二氢杨梅素通过调节肠道菌群-BDNF信号轴缓解高原低氧诱导记忆损伤的作用及机制研究

Acute high-altitude hypoxia-induced memory impairment seriously endangers the construction and development of the plateau. However, there are no ideal prevention and control measures. Dihydromyricetin(DHM) is one of the most common dietary flavonoids, has known anti-inflammatory effects and neuroprotection. The protection of dihydromyricetin on memory of rats under high-altitude hypoxia was observed in our previous research. It is speculated that DHM may be an ideal phytochemical for memory protection in high altitude hypoxia environment, but the mechanism is still unclear. Recent studies suggest that the gut microbiota dysfunction could obviously influence memory maintenance, which is closely related to the BDNF pathway. And high-altitude hypoxia could easily lead to intestinal barrier damage and changes of gut microbiota composition. Based on recent findings that DHM could markedly alter the richness and diversity of the gut microbiota and modulate the gut microbiota composition, we hereby propose the hypothesis that DHM can significantly improve the high-altitude hypoxia-induced memory impairment via the regulation of gut microbiota-BDNF signaling axis. Based on the animal study, this project is designed to comprehensively evaluate the effects of DHM on high-altitude hypoxia-induced memory impairment on the regulation of gut microbiota-BDNF signaling axis, by using the techniques of memory behavior test, electro-neurophysiology, metagenomic detection and Cas9 transfection. Our study is of great significance in further clarifying the effects and mechanism of gut microbiota-BDNF signaling axis regulation on high-altitude hypoxia-induced memory impairment, and also provides scientific evidence for the prevention and treatment of hypobaric hypoxia-induced memory impairment through the dietary management.

高原低氧暴露导致的记忆损伤严重危害高原地区建设发展，且缺乏理想防治措施。二氢杨梅素（DHM）具有抗炎、保护神经的作用，我们发现DHM可显著缓解高原低氧诱导的大鼠记忆损伤，推测DHM可能成为高原低氧暴露后记忆保护的理想植物化学物，但其中机制尚不明确。新近研究发现肠道菌群紊乱显著影响记忆维持，且与BDNF信号通路密切相关；而高原低氧暴露易导致肠道菌群紊乱，结合DHM能调节大鼠肠道菌群的组成，本项目提出“二氢杨梅素通过调节肠道菌群-BDNF信号轴，发挥神经保护作用，缓解高原低氧急性暴露导致记忆损伤”的研究假说。通过动物实验，运用行为学检测、神经电生理、宏基因组测序、Cas9转染等技术，率先研究高原低氧环境下DHM诱导肠道菌群的特征性变化，同时围绕肠道菌群-BDNF信号轴开展DHM缓解低氧诱导记忆损伤的效应机制研究；为研发新的针对高原低氧暴露诱导记忆损伤的防治策略提供研究依据。

高原低氧暴露导致的记忆损伤严重危害高原地区建设发展，其中确切机制尚不十分清楚且缺乏理想防治措施。二氢杨梅素（DHM）具有抗炎、保护神经的作用，前期发现DHM可显著缓解高原低氧诱导的大鼠记忆损伤，推测DHM可能成为高原低氧暴露后记忆保护的理想植物化学物，但其中机制尚不明确。研究内容：（1）利用低压氧舱建立低氧诱导大鼠记忆损伤模型，通过Morris水迷宫检测大鼠空间记忆能力，发现暴露于模拟海拔6000米低压低氧环境下7天大鼠空间记忆能力显著下降，DHM干预能有效改善低压低氧诱导的记忆损伤。（2）透射电镜检测显示DHM干预缓解低压低氧刺激导致大鼠海马神经元超微结构损伤（线粒体肿胀、嵴消失，突触结构改变），并增加了海马组织神经元突触结构相关蛋白表达，提示DHM改善低压低氧诱导的记忆损伤与海马神经元突触可塑性改变相关。（3）率先研究高原低氧环境下DHM诱导肠道菌群的特征性变化，发现DHM干预显著影响肠道菌群的结构、丰度，同时增加特定菌属的丰度，且减轻了低压低氧诱导的肠道黏膜屏障损伤。（4）围绕BDNF信号轴开展DHM缓解低氧诱导记忆损伤的效应机制研究，提示DHM是通过BDNF影响ERK/CREB 通路、PI3K/Akt 通路保护神经元、减少神经元变性、促进神经元存活最终改善记忆能力。本研究为研发新的针对高原低氧暴露诱导记忆损伤的防治策略提供研究依据。