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Priming of microglia with IFN-γ impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects.
Glia ( IF 5.4 ) Pub Date : 2020-07-11 , DOI: 10.1002/glia.23878 Jinqiang Zhang 1, 2 , Hui He 2 , Yan Qiao 3 , Tao Zhou 1 , Haili He 1 , Saini Yi 1 , Lijuan Zhang 2 , Li Mo 2 , Yahui Li 1 , Weike Jiang 1 , Zili You 2
Glia ( IF 5.4 ) Pub Date : 2020-07-11 , DOI: 10.1002/glia.23878 Jinqiang Zhang 1, 2 , Hui He 2 , Yan Qiao 3 , Tao Zhou 1 , Haili He 1 , Saini Yi 1 , Lijuan Zhang 2 , Li Mo 2 , Yahui Li 1 , Weike Jiang 1 , Zili You 2
Affiliation
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Neuroinflammation driven by interferon‐gamma (IFN‐γ) and microglial activation has been linked to neurological disease. However, the effects of IFN‐γ‐activated microglia on hippocampal neurogenesis and behavior are unclear. In the present study, IFN‐γ was administered to mice via intracerebroventricular injection. Mice received intraperitoneal injection of ruxolitinib to inhibit the JAK/STAT1 pathway or injection of minocycline to inhibit microglial activation. During a 7‐day period, mice were assessed for depressive‐like behaviors and cognitive impairment based on a series of behavioral analyses. Effects of the activated microglia on neural stem/precursor cells (NSPCs) were examined, as was pro‐inflammatory cytokine expression by activated microglia. We showed that IFN‐γ‐injected animals showed long‐term adult hippocampal neurogenesis reduction, behavior despair, anhedonia, and cognitive impairment. Chronic activation with IFN‐γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, MHC II and CD68 up‐regulation, and pro‐inflammatory cytokine (IL‐1β, TNF‐α, IL‐6) and nitric oxide (NO) release. Microglia isolated from the hippocampus of IFN‐γ‐injected mice suppressed NSPCs proliferation and stimulated apoptosis of immature neurons. Inhibiting of the JAK/STAT1 pathway in IFN‐γ‐injected animals to block microglial activation suppressed microglia‐mediated neuroinflammation and neurogenic injury, and alleviated depressive‐like behaviors and cognitive impairment. Collectively, these findings suggested that priming of microglia with IFN‐γ impairs adult hippocampal neurogenesis and leads to depression‐like behaviors and cognitive defects. Targeting microglia by modulating levels of IFN‐γ the brain may be a therapeutic strategy for neurodegenerative diseases and psychiatric disorders.
中文翻译：
用 IFN-γ 激活小胶质细胞会损害成年海马神经发生并导致抑郁样行为和认知缺陷。
由干扰素-γ（IFN-γ）和小胶质细胞激活驱动的神经炎症与神经系统疾病有关。然而，IFN-γ激活的小胶质细胞对海马神经发生和行为的影响尚不清楚。在本研究中，IFN-γ 通过脑室内注射给药于小鼠。小鼠接受腹腔注射鲁索替尼以抑制 JAK/STAT1 通路或注射米诺环素以抑制小胶质细胞活化。在 7 天的时间内，基于一系列行为分析评估小鼠的抑郁样行为和认知障碍。检查了激活的小胶质细胞对神经干/前体细胞 (NSPC) 的影响，以及激活的小胶质细胞的促炎细胞因子表达。我们发现注射 IFN-γ 的动物表现出长期的成年海马神经发生减少，行为绝望、快感缺乏和认知障碍。IFN-γ 的慢性激活诱导与形态变化、种群扩张、MHC II 和 CD68 上调以及促炎细胞因子（IL-1β、TNF-α、IL-6）和一氧化氮（NO ） 发布。从注射 IFN-γ 的小鼠海马体中分离出的小胶质细胞抑制 NSPCs 增殖并刺激未成熟神经元的凋亡。在注射 IFN-γ 的动物中抑制 JAK/STAT1 通路以阻断小胶质细胞激活可抑制小胶质细胞介导的神经炎症和神经源性损伤，并减轻抑郁样行为和认知障碍。总的来说，这些发现表明用 IFN-γ 启动小胶质细胞会损害成年海马神经发生并导致抑郁样行为和认知缺陷。
更新日期：2020-07-11
中文翻译：
用 IFN-γ 激活小胶质细胞会损害成年海马神经发生并导致抑郁样行为和认知缺陷。
由干扰素-γ（IFN-γ）和小胶质细胞激活驱动的神经炎症与神经系统疾病有关。然而，IFN-γ激活的小胶质细胞对海马神经发生和行为的影响尚不清楚。在本研究中，IFN-γ 通过脑室内注射给药于小鼠。小鼠接受腹腔注射鲁索替尼以抑制 JAK/STAT1 通路或注射米诺环素以抑制小胶质细胞活化。在 7 天的时间内，基于一系列行为分析评估小鼠的抑郁样行为和认知障碍。检查了激活的小胶质细胞对神经干/前体细胞 (NSPC) 的影响，以及激活的小胶质细胞的促炎细胞因子表达。我们发现注射 IFN-γ 的动物表现出长期的成年海马神经发生减少，行为绝望、快感缺乏和认知障碍。IFN-γ 的慢性激活诱导与形态变化、种群扩张、MHC II 和 CD68 上调以及促炎细胞因子（IL-1β、TNF-α、IL-6）和一氧化氮（NO ） 发布。从注射 IFN-γ 的小鼠海马体中分离出的小胶质细胞抑制 NSPCs 增殖并刺激未成熟神经元的凋亡。在注射 IFN-γ 的动物中抑制 JAK/STAT1 通路以阻断小胶质细胞激活可抑制小胶质细胞介导的神经炎症和神经源性损伤，并减轻抑郁样行为和认知障碍。总的来说，这些发现表明用 IFN-γ 启动小胶质细胞会损害成年海马神经发生并导致抑郁样行为和认知缺陷。
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