进行性认知障碍是阿尔茨海默病（Alzheimer disease, AD）的主要临床特征。在发病初的第Ⅰ期，AD患者即出现空间关联认知障碍。内嗅皮质-海马CA1环路是空间信息加工的重要网络，项目组研究发现AD转基因鼠内嗅皮质和海马CA1区GDNF及受体GFRα1表达下调，而通过上调GFRα1，能增强内嗅皮质和海马CA1区神经元突触的可塑性。因此，我们推测GDNF/GFRα1信号衰减介导的内嗅皮质-海马CA1区功能缺陷在AD发病过程中发挥重要的作用。本研究拟运用自然衰老、早老、APP/PS1小鼠和hSyn-DIO-GFRα1-ChR2(H134R)-EYFP鼠，通过行为学、电生理、光遗传学和分子生物学交叉研究，探讨GDNF/GFRα1/RET通路对内嗅皮质-海马CA1突触可塑性的影响及对信息加工和记忆关联的作用，为研究AD认知功碍的机制提供实验依据，为AD的治疗提供新思路。

Alzheimer disease is clinically characterized by progressive memory deficits. In the first stage of AD onset, spatial cognitive impairment on objective association occurs in the patients. The encoding of spatial cognition requires an intact entorhinal-hippocampal circuit. We previously observed that the glia-derived neurotrophic factor (GDNF) and GDNF family receptor-α1 (GFRα1) were reduced the protein expressions of GDNF and GFRα1 were reduced in the entorhinal cortex and in the hippocampal CA1 region in an Alzheimer’s transgenic mouse brain. We have also observed that upregulated mediated by LV- GFRα1 could enhance the synaptic plasticity in the entorhinal cortex and in the hippocampal CA1 region. Therefore, we raise the hypothesis that the impairment of GDNF/GFRα1 signaling induced the dysregulation of entorhinal-hippocampal circuit plays an important role in the pathogenesis process of AD. IN the present study, we will investigate the effects of GDNF and GFRα1 using natural aging, premature senescence and APP/PS1 transgenic mouse, combining the hSyn-DIO-GFRα1-ChR2(H134R)-EYFP mouse. The effects of GDNF on synaptic function and learning and memory, and the potential mechanism of abnormal GDNF-GFRα1 interaction in the dysfunction of information processing and memory association in the brain will be clarified using behavioral, electrophysiological, optogenetic and molecular biological tests in the study. The project provides experimental basis and theoretical support for exploring the mechanism of memory impairment with age, and provides us novel approaches on seeking effective interfere and therapeutic strategies for AD by targeting intact entorhinal-hippocampal CA1 circuit via keeping GDNF/GFRα1/RET homeostasis.