Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453002, China.
Henan Key Lab of Biological Psychiatry, Xinxiang Medical University, Xinxiang, Henan 453002, China.
Brain Res Bull. 2021 Dec;177:252-262. doi: 10.1016/j.brainresbull.2021.10.005. Epub 2021 Oct 12.
Inflammation mediated by microglia has been shown to be involved in the pathogenesis of depression. The enriched environment (EE) can improve depression-like behaviors and reduce inflammatory reactions, but it is unclear whether this is by changing the inflammatory activation phenotype of microglia.
A depression rat model was established using chronic unpredictable stress (CUS) for four weeks. The rats were then treated with EE or fluoxetine administration during the following three weeks. Behavior tests including sucrose preference, forced swimming and open field were applied to evaluate the depression-like behaviors of rats at the baseline period prior to CUS, the end of fourth week and at the end of the seventh week. Microglial activation and hippocampal neuro-inflammation were detected on postmortem using immunofluorescence, western blotting, and real-time polymerase reaction (PCR).
The results showed that severe depressive-like behavior was induced by four weeks of CUS. Changes in peripheral blood inflammatory cytokines were detected by ELISA. Immunofluorescent staining showed the IBA-1 of microglia activation marker level significantly increased in affected rats. The hippocampal microglial activation state was determined by measuring the increased levels of iNOS an M1 marker and the decreased levels of CD206, an M2 marker. The activation of NF-κB upregulation of inflammatory cytokines in the hippocampus and factors such as IL-10 were decreased. This study showed that EE and chronic fluoxetine treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation, activated NF-κB inflammasome and increased pro-inflammatory cytokines.
EE can alleviate depression-like behavior by modulating the phenotype of microglia, inhibiting pro-inflammatory genes, and promoting anti-inflammatory genes. Furthermore, EE can effectively reduce the phosphorylation and expression levels of NF-κB.
研究表明，小胶质细胞介导的炎症参与了抑郁症的发病机制。丰富环境（EE）可以改善抑郁样行为并减少炎症反应，但尚不清楚这是否是通过改变小胶质细胞的炎症激活表型来实现的。
采用慢性不可预知应激（CUS）建立大鼠抑郁模型 4 周。然后，在接下来的 3 周内，用 EE 或氟西汀进行治疗。在 CUS 前、第 4 周末和第 7 周末，使用糖水偏好、强迫游泳和旷场实验等行为测试评估大鼠的抑郁样行为。在死后使用免疫荧光、Western blot 和实时聚合酶反应（PCR）检测小胶质细胞激活和海马神经炎症。
结果表明，4 周的 CUS 可诱导严重的抑郁样行为。通过 ELISA 检测外周血炎症细胞因子的变化。免疫荧光染色显示，受影响大鼠的小胶质细胞激活标志物 IBA-1 水平显著升高。通过测量 iNOS（M1 标志物）水平升高和 CD206（M2 标志物）水平降低来确定海马小胶质细胞的激活状态。海马中 NF-κB 的激活导致炎症细胞因子的上调和 IL-10 等因子的减少。本研究表明，EE 和慢性氟西汀治疗可缓解慢性应激引起的抑郁样行为，并显著抑制小胶质细胞激活、激活 NF-κB 炎症小体和增加促炎细胞因子。
EE 可以通过调节小胶质细胞表型、抑制促炎基因和促进抗炎基因来缓解抑郁样行为。此外，EE 可以有效降低 NF-κB 的磷酸化和表达水平。
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