Elsevier

Brain, Behavior, and Immunity

Volume 28, February 2013, Pages 170-181
Brain, Behavior, and Immunity

Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours, kynurenine pathway activation and reduced BDNF expression

https://doi.org/10.1016/j.bbi.2012.11.010Get rights and content

Abstract

In this study we characterised the ability of the viral mimetic poly I:C to induce a neuroinflammatory response and induce symptoms of depression and anxiety in rats. Furthermore, the ability of poly I:C to deplete central tryptophan and serotonin via induction of indolamine 2,3 dioxygenase (IDO), and also the ability of poly I:C to impact upon expression of the neurotrophin BDNF and its receptor TrkB were examined as potential mechanisms to link inflammation to depression. Poly I:C induced a neuroinflammatory response characterised by increased expression of IL-1β, IL-6, TNF-α and CD11b in frontal cortex and hippocampus. In the first 24 h following poly I:C administration rats displayed sickness behaviour characterised by reduced locomotor activity and weight gain. Anhedonia measured using the saccharin preference test was used as an indicator of depressive behaviour, and poly I:C induced depressive behaviour that persisted for up to 72 h following administration. Anxiety was measured using the open field test and anxious behaviour was observed 24 h following poly I:C, a time-point when sickness behaviour had resolved. These behavioural changes were accompanied by decreased expression of BDNF and TrkB in hippocampus and frontal cortex. In addition, poly I:C increased central IDO expression and increased concentrations of tryptophan, and its metabolite kynurenine. However this activation of the kynurenine pathway did not result in reduced central serotonin concentrations. These findings suggest that depressive and anxiety-like behaviours elicited by poly I:C are associated with a reduction in BDNF signalling, and activation of the kynurenine pathway, but not a reduction in serotonin.

Highlights

► Depressive and anxiety-like behaviours elicited by poly I:C are associated with a reduction in BDNF signalling, and activation of the kynurenine pathway, but not a reduction in serotonin.

Introduction

Whilst the pathophysiological mechanisms that underlie depression have not been fully elucidated, increasing evidence suggests that inflammation may play a role in the development of this disorder (Anisman, 2011, Dantzer et al., 2008, Leonard and Maes, 2012, Miller et al., 2009). Specifically, it has been reported that depression is associated with increased circulating concentrations of inflammatory cytokines, soluble cytokine receptors, chemokines and acute phase proteins (Cizza et al., 2008, Diniz et al., 2010, Grassi-Oliveira et al., 2009, Lanquillon et al., 2000, Maes et al., 1995, Simon et al., 2008). Also, cytokine immunotherapy with IFN-α or IL-2 can induce depressive symptoms in otherwise psychiatrically normal individuals (Alavi et al., 2012, Capuron et al., 2003, Capuron et al., 2000, Capuron et al., 2001, Loftis and Hauser, 2004, Raison et al., 2005, Udina et al., 2012). Further evidence supporting an inflammatory basis to depression comes from studies reporting an association of inflammatory and infectious diseases with depressive symptoms (Gao et al., 2009, Lehman and Cheung, 2002, Loftis et al., 2008, Owen et al., 2001, Pollak and Yirmiya, 2002, Sakic et al., 1996), and the induction of depressive-like behaviours in animals upon the administration of inflammatory cytokines (Dantzer et al., 2008, Dunn et al., 2005, Hayley et al., 2012, Miller et al., 2009, Raison et al., 2006).

Animal models are useful tools that allow the investigator to probe biological mechanisms that would not be possible in humans. Polyinosinic:polycytidylic acid (poly I:C) is a toll-like receptor-3 (TLR3) agonist that has been shown to initiate inflammatory responses comparable to that of a systemic viral infection. Systemic injection of poly I:C has been reported to induce an inflammatory response coupled with several symptoms of sickness behaviour (Cunningham et al., 2007, Gandhi et al., 2007, Gibb et al., 2011, Katafuchi et al., 2003, McLinden et al., 2012). Moreover, poly I:C has also been shown to affect memory consolidation in adults, anxiety-like behaviours in neonates and behavioural alterations in the offspring of dams challenged during pregnancy (Kent et al., 2007, Konat et al., 2011, Kranjac et al., 2012, Meyer and Feldon, 2012, Meyer et al., 2006, Meyer et al., 2008, Yee et al., 2011, Yee et al., 2012). However, to date depressive or anxiety-like behaviours in adults have not been comprehensively examined following poly I:C administration, and we suggest that poly I:C administration may represent a useful model of post-viral depression.

A specific mechanistic link between inflammation and depression remains elusive, however evidence suggests that alterations in tryptophan metabolism may play a role. Whilst a functional deficit in the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is well-established as a contributor to the pathogenesis of depression (Coppen and Doogan, 1988, Cryan and Leonard, 2000), it is only in recent years that theories have emerged to suggest a correlation between inflammation and low serotonin (Leonard and Maes, 2012, Maes et al., 2011). The synthesis of serotonin is dependent on tryptophan availability (Russo et al., 2009). In this regard, the kynurenine pathway (KP) is the major metabolic pathway for tryptophan in the body resulting in the production of kynurenine and several downstream metabolites (Stone and Darlington, 2002), and induction of the rate limiting enzyme in the KP, indolamine 2,3-dioxygenase (IDO) is driven by inflammatory cytokines (Carlin et al., 1989, Fujigaki et al., 2006, Zunszain et al., 2012). Consequently, IDO induction has been proposed as a mechanism by which inflammation can precipitate depression via tryptophan depletion (Christmas et al., 2011, Maes et al., 2011, Raison et al., 2009). As well as potentially reducing the availability of tryptophan for serotonin synthesis, activation of the KP can also lead to the formation of neuroactive metabolites which have been shown to be neuroprotective or neurotoxic, and in the central nervous system are primarily generated by glial cells (Schwarcz and Pellicciari, 2002). It is proposed that a shift in balance towards the neurotoxic arm of this pathway can lead to neurodegeneration and reduced neurogenesis in the brain which may be a contributing factor to depressive behaviour that occurs secondary to inflammation (Muller and Schwarz, 2007, O’Connor et al., 2009a, O’Connor et al., 2009c, Raison et al., 2010). In fact a recent study demonstrated that inhibition of the neurotoxic arm of the kynurenine pathway prevented the ability of the inflammatory cytokine IL-1β to inhibit neurogenesis in vitro (Zunszain et al., 2012). Also a systemic inflammatory challenge with bacterial LPS reduces expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF) in rat brain (Guan and Fang, 2006) and intrahippocampal LPS administration has been shown to inhibit expression of BDNF and also its receptor TrkB (Tanaka et al., 2006). These are important findings considering the role that BDNF plays in driving neurogenesis (Henry et al., 2007, Lee et al., 2002); a process implicated in the pathogenesis of depression and in therapeutic response to antidepressants (Nibuya et al., 1995, Saarelainen et al., 2003).

The objective of this study was to characterise the ability of the viral mimetic poly I:C to induce symptoms of depression and anxiety in rats secondary to its inflammatory actions. The ability of poly I:C to induce the tryptophan degrading enzyme IDO and impact upon central serotonin and kynurenine concentrations, and also to impact upon expression of the neurotrophin BDNF and its receptor TrkB were examined as potential mechanisms to link inflammation to depression.

Section snippets

Animals

Male Sprague–Dawley rats (250–350 g) were obtained from Harlan, UK. Rats were maintained on a 12 h light:12 h dark cycle (lights on at 08:00 h) in a temperature controlled room (22 ± 2 °C) and food and water were available ad libitum. All animals were singly housed for one week prior and for total duration of the study to facilitate accurate measurements of food, water and saccharin intake. The experimental protocols were in compliance with the European Communities Council directive (86/609/EEC).

Systemic poly I:C challenge

Poly

Poly I:C induces sickness behaviour characterised by reduced bodyweight gain and reduced locomotor activity

Poly I:C induced a significant decrease in body weight gain at 24 h post injection when compared to vehicle treated animals (p < 0.01) (Interaction, F(4, 36) = 32.04, p < 0.0001). By 48 h the change in body weight gain had returned to control levels (Fig. 1A). When poly I:C and vehicle treated animals were compared in the home-cage a significant decrease in locomotor activity was observed 6 h post injection (p < 0.01) (Interaction, F(4, 36) = 46.86, p < 0.0001) which had returned to baseline levels by 24 h (

Discussion

In the present study we used poly I:C to study inflammation-induced depression and anxiety behaviours in rats, and we determined the impact of this inflammatory challenge on the BDNF neurotrophin system and on the kynurenine/serotonin axis; two systems implicated in the pathogenesis of depression (Christmas et al., 2011, Maes et al., 2011, Muller and Schwarz, 2007, Nibuya et al., 1995, Raison et al., 2009, Saarelainen et al., 2003).

Conclusion

In this study we demonstrated that administration of the viral mimetic poly I:C to rats induced symptoms of depression and anxiety that could be distinguished from acute sickness behaviour in a temporal fashion. The initial sickness behaviours seem to correlate with a robust increase in poly I:C-induced cytokine expression, whereas the subsequent anxiety and depressive-like behaviours observed may be related to cytokine-induced changes in tryptophan metabolism and/or effects on the neurotrophin

Acknowledgments

The authors would like to acknowledge grant support from the EUFP7 MOODINFLAME consortium. BMcG is funded by a postgraduate award from Trinity College Dublin.

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