Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior
Introduction
Major depressive disorders are commonly observed in many medical illnesses that share chronic inflammation as a common denominator (Evans et al., 2005, Raison et al., 2006). Inflammation-associated sickness behavior can be a confounding factor since it partially overlaps with several clinical symptoms of depression, including mood and cognitive changes, decreased motor activity, anhedonia (reduced sensitivity to reward), anorexia, alterations in brain monoaminergic neurotransmission and activation of the hypothalamic–pituitary–adrenal axis (reviewed in Castanon et al., 2002, Dantzer et al., 2008). However, longitudinal clinical studies performed on patients undergoing cytokine immunotherapy for the treatment of viral diseases or certain cancers (Capuron et al., 2001, Raison et al., 2005) have revealed that the overlap between cytokine-induced sickness and depression is only partial. Whereas sickness symptoms invariably appear in all patients immediately after the first administration of recombinant cytokines, only one-third of patients who receive cytokine immunotherapy eventually develop delayed major depressive disorders (Capuron et al., 2000, Capuron et al., 2001). Furthermore, pre-treatment with the selective serotonin reuptake inhibitor paroxetine prevents the occurrence of symptoms of depression, but not sickness (Capuron et al., 2002a). Together, these data point to a functional dissociation between the cytokine-induced sickness response and depression.
Patients who receive cytokine immunotherapy and develop major depression exhibit a prolonged decrease in circulating concentrations of tryptophan (TRP) that is accompanied by elevated concentrations of kynurenine (KYN) compared to non-depressed patients (Capuron et al., 2003). Since KYN is the major product of TRP degradation (Dale et al., 2000), these results can be explained by an enhanced activation of the TRP-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) (Wirleitner et al., 2003). This extrahepatic enzyme is activated in monocytes, macrophages and brain microglia in response to proinflammatory cytokines, mainly interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) (Fujigaki et al., 2006, Takikawa et al., 1999). In cancer patients treated by cytokine immunotherapy, the fall in plasma levels of TRP is correlated with the intensity of depressive symptoms (Capuron et al., 2002b), indicating that IDO activation might play a role in cytokine-induced depressive symptoms (Dantzer et al., 2008). By reducing TRP availability, IDO activation may impact brain serotoninergic neurotransmission, as TRP is the limiting factor for the synthesis of serotonin that plays a crucial role in the regulation of mood (Mattson et al., 2004). Concurrently, IDO activation results in an increased production of several neuroactive glutamatergic metabolites (Guillemin et al., 2005), and heightened glutamate receptor activity has been recently evidenced in major depression (Muller and Schwarz, 2007, Wichers et al., 2005).
Most studies aimed at identifying mechanisms of the depressive-like effects of cytokines have been carried out in rodents and are based on acute immune activation by the cytokine inducer lipopolysaccharide (LPS). The results of these studies can therefore be biased by the profound lethargy and motor impairment that occurs in the first few hours following immune stimulation (Deak et al., 2005, Dunn and Swiergiel, 2005, Renault and Aubert, 2006, Yirmiya, 1996). However, there are ways to circumvent this problem. In particular, it is possible to differentiate the initial phase of decreased motor activity induced by LPS with the delayed depressive-like behavior, measured by increased immobility in the forced swim and tail suspension tests, by carrying out these tests of depressive-like behavior 24 h after administration of LPS, when the sickness has dissipated and locomotor activity returns to normal (Frenois et al., 2007). In a similar manner, LPS-induced anhedonia, as assessed by reduced consumption of a sweetened solution, can be observed even after normalization of food intake (Frenois et al., 2007). More importantly, blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, or directly with the IDO competitive antagonist 1-methyltryptophan, prevents the LPS-induced development of depressive-like behavior, but not sickness behavior (O’Connor et al., in press). Taken together, these results clearly show that it is possible to dissociate sickness from depression in an acute model of immune activation. However, similar findings have not yet been reported in a chronic model of immune activation that would certainly be more relevant to the clinical situation.
We have selected for this purpose the inoculation of mice with Bacillus Calmette-Guerin (BCG), an attenuated form of Mycobacterium bovis that is used in several countries outside the United States as a vaccine for tuberculosis (Brewer, 2000). Intraperitoneal administration of BCG to mice is rapidly followed by long-lasting mycobacterial dissemination in all organs (particularly the lungs) except the brain (Tsenova et al., 1999) and by a drastic increase in circulating IFN-γ (Sander et al., 1995), a key cytokine for the activation of IDO (Takikawa et al., 1999). We first demonstrated that BCG inoculation causes a persistent activation of peripheral and brain IDO in mice for up to 3 weeks, resulting in decreased TRP levels (Moreau et al., 2005). The present series of studies was carried out to assess the short- and long-term behavioral consequences of BCG inoculation in mice. We hypothesized that the initial macrophage activation by BCG should be associated with a transient episode of sickness behavior followed by a longer occurrence of depressive-like behavior temporarily associated to IFN-γ-related IDO activation. Using various measures of sickness and depressive-like behaviors, we present exciting new data that are consistent with this hypothesis.
Section snippets
Animals and treatments
Male CD1 mice 8- to 10-week old were obtained from Charles River Laboratories. They were housed individually under a normal 12:12 h light:dark cycle (lights on at 08:00). Food and water were available ad libitum and room temperature was controlled (22 ± 1 °C). Mice were handled daily for at least 1 week before the onset of the experiment to minimize stress reactions to manipulation. They were randomly allocated to treatment conditions and tested in counterbalanced order. All animal care and use
BCG induces transient symptoms of sickness behavior
In order to assess sickness behavior induced by BCG, 3 classical sickness symptoms have been assessed, namely body weight loss, locomotor impairment and febrile response (Dantzer, 2006). Fig. 1 represents the time-course of the effect of BCG on body weight. Treatment (F(1, 210) = 13.8, p < .01) and time (F(10, 210) = 183.3, p < .001) factors, as well as their interaction (F(10, 210) = 6.8, p < .001) were significant. Both groups presented the same growth curve before treatment. BCG inoculation induced a
Discussion
Although cytokine-induced sickness behavior is no longer a curiosity, the mechanisms by which chronic inflammation and depression are linked still remain elusive (Dantzer et al., 2008, Raison et al., 2006). Attempts to elucidate these mechanisms have been hampered by the lack of a suitable animal model to study the delayed behavioral and neurochemical alterations induced by chronic systemic inflammation. In the present study, the use of a murine model of chronic immune activation by BCG
Acknowledgments
MM was supported by a doctoral fellowship from the FRM (Fondation pour la Recherche Médicale). This study was funded by INRA, CNRS, Région Aquitaine, the French Ministry of Research (ACI “Neurosciences Intégratives et Computationnelles” to N.C.) and National Institutes of Health (NIH) to KWK (MH-51569 and AG-029573) and RD (R01 MH-71349 and MH-079829).
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