电针调控miR-219a促进VD空间记忆信息编码的机制研究

On vascular dementia (VD) caused by cerebral ischemia, the previous study funded by the National Natural Science Foundation of China showed that electroacupuncture (EA) at the Baihui and Shenting acupoints could improve the ability of spatial learning memory after cerebral ischemia, which is related to the down-regulated expression of miR-219a in the entorhinal cortex, hippocampal CA1 regions. This project will further investigate that EA promotes the balance of entorhinal cortex to hippocampus CA1 neural circuits excitatory and inhibitory and coordinates the synchronization of entorhinal cortical grid cells and hippocampal CA1 place cellsγrhythms to encoding spatial memory via regulating miR-219a in VD. In this research, the VD model were developed and the miR-219a was overexpressed in VD model. The EA treatment was performed for 4 weeks and the behavior tests were observed to define the roles of miR-219a on the promotion of spatial memory encoding by EA. The animal functional magnetic resonance imaging and chemical genetics techniques are used to reveal the effects of EA on the entorhinal cortex to hippocampus CA1 neural circuit via miR-219a. And further to elucidate the electrophysiological mechanisms of entorhinal cortex to hippocampal CA1 neural circuit Glu excitatory and PV and SOM inhibitory balance as well as the synchronous discharging between grid cells and place cells in the process of spatial memory encoding. The results obtained will provide a reliable experimental basis for clinical application.

针对脑缺血引起的血管性痴呆（vascular dementia，VD），在前一项国基金研究已表明电针“百会”、“神庭”穴可改善脑缺血后空间学习记忆功能，与内嗅皮层、海马CA1区miR-219a表达共下调有关。本课题拟深入探讨电针通过miR-219a调控内嗅皮层-海马CA1神经环路兴奋/抑制平衡以及协调内嗅皮层网格细胞、海马CA1位置细胞γ节律同步化，从而促进VD空间记忆信息编码。拟复制VD模型并过表达miR-219a，电针干预4周，行为学观察明确miR-219a在电针促进空间记忆信息编码中的作用；小动物MRI脑功能成像结合化学遗传学揭示电针调控miR-219a对内嗅皮层-海马CA1神经环路的影响；并进一步阐明内嗅皮层-海马CA1神经环路兴奋（Glu）/抑制（PV、SOM）平衡以及网格细胞与位置细胞同步放电节律促进空间记忆信息编码的电生理机制。所获结果将为其临床应用提供可靠的实验依据。

血管性痴呆（vascular dementia，VD）由缺血、缺氧等因素所致脑区低灌注损伤逐步引起认知功能下降。中医病机为“髓减脑消、神经失用”，针对该病机本课题采用“通督调神”电针“百会”、“神庭”穴在血管性痴呆早期进行了干预研究，基于前期通过基因芯片发现电针改善血管性认知障碍与内嗅皮层、海马CA1区miR-219a共表达下调有关。本课题通过特异性过表达miR-219a明确了电针调控miR-219a表达可影响血管性认知障碍模型大鼠内嗅皮层、海马CA1区兴奋/抑制平衡改善血管性认知障碍的作用；阐明了miR-219a的作用靶点NMDA受体，通过miR-219a激动剂和抑制剂干预实验明确了miR-219a对NMDA受体介导突触后膜电生理功能的改变，同时对内嗅皮层-海马CA1长时程增强（LTP）和兴奋性突触后电流（EPSC）的影响；揭示了电针调控miR-219a促进内嗅-海马CA1区LTP和内嗅、CA1神经元EPSC的电生理机制；阐明了电针调控miR-219a影响NMDA受体及其下游CaMKII磷酸化介导内嗅-海马CA1区突触可塑性的潜在分子机制。发表SCI论文3篇，在投SCI论文1篇，授权专利1项，培养研究生3名。