Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior.
Although cytokine-induced sickness behavior is now well-established, the mechanisms by which chronic inflammation and depression are linked still remain elusive. Therefore this study aimed to develop a suitable model to identify the neurobiological basis of depressive-like behavior induced by chronic inflammation, independently of sickness behavior. We chose to measure the behavioral consequences of chronic inoculation of mice with Bacillus Calmette-Guerin (BCG), which has been shown to chronically activate both lung and brain indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates the occurrence of depressive-like behavior following acute innate immune system activation. BCG inoculation induced an acute episode of sickness (approximately 5 days) that was followed by development of delayed depressive-like behaviors lasting over several weeks. Transient body weight loss, reduction of motor activity and the febrile response to BCG were dissociated temporarily from a sustained increase in the duration of immobility in both forced swim and tail suspension tests, reduced voluntary wheel running and decreased preference for sucrose (a test of anhedonia). Moreover, we show that a distinct pattern of cytokine production and IDO activation parallels the transition from sickness to depression. Protracted depressive-like behavior, but not sickness behavior, was associated with sustained increase in plasma interferon-gamma and TNF-alpha concentrations and peripheral IDO activation. Together, these promising new data establish BCG inoculation of mice as a reliable rodent model of chronic inflammation-induced depressive-like behaviors that recapitulate many clinical observations and provide important clues about the neurobiological basis through which cytokines may have an impact on affective behaviors.
Moreau
Maïté
M
INRA, UMR 1286 PsyNuGen, Bâtiment UFR Pharmacie - 2° Tranche - 2° Etage, Case courrier 34, Université Victor Ségalen Bordeaux 2, 146 rue Léo Saignat, CNRS, UMR 5226, IFR8, F-33076 Bordeaux, France.
André
Caroline
C
INRA, UMR 1286 PsyNuGen, Bâtiment UFR Pharmacie - 2° Tranche - 2° Etage, Case courrier 34, Université Victor Ségalen Bordeaux 2, 146 rue Léo Saignat, CNRS, UMR 5226, IFR8, F-33076 Bordeaux, France.
O'Connor
Jason C
JC
Integrative Immunology and Behavior Program, Department of Animal Sciences, College of Agricultural, Environmental and Consumer Sciences, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Dumich
Sara A
SA
Department of Kinesiology, College of Applied Health Studies, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Woods
Jeffrey A
JA
Department of Kinesiology, College of Applied Health Studies, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Kelley
Keith W
KW
Integrative Immunology and Behavior Program, Department of Animal Sciences, College of Agricultural, Environmental and Consumer Sciences, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Dantzer
Robert
R
Integrative Immunology and Behavior Program, Department of Animal Sciences, College of Agricultural, Environmental and Consumer Sciences, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Lestage
Jacques
J
INRA, UMR 1286 PsyNuGen, Bâtiment UFR Pharmacie - 2° Tranche - 2° Etage, Case courrier 34, Université Victor Ségalen Bordeaux 2, 146 rue Léo Saignat, CNRS, UMR 5226, IFR8, F-33076 Bordeaux, France.
Castanon
Nathalie
N
INRA, UMR 1286 PsyNuGen, Bâtiment UFR Pharmacie - 2° Tranche - 2° Etage, Case courrier 34, Université Victor Ségalen Bordeaux 2, 146 rue Léo Saignat, CNRS, UMR 5226, IFR8, F-33076 Bordeaux, France. Electronic address: nathalie.castanon@bordeaux.inra.fr.
D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003863:Depression / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D013550:Swimming / Q000523:psychology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*
D001500:BCG Vaccine; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma