背景:睡眠不足(SD)是现代社会中常见的疾病。海马是大脑学习的重要区域,记忆,和情感。海马功能障碍可导致严重的学习记忆障碍,显著影响生活质量。SD伴随着海马小胶质细胞的激活和炎症因子的激增,但确切的机制尚不清楚。此外,关于SD中激活的小胶质细胞如何导致神经元损伤的持续未知。拓扑异构酶1(TOP1)在炎症过程中起着至关重要的作用,包括肿瘤系统和病毒感染。在这项研究中,我们观察到接受SD的小鼠海马中TOP1水平显着升高。因此,我们假设TOP1可能与SD诱导的小胶质细胞激活和神经元损伤有关.
目的:研究TOP1在SD诱导的小胶质细胞活化中的作用,神经元损伤,和神经行为障碍,以及SD诱导的TOP1水平升高的分子基础。
方法:使用小胶质细胞中的TOP1特异性敲除小鼠来研究TOP1对小胶质细胞活化和神经元损伤的影响。转录因子预测,RNA干扰,ChIP-qPCR,ChIP-seq数据库分析,并进行荧光素酶报告基因测定以探索YY1转录激活的分子机制。非靶向代谢谱用于研究YY1转录激活的物质基础。
结果:海马小胶质细胞中TOP1的敲低可改善SD诱导的小胶质细胞活化,炎症反应,和神经元损伤。机械上,TOP1介导小胶质细胞释放IL-6,从而导致神经元功能障碍。此外,SD导致的TOP1升高与新蝶呤相关,这归因于其通过破坏YY1和HDAC1的结合而促进TOP1启动子区域中H3K27ac水平升高。
结论:本研究表明,TOP1介导的小胶质细胞活化对SD诱导的海马神经元损伤和行为障碍至关重要。
BACKGROUND: Sleep deprivation (SD) is a common disorder in modern society. Hippocampus is an important region of the brain for learning, memory, and emotions. Dysfunction of hippocampus can lead to severe learning and memory disorder, significantly affecting quality of life. SD is accompanied by hippocampal microglia activation and a surge in inflammatory factors, but the precise mechanism remains unclear. Moreover, the ongoing unknown persists regarding how activated microglia in SD lead to neuronal damage. Topoisomerase 1 (TOP1) plays an essential role in the inflammatory process, including the tumor system and viral infection. In this study, we observed a significant elevation in TOP1 levels in the hippocampus of mice subjected to SD. Therefore, we hypothesize that TOP1 may be implicated in SD-induced microglia activation and neuronal damage.
OBJECTIVE: To investigate the role of TOP1 in SD-induced microglial activation, neuronal damage, and neurobehavioral impairments, and the molecular basis of SD-induced elevated TOP1 levels.
METHODS: TOP1-specific knockout mice in microglia were used to study the effects of TOP1 on microglial activation and neuronal damage. Transcription factor prediction, RNA interference, ChIP-qPCR, ChIP-seq database analysis, and luciferase reporter assays were performed to explore the molecular mechanisms of YY1 transcriptional activation. Untargeted metabolic profiling was employed to investigate the material basis of YY1 transcriptional activation.
RESULTS: Knockdown of TOP1 in hippocampal microglia ameliorates SD-induced microglial activation, inflammatory response, and neuronal damage. Mechanistically, TOP1 mediates the release of IL-6 from microglia, which consequently leads to neuronal dysfunction. Moreover, elevated TOP1 due to SD were associated with neopterin, which was attributed to its promotion of elevated levels of H3K27ac in the TOP1 promoter region by disrupting the binding of YY1 and HDAC1.
CONCLUSIONS: The present study reveals that TOP1-mediated microglial activation is critical for SD induced hippocampal neuronal damage and behavioral impairments.