Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice.

Yvonne Couch,Vladimir Chekhonin,Klaus-Peter Lesch,Harry W Steinbusch,Tatyana Strekalova,Careen Schroeter,Daniel C Anthony,Natalyia Markova,Vladimir Nikolenko,Alexander Trofimov

doi:10.1186/s12974-016-0572-0

Abstract

BackgroundAggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive.MethodsChanges in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress.ResultsWhen combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels.ConclusionsIt is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0572-0) contains supplementary material, which is available to authorized users.

Highlights

Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges
We examined behavioural parameters of aggression and impulsivity/hyperactivity, anhedonia and helplessness, as well as the expression of inflammatory and serotonergic markers of the periphery and specific brain areas, including the medial pre-frontal cortex and hippocampus as these sites are well recognized to play a crucial role in the stress response [34], and we have previously found that 5-HT2A and serotonin transporter (SERT) expression levels change in response to systemic inflammation [35] and chronic stress paradigms [29] in these regions
In the elevated O-maze, there was a main effect of LPS dose, but not time postchallenge, on the overall latency to exit to the open arms (Fig. 2a; two-way ANOVA dose p < 0.01 F2,34 = 7.89; time post-challenge p = 0.06 F1,34 = 0.55; dose:time postchallenge p = 0.78 F2,34 = 0.25)

Summary

Introduction

Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. Chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. While the impact of inflammatory challenges on the negative affect component of depression has been examined, the impact of inflammation on other accompanying behaviours has often been overlooked. Altered neuroimmune responses are known to contribute to the neurobiology of aggression [8], and pro-inflammatory cytokine production, in particular, has been implicated in the mechanisms underpinning the stress response [5, 9] as well as aggressive behaviour [10,11,12,13]

Methods

Results

Discussion

Conclusion