Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress
Introduction
Depression is a common psychiatric disorder which causes severe social and economic burdens. Drugs that are available in clinic, such as the monoamine oxidase inhibitors and the selective serotonin reuptake inhibitors, are developed according to the monoamine dysfunction hypothesis (Shulman et al., 2013; Clevenger et al., 2018). However, only one-third of patients taking these drugs exhibit relatively good therapeutic effects after several weeks of treatment (Schwartz et al., 2016), and these drugs have multiple side-effects (Gelenberg and Chesen, 2000; Insel and Scolnick, 2006). It is therefore necessary to explore novel mechanism-based antidepressants.
Microglial cells are the innate immune cells in the nervous system. Increasing evidence has shown that they are actively involved in the pathogenesis of neurodegenerative and psychiatric disorders via producing huge amounts of pro-inflammatory mediators, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) (Main et al., 2016; Stone et al., 2018; Huang et al., 2018a). The role of microglia in depression has been well-documented in previous studies, and the reactive microglia have been shown to be associated with depression onset and/or progression. Hence, microglial inhibition is considered a potential strategy for depression treatment (Huang et al., 2016; Li et al., 2018; Wang et al., 2018). However, in recent years some other voices, which do not support the microglia inhibition strategy, have been raised. For example, researchers have found that administration of non-steroidal anti-inflammatory drugs (NSAIDs) in depressed patients exacerbates but not ameliorates depressive symptoms (Warner-Schmidt et al., 2011), and in some cases, the levels of C-reactive protein (CRP), a classical inflammatory marker, are normal or even lower than that in normal individuals (Almeida et al., 2009; Carboni et al., 2010). Further, infliximab, an inhibitor of TNF-α, has been reported to exacerbate depressive symptoms in patients with low levels of CRP (Raison et al., 2013). Recently, we and others have reported that the decrease in microglia in hippocampal dentate gyrus (DG) plays a key role in major depression, and drugs which activate the microglia, like lipopolysaccharide (LPS) and macrophage colony-stimulating factor (M-CSF), can reverse chronic stress-induced depression-like behaviors in mice (Kreisel et al., 2014; Tong et al., 2017; Gong et al., 2018). Within this context, we and others have raised a hypothesis that depression should be treated by personalized medical approaches, which could be guided by personalized status of microglia in the hippocampus.
The antidepressant effect of the most anti-neuroinflammatory agents has been described in previous studies (Tomaz et al., 2014; Kopschina Feltes et al., 2017), but how the chronically-stressed mice respond to the microglial activators remains unknown. Further exploration of this issue would promote the understanding about the microglia decrease hypothesis of depression. To this end, we investigate the rapid and sustained effects of LPS on chronic unpredictable stress (CUS)-induced depression-like behaviors in mice. We also evaluate the effect of a second LPS injection in chronically-stressed mice who re-displayed depression-like behaviors, as well as the potential role of the hippocampal microglia in the antidepressant effect of LPS.
Section snippets
Materials
LPS (Escherichia coli, serotype 0111: B4) and PLX3397 were purchased from Sigma (Saint Louis, MO, USA) and MedChem Express (Monmouth, NJ, USA), respectively. Minocycline is the product of Selleck (Shanghai, China). The antibody against Iba-1 is the product of Abcam (#ab178847, Cambridge, MA, USA). Both LPS and PLX3397 were prepared as stocked solutions and were stored at −20 °C. The stock solutions for LPS were diluted to work concentration immediately before use.
Animals use
Six-week old C57BL6/J mice
Dose-dependent effect of LPS on CUS-induced depression-like behaviors in mice
We first evaluated the antidepressant effect of a single LPS injection in CUS mice at doses ranging from 30, 50, 75 to 100 μg/kg (schematic diagram, Fig. 1A). In the TST, two-way ANOVA revealed a significant effect for LPS × stress interaction (F4,90 = 14.25, p < .001), but not for stress (F1,90 = 1.95, p = .17) and LPS (F4,90 = 0.40, p = .81) treatment (Fig. 1B). In the FST, the two-way ANOVA revealed a significant effect for LPS × stress interaction (F4,90 = 14.35, p < .001), but not for
Discussion
In recent years, we and others have reported that chronic stress-induced decrease in hippocampal microglia numbers underlies an important aspect of depression pathogenesis, and a single LPS injection has been shown to reverse depression-like behaviors in rodents (Kreisel et al., 2014; Tong et al., 2017; Gong et al., 2018). LPS is a well-known activator of microglia, but whether the herein-observed effect of LPS is indeed dependent on microglia remains unclear. Our results showed that inhibition
Conclusions
Our results evaluate for the first time the responsive properties of the chronically-stressed mice to LPS, a classical activator of microglia, and reveal that the reactive microglia in the hippocampus may be required for the antidepressant effect of LPS. These results may be beneficial to understand the pharmacological properties of microglial activators in depression treatment, and may help explore the values of the microglia decrease hypothesis-based antidepressive strategies. But before we
Ethical Statements
All animal experiments in this study were conducted in accordance with internationally accepted guidelines for the use of animals in toxicology as adopted by the Society of Toxicology in 1999 and approved by the University Animal Ethics Committee of Nantong University (Permit Number: 2110836).
Declaration of Competing Interest
The authors declare no competing financial interests.
Acknowledgements
This work was supported by the Natural Science Foundation of China (81771467, 81571323, 81701286, and 81974216), the Science and Technology Project of Nantong City (MS12018078 and JC2018057), the Six Talent Peaks Project in Jiangsu Province (SWYY-071), and the Scientific Research Project of the People's Hospital of Taizhou (ZL201950).
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Zixuan Cai and Ting Ye contribute equally to this work