随着人类寿命不断延长,神经退行性疾病在人群中的发病率逐年上升。神经退行性疾病主要特征是神经元的死亡，病变造成患者记忆丢失、学习能力衰退、认知能力下降。对于神经元死亡的病理观察和生物学机制研究已有一定的基础，但具体的生物学过程仍不清楚。过去的研究主要关注神经元胞体处发生的变化，及其进一步导致细胞死亡的机制。但由于技术手段的限制，对于轴突在神经退行性疾病发病过程中的病变，特别是轴突处病变和胞体处病变的相互关系仍缺乏深入研究。本项目拟开发一套新颖特异性神经元标记方法用以标记单个神经元的完整形态，同时开发获取神经元完整形态的高分辨成像方法和系统。利用新型标记和成像系统，本项目旨在从单细胞水平重构正常生理条件下基底前脑胆碱能神经元和中脑多巴胺神经元的完整形态。以此为基础，结合神经退行性疾病模型小鼠，研究神经退行性疾病不同阶段这两类神经元的单细胞形态变化和病变发展过程，并解析相伴随的认知功能缺陷。

Increasing prevalence rate of neurodegenerative diseases calls for systematic studies of the underlying etiology. Although neuronal death contributes to the devastating cognitive, motor, and mood impairments, it remains unclear whether neurodegeneration starts at the neuron somata or axons. Previous studies mainly focused pathological changes at the somata, but some hints indicate that the changes of axons occur earlier during the process of neurodegeneration, leading to the dying-back hypothesis. Studying the relationship between changes at axons and somata requires precise dissection of neuronal morphology at the single-cell level. Here, we propose to address this challenging question by developing and applying the state-of-art techniques for reconstructing the morphology of single cells at the whole-brain level. First, we will develop a novel virus system to sparsely label individual neurons. Second, we will improve the high-resolution imaging system and automatic reconstruction technique to map the complete morphology of individual neurons. Third, we plan to use the newly developed techniques to map the morphology of cholinergic neurons in the basal forebrain and dopaminergic neurons in the midbrain at single-cell level under normal physiological condition. Finally, we will examine the morphological changes of these two types of neurons during the process of neurodegeneration in Alzheimer’s disease and Parkinson’s disease mouse model. These efforts will help elucidate the etiology of two major neurodegenerative disorders. Moreover, our new technologies will transfer the study of neural circuit into the level of single-cell resolution and will have a broad impact in neuroscience.