CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

Abstract

The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. AbstractThe similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immuneinflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3 days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxyg...

Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice

“…At day 5 after CD40AB, CS fear learning is impaired, in the absence of an additional memory deficit at day 6 (Cathomas et al, 2015b;Gast et al, 2013).…”

“…The findings that IP TNF induces sickness and reduces saccharin drinking add to the evidence that these two states co-occur. Previously, we have proposed that under these conditions reduced reward drinking is more parsimoniously referred to as extended sickness (Cathomas et al, 2015b;Pryce and Fontana, 2016). This is because immune-inflammatory challenges produce a different constellation of behavioral changes e.g.…”

“…There is interest in the inter-relationship between reduced reward interest and the decreased appetite/weight loss of sickness with respect to there being a common pathophysiology (Dantzer et al, 2008;Raison et al, 2013). Immune-inflammatory challenges such as LPS and CD40AB induce sickness including weight loss, and co-occurring with this and extending beyond it is a reduction in reward drinking (Aubert and Dantzer, 2005;Biesmans et al, 2013;Cathomas et al, 2015b;Salazar et al, 2012). The findings that IP TNF induces sickness and reduces saccharin drinking add to the evidence that these two states co-occur.…”

“…A divider was used to form two compartments in the home-cage, and mice were habituated to being in separate compartments and to drinking from 15 ml polypropylene centrifuge tubes (Falcon, BD, Franklin Lakes, USA) from which the tip had been removed (Cathomas et al, 2015b). Each mouse was presented with two such tubes placed adjacently and fixed to the cage lid.…”

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

“…Circadian activity of individual mice was studied using IntelliCage (TSE), an automated system for monitoring home-cage activity [48]. Each mouse is fitted with a subcutaneous transponder that records: visits to the operant devices located in the cage corners; operant nosepokes into a sensor …”