BACKGROUND Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. METHODS Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. RESULTS The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. CONCLUSIONS Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure.

中文翻译：

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小胶质细胞 RAGE 的持续增加导致慢性压力诱发抑郁样行为

背景慢性应激诱导的炎症反应部分通过危险相关分子模式 (DAMP) 分子发生，例如高迁移率族框 1 蛋白 (HMGB1)，但尚未鉴定出 DAMP 信号传导背后的受体。方法 在慢性不可预测压力 (CUS) 诱导的行为缺陷（包括 CUS 后的长期持续变化）的发展和表达过程中，检查了富集的大鼠海马小胶质细胞中的小胶质细胞形态和 DAMP 信号传导。结果 结果表明，CUS 促进了显着的形态变化，并导致富集的海马小胶质细胞中 HMGB1 信使 RNA 的强烈上调，这种作用在 CUS 暴露后持续长达 6 周。这与晚期糖基化终产物 (RAGE) 信使 RNA 受体的稳健和持续上调相吻合，但不是海马小胶质细胞中的 toll 样受体 4。通过流式细胞术测定，CUS 还增加了海马小胶质细胞上 RAGE 蛋白的表面表达，并在 CUS 后 5 周恢复到基础水平。重要的是，暴露于短期压力足以增加 RAGE 表面表达以及快感行为，反映了 RAGE 信使 RNA 表达持续增加导致的启动状态。行为反应中 DAMP 信号传导的进一步证据是，HMGB1 注入海马体足以引起快感缺失行为的证据，以及 RAGE 基因敲除小鼠对压力引起的快感缺乏有弹性的证据。结论 一起，