Brain Regeneration - in vitro and in vivo studies of exercise-related effects on brain plasticity

Neural stem and progenitor cells in the central nervous system provide a source of new neurons, astrocytes, and oligodendrocytes during development, as well as during adulthood. Germinal regions of the adult brain, such as the hippocampus, subventricular zone, and the subcallosal zone, are of great interest, because they provide the possibility for enhancing brain plasticity or contributing to endogenous cell replacement after injury or disease. Voluntary exercise has been recently shown to robustly induce cellular and structural plasticity, thereby contributing to overall brain health. This thesis focuses on exercise-related effects on cell genesis of neurons and oligodendrocytes in vitro and in vivo. In Paper I, we demonstrated that exercise-induced, endogenously released opioid peptide β-endorphin enhanced oligodendrogenesis in adult hippocampal progenitors in vitro. Adult hippocampal progenitors were further used as a model system to study the signaling pathways that lead to β-endorphin-induced oligodendrogenesis. Results revealed a requirement for the helix-loop-helix transcriptional regulator “Inhibitor of Differentiation” (Id)-1 in opioid-induced oligodendrogenesis, and concomitant decreased expression of the proneural transcriptional activator Mash-1. In Paper II, we study the effects of voluntary exercise during adulthood on neurogenesis and behavior, subsequent to irradiation in the young mouse brain. The immature brain is extremely vulnerable to irradiation, including long-lasting detrimental effects to hippocampal neurogenesis and behavior. The brains of young mice were irradiated, and the acute effects of irradiation were measured, as well as the effects of voluntary running on hippocampal neurogenesis three months after irradiation. Voluntary exercise following irradiation restored the hippocampal stem cell pool and increased neurogenesis. Additionally, voluntary exercise ameliorated irradiation-induced alterations in behavior. Moreover, the orientation of immature neurons in the dentate gyrus of the hippocampus was perturbed after irradiation; however, voluntary exercise restored the proper orientation. In Paper III, we proceeded to investigate potential effects of voluntary exercise on oligodendrogenesis. By irradiating the brains of young mice, we have demonstrated an efficient reduction in the total number of Olig2-positive cells, which are considered to be mainly oligodendroglial cells, of the corpus callosum without affecting the number of newborn glial progenitor cells. We determined that, with time, the irradiation effects on the number of Olig2-positive cells in the corpus callosum was reduced, probably due to an overproduction of oligodendrocytes during the juvenile stage. Voluntary running had no effect on cell survival, oligodendrogenesis or myelin density in the corpus callosum. These results suggest that a neurogenic niche, such as the subgranular zone of the hippocampus, might be more responsive to exercise-induced signals regulating cell genesis. Brain regeneration: in vitro and in vivo studies of exercise-related effects 5 In conclusion, this thesis demonstrates the usefulness of physical exercise for functional and structural brain recovery, with special emphasis on insults to the juvenile brain. In addition, these results highlight the capacity of the adult brain to regenerate through activation of endogenous neural progenitors and stem cells.