Behavioral effects of infection with interferon-gamma adenovector

Abstract

Anxiety and depression of unknown etiology are frequent complications of the systemic autoimmune disease lupus erythematosus (SLE). To elucidate key pathogenic factors we study the “autoimmunity-associated behavioral syndrome” (AABS) in lupus-prone MRL-lpr mice. Based on the evidence that serum levels of the neuroactive cytokine interferon-gamma (IFN-gamma) are increased both in human and murine forms of SLE, the present study examines whether sustained IFN-gamma production in non-autoimmune mice induces deficits comparable to AABS, particularly in tasks reflective of emotional reactivity and motivated behavior. For this purpose, wild-type and IFN-gamma knockout C57BL/6J mice were infected with adenovirus carrying the cDNA for murine IFN-gamma (i.p. 2×10 8 pfu of virus per mouse) and shortly thereafter tested in the behavioral battery used in the detection of AABS. Serum levels of IFN-gamma were found to peak 24 h after the infection, normalized within 5 days. Although all infected animals showed reduced food/water intake and body weight, the recovery rate was slower in groups injected with IFN-gamma virus. No deficits were observed in the models of anxiety, but blunted responsiveness in the sucrose preference test (a putative model of anhedonia) lasted well beyond the IFN-gamma clearance period. These results suggest that a relatively brief elevation in systemic IFN-gamma levels impairs ingestive behavior and leads to prolonged changes in motivated behavior. As such, they are consistent with the hypothesis that upregulation in synthesis of pro-inflammatory cytokines contributes to induction of AABS and more specifically, to limbic system dysfunction during lupus-like disease.