Wnt/β-catenin信号介导的小鼠海马神经元发生参与睡眠剥夺引起的学习记忆下降
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摘要
目的:研究睡眠剥夺对小鼠行为及海马神经元发生的影响。从Wnt/β-catenin信号的角度探索其相关的分子机制,以及干预Wnt/β-catenin信号的改善作用。方法:采用改良多平台水环境法制作小鼠睡眠剥夺模型(SD)。利用Brd U/DCX免疫荧光双标研究海马神经元发生;采用Wnt信号报告基因Topgal小鼠研究Wnt信号的改变;利用Nestin/ROSA/EX3基因修饰小鼠研究激活Wnt信号对睡眠剥夺小鼠海马神经元发生及学习记忆的影响;采用高架十字迷宫和旷场实验评估小鼠的焦虑情绪;运用Morris水迷宫评估小鼠的空间学习记忆能力。结果:与正常小鼠相比,SD处理组小鼠无焦虑样行为,但空间学习记忆能力显著下降。Brd U/DCX免疫荧光双标染色显示SD 5 d后小鼠海马神经元发生明显减弱。Wnt信号报告基因β-gal在海马神经干细胞表达降低。在Nestin/ROSA/EX3基因修饰小鼠激活Wnt信号后,可显著促进海马神经元发生,并改善SD小鼠的空间记忆能力。结论:Wnt/β-catenin信号参与睡眠剥夺引起的小鼠海马神经元发生减弱,增强Wnt信号可改善SD小鼠海马的神经元发生及其学习记忆能力。
Objective: This study is aimed to investigate the effects of sleep-deprivation( SD) on mouse behavior and hippocampal neurogenesis,explore the underlying mechanism from the viewpoint of Wnt/β-catenin signaling,and attenuate the impairment by interfering Wnt/β-catenin signaling. Methods: Sleep-deprivation was achieved by a modified water-platform environment. Neurogenesis was assessed by double-immunostaining of Brd U/DCX. Wnt signaling was read out by Wnt signaling reporting transgenic mouse line Topgal mice. Nestin-CreER: ROSA-YFP: β-catenin EX3~(loxp/+)mice were adopted to evaluate the effects of activating Wnt signaling on neurogenesis and learning and memory. Anxiety was evaluated by open field assay and elevated plus assay. Spatial memory was examined by Morris water maze test. Results: In comparison with control mice,SD mice showed significantly lower level of memory ability,but no change of anxiety. Brd U/DCX double-immunostaining showed that the number of new-born neurons was significantly decreased in the hippocampus of mice at 5 days after sleep-deprivation. The expression of Wnt signaling reporter gene,β-gal,was decreased in the hippocampal neural stem cells in SD mice. Over-expressing β-catenin in the adult neural progenitor cells of SD mice significantly stimulated neurogenesis and the learning ability of mice. Conclusion:Wnt/β-catenin signaling mediated mouse hippocampal neurogenesis is involved in sleep-deprivation induced memory impairment.
Objective: This study is aimed to investigate the effects of sleep-deprivation( SD) on mouse behavior and hippocampal neurogenesis,explore the underlying mechanism from the viewpoint of Wnt/β-catenin signaling,and attenuate the impairment by interfering Wnt/β-catenin signaling. Methods: Sleep-deprivation was achieved by a modified water-platform environment. Neurogenesis was assessed by double-immunostaining of Brd U/DCX. Wnt signaling was read out by Wnt signaling reporting transgenic mouse line Topgal mice. Nestin-CreER: ROSA-YFP: β-catenin EX3~(loxp/+)mice were adopted to evaluate the effects of activating Wnt signaling on neurogenesis and learning and memory. Anxiety was evaluated by open field assay and elevated plus assay. Spatial memory was examined by Morris water maze test. Results: In comparison with control mice,SD mice showed significantly lower level of memory ability,but no change of anxiety. Brd U/DCX double-immunostaining showed that the number of new-born neurons was significantly decreased in the hippocampus of mice at 5 days after sleep-deprivation. The expression of Wnt signaling reporter gene,β-gal,was decreased in the hippocampal neural stem cells in SD mice. Over-expressing β-catenin in the adult neural progenitor cells of SD mice significantly stimulated neurogenesis and the learning ability of mice. Conclusion:Wnt/β-catenin signaling mediated mouse hippocampal neurogenesis is involved in sleep-deprivation induced memory impairment.
引文
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[3]Gerhardsson A,Akerstedt T,Axelsson J,et al.Effect of sleep deprivation on emotional working memory[J].J Sleep Res,2018:p.e12744.DOI:10.1111/jsr.12744.
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[5]Cheng O,Li R,Zhao L,et al.Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion[J].PLo S One,2015.10(6):p.e0125877.DOI:10.1371/journal.pone.0125877.
[6]Chauhan G,Ray K,Sahu S,et al.Adenosine A1 receptor antagonist mitigates deleteriouseffects of sleep deprivation on adult neurogenesis and spatial reference memory in rats[J].Neuroscience,2016.337:p.107-116.DOI:10.1016/j.neuroscience.2016.09.007.
[7]Al-Harthi L.Wnt/beta-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders[J].J Neuroimmune Pharmacol,2012.7(4):p.725-30.DOI:10.1007/s11481-012-9412-x.
[8]Marchetti B.Wnt/beta-catenin signaling pathway governs a full program for dopaminergic neuron survival,neurorescue and regeneration in the MPTP mouse model of Parkinson’s Disease[J].Int J Mol Sci,2018.19(12).DOI:10.3390/ijms19123743.
[9]Qu Z,Su F,Qi X,et al.Wnt/beta-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy[J].Cell Biochem Funct,2017.35(7):p.472-476.DOI:10.1002/cbf.3306.
[10]Lie DC,Colamarino SA,Song HJ,et al.Wnt signalling regulates adult hippocampal neurogenesis[J].Nature,2005.437(7063):p.1370-5.DOI:10.1038/nature04108.
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[14]Alzoubi KH,Mayyas FA,Khabour OF,et al.Chronic melatonin treatment prevents memory impairment induced by chronic sleep deprivation[J].Mol Neurobiol,2016.53(5):p.3439-3447.DOI:10.1007/s12035-015-9286-z.
[15]Kreutzmann JC,Havekes R,Abel T,et al.Sleep deprivation and hippocampal vulnerability:changes in neuronal plasticity,neurogenesis and cognitive function[J].Neuroscience,2015.309:p.173-90.DOI:10.1016/j.neuroscience.2015.04.053.
[16]Cooper LN,Mishra I,Ashley NT.Short-term sleep loss alters cytokine gene expression in brain and peripheral tissues and increases plasma corticosterone of zebra finch(Taeniopygia guttata)[J].Physiol Biochem Zool,2019.92(1):p.80-91.DOI:10.1086/701170.
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