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Per2 在中枢炎性免疫诱导的抑郁样行为中的作用
Alternative TitleThe role of Per2 in depressive-like behavior induced by neuroinflammation
Abstract脂多糖(lipopolysaccharide ,LPS)免疫激活模型是研究抑郁症细胞因子假说的重要动物模型,目前国际上常用外周单次LPS 注射诱发抑郁样行为,但该模型中抑郁样行为一般仅持续数小时。为建立一种稳定的较长时程免疫激活抑郁动物模型,我们实验室以大鼠为模型,侧脑室重复LPS 注射激活中枢炎性反应,最终诱导超过24h 的抑郁样行为。有文献报道Per2Brdm1 小鼠能够抵抗LPS 的致炎性效应,但其分子机制仍不清楚。本研究结合上述两点,探讨核心钟基因Per2在中枢炎性免疫诱导的抑郁样行为中的作用。
本研究包括以下五个实验。实验一:为研究LPS 诱发小鼠抑郁样行为是否具有节律性,我们分别在ZT10/18 给野生型小鼠和Per2Brdm1 小鼠外周注射LPS,以强迫游泳不动时间为观察行为指标。结果显示LPS 诱发的抑郁样行为不存在昼夜节律,Per2Brdm1 小鼠能够抵抗LPS 的致抑郁效果。实验二:为建立稳定的较长时程免疫激活动物模型,重复中枢LPS 注射诱发小鼠抑郁样行为,以体重变化、自发活动、高架十字迷宫、强迫游泳和悬尾测试等结果为观察指标。重复中枢LPS 注射后24h 诱发小鼠体重减轻、自发活动和探索行为减少、强迫游泳和悬尾测试不动时间增加等行为。这些结果表明,脑室重复LPS 注射可诱发小鼠较长时程的抑郁样行为。实验三:为研究Per2 基因在中枢炎症反应中的作用,以Per2Brdm1 小鼠为模型,重复中枢LPS 注射。各项行为结果显示,Per2Brdm1 小鼠能够抵抗中枢LPS 的致抑郁效应。实验四:为进一步探讨Per2 基因影响抑郁样行为的分子机制,利用高效液相芯片技术和Westernblot 等技术,检测野生型小鼠和Per2Brdm1 小鼠海马中细胞因子的表达。结果显示,野生型小鼠实验组中枢注射LPS 后趋化因子CCL5、CCL4、CCL2 含量上升,Per2Brdm1 小鼠实验组没有明显变化。TNF-α 表达在野生型和Per2Brdm1 小鼠实验组间存在差异。实验五:为进一步探讨中枢LPS 的致抑郁效应是否是TLR4 依赖的,检测TLR4 (-/-)小鼠中枢重复LPS 注射的抑郁和焦虑行为,结果发现TLR4 (-/-)可以抵抗重复LPS 注射的导致的抑郁样行为,提示LPS 的这些效应是TLR4 依赖的,但Per2 是否是通过TLR 发挥作用还需要进一步地研究。
综上所述:趋化因子CCL5、CCL4、CCL2 可能是中枢免疫激活诱发小鼠抑郁样行为的重要调控因子。Per2 基因可能在介导这些趋化因子的产生中发挥重要作用。
Other AbstractThe administration of lipopolysaccharide(LPS),is commonly-used method to cause immune activation and the release of cytokines both in the periphery and in the brain in rodents. The cytokine theory of depression indicated that pro-inflammatory cytokines play an important role in the pathological mechanism of depression. Many studies used the peripheral administration of LPS to induce depressive-like behavior .However, in these studies, the altered behaviors usually last only a few hours. A new model of depression with apparent depressive-like behavior was developed after 24h post-LPS injection based on the rat. Triple central LPS administration was used to induce depressive-like behavior. It was reported Per2Brdm1
mice displayed a down-regulated circadian immune response to lipopolysaccharide (LPS) challenge. The aim of the present study was to investigate the role of Per2 in depressive-like behavior induced by neuroinflammation .
The following experiments were carried out in the investigation. In experiment 1, we investigated the circadian characteristics of immobility behavior in wild type (WT) mice and Per2Brdm1 mice injected by LPS at ZT10/18.The depressive-like behavior induced by LPS showed no circadian rhythm. The Per2Brdm1 mice were more resistant to lipopolysaccharide (LPS)-induced endotoxic shock than control wild-type mice. In experiment 2,the aim was to develop a new model of depression with apparent depressive-like behavior post LPS injection based on the wild type mice. Triple central LPS or saline was administered by intracerebroventricular microinjection. The animals with triple LPS exhibited less locomotor activity, less exploring activity, maintained more immobility time in forced swimming test and tail suspense test. In experiment 3, to investigate the role of Per2 in depressive-like behavior induced by neuroinflammation , the Per2Brdm1mice accepted triple LPS or saline administration by intracerebroventricular microinjection. The LPS group showed no significant difference compared to control group in those behavior tests. In experiment 4, to explore the underlying mechanism of Per2 in depressive-like behavior, we tested 24 cytokines expression in the hippocampus.CCL5、CCL4、CCL2 were higher in LPS group of wild type mice compared to control group . there was significant difference of TNF-α expression between the wild type and Per2Brdm1.In experiment 5,to verify the relationship between Per2 and TLR4, the TLR4(-/-) mice was administered triple LPS by intracerebroventricular microinjection,too. While the animals showed no anxiety-like and depressive-like behavior.
In conclusion, the chemokines of CCL5,CCL4,CCL2 may be important mediators in the chronic immune activation.Per2 is likely play an important role in the central immune activation.
Subject Area医学心理学
Degree Discipline心理学
Degree Grantor中国科学院研究生院
Place of Conferral北京
Document Type学位论文
Recommended Citation
GB/T 7714
陈小娟. Per2 在中枢炎性免疫诱导的抑郁样行为中的作用[D]. 北京. 中国科学院研究生院,2016.
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