Chronic psychosocial stress down-regulates central cytokines mRNA

doi:10.1016/j.brainresbull.2003.09.009

Brain Research Bulletin

Volume 62, Issue 3, 30 December 2003, Pages 173-178

https://doi.org/10.1016/j.brainresbull.2003.09.009 Get rights and content

Abstract

Brain cytokines have been implicated in brain plasticity and mood alterations. We present here the first evidence of a chronic stress-induced modulation of central cytokines, in absence of experimentally induced inflammatory processes. Several brain areas were extracted from stressed and control mice and cytokines mRNA analyzed with semi-quantitative RT-PCR. Mice subjected to chronic psychosocial stress showed decreased interleukin (IL)-1β mRNA levels in the hippocampus, decreased IL-1Receptor antagonist in the striatum and pituitary, decreased tumor necrosis factor (TNF)-α in the striatum and hippocampus, and decreased glucocorticoid receptor (GR) in the striatum and hippocampus compared to group housed sibling mice. An independent group of mice subjected to chronic psychosocial stress also showed increased plasma corticosterone. These findings may open new perspectives for understanding the pathophysiological basis of chronic stress-induced disorders.

Introduction

Cytokines are potent, multifunctional, pleiotropic proteins that have been initially characterized in the context of cellular activation and cellular communication in the immune system. The first direct evidence of the presence and activity of cytokines in the brain was obtained two decades ago and regarded interleukin (IL)-1β in humans and tumor necrosis factor (TNF)-α in the rat brain 8., 35.. Cytokines are present in several brain structures and cellular types, e.g. glia, neurons, and macrophages, in form of proteins and their receptors 15., 29., 30., 34., 35.. Besides their well characterized role in mediating the central components of the host innate immune response, convergent findings point to a direct or indirect role for cytokines in stress-related disorders, including depression 10., 19.: (i) cytokines administered to patients and laboratory animals induce symptoms of depression 9., 17.; (ii) exposure to acute stressors can induce the expression of cytokines at the periphery and in the brain (e.g. [26]); (iii) somatic disorders with an inflammatory component are associated with a high prevalence of depressive disorders and cytokines imbalance [21]. Because of their potent activatory effect on the HPA axis, proinflammatory cytokines could contribute to the elevated levels of glucocorticoids that are observed in depressed patients 16., 21.. Reciprocally, activation of glucocorticoid receptors leads to down regulation of peripheral and central expression of proinflammatory cytokines, via modulation of AP-1 and NFkB transcription [36]. Accordingly, it has been suggested that glucocorticoids and central/peripheral cytokines are finely balanced to maintain homeostasis with reciprocal inhibitory/activatory pathways being present 8., 29., 36.. This complex balance appears critical and, if not maintained, it can have clinical consequences in the form for instance of neuronal death or reduced brain plasticity 1., 19., 21., 31.. Conventional models of stress in laboratory rodents, however, show little face validity with the chronic human psychopathologies. Models of social stress based on the naturalistic events of interactions between conspecifics offer a realistic tool to induce chronic stress in animal models [18]. In recent years we developed a naturalistic and ethologically-oriented model of chronic psychosocial stress, which is based on a natural behavior of male mice, i.e. acquiring and defending a territory. When forcing two adult males in a chronic sensory contact and with a brief daily agonistic encounter, mice seem to live under a constant threat and activation 2., 3., 5., 6.. From previous investigations it becomes evident that social status and territory ownership are factors determining the vulnerability to chronic stress exposure. This seem true for behavioral, autonomic, metabolic and immune functions, but not for the regulation of the HPA axis. Indeed all animals under chronic stress showed high corticosterone both in basal condition and after dexamethasone challenge. Given the key regulatory role of corticosterone on cytokines expression [36], our aim was to investigate whether subjecting male mice to such a naturalistic stressor would result in a modulation of the central cytokines network (IL-1β, IL-1Ra, TNF-α, IL-6, IL-10) and glucocorticoids receptors (GR) in basal conditions (e.g. [37]), i.e. in absence of any further acute stressor such as restraint stress or lypopolisaccaride (LPS) injection (e.g. [26]).

Section snippets

Animals

The subjects were adult, males Swiss CD-1 mice originally obtained from Charles River Italia (Calco, Italy). The mice were born and reared at 22±2 °C, with lights ‘on’ at 7.00 and ‘off’ at 19.00. After weaning they were housed in same sex-sibling groups (4–7 per group). Food and water were available ad libitum. Experiment was conducted in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and approved by Italian Institute of Health.

Procedure

The procedure was

Results

A preliminary analysis (two-way ANOVA for each variable, see below) was conducted to compare the four categories of mice under chronic stress, i.e. RD, RS, InD and InS. Since no difference emerged between the four categories, all the animals under stress were pooled and compared to control group-housed mice (IL-1β F(3,20)=0.6, NS; IL-1Ra F(3,20)=0.2, NS; IL-6 F(3,15)=0.3, NS; IL-10 F(3,15)=1.5, NS; TNF-α F(3,20)=0.1, NS; GR F(3,20)=0.8, NS). There was a clear alteration of central cytokines and

Discussion

The results of the present study provide the first evidence of a modulation of the cytokines network by chronic social stress. In contrast, in a recent report rats intermittently exposed to a natural predator odors showed no change in a similar panel of central cytokines mRNA when compared with unexposed controls [28]. The implication of the present findings stands in the observation that under a naturalistic paradigm of chronic psychological challenge, and in the absence of any inflammatory

Acknowledgements

Supported by Italian MURST (COFIN 2000) and University of Parma (FIN 2000-01) and DGA (agreement no. 00.34.060.00.470.75.01). Authors wish to thank all the colleagues of the U394-INSERM of Bordeaux, and in particular J. Arsaut, G. Hebert, J.P. Konsman, E. Moze, for their kind help provided in several phases of the present study. V. Vascelli is acknowledged for technical assistance.

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Chronic psychosocial stress down-regulates central cytokines mRNA

Abstract

Introduction

Section snippets

Animals

Procedure

Results

Discussion

Acknowledgements

Cytokine Growth Factor Rev.

Physiol. Behav.

Physiol. Behav.

Psychoneuroendocrinology

J. Neuroimmunol.

Psychoneuroendocrinology

Mol. Brain Res.

Brain Behav. Immun.

Neuropsychopharmacology

Trends Neurosci.

Curr. Opin. Neurobiol.

Neurosci. Lett.

Brain Res. Bull.

Brain Res. Bull.

J. Neuroimmunol.

Control of synaptic strenght by glial TNF-α

Science

Immuno-neuro-endocrine interactions: facts and hypotheses

Endocr. Rev.