Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats

Ya-Lin Wang,Qiu-Qin Han,Wei Hu,Bing Li,Qiong Liu,Wen-Qing Gong,Jin Yu,Dong-Hui Pan,Li-Zheng Wang,Min Yang

doi:10.1186/s12974-018-1054-3

Abstract

BackgroundDepression 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.MethodsWe 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.ResultsThe 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.ConclusionThese results together indicate that microglial activation mediates the chronic mild stress-induced depressive- and anxiety-like behavior and hippocampal neuro-inflammation.

Highlights

Depression is a heterogeneous disorder, with the exact neuronal mechanisms causing the disease yet to be discovered
The results showed that NOD-like receptor protein 3 (NLRP3) was predominantly expressed by microglia (Fig. 5a) and the three components of the NLRP3 inflammasome, including NLRP3 (Fig. 5b, c), Apoptosis-associated speck-like protein containing a CARD (ASC) (Fig. 5d, e), and caspase-1 (Fig. 5f, g), displayed significantly higher protein and mRNA expression levels in the rats exposed to chronic mild stress (CMS) compared to the control group
We detected an increase of NLRP3 inflammasome and some inflammatory mediators in the hippocampus after chronic stress and found that minocycline treatment can alleviate the depressive- and anxiety-like behavior and neuro-inflammation induced by chronic stress

Summary

Introduction

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. Interleukin-1 beta (IL-1β) is one of the many important proinflammatory cytokines and has been proven to participate in the inflammatory responses that take place in the brain These inflammatory responses eventually lead to cellular damage in stress-relevant neuropsychiatric diseases, such as co-inherited MDD [7]. A meta-analysis demonstrated that antidepressant therapies resulted in a reduction in IL-1β serum level and simultaneously alleviated depressive symptoms [9] This phenomenon suggests that IL-1β plays a key role in the pathogenesis of depression. Various novel studies implied that the NLRP3 inflammasome is involved in stressinduced depression and, may be a potential target for the treatment of depression [13]

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