增强反应性星形胶质细胞Wnt/β-catenin信号改善小鼠脑创伤后焦虑

Enhancing Wnt/β-catenin signaling in reactive astrocytes attenuates anxiety induced by traumatic brain injury in mice

目的:探索脑创伤(TBI)后焦虑的发生机制及干预策略。从星形胶质细胞中Wnt/β-catenin信号活化的角度探索脑创伤后焦虑的分子机制,并通过调节Wnt/β-catenin信号探索干预策略。方法:采用可控性颅脑打击模型(CCI)制作小鼠颅脑冲击伤。利用旷场、高架十字迷宫法研究小鼠颅脑创伤后焦虑的发生;采用Wnt信号报告基因Topgal小鼠、免疫组化、TUNEL染色、Western Blot等方法研究Wnt信号及细胞凋亡的改变;利用Nestin-CreER:β-catenin EX3^(loxp/+)(Nestin-CreER/EX3)基因修饰小鼠研究条件性激活反应性星形胶质细胞中的Wnt信号对脑创伤后细胞凋亡及小鼠焦虑行为的影响。结果:与正常对照组小鼠相比,CCI组小鼠在脑创伤后2周出现明显焦虑样行为。Wnt信号报告基因β-gal在损伤区星形胶质细胞表达上调。采用Nestin-CreER/EX3基因修饰小鼠,在CCI损伤后激活Wnt信号,可显著减轻损伤区的细胞凋亡,并改善小鼠的焦虑行为。结论:脑创伤可激活反应性星形胶质细胞中Wnt/β-catenin信号并可减轻CCI后的细胞凋亡,改善小鼠的焦虑行为。

Objective:This study is aimed to investigate the possible mechanisms and corresponding interference for traumatic brain injury(TBI)induced anxiety from the viewpoint of Wnt/β-catenin signaling in reactive astrocytes.Methods:TBI was made using controlled cortical impact(CCI)model.Open field tests and elevated plus maze tests were adopted to evaluate the development of anxiety post TBI.Wnt signaling reporting transgenic mouse line Topgal mice,immunohistochemistry,Western Blot and TUNEL staining were adopted to read out Wnt signaling and assess apoptosis.Nestin-CreER:β-catenin EX3^(loxp/+)(Nestin-CreER/EX3)mice were adopted to evaluate the effects of conditioned activation of Wnt signaling in reactive astrocytes on apoptosis and anxiety following TBI.Results:In comparison with control mice,CCI-treated mice showed obvious anxiety-like behaviors at 14 days post injury.The expression of Wnt signaling reporter gene,β-gal,was up-regulated in reactive astrocytes around lesion site.Over-activating Wnt/β-catenin signaling in Nestin-CreER/EX3 mice after CCI significantly reduced apoptosis in the lesion area and attenuated the anxiety-like behaviors.Conclusion:TBI activates Wnt/β-catenin signaling in reactive astrocytes and reduces apoptosis and attenuates anxiety of mice.