吸入麻醉后认知功能障碍的新机制：中枢组胺能神经环路的作用

The relationship between anesthesia and postoperative cognitive dysfunction(POCD) is one of the frontier hot topics in anesthesiology and neuroscience research. However, there has been no study reporting whether some neural pathways are involved in the memory deficits after general anesthesia. The applicant has previously found that histaminergic tuberomamillary nucleus (TMN) is involved in the sedative/hypnotic effects of isoflurane, and histaminergic neurons modulate hippocampal long-term potentiation through dense histaminergic output from TMN to the medial septum. In this project, we aim to explore whether histaminergic system participates in memory deficits after isoflurane anesthesia. First, we will investigate whether histamine or various histaminegic agonists and antagonists given into the medial septum can affect retention of one-trial inhibitory avoidance in SD rats. Then, we will explore the effect of histaminergic modulation on long-term potentiation of synaptic plasticity in the CA1 of hippocampus in freely behaving rats after isoflurane anesthesia. We will also address whether the treatment conditions used above had any effects on brain-derived neurotrophic factor mediated signaling pathway. In the end, the role of central histamine in mediating memory deficits after inhaled anesthesia will be assessed in histamine-deficient HDC-KO mice. The project will provide important information regarding the mechanism and the design of targeted prevention and treatment strategies for POCD.

麻醉与术后认知功能障碍的关系是目前国际麻醉学与神经科学研究的热点和前沿科学问题之一。麻醉药是否通过一定的神经环路机制导致麻醉后记忆功能受损尚未见报道。申请者前期研究发现下丘脑TMN组胺能神经元是介导异氟烷麻醉效应的重要核团；同时发现TMN组胺能神经核团可通过向内侧隔核-海马的神经投射调节海马突触可塑性长时程增强。本项目将在前期研究和预实验基础上采用海马依赖的抑制性逃避记忆模型，研究组胺通过内侧隔核-海马神经环路对SD大鼠异氟烷麻醉后学习记忆功能的调节作用，同时采用电生理方法记录自由活动大鼠海马CA1区突触可塑性变化；并探讨组胺能神经介导的BDNF信号通路在异氟烷诱导记忆受损的分子机制；最后，我们将采用组胺酸脱羧酶HDC基因敲除小鼠从行为学和分子生物学角度进一步验证吸入麻醉药诱导记忆功能受损的中枢组胺能神经机制。通过本项目研究，为术后认知功能障碍的防治提供新的理论依据。

麻醉与术后认知功能障碍的关系是目前国际麻醉学与神经科学研究的热点和前沿科学问题之一。麻醉药是否通过一定的神经环路机制导致麻醉后记忆功能受损尚未见研究报道。本项目通过运用行为学、电生理学及分子生物学研究方法，探讨了吸入麻醉后认知功能障碍的神经生物学机制。结果表明: (1)健康成年小鼠，吸入麻醉引起的记忆障碍为短期可逆现象; (2)下丘脑结节乳头核微量注射GABAa 受体拮抗剂荷包牡丹碱可逆转吸入麻醉后抑制性回避记忆受损，提示中枢组胺能神经环路参与吸入麻醉后认知功能障碍；(3)吸入麻醉剂引起海马脑源性神经营养因子表达下降和长时程增强受抑制，为吸入麻醉后认知功能障碍的分子和电生理机制之一；(4)组胺H3受体拮抗剂可有效干预麻醉后认知功能障碍，但对运动、焦虑及疼痛功能无显著影响。本项目研究为深入阐明术后认知功能障碍的发生机制、降低术后认知功能障碍发生率、提高麻醉手术患者生活质量提供了新的科学依据。