基于基底前脑-海马DG环路探讨早期电针对AD事物辨别障碍的作用及机制

The process of memory encoding and distinguishing similar events or environments are impaired would cause pattern separation dysfunction, which leads to a decline in the ability of object discrimination in the early state of Alzheimer's disease (AD). Previous studies have suggested that the cholinergic neural circuits in the basal forebrain (BF) directly innervate the dentate gyrus (DG) of hippocampus are impaired by the decrease of neurogenesis in hippocampal DG region and the loss of cholinergic neural system. However, studies have demonstrated that electroacupuncture (EA) could promote endogenous neurogenesis in the hippocampal DG region and enhance the hippocampal cholinergic neural system. Based on this, the study would propose a hypothesis that early EA intervention could regulate the BF to hippocampal DG circuits facilitating pattern separation to prevent or delay the object discrimination impairments in early AD. The animal touch screen behavior test and functional magnetic resonance imaging (fMRI) are applied to define the effect of early EA intervention on the functional connection from BF to hippocampal DG region and the roles of the discrimination behavior in AD model mice. And the virus tracing, optogenetics and chemical genetic techniques are applied to reveal the effects of early EA intervention on the structure and function of BF to hippocampal DG circuits in AD model mice, and further to elucidated the possible cellular and molecular mechanisms of early EA intervention for the BF to hippocampal DG cholinergic neural circuits facilitating pattern separation. The obtained results will provide experimental evidence and theoretical basis of early EA prevention and treatment for AD.

阿尔茨海默病（AD）早期大脑记忆编码并区分相似事件或环境的模式分离障碍，导致事物辨别能力下降。研究表明这与海马DG区神经新生减少以及胆碱能系统丢失引起基底前脑-海马DG区胆碱能神经功能异常密切相关。而前期发现电针能促进DG区内源性神经新生，增加海马胆碱能化合物含量。基于以上本课题提出研究假说：早期电针干预调节基底前脑-海马DG区神经环路功能易化模式分离，从而防治/延缓AD早期事物辨别障碍。拟在前期研究基础之上，采用动物触摸屏行为学和小动物功能核磁观察早期电针干预对AD模型小鼠基底前脑与海马DG区功能连接及其事物辨别行为学的影响；嗜神经病毒示踪、光/化学遗传学技术揭示早期电针对AD模型小鼠基底前脑-海马DG区胆碱能神经环路结构和功能的影响；并进一步阐明基底前脑-海马DG胆碱能神经环路易化模式分离可能的细胞和分子机制。所获结果将为早期电针干预AD的临床应用提供部分实验证据和理论基础。

阿尔茨海默病（AD）早期大脑记忆编码并区分相似事件或环境的模式分离障碍，导致事物辨别能力下降。本课题采用多种动物行为学明确了电针“百会”、“神庭”穴可改善AD模型小鼠早期空间模式分离能力。研究表明海马DG区分化新生神经元表达胆碱能受体与基底前脑核团投射来的胆碱能神经元形成单突触神经环路在模式分离中扮演了重要作用。本研究验证了基底前脑MS/VDB-海马DG存在直接的胆碱能神经元投射，发现电针可调节AD模型小鼠基底前脑MS/VDB-海马DG区胆碱能神经环路进而改善AD模型小鼠模式分离能力；利用化学遗传学技术明确了电针通过基底前脑MS/VDB-海马DG区神经环路调节模式分离能力，揭示了电针通过调节基底前脑MS/VDB、海马DG区Cho水平、胆碱能M1受体表达，并促进海马神经发生，改善其模式分离能力；利用Wnt敲减病毒明确了电针“百会”、“神庭”穴可通过调控Wnt信号通路促进AD模型小鼠海马DG区未成熟颗粒细胞新生改善其模式分离能力。提示电针“百会”、“神庭”穴可改善AD模型小鼠早期事物辨别和模式分离能力，其机制与激活基底前脑MS/VDB-海马DG神经环路，增加胆碱能神经投射，并调节Wnt信号通路促进海马DG区未成熟颗粒细胞新生有关，所获结果丰富其理论基础与实验依据，为促进临床应用具有重要的科学意义。发表SCI论文4篇，入选国家中医药 “青年歧黄学者”；培养博士研究生1名，硕士研究生2名。