吸入麻醉与认知功能损伤：NRG1/ErbB4介导神经网络异常的作用及分子机制

Currently, the study of inhalation anesthesia-induced cognitive impairments is one of the research hotspots in anesthesiology. Our previous studies have shown that isoflurane anesthesia may induce cognitive impairments by causing the dysfunction of parvalbumin (PV) interneurons with abnormal γ oscillations in aged mice. Moreover, the available data have shown that 1) the "dynamic balance of inhibition-excitation" between PV interneurons and pyramid neurons is an essential neural network for the performance of cognitive function; 2) γ oscillations result from the synchronized activity of PV interneurons and mediate the performance of cognitive function; and 3) the distribution of ErbB4 is largely restricted to PV interneurons and the activation NRG1/ErbB4 signaling facilitates the formation of excitatory synapses on PV interneurons and then up-regulates the power of γ oscillations. Based on the aforementioned findings and the results of our preliminary studies showing that the reduced power of γ oscillations elicits the neuronal network hypersynchrony in the mice with cognitive impairments induced by isoflurane anesthesia, the hypothesis to be tested is: isoflurane anesthesia → inhibition of NRG1/ErbB4 signaling → reduction of excitatory synapses on PV interneurons → impaired function of PV interneurons → decreased power of γ oscillations → neural network hypersynchrony → cognitive impairments. To test this hypothesis, we will apply behavioral tests, electrophysiology, molecular biology, and transgenic techniques to study the novel mechanism underlying the isoflurane-induced cognitive impairments at multiple aspects of behavior, neural network, cell function, synapse formation, and molecular signaling. The proposed studies will provide new scientific concepts of anesthesia neurotoxicity, which could lead to the prevention and treatment of postoperative cognitive dysfunction.

吸入麻醉所致认知功能损伤是目前麻醉学研究热点。我们前期研究发现：异氟醚麻醉引起老年小鼠认知损伤、PV中间神经元功能下降伴γ振荡异常。已知：1）PV中间神经元与锥体神经元间"抑制-兴奋动态平衡"是维系认知功能的重要神经网络；2）PV中间神经元同步电活动产生的γ振荡是认知功能的基础；3）NRG1与主要表达于PV中间神经元的ErbB4结合，促进PV中间神经元兴奋性突触形成，从而上调γ振荡功率。结合预实验结果：异氟醚所致认知损伤小鼠γ振荡功率下降引起神经网络过度同步化，我们假设：异氟醚麻醉→NRG1/ErbB4信号抑制→PV中间神经元兴奋性突触减少→PV中间神经元功能降低→γ振荡功率下降→神经网络过度同步化→认知损伤。本项目采用行为学、电生理学、分子生物学、转基因等技术，从整体行为-神经网络-细胞功能-突触形成-分子信号多层次揭示异氟醚所致认知功能损伤的新机制，为术后认知功能障碍防治提供新依据。

术后认知功能障碍（POCD）是老年患者麻醉手术后常见的并发症，其临床表现主要为患者在手术麻醉后出现认知功能（包括学习、记忆、情绪、情感、判断力等）下降。POCD延长住院时间、术后生活质量下降并且是老年患者术后生活障碍和死亡的重要病因，因而过去几十年越来越引起社会的广泛关注。然而，其发病机制至今尚未明确。本课题主要从微清蛋白（PV）中间神经元功能及其抑制性神经微环路γ振荡异常角度探讨POCD的发病机制。. 通过前期研究，我们得出一些关键结果。. （1）应用上述技术进一步阐明PV中间神经元神经调节蛋白-1（NRG1）-表皮生长因子4（ErbB4）功能紊乱异常可能是引起POCD的重要机制。同时，发现NRG1-ErbB4-PV信号通路参与氯胺酮的抗抑郁作用。（2）神经网络过度活化在POCD中发挥重要作用；（3）证实了氧化应激及炎症反应是POCD发病的始动环节，其通过影响PV中间神经元发挥作用，而NADPH氧化酶很可能介导这一作用。（4）PV中间神经元介导反复七氟烷暴露引起幼鼠的远期认知功能障碍。（5）运用蛋白组学及磷酸化组学筛查影响POCD发病的关键因素是炎症反应与突触蛋白丢失。