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We here report that voluntary wheel running led to a regional increase in the number of newly generated cortical microglia. We asked how adult cortical cell genesis would respond to environmental enrichment and physical activity, both stimuli that robustly induce adult hippocampal neurogenesis. After labeling proliferating cells with bromodeoxyuridine (BrdU) and immunohistochemical detection of BrdU, we found that both experimental paradigms did not result in general effects on cell proliferation and cell genesis in the neocortex. However, there were regionally and layer specific changes in the number of BrdU marked cells, both 1 day and 4 weeks after BrdU. Environmental enrichment led to a significant increase in the number of new astrocytes in layer 1 of the motor cortex. Voluntary wheel running, in contrast, caused an induction in the proliferation of microglia in superficial cortical layers of several brain regions. Under no condition was the number of new oligodendrocytes measurably enhanced. In contrast to the hippocampus, we did not find any new neurons in the cortex. The physiological ‘activation’ of microglia adds a new aspect to the question of microglial function in the healthy brain and of how adult brain cells can plastically react to physiological stimuli.