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

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.

Bulleyaconitine A Exerts Antianxiety and Antivisceral Hypersensitivity Effects

“…It has been suggested that chronic stress increased gene expression of some inflammatory factors in the hippocampus such as IL-1b, IL-18, and IL-6. IL-1b is an important mediator of stress-induced anxiety-like behavior and it has been reported that the hippocampal IL-1b mRNA was upregulated in stressed rats (Jones et al, 2018;Wang et al, 2018). More importantly, the mature form of IL-1b as well as its convertase, cleaved caspase-1, were both increased in the hippocampus after exposure to chronic stress .…”

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…In contrast to the acute stress models shown in this figure, unpredictable chronic mild stress (UCMS) is delivered for prolonged periods of 8-12 weeks and includes once daily, for example, immobilization, food deprivation, light/dark phase reversal, hot environment, and cage shaking. This procedure leads to depressive-like behavior as measured by reduced sucrose consumption and prolonged immobility in the tail suspension test (TST) and forced swim test (FST) in rodents (Zhang et al, 2015;Su et al, 2017;Wang et al, 2018;Feng et al, 2019). UCMS also resulted in higher protein levels of NLRP3, caspase-1, and IL-1β in the hippocampus of stress-exposed mice (Zhang et al, 2015) and rats (Wang et al, 2018;Feng et al, 2019).…”

“…This procedure leads to depressive-like behavior as measured by reduced sucrose consumption and prolonged immobility in the tail suspension test (TST) and forced swim test (FST) in rodents (Zhang et al, 2015;Su et al, 2017;Wang et al, 2018;Feng et al, 2019). UCMS also resulted in higher protein levels of NLRP3, caspase-1, and IL-1β in the hippocampus of stress-exposed mice (Zhang et al, 2015) and rats (Wang et al, 2018;Feng et al, 2019). Pharmacological blockade of NLRP3 (Zhang et al, 2015) or its genetic deletion (Su et al, 2017) decreased the level of inflammatory mediators and counteracted the symptoms of depressive-like behavior.…”

“…Pharmacological blockade of NLRP3 (Zhang et al, 2015) or its genetic deletion (Su et al, 2017) decreased the level of inflammatory mediators and counteracted the symptoms of depressive-like behavior. Microglia has been shown to be essential for these effects, because chronic minocycline treatment known to block the activation of microglia inhibited the following engagement of the NLRP3 inflammasome and the ensuing increased release of inflammatory mediators (Wang et al, 2018). Further, the inflammasome inhibitor Ac-Tyr-Val-Ala-Asp-chloromethyl ketone blocked the behavioral alterations and the production of inflammatory mediators caused by systemic injection of LPS to mice (Zhu et al, 2017).…”

Cultivating a healthy neuro‐immune network: A health psychology approach

“…Of note, animals exposed to this paradigm do not uniformly develop depressive‐like behaviors; those who are “stress susceptible” (the majority of animals) show increases in inflammation‐related microglia gene expression, whereas “resilient” animals show activation of gene transcripts implicated in cellular and behavioral plasticity to stress (Lehmann et al, ). Chronic unpredictable stress also induces microglial activation which mediates stress effects on anxiety and depressive‐like behavior (Wang et al, ). Prenatal and early life stress exposure lead to elevated microglial activity (Calcia et al, ), which may persist over time and have long‐term consequences for neural function, mood, and cognition (Bilbo & Schwarz, ).…”