内侧隔核/斜角带核复合体–背侧海马CA1区CCK能神经元环路参与术后神经认知恢复延迟的机制研究

背侧海马“胶质细胞-神经元对话”异常是术后神经认知恢复延迟（dNCR）的重要原因，其神经环路机制尚不清楚。我们前期研究表明：术后dNCR小鼠背侧海马CA1区胆囊收缩素8（CCK8）含量减少、小胶质细胞激活、星型胶质细胞异常极化及兴奋性突触可塑性下降；而给予外源性CCK8可有效逆转上述改变，提示背侧海马CA1区CCK能中间神经元可能在术后dNCR的发生中具有重要作用。鉴于基底前脑内侧隔核/斜角带核（MS/DB）复合体对背侧海马CA1区CCK能神经元具有直接投射关系，我们推测该神经环路参与术后dNCR的发生。本项目以CCK能神经元为切入点，利用光化学遗传、膜片钳等技术，分别从整体动物和离体脑片水平探究该环路在dNCR中的作用；在此基础上，从“胶质细胞-神经元对话”的角度观察该环路的下游效应，并探究其在dNCR中的调控机制。研究结果将有助于阐明术后dNCR的环路机制，为其预防和治疗提供实验依据。

Abnormal communication between glia and neurons in the dorsal hippocampus plays a key role in the delayed neurocognitive recovery (dNCR) after surgery. Nevertheless, its underlying neural circuit mechanism is still unclear. Our previous studies revealed that the postoperative neurocognitive function of the aged mice was significantly impaired. In addition, compared with the controls, there were several significant changes in dorsal hippocampal CA1 area of dNCR mice, including the decreased content of cholecystokinin 8 (CCK8), activated microglia, abnormally transformed astrocytes and decreased synaptic plasticity of the excitatory neurons. The exogenous CCK8 can effectively reverse the above changes, suggesting that CCKergic neurons in the CA1 of the dorsal hippocampus are crucial in the development of postoperative dNCR. Based on the fact that there are direct projections from medial septum/diagonal band (MS/DB) complex of basal forebrain to the CCKergic neurons in the dorsal hippocampal CA1, we therefore speculate that this neural circuit participates in the development of postoperative dNCR. From the perspective of CCKergic neurons, we herein explore the role of the neural circuit from the MS/DB complex to the CCKergic neurons in the development of dNCR by the optogenetics, chemical genetics and patch clamp in animal models and brain slices. Furthermore, the activation of microglia, transform of astrocytes, and synaptic plasticity of the excitatory neurons will also be examined to study the downstream effects of the above neural circuit. Our results will be helpful to clarify the neural circuit mechanisms of postoperative dNCR and provide experimental evidence for the prevention and treatment of postoperative dNCR.