title: Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.
abstract: Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143  Rome, Italy. stefano.farioli@inmm.cnr.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattera
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.forename: Manuela
authors.initials: M
authors.lastname: Ceccarelli
authors.forename: Luca
authors.initials: L
authors.lastname: Leonardi
authors.forename: Daniele
authors.initials: D
authors.lastname: Saraulli
authors.forename: Marco
authors.initials: M
authors.lastname: Costanzi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cestari
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rouault
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D012420:Running / Q000502:physiology*
chemical_list: C489552:Btg1 protein, mouse; D009363:Neoplasm Proteins
keywords: Adult neurogenesis; Cell cycle kinetics; Differentiation; Neural stem/progenitor cells; Pattern separation; Proliferation; Running