脑功能重塑在针刺改善3xTg-AD小鼠认知功能的作用及分子机制研究

Alzheimer's disease (AD) is a central neurodegenerative disease. The mainly clinical manifestations is progressive cognitive impairment. The characteristics of AD are high morbidity, high disability rate and refractory treatment. Acupuncture has a good clinical effect in treating AD and improve memory ability, but its mechanism is still unclear. Neuronal autophagy dysfunction plays an important role in the pathological development of AD. Our previous study found that the therapeutic effect of acupuncture on AD may be related to the metabolism activation in memory-related brain areas, in order to further explore its mechanism, 3xTg-AD mice were used to carry out the following experiments: ①To observe the effects of acupuncture on cognitive function of 3xTg-AD mice; ②fMRI and DTI multi-modal image fusion are used to observe the functional network connectivity changes of the target brain areas before acupuncture, immediately after the first acupuncture and after the last acupuncture to explore the acupuncture regulation mechanism of cerebral neuroplasticity;③Further pathomorphological observation and behavioral evaluation were combined to reveal the molecular mechanism of acupuncture regulation of autophagy in the targeted brain areas. Therefore, our project is based on multi-discipline coordination to study the central mechanism of acupuncture treatment of AD, which will definitely establish an experimental and theoretical foundation for clinical application of acupuncture treatment on AD .

阿尔茨海默病(AD)是中枢神经系统退行性疾病，临床主要表现为进行性认知功能障碍。具有高发病率、高致残率、难治性的特点。针刺在治疗AD改善记忆能力方面有较好的临床疗效，然其具体机制不清。研究表明神经细胞自噬功能紊乱在AD病理发展过程起重要作用。申请人前期研究发现针刺对AD的疗效可能与激活记忆相关脑区代谢有关，为进一步探索其机制，本项目拟采用3xTg-AD小鼠开展如下工作：①观察针刺对3xTg-AD小鼠认知功能的影响；②以fMRI与DTI多模态图像融合，观察针刺前、即刻针刺后及针刺疗程后所激活的靶效应脑区的功能网络连接变化，探讨针刺对3xTg-AD小鼠的脑功能网络神经可塑性调节机制；③在此基础上结合病理形态学观察与行为学评估等进一步揭示针刺调控靶向脑区自噬水平分子机理。上述多层次、多角度进行针刺治疗AD的中枢机制研究，为临床推广应用针刺治疗AD及阐明针刺治疗AD获效机制奠定实验和理论基础。

阿尔茨海默病（AD）是中枢神经系统退行性疾病，临床主要表现为进行性认知功能障碍，具有高发病率、高致残率、难治性的特点。针刺在治疗AD改善记忆能力方面有较好的临床疗效，然其具体机制不清。申请人前期研究发现针刺对AD的疗效可能与激活记忆相关脑区代谢有关，为进一步探索其机制，本项目采用5xFAD小鼠开展如下工作：①观察针刺对5xFAD小鼠认知功能的影响；②基于fMRI技术观察针刺前及针刺疗程后所激活的靶效应脑区的功能网络连接变化，探讨针刺对5xFAD小鼠的脑功能网络神经可塑性调节机制；③在此基础上结合免疫生化检测与行为学评估等进一步揭示针刺调控靶向脑区自噬水平分子机理。结果：①fMRI显示5xFAD小鼠嗅结节（OT）的功能性脑网络减少，体感皮层的功能连接强度也随之改变。②与模型组相比，针刺组跨越平台的数量和在目标象限花费的时间增加（P＜0.05）。针刺后5xFAD小鼠边缘系统（海马、尾壳核）和新皮质（运动皮层、体感皮层和颞叶）之间的rsfMRI功能连接增强。③与模型组相比，针刺组SYN、PSD-95、Aβ、BCL2、BAX和Casepase-3等表达均存在差异（P＜0.05）；与野生组相比，针刺组SYN、PSD-95和Casepase-3表达无明显差异（P＞0.05），但Aβ差异有显著性意义（P＜0.01）。结论：①5xFAD小鼠体感皮层的功能变化可能存在代偿性神经可塑性重组来维持其认知功能以应对因Aβ沉积和脑萎缩引起的AD记忆和认知功能下降，其OT功能性脑网络降低可能与其认知功能降低密切相关。②针刺可以改善5xFAD小鼠的学习记忆能力，其机制可能是通过增强边缘-皮层神经回路的静息态功能活动和连接性来完成。③针刺能调控5xFAD小鼠大脑自噬水平，抑制细胞凋亡，增加神经突触可塑性，促进神经元修复。本研究多层次、多角度进行针刺治疗AD的中枢机制研究，为临床推广应用针刺治疗AD及阐明针刺治疗AD获效机制提供实验依据和理论支持。