神经营养因子受体p75NTR缺失导致再认记忆障碍的脑区结构基础与分子机制

The incidence of Alzheimer's disease is increasing rapidly in our aging society. Saving the aging society is of top priority by studying the neuropathological mechanism and discovering effective therapeutics for patients at early stage. Loss of recognition memory is a prominent feature of Alzheimer's disease and other human classical amnesic syndrome. Recognition memory is a form of explicit memory characterized by a feeling of familiarity when something previously experienced is encountered again. Previous studies indicate that recognition memory operates through the coordinated activities among perirhinal cortex, hippocampus and medial prefrontal cortex. Our previous data indicates recognition memory deficits in p75 NTR -/-mice. By studying p75 NTR -/-mice (p75 neurotrophic receptor), a model for recognition memory deficits, we emphasized a role of cholinergic regulation of the neuronal network in the cortex and hippocampus, which serves as the brain basis and neuronal substrate of recognition memory. We plan to explore the modulation of p75NTR in the cholinergic neuron activity and its regulaton of pyramidal neuron function in the prefrontal cortex, perirhinal cortex and hippocampus. In sum, the project aims to provide novel insights into the neuronal substrate in recognition memory and bring in molecular evidence for the discovery of early stage therapy for the patients of Alzheimer and other human classical amnesic syndrome.

随着社会老龄化趋势发展，阿尔兹海默症在我国发病率逐年升高。研究阿尔茨海默症的发病机理和早期干预策略已经成为迫在眉睫并事关社会公共健康的重要科学问题。再认记忆障碍为阿尔茨海默症患者及多种失忆综合症的早期症状之一。再认记忆是一种外显记忆，表现为当再一次遇到之前经历过的事物时所产生的一种熟悉感。既往研究提示，再认记忆依赖于嗅周皮层，海马和前额叶皮层间的协同作用。本申请者前期研究发现神经因子广泛性受体p75NTR-/-小鼠出现再认记忆障碍。本项目以p75NTR-/-小鼠为再认记忆障碍研究模型，将胆碱能神经元对于皮层与海马神经环路的调节及功能整合为主线，探索再认记忆的分子调控机制。本项目期望评价p75NTR对于胆碱能神经元及其投射，在调节皮层与海马神经环路中的功能影响，为解释再认记忆障碍的发病原理提供线重要线索，为阿尔兹海默症及多种失忆综合症患者提供早期治疗的分子基础。

再认记忆表现为再次遇到之前经历过的事物时所产生的一种熟悉感。再认记忆障碍是阿尔兹海默症及多种类型痴呆疾病的重要表现。再认记忆形成依赖于多个脑区的协同作用，而胆碱能神经元是调控多脑区神经环路可塑性的重要组成。本研究充分利用p75NTR仅表达于成年小鼠胆碱能神经元这一特点，深入剖析了基底核-前额叶皮层通路对于时间次序再认记忆的调节机制。本研究的结论分为四个层面：（1）基底核-前额叶皮层通路调节时间次序再认记忆，而内侧隔核-海马通路并不参与调节过程；（2）胆碱能神经元通过控制抑制性神经环路而调节环路同步化；（3）钾-氯共转运通道KCC2是胆碱能控制抑制性神经环路的分子靶点；（4）N型胆碱能受体介导环路同步化及时间次序再认记忆。综上所述，本研究解析了介导再认记忆的神经通路以及胆碱能神经元对于神经环路的调控机制以及分子靶点，为再认记忆障碍的治疗提供崭新的线索。