运用光遗传可调控性转基因小鼠模型研究基底前脑-海马DG胆碱能神经环路损伤在阿尔茨海默病早期模式分别障碍中的作用

Alzheimer’s disease (AD) is a neurodegenerative disease that jeopardize the physical and mental health in eldly. Recent studies revealed that cognitive impairments in early AD patients are characterized by a deficit in pattern separation, but the underlying mechanisms are poorly understood yet. It has already known that the cholinergic neurons in the basal forebrain are degenerated severely in the early stage of AD, which leads to the reduction of cholinergic fibers and the decrement of neurogenesis in the dentate gyrus of hippocampus, the latter is important to pattern separation. Herein, we speculate that the dyfunction of basal forebrain-hippocampal cholinergic neural circuit mediates the pattern separation impairment in the early stage of AD. However, the applicable mouse model assessing the function of such neural circuit is absent. In this study, taking advantage of the inducible transgenic mouse model that sepecific labled the basal forebrain-hippocampal cholinergic neural circuit which is recently established in our lab, we will employ the optogentic approaches to mimic the characterized cholinergic neurodegeneration in early stage of AD and further investigate behavioral phenotype of the spatial pattern separation impairment. On this basis, we will also examine the role of dysfunction of basal forebrain-hippocampal cholinergic neural circuit in the pattern separation impairment and explore the underlying mechanisms. Our study will provide experimental evidences and discover novel drug targets for the prevention and treatment of cognitive disorder in the early stage of AD.

阿尔茨海默病（AD）是一类严重危害老年人群身心健康的神经退行性疾病。最近报道显示AD患者早期出现模式分别能力降低的特征性认知功能障碍，但机制不清。已知AD早期脑内基底前脑胆碱能神经元严重退化，导致投射到海马DG区的胆碱能纤维减少并进而下调神经发生（对模式分别功能至关重要）。因此我们推测，AD早期基底前脑-海马DG区胆碱能神经环路的损伤介导了模式分别功能障碍，但目前国内外尚无适合的动物模型用于研究该环路功能。本项目拟基于申请者最近建立的可诱导性特异标记基底前脑-海马DG区胆碱能神经环路的转基因小鼠模型，运用光遗传可控性模拟AD患者早期胆碱能神经元退变的病理特征并深入研究空间模式识别能力降低的行为学表型，在此基础上分析引起该环路功能异常在AD早期模式分别功能下调中的作用和分子调控机制，为AD早期的认知功能障碍的防治提供实验学依据和新的药物靶点。

阿尔茨海默病（AD）是一类严重危害老年人群身心健康的神经退行性疾病。最近报道显示AD患者早期出现模式分别能力降低的特征性认知功能障碍，但机制不清。已知AD早期脑内基底前脑胆碱能神经元严重退化，导致投射到海马DG区的胆碱能纤维减少并进而下调神经发生（对模式分别功能至关重要）。因此我们推测，AD早期基底前脑-海马DG区胆碱能神经环路的损伤介导了模式分别功能障碍，但目前国内外尚无适合的动物模型用于研究该环路功能。本项目拟基于申请者最近建立的可诱导性特异标记基底前脑-海马DG区胆碱能神经环路的转基因小鼠模型，运用光遗传可控性模拟AD患者早期胆碱能神经元退变的病理特征并深入研究空间模式识别能力降低的行为学表型，在此基础上分析引起该环路功能异常在AD早期模式分别功能下调中的作用和分子调控机制，为AD早期的认知功能障碍的防治提供实验学依据和新的药物靶点。