Hippocampal structure and function are maintained despite severe innate peripheral inflammation
Hippocampal structure and function are maintained despite severe innate peripheral inflammation
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DOI：
10.1016/j.bbi.2015.05.011
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
P. Süß;L. Kalinichenko;W. Baum;M. Reichel;J. Kornhuber;Sandra Loskarn;Benjamin Ettle;J. Distler
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文献类型：
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作者：
P. Süß;L. Kalinichenko;W. Baum;M. Reichel;J. Kornhuber;Sandra Loskarn;Benjamin Ettle;J. Distler
由细胞因子如肿瘤坏死因子α、白介素1β和白介素6等介导的慢性外周炎症与抑郁和焦虑等精神障碍有关。然而，目前还不清楚是哪种不同类型的外周炎症触发了神经炎症，并影响了海马区的可塑性，从而导致了抑郁样行为。我们假设人肿瘤坏死因子-α转基因小鼠模型的慢性外周炎症扩散到中枢神经系统，导致抑郁状态，表现为特定的行为模式，并损害成年海马神经发生。TnFtg小鼠表现为严重的侵蚀性关节炎，关节中IL-1β和IL-6的表达增加，血清中人肿瘤坏死因子-α水平显著升高。有趣的是，在TNFtg小鼠的海马区，IL-1mRNA和IL-6mRNA水平并没有改变。与TNFtg小鼠关节和脾中明显的单核细胞增多症相比，缺乏海马区小胶质细胞增多症或星形胶质细胞增多症的迹象。此外，在TNFtg小鼠中，运动能力受损，但没有运动非依赖性抑郁行为。海马神经前体细胞的增殖和成熟以及新生神经元的存活在TNFtg小鼠的齿状回中得以保存，尽管运动活动减少和外周炎症征象。我们得出结论，TNFtg小鼠的外周炎症是由先天性免疫系统的慢性激活所介导的。然而，严重的外周炎症虽然会损害运动能力，但不会引发抑郁样行为。这些结构和功能的发现表明，尽管外周先天炎症，但海马体的免疫、细胞可塑性和行为仍保持不变。
Chronic peripheral inflammation mediated by cytokines such as TNFα, IL-1β, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-α transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1β and IL-6 expression in tarsal joints with highly elevated human TNF-α levels in the serum. Intriguingly, IL-1β and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.