Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.
Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.
复制标题
DOI：
10.1016/j.biopsych.2017.06.034
复制
发表时间：
2018-01-01
影响因子：
10.6
通讯作者：
Duman RS
中科院分区：
文献类型：
--
作者：
Franklin TC;Wohleb ES;Zhang Y;Fogaça M;Hare B;Duman RS
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，如HMGB1，但潜在的DAMP信号传导受体尚未确定。在慢性不可预测应激（CUS）诱导的行为缺陷的发育和表达过程中，包括CUS后长期持续的变化，研究了富集的大鼠海马小胶质细胞的DAMP信号和小胶质细胞形态学。结果表明，CUS可促进海马小胶质细胞显著的形态学改变，并引起HMGB1 mRNA的强烈上调，这种影响在暴露于CUS后持续长达6周。这与海马小胶质细胞中晚期糖基化终产物受体（RAGE） mRNA的强劲和持续上调相一致，而不是toll样受体4 （TLR4）。流式细胞术检测小鼠海马小胶质细胞表面RAGE蛋白表达增加，5周后恢复到基础水平。重要的是，暴露于短期应激足以增加RAGE表面表达和快感缺乏行为，这反映了RAGE mRNA表达持续增加所导致的启动状态。进一步的证据表明，海马HMGB1输注足以引起快感缺乏行为，并且RAGE KO小鼠对应激性快感缺乏具有弹性，这为行为反应中的DAMP信号传导提供了证据。总之，这些结果提供了持续的小胶质HMGB1-RAGE表达的证据，表明慢性应激暴露后长时间增加了抑郁样行为的易感性。
Chronic stress-induced inflammatory responses occur in part via danger associated molecular pattern (DAMP) molecules, such as HMGB1 but the receptor(s) underlying DAMP signaling have not been identified. DAMP signaling and microglia morphology were examined in enriched rat hippocampal microglia during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. The results show that CUS promotes significant morphological changes and causes robust up-regulation of HMGB1 mRNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent up-regulation of receptor for advanced glycation end products (RAGE) mRNA, but not toll-like receptor 4 (TLR4) in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia 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 mRNA 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 evidence that RAGE KO mice were resilient to stress-induced anhedonia. Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure.
登录
查看更多内容
影响因子：
4.4
作者：
Chen, Yali;Akirav, Eitan M.;Chen, Wei;Henegariu, Octavian;Moser, Bernhard;Desai, Dharmesh;Shen, Jane M.;Webster, Jeffery C.;Andrews, Robert C.;Mjalli, Adnan M.;Rothlein, Robert;Schmidt, Ann Marie;Clynes, Raphael;Herold, Kevan C.
通讯作者：
Herold, Kevan C.
影响因子：
5.1
作者：
Alcocer-Gomez, Elisabet;Ulecia-Moron, Cristina;Cordero, Mario D.
通讯作者：
Cordero, Mario D.
DOI：
10.1016/j.bbi.2015.12.012
发表时间：
2016-03
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Cheng Y;Pardo M;Armini RS;Martinez A;Mouhsine H;Zagury JF;Jope RS;Beurel E
通讯作者：
Beurel E
DOI：
10.1016/j.bbi.2015.10.009
发表时间：
2016-07
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Frank MG;Weber MD;Fonken LK;Hershman SA;Watkins LR;Maier SF
通讯作者：
Maier SF
影响因子：
15.1
作者：
Johnson, JD;O'Connor, KA;Maier, SF
通讯作者：
Maier, SF