TNF signaling pathway-mediated microglial activation in the PFC underlies acute paradoxical sleep deprivation-induced anxiety-like behaviors in mice

• Published in: Brain, behavior, and immunity behavior, and immunity, 2022-02, Vol.100, p.254-266
• Main Authors: Liu, Haiying, Huang, Xin, Li, Yaohao, Xi, Kaiwen, Han, Yiting, Mao, Honghui, Ren, Keke, Wang, Wenting, Wu, Zhongliang
• Format: Article
• Language: English
• Subjects: Animals; Anxiety - metabolism; Anxiety-like behavior; Bioinformatics analysis; Mice; Microglia; Microglia - metabolism; Neuro-inflammatory; Prefrontal Cortex - metabolism; Signal Transduction; Sleep deprivation; Sleep Deprivation - complications; Sleep Deprivation - metabolism; Sleep, REM
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2021.12.006

•6 h of acute paradoxical sleep deprivation induced significant anxiety-like behaviors in mice.•key genes from the TNF signaling pathway are involved in acute sleep deprivation.•Microglial cells in the prefrontal cortex were activated through Ptgs2.•Minocycline administration ameliorates anxiety through Ptgs2-labelled microglia. Acute sleep deprivation is a common condition in modern life and increases anxiety symptoms in healthy individuals. The neuroinflammatory response induced by microglial activation could be an important contributing factor, but its underlying molecular mechanisms are still unclear. In the present study, we first found that acute paradoxical sleep deprivation (PSD) induced by the modified multiple platform method (MMPM) for 6 h led to anxiety-like behavior in mice, as verified by the open field test, elevated plus maze test, light–dark box test, and marble burying test. In addition, bioinformatic analysis suggested an important relationship between acute sleep deprivation and brain inflammatory signaling pathways. Key genes enriched in the TNF signaling pathway were confirmed to be altered during acute PSD by qPCR and Western blot analyses, including the upregulation of the prostaglandin-endoperoxide synthase 2 (Ptgs2) and suppressor of cytokine signaling 3 protein (Socs3) genes and the downregulation of the cysteine-aspartic acid protease 3 (Casp3) gene. Furthermore, we found that microglial cells in the prefrontal cortex (PFC) were activated with significant branch structure changes and that the cell body area was increased in the PSD model. Finally, we found that minocycline, a tetracycline with anti-inflammatory properties, may ameliorate the anxiogenic effect and microglial activation. Our study reveals significant correlations of anxiety-like behavior, microglial activation, and inflammation during acute PSD.