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Peripheral inflammatory stimuli increase proinflammatory cytokines in the bloodstream and central nervous system and activate microglial cells. Here we tested the hypothesis that contrasting environments mimicking sedentary and active lives would be associated with differential microglial morphological responses, inflammatory cytokines concentration, and virus load in the peripheral blood. For this, mice were maintained either in standard (standard environment) or enriched cages (enriched environment) and then subjected to a single (DENV1) serotype infection. Blood samples from infected animals showed higher viral loads and higher tumor necrosis factor-α (TNFα) mRNA concentrations than control subjects. Using an unbiased stereological sampling approach, we selected 544 microglia from lateral septum for microscopic 3D reconstruction. Morphological complexity contributed most to cluster formation. Infected groups exhibited significant increase in the microglia morphological complexity and number, despite the absence of dengue virus antigens in the brain. Two microglial phenotypes (type I with lower and type II with higher morphological complexity) were found in both infected and control groups. However, microglia from infected mice maintained in enriched environment showed only one morphological phenotype. Two-way ANOVA revealed that environmental changes and infection influenced type-I and II microglial morphologies and number. Environmental enrichment and infection interactions may contribute to microglial morphological change to a point that type-I and II morphological phenotypes could no longer be distinguished in infected mice from enriched environment. Significant linear correlation was found between morphological complexity and TNFα peripheral blood. Our findings demonstrated that sedentary-like and active murine models exhibited differential microglial responses and peripheral inflammation to systemic non-neurotropic infections with DENV1 virus.