Notch信号通路在婴幼儿期七氟烷麻醉所致神经发生抑制中的作用研究

With the developments of the surgical technology and interventional therapies, the number of the cases using general anesthesia in children has been increased in recent years. However, several retrospective clinical studies revealed that children exposed to general anesthesia in early life have a higher incidence of learning deficits and abnormal social behaviors in their adolescence. The postnatal growth peak of the central nervous system is in the early childhood, during which the neurogenesis is much more active than during adult hood. As postnatal hippocampal neurogenesis is vital for learning and memory process, and recent studies suggest that inhaled anesthetics such as isoflurane and sevoflurane exposure inhibited hippocampal neurogenesis in infantile animals, it is reasonable to conclude that the learning deficits occurring after general anesthesia is due to the effect of anesthetics on hippocampal neurogenesis. Since Notch pathway is generally known to regulate neurogenesis, which is also involved in learning and memory process, we hypothesized that the reduced Notch signal after anesthesia in infantile mice is important for the inhibition of hippocampal neurogenesis as well as the declined learning ability in their later life. The results of our preliminary experiment revealed that long but not short term exposure of sevoflurane (the most commonly used inhaled anesthetic in pediatric anesthesia) reduced the self-renew ability of cultured hippocampal neural stem cells. The expression of NICD and Hes1 in hippocampus of the postnatal 7 day mice decreased at 24h after 6h sevoflurane anesthesia, indicating Notch signal is inhibited in the immature rodent brain after sevoflurane anesthesia for a long period. Therefore, the current study is designed to investigate whether and how Notch pathway is involved in the hippocampal neurogenesis inhibition after sevoflurane anesthesia in the immature brain by using behavioral test, morphological, electro physiological and gene regulation methods.

随着手术和介入治疗的不断发展，婴幼儿全身麻醉的比例逐年增加。新近报道婴幼儿接受全麻数年后可能导致学习、记忆能力下降和社会行为改变，敲响了婴幼儿全麻安全性的警钟，引起全社会广泛关注。婴幼儿期是神经系统发育的关键时期，文献报道全麻药可能影响早期神经发育而产生迟发的学习记忆障碍，但其具体机制不明。Notch通路是调控神经发生的经典通路，并参与了学习、记忆形成过程。我们前期的实验显示：吸入麻醉剂七氟烷长时间暴露可降低海马神经干细胞的自我更新能力；新生小鼠吸入七氟烷后，海马的Notch1受体胞内活化片断和靶基因Hes1的表达明显降低。因而我们推测：七氟烷通过抑制Notch通路，进而影响海马的神经发生是其导致学习、记忆能力下降的关键机制。本研究拟运用行为学、免疫组化、电生理和基因调控等技术验证上述假说，为探索改善全麻后学习、记忆能力下降的应对策略，寻找药物干预靶点提供新的思路。

随着手术和介入治疗的不断发展，婴幼儿全身麻醉的比例逐年增加。新近报道婴幼儿接受全麻数年后可能导致学习、记忆能力下降和社会行为改变，敲响了婴幼儿全麻安全性的警钟，引起全社会广泛关注。婴幼儿期是神经系统发育的关键时期，文献报道全麻药可能影响早期神经发育而产生迟发的学习记忆障碍，但其具体机制不明。Notch通路是调控神经发生的经典通路，并参与了学习、记忆形成过程。我们前期的实验显示：吸入麻醉剂七氟烷长时间暴露可降低海马神经干细胞的自我更新能力；新生大鼠吸入七氟烷后，海马的Notch1受体胞内活化片断和靶基因Hes1的表达明显降低。因而我们推测：七氟烷通过抑制Notch通路，进而影响海马的神经发生是其导致学习、记忆能力下降的关键机制。本研究显示：1） 幼年大鼠长时程七氟醚麻醉后学习、记忆能力降低, 短时程麻醉无影响；2）幼年大鼠七氟醚长时程麻醉后海马神经发生受到抑制,短时程无明显影响；3）七氟醚麻醉后Notch1 和Hes5 mRNA 明显下降，长时程吸入组下降更为明显；4）幼年大鼠长时七氟醚麻醉后过表达NICD 可减轻海马神经发生抑制和成长后的记忆受损。