroligin-2，抑制性的中心组织者突触，使用细胞类型和电路特定的操作。 Neuroligin-2是一种细胞粘附蛋白，充当脚手架以调节一般抑制性突触功能，最近被视为独立调节剂细胞内信号传导和疾病。我证明了Neuroligin-2操纵调节搅拌和鼠标模型中的相关行为。我在压力引起的抑制性突触可塑性方面已建立的专业知识为以下三个互补研究领域提供了坚实的基础，调查了一般麻醉出现。（1）麻醉出现的抑制性细胞可塑性：研究区域1将关注全身麻醉对抑制性细胞可塑性的影响，从研究使用靶向敲低和电生理学研究，关键的抑制性突触后基因（如神经素2）。单细胞测序转录组研究将表征所有细胞类型和突触成分通过出现修改。（2）出现的脑范围范围细胞类型特异性电路活性：研究区域2 将研究通过活动映射引起的全身麻醉引起的全脑回路变化在单细胞分辨率下的光片显微镜以及使用遗传学的神经元活性的记录在麻醉调节的电路中表达的编码光传感器。（3）出现的临床前模型整个生命周期中的del妄：研究区3将发展并验证临床前啮齿动物模型使用机器学习方法的出现del妄，以研究麻醉引起的脆弱性整个生命周期中的ir妄。这三个项目一起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分析水平的出现机制，提供了对出现的整体看法。我们必须了解整个麻醉剂出现的机制所有级别以设计药物干预措施以实现更安全和可预测的出现。这主要设备补充剂的应用将支持研究区域2中的轻度显微镜研究。