The mechanisms underlying in vivo activation of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates in the brain the induction of depressive-like behavior by peripheral innate immune system stimulation are still poorly understood. By monitoring how cytokines parallel IDO mRNA expression in the brain in response to intraperitoneal lipopolysaccharide injection in mice, we report a time-dependent induction of IDO expression in both the hippocampus and hypothalamus that was associated with a specific structure-dependent expression of proinflammatory cytokines, particularly interferon-γ. This study suggests that different mechanisms regulate the activation of IDO by lipopolysaccharide in various brain structures.