The Influence of Microglial Elimination and Repopulation on Stress Sensitization Induced by Repeated Social Defeat
The Influence of Microglial Elimination and Repopulation on Stress Sensitization Induced by Repeated Social Defeat
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DOI：
10.1016/j.biopsych.2018.10.009
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发表时间：
2019-04-15
影响因子：
10.6
通讯作者：
Godbout, Jonathan P.
中科院分区：
文献类型：
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作者：
Weber, Michael D.;McKim, Daniel B.;Godbout, Jonathan P.
背景：压力与焦虑和抑郁的患病率增加有关。小鼠的反复社交失败（RSD）压力会增加骨髓中单核细胞的释放，这些单核细胞被小胶质细胞招募到大脑。这些单核细胞增强炎症信号并加剧焦虑。此外，RSD 会促进压力敏化，停止 RSD 24 天后暴露于急性压力会导致焦虑复发。本研究的目的是确定小胶质细胞是否对应激敏化至关重要，并表现出对随后的急性应激或免疫挑战的反应性增加。 方法：将小鼠暴露于 RSD，小胶质细胞被集落刺激因子 1 受体拮抗剂 (PLX5622) 消除并允许重新增殖，并在 RSD 敏化后 24 天测定对急性应激或免疫挑战（脂多糖）的反应。 结果：小胶质细胞保持了独特的RSD 后 24 天的信使 RNA 签名。此外，消除 RSD 敏感的小胶质细胞可以防止单核细胞在大脑中积聚，并阻止急性应激（24 天）后焦虑的复发。当小胶质细胞在 RSD 之前被消除并重新增殖并且小鼠受到急性应激时，RSD 致敏小鼠的大脑中会出现单核细胞积聚和焦虑。这些反应不受小胶质细胞消除/再增殖的影响。这可能与 RSD 后持续 24 天的神经元敏化有关。免疫攻击后，RSD 致敏小鼠中存在与长期患病行为相关的强烈小胶质细胞反应性。在这里，小胶质细胞消除/再增殖阻止了 RSD 致敏小鼠体内和体外放大的免疫反应性。结论：小胶质细胞和神经元在 RSD 后数周仍保持致敏，并且只有 RSD 致敏小胶质细胞的免疫反应成分通过消除/再增殖而被阻止。
BACKGROUND: Stress is associated with an increased prevalence of anxiety and depression. Repeated social defeat (RSD) stress in mice increases the release of monocytes from the bone marrow that are recruited to the brain by microglia. These monocytes enhance inflammatory signaling and augment anxiety. Moreover, RSD promotes stress sensitization, in which exposure to acute stress 24 days after cessation of RSD causes anxiety recurrence. The purpose of this study was to determine whether microglia were critical to stress sensitization and exhibited increased reactivity to subsequent acute stress or immune challenge.METHODS: Mice were exposed to RSD, microglia were eliminated by colony-stimulating factor 1 receptor antagonism (PLX5622) and allowed to repopulate, and responses to acute stress or immune challenge (lipopolysaccharide) were determined 24 days after RSD sensitization.RESULTS: Microglia maintained a unique messenger RNA signature 24 days after RSD. Moreover, elimination of RSD-sensitized microglia prevented monocyte accumulation in the brain and blocked anxiety recurrence following acute stress (24 days). When microglia were eliminated prior to RSD and repopulated and mice were subjected to acute stress, there was monocyte accumulation in the brain and anxiety in RSD-sensitized mice. These responses were unaffected by microglial elimination/repopulation. This may be related to neuronal sensitization that persisted 24 days after RSD. Following immune challenge, there was robust microglial reactivity in RSD-sensitized mice associated with prolonged sickness behavior. Here, microglial elimination/repopulation prevented the amplified immune reactivity ex vivo and in vivo in RSD-sensitized mice.CONCLUSIONS: Microglia and neurons remain sensitized weeks after RSD, and only the immune reactivity component of RSD-sensitized microglia was prevented by elimination/repopulation.