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. 2016 May 16;13(1):108.
doi: 10.1186/s12974-016-0572-0.

Low-dose Lipopolysaccharide (LPS) Inhibits Aggressive and Augments Depressive Behaviours in a Chronic Mild Stress Model in Mice

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Free PMC article

Low-dose Lipopolysaccharide (LPS) Inhibits Aggressive and Augments Depressive Behaviours in a Chronic Mild Stress Model in Mice

Yvonne Couch et al. J Neuroinflammation. .
Free PMC article

Abstract

Background: 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. 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.

Methods: Changes 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.

Results: When 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.

Conclusions: It 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.

Keywords: 5-HT; Aggressive behaviour; Chronic stress; Cytokines; LPS; SERT.

Figures

Fig. 1
Fig. 1
Schematic outline of the behavioural studies for a LPS-challenged stress-naïve mice and b LPS-challenged or vehicle-challenged stressed/non-stressed animals compared with control animals. The numbers in each group and total numbers are shown
Fig. 2
Fig. 2
The effect of low doses of LPS on behavioural outcomes at 24 and 48 hours post-challenge innaïve mice. Animals were subjected to a single dose of LPS: 0.1 mg/kg or 0.5 mg/kg (n=7 in each group)or vehicle administration (n=6), and were tested 24 h or 48 h thereafter in the elevated O-maze for (a) latency to exit to open arm, (b) number of exits into open arms, and (c) the time spent in the open arms. Subsequently, mice were observed for (d) latency and (e) duration of social interaction in a resident-intruder test. Mean speed (f) was also recorder in the open field. Data are mean ± SEM; *p < 0.05 when compared to control animals
Fig. 3
Fig. 3
The effect of low-dose LPS on depressive-like behaviours in stressed mice. Naïve and stressed animals were subjected to either a single dose of LPS (0.1 mg/kg) or vehicle injection and tested 24 h thereafter in a two-bottle sucrose preference test investigating a overall preference for sucrose, b total sucrose consumption, c water intake in a sucrose test, d the period of immobility in the tail suspension test, and in the forced swim test for e latency to floating and f total time spent floating. All animals showed >65 % preference for sucrose at baseline and similar sucrose preference prior to bolus injection of LPS or vehicle (Additional file 1: Figure S2). Data are mean ± SEM; *p < 0.05, **p < 0.01 and ***p < 0.001 when compared to controls; +p < 0.05 and +++p < 0.001 compared to stressed animals
Fig. 4
Fig. 4
The effect of low-dose LPS on anxiety and aggression-like behaviours in stressed mice. Naïve and stressed animals were challenged with a single dose of LPS (0.1 mg/kg) or vehicle (saline) and tested 24 h thereafter in the elevated O-maze for the a latency to exit to the open arms and b number of exits to the open arms; in the resident-intruder paradigm for c duration of social interaction and d latency to attack conspecific, e total number of attacks and f duration of crawl over behaviour. Data are mean ± SEM; *p < 0.05, **p < 0.01 and ***p < 0.001 compared to control animals; +++p < 0.001 and ++++p < 0.0001 compared to stressed animals
Fig. 5
Fig. 5
Cytokine mRNA in the liver and blood corticosterone levels in control, stressed and LPS-treated animals. mRNA levels of a TNFα and b IL-1β were measured by qPCR in the liver of animals after either 10 days of chronic stress, an acute LPS challenge (0.1 mg/kg) or a combination of both. Corticosterone levels in blood (c) were measured by HPLC. qPCR data are expressed as relative-fold expression normalized to GAPDH and naïve mice. Bars are mean ± SEM, (n = 5 in each group), **p < 0.01 and ***p < 0.001 compared to control animals
Fig. 6
Fig. 6
IL-1β, TNFα, 5-HT2A receptor and SERT mRNA expression in the brain structures of animals challenged with chronic stress, LPS or a combination of both. mRNA levels of a IL-1β, b TNFα, c 5-HT2A and d SERT were measured by qPCR in the pre-frontal cortex, striatum, hippocampus and raphe of animals after either 10 days of chronic stress, an acute LPS challenge (0.1 mg/kg) or a combination of both. Values are expressed as relative-fold expression normalized to housekeeping gene GAPDH and to control values within each region. Data are mean ± SEM; n = 5 in each group; *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 compared to control animals

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