Microglia modulate hippocampal neural precursor activity in response to exercise and aging

Abstract

Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX 3CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blocking antibody against the CX 3CL1 receptor, CX 3CR1, but not control IgG, dramatically reduced then eurosphere formation frequency in mice that had exercised. While an increase in soluble CX 3CL1 was observed following running, reduced levels ofthis chemokine were found in the aged brain. Lower levelso f CX 3CL1 with advancing age correlated with the natural decline in neural precursor cell activity, a state that could bepartially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX 3CL1-CX 3CR1 axis critically contributes toward this process. © 2012 the authors.