Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats
Ya-Lin Wang1, Qiu-Qin Han1, Wen-Qing Gong2,3
1Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Background:
Depression is a heterogeneous disorder, with the exact neuronal mechanisms causing the disease yet to be discovered. Recent work suggests it is accompanied by neuro-inflammation, characterized, in particular, by microglial activation. However, microglial activation and its involvement in neuro-inflammation and stress-related depressive disorders are far from understood.
Methods:
We utilized multiple detection methods to detect the neuro-inflammation in the hippocampus of rats after exposure to chronic mild stress (CMS). Male Sprague Dawley (SD) rats were subjected to chronic mild stressors for 12 weeks. Microglial activation and hippocampal neuro-inflammation were detected by using a combinatory approach of in vivo [18F] DPA-714 positron emission computed tomography (PET) imaging, ionized calcium-binding adapter molecule 1 and translocator protein (TSPO) immunohistochemistry, and detection of NOD-like receptor protein 3 (NLRP3) inflammasome and some inflammatory mediators. Then, the rats were treated with minocycline during the last 4 weeks to observe its effect on hippocampal neuro-inflammation and depressive-like behavior induced by chronic mild stress.
Results:
The results show that 12 weeks of chronic mild stress induced remarkable depressive- and anxiety-like behavior, simultaneously causing hippocampal microglial activation detected by PET, immunofluorescence staining, and western blotting. Likewise, activation of NLRP3 inflammasome and upregulation of inflammatory mediators, such as interleukin-1β (IL-1β), IL-6, and IL-18, were also observed in the hippocampus after exposure to chronic stress. Interestingly, the anti-inflammatory mediators, such as IL-4 and IL-10, were also increased in the hippocampus following chronic mild stress, which may hint that chronic stress activates different types of microglia, which produce pro-inflammatory cytokines or anti-inflammatory cytokines. Furthermore, chronic minocycline treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation. Similarly, the activation of NLRP3 inflammasome and the increase of inflammatory mediators were not exhibited or significantly less marked in the minocycline treatment group.
Conclusion:
These results together indicate that microglial activation mediates the chronic mild stress-induced depressive- and anxiety-like behavior and hippocampal neuro-inflammation.
Insights
Chronic mild stress activates microglia in the hippocampus, leading to neuro-inflammation and depressive behaviors in rats. Minocycline treatment reduced these effects, suggesting microglial activation mediates stress-induced depression.
Area of Science:
- Neuroscience
- Psychiatry
- Immunology
Background:
- Depression is a complex disorder with unclear neuronal mechanisms.
- Neuro-inflammation and microglial activation are increasingly implicated in depression.
- The precise role of microglial activation in stress-related depression requires further investigation.
Purpose of the Study:
- To investigate the role of hippocampal neuro-inflammation and microglial activation in chronic mild stress (CMS)-induced depression in rats.
- To evaluate the therapeutic potential of minocycline in mitigating CMS-induced depressive behaviors and neuro-inflammation.
Main Methods:
- Rats were exposed to chronic mild stress (CMS) for 12 weeks.
- Neuro-inflammation was assessed using in vivo PET imaging ([18F] DPA-714), immunohistochemistry (Iba1, TSPO), and molecular detection of NLRP3 inflammasome and inflammatory mediators.
- Minocycline was administered during the final 4 weeks of CMS to assess its effects.
Main Results:
- CMS induced depressive- and anxiety-like behaviors, accompanied by hippocampal microglial activation and NLRP3 inflammasome activation.
- Pro-inflammatory mediators (IL-1β, IL-6, IL-18) and anti-inflammatory mediators (IL-4, IL-10) were upregulated.
- Minocycline treatment alleviated depressive behaviors and significantly reduced microglial activation and associated neuro-inflammation.
Conclusions:
- Microglial activation is a key mediator of chronic mild stress-induced depressive and anxiety-like behaviors.
- Hippocampal neuro-inflammation plays a significant role in the pathophysiology of stress-induced depression.
- Minocycline demonstrates potential as a therapeutic agent for stress-related depressive disorders by targeting microglial activation.
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