成年海马齿状回Notch1信号调控应激致情感及认知功能障碍作用机制研究

Abstract: Notch1 plays a crucial role in the regulation of embryonic development, but its function in mature neurons is quite limited. Recently, researches shows that, Notch1 signal can regulate synaptic plasticity in mature hippocampal neurons. The pathophysiology mechanism of depression and hippocampal synaptic plasticity are closely related. Moreover, the depression patients with antidepressant therapy can activate the hippocampus Notch1 signaling system, but the exact mechanism of Notch1 signal in the depression remains unclear. Our preliminary results showed that Notch1 receptor expressed in the adult mouse dentate gyrus (DG) Pyramidal neurons, and stress can increase Notch1 expression. Notch1 signaling inhibitors DAPT treatment can decline DG neurons firing rate. To further explore the functions of DG Notch1signaling in the pathophysiology of depression, by using the Cre-loxP strategy, we get the DG cell-specific knockout or activation of Notch1 signaling mutant mice. The results show that the adult DG Notch1 gene knockout can lead to reduced synaptic plasticity, and produce anxiety and depression-like behavior. Therefore, this project intends to combine with genetics, electrophysiology and behavioral methods to explore hippocampus DG region Notch1 signaling in the pathophysiology of depression, and further provide the evidence to explore the new target of medicine.

Notch1信号可调控成年海马神经元的突触可塑性，而海马神经元突触可塑性改变可能与抑郁症发生密切相关，且抑郁症患者抗抑郁治疗可激活海马Notch1信号系统，但Notch1在抑郁症发生中的功能及病生机制目前仍不明了。我们前期研究显示，Notch1表达于成年小鼠海马齿状回颗粒层神经元，Notch1信号抑制剂DAPT处理可导致齿状回神经元放电频率下降。为深入探讨齿状回Notch1信号在抑郁症发生中的功能，通过采用Cre-loxP策略，我们获得了海马齿状回细胞特异性Notch1信号敲除小鼠。结果表明，在成年海马齿状回敲除Notch1信号可产生抑郁样行为，内嗅皮层前穿通支-齿状回（PP-DG）的突触可塑性改变。因此，本项目通过结合遗传学、电生理和行为学等手段，系统研究海马齿状回Notch1信号在应激导致情感和认知功能障碍中的可能作用机制，为揭示Notch1在抑郁症发生中的病生机制奠定基础。

抑郁障碍神经生物学基础及发病机制是精神医学前沿课题，但病生机制目前并不十分明确。研究发现：Notch1信号通路的改变与抑郁障碍密切相关，且抑郁障碍患者抗抑郁治疗可激活海马Notch1信号系统。但Notch1在抑郁障碍发生中病生机制目前仍不明了，Notch1信号通路在成年后的功能及作用机制仍是目前研究的热点和难点问题。为深入探讨Notch1信号在内源性抑郁障碍及应激致情绪障碍中的作用机制，通过采用Cre-loxP策略，我们获得了海马齿状回细胞特异性Notch1信号敲除小鼠。结果表明，成年海马齿状回条件敲除Notch1信号可产生抑郁样情绪及认知行为障碍，内嗅皮层前穿通支-齿状回(PP-DG)的突触可塑性改变，可能与减少新生神经元存活，影响海马树突分支形态，及cAMP 反应元件结合蛋白CREB磷酸化减少密切相关。此外构建了观察性恐惧应激-负性情绪传染模型 (Observation fear learning-Negative emotion contagion, OFL-NEC)，并对该模型进行不断优化改进，并通过特定脑区条件操控Notch1信号受体，对Notch1信号通路在应激致情绪障碍中可能作用机制提供初步实验探索。但是Notch1受体如何调控DG区成熟神经元突触可塑性发生变化，进而在整体水平改变了动物对外界应激的反应性和行为学变化，调控其变化的上下游机制及与其他通路之间的相互作用目前并不十分清楚，更多的实验研究需要深入。