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李慧娟, 苏玺, 张露文, 张楚祎, 王路, 李文强, 杨勇锋, 吕路线, 李明, 肖潇. 2020: 基于人与小鼠大脑转录组的抑郁症机制解析. 动物学研究, 41(6): 632-643. DOI: 10.24272/j.issn.2095-8137.2020.174
引用本文: 李慧娟, 苏玺, 张露文, 张楚祎, 王路, 李文强, 杨勇锋, 吕路线, 李明, 肖潇. 2020: 基于人与小鼠大脑转录组的抑郁症机制解析. 动物学研究, 41(6): 632-643. DOI: 10.24272/j.issn.2095-8137.2020.174
Hui-Juan Li, Xi Su, Lu-Wen Zhang, Chu-Yi Zhang, Lu Wang, Wen-Qiang Li, Yong-Feng Yang, Lu-Xian Lv, Ming Li, Xiao Xiao. 2020: Transcriptomic analyses of humans and mice provide insights into depression. Zoological Research, 41(6): 632-643. DOI: 10.24272/j.issn.2095-8137.2020.174
Citation: Hui-Juan Li, Xi Su, Lu-Wen Zhang, Chu-Yi Zhang, Lu Wang, Wen-Qiang Li, Yong-Feng Yang, Lu-Xian Lv, Ming Li, Xiao Xiao. 2020: Transcriptomic analyses of humans and mice provide insights into depression. Zoological Research, 41(6): 632-643. DOI: 10.24272/j.issn.2095-8137.2020.174

基于人与小鼠大脑转录组的抑郁症机制解析

Transcriptomic analyses of humans and mice provide insights into depression

  • 摘要: 近年来,累积研究针对抑郁症风险基因与相关生物学机制展开了探索,其中,利用抑郁症有关认知和情感调控相关脑区(例如背外侧前额叶皮层)转录组数据开展的测序分析提供了大量重要信息。该研究基于三个相互独立的背外侧前额叶皮层脑组织RNA测序数据(79例抑郁症患者及75例健康对照),采用两种不同的方法分析了在抑郁症患者大脑中相对健康个体显著差异表达的基因。同时,本研究亦针对受到慢性可变压力或慢性社会失败压力刺激的小鼠大脑转录组进行了分析,寻找它们脑中相对无刺激处理小鼠或压力抗性小鼠差异表达的基因。最终,我们鉴定到12个通过两种方法均证实在抑郁症患者脑中相对健康个体显著差异表达的基因,且其中的大部分基因在压力刺激小鼠脑中也出现了相对无刺激处理小鼠或压力抗性小鼠的显著表达差异。值得注意的是,一个即刻反应基因FOS 在抑郁症患者与慢性可变压力刺激小鼠中表达均显著降低,且在慢性社会失败压力小鼠中相比压力抗性小鼠出现了更大的降低幅度。因此,这个基因很可能在压力刺激有关的抑郁症发生机制中起到重要作用,亦表明抑郁症患者背外侧前额叶皮层中转录组的部分改变可能是压力刺激的结果,证实压力是抑郁症的一个重要风险因素。

     

    Abstract: Accumulating studies have been conducted to identify risk genes and relevant biological mechanisms underlying major depressive disorder (MDD). In particular, transcriptomic analyses in brain regions engaged in cognitive and emotional processes, e.g., the dorsolateral prefrontal cortex (DLPFC), have provided essential insights. Based on three independent DLPFC RNA-seq datasets of 79 MDD patients and 75 healthy controls, we performed differential expression analyses using two alternative approaches for cross-validation. We also conducted transcriptomic analyses in mice undergoing chronic variable stress (CVS) and chronic social defeat stress (CSDS). We identified 12 differentially expressed genes (DEGs) through both analytical methods in MDD patients, the majority of which were also dysregulated in stressed mice. Notably, the mRNA level of the immediate early gene FOS (Fos proto-oncogene) was significantly decreased in both MDD patients and CVS-exposed mice, and CSDS-susceptible mice exhibited a greater reduction in Fos expression compared to resilient mice. These findings suggest the potential key roles of this gene in the pathogenesis of MDD related to stress exposure. Altered transcriptomes in the DLPFC of MDD patients might be, at least partially, the result of stress exposure, supporting that stress is a primary risk factor for MDD.

     

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