食蟹猴脑梗死后肠道菌群紊乱致下丘脑GABA能神经元继发性损害与睡眠-觉醒障碍的机制研究

脑梗死后失眠发生率高且影响预后，但发生机制未明，并缺乏有效干预措施。研究发现，脑外伤后失眠与未伤及的下丘脑继发性炎性反应有关；肠道菌群紊乱对脑内GABA代谢和系统性炎性反应有重要作用。课题组前期研究并发表论文证实，脑梗死可导致脑部非缺血区继发性损害；预实验发现脑梗死后有肠道菌群紊乱并激活系统性炎症反应。提示脑梗死后可由肠道菌群紊乱、GABA代谢改变和炎症反应激活，致下丘脑GABA能神经元继发性损害而引起失眠。由于临床研究难于探索机制，啮齿类动物脑、睡眠和肠道菌群特征与人类不同，而非人灵长类动物更接近人类，因此，本项目拟动态评估食蟹猴脑梗死后睡眠-觉醒节律、肠道菌群、GABA代谢、炎症反应以及下丘脑GABA能神经元继发性结构和功能损害的关系；然后移植健康肠道菌群，观察其改善失眠和下丘脑GABA能神经元继发性损害作用。该为阐明脑梗死后失眠发生机制、探讨治疗新靶点和从源头进行干预提供实验依据。

The incidence of insomnia after cerebral infarction is high and affects prognosis, but the mechanism remains unclear and there is no effective intervention. The study found that insomnia after traumatic brain injury is related to the secondary inflammation in the uninjured hypothalamus. Gut microbiota dysbiosis plays an important role in cerebral GABA metabolism and systemic inflammatory response. Our previous research and published articles confirmed that cerebral infarction can cause secondary damage in the non-ischemic area of the brain. The pilot experiment of this projects found that there was gut microbiota dysbiosis after cerebral infarction and activated systemic inflammatory response. It suggests that cerebral infarction can cause secondary damage to hypothalamic GABAergic neurons and cause insomnia by gut microbiota dysbiosis, GABA metabolism and inflammatory reaction activation. Clinical research is difficult to explore the mechanism. Brain structure, sleep and gut microbiota of rodents are distinct from humans. Non-human primates share more similarities with humans in terms of brain structure, sleep and gut microbiota. Therefore, this project aims to dynamically assess sleep-wake rhythm, gut microbiota, GABA metabolism, inflammatory response, as well as secondary structural and functional impairment of GABAergic neurons in the hypothalami after cerebral infarction in cynomolgus monkeys. Then, healthy gut microbiota from healthy monkeys are transplanted to the monkeys with cerebral infarction to ameliorate insomnia and secondary hypothalamic GABAergic neurons damage. The results provide an experimental basis for elucidating the mechanism of insomnia after cerebral infarction, exploring new targets for treatment and intervention from the source, and are value for clinical translation.