Jing-Yang Gu1, Yao-Wei Xu1, Lai-Peng Feng2, Jiao Dong1, Li-Qin Zhao1, Cong Liu1, Hui-Ying Wang2, Xiang-Yang Zhang3, Cai Song4, Chang-Hong Wang5. 1. Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453002, China. 2. Henan Key Lab of Biological Psychiatry, Xinxiang Medical University, Xinxiang, Henan 453002, China. 3. CAS Key Laboratory of Mental Health, Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China. 4. Research Institute for Marine Drugs and Nutrition, Guangdong Ocean University, Zhanjiang 524088, China. Electronic address: cai.song@dal.ca. 5. Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453002, China. Electronic address: wangchdr@163.com.
Abstract
BACKGROUND: 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. METHOD: 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). RESULT: 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. CONCLUSION: 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.
BACKGROUND: 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. METHOD: 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). RESULT: 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. CONCLUSION: 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.