中缝核－海马五羟色胺通路异常在hAPP小鼠病变中的作用和机制

海马CA1锥体神经元活性异常可引起神经环路功能损伤，与阿尔茨海默症（AD）的认知障碍密切相关。然而，AD海马中CA1神经元活性异常的机制尚不十分清楚。中缝核五羟色胺神经元的轴突可投射至海马并调控CA1神经元的活性，而我们前期研究初步发现，AD小鼠中缝核至海马的五羟色胺通路发生异常，提示其可能在AD小鼠CA1神经元活性异常及相关病变中起作用。本项目拟以hAPP-J20小鼠为AD模型，首先通过免疫染色、原位杂交、病毒逆/顺向追踪及免疫印迹等方法系统检测其中缝核至海马的五羟色胺通路；然后利用化学遗传及光遗传学技术调控该通路，结合免疫染色、生化、电生理及行为学等技术，检测调控该通路对hAPP小鼠海马内神经元活性、突触及认知功能等的影响，并通过拮抗剂或抑制剂调控五腔色胺受体及其下游信号分子，以探究调控中缝核－海马五羟色胺通路影响AD小鼠病变的机制。研究结果将为深入理解AD发病机制提供新的认识。

Aberrant activity of the CA1 pyramidal neurons may lead to abnormal function of neural circuits and then causes cognitive impairments in Alzheimer’s disease (AD). However, the mechanisms underlying the aberrant activity of CA1 pyramidal neurons in AD remain elusive. Previous studies have demonstrated that serotonin (5-HT) neurons in the raphe nucleus project to the hippocampus and regulate the activity of CA1 neurons, and our preliminary data indicate that the raphe-hippocampus 5-HT pathway is impaired, suggesting that the impaired 5-HT pathway may be associated with the abnormal activity of CA1 neurons and other related pathologies in AD. In the present project, we will further investigate the raphe-hippocampus 5-HT pathway in hAPP-J20 mice, a mouse model of AD, by applying interdisciplinary approaches such as staining, in situ hybridization, western blot and retrograde or antegrade tracing. Then, we will assess the effects of chemogenetic or optogenetic modulation of the raphe-hippocampus 5-HT pathway on the activity of CA1 pyramidal neurons, synaptic and cognitive functions in hAPP-J20 mice. Finally, we will dissect the mechanisms underlying the neuropathogenesis associated with the impaired raphe-hippocampus 5-HT pathway. Our study will provide new insights into the pathogenesis of AD.