AI Article Synopsis
- Sleep deprivation (SD) leads to hippocampal microglia activation and inflammation, which can impair learning and memory; however, the exact mechanisms behind this damage are not fully understood.
- In this study, researchers hypothesized that Topoisomerase 1 (TOP1) could play a role in SD-induced microglial activation and neuronal damage, based on the observed increase in TOP1 levels in the hippocampus of SD mice.
- Experiments using TOP1 knockout mice demonstrated that reducing TOP1 in microglia lessened inflammatory responses and neuronal damage, suggesting TOP1 mediates the release of harmful inflammatory factors like IL-6 during sleep deprivation.
Article Abstract
Introduction: 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.
Objectives: 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.
Conclusion: The present study reveals that TOP1-mediated microglial activation is critical for SD induced hippocampal neuronal damage and behavioral impairments.
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| http://dx.doi.org/10.1016/j.jare.2024.07.017 | DOI Listing |
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