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 wildtype 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 1 and Sox2 1 ) and progenitor (NeuroD1 1 ) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null earlypostnatal 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. STEM

Terminal Differentiation of Adult Hippocampal Progenitor Cells Is a Step Functionally Dissociable from Proliferation and Is Controlled by Tis21, Id3 and NeuroD2

“…Remarkably, despite the strong neurogenic action, we did not uncover any effect of fluoxetine on the length of the cycle of wild-type stem and progenitor cells, unlike what we have observed for another neurogenic stimulus, i.e., physical exercise (Farioli-Vecchioli et al, 2014b). This indicates that a neurogenic stimulus can induce neural proliferation without necessarily altering cell cycle length.…”

“…For this, we calculated the S phase length (Ts)—which is the main determinant of cell cycle duration—using a new accurate procedure (Brandt et al, 2012; Farioli-Vecchioli et al, 2014b; Figures 2A–D). We treated 39-day-old mice with fluoxetine daily for 21 days; this protocol was used in order to maximize the proliferative effects of fluoxetine.…”

Changes in hippocampal neurogenesis throughout early development

“…Physical activity is a robust stimulus for adult hippocampal neurogenesis in rodents from birth to the oldest age (Kannangara et al, 2011;Kronenberg et al, 2003;Marlatt et al, 2012;Steiner et al, 2008;van Praag et al, 2005van Praag et al, , 1999Wu et al, 2008). Running has the potential to limit the massive decrease in neurogenesis observed in aged animals , an action which seems directly linked to the stimulation of NPC proliferation (Kronenberg et al, 2003;Lugert et al, 2010;Steiner et al, 2008) and/or shortening of cell cycle length (Farioli-Vecchioli et al, 2014). Housing rodents in enriched environments has also been shown to increase hippocampal neurogenesis, an effect maintained in old age (Kempermann et al, 1998).…”

On the Run for Hippocampal Plasticity

“…Running may shorten the cell cycle of rapidly amplifying progenitor cells (Farioli-Vecchioli et al 2014; see, however, Fischer et al 2014) and accelerate neuronal maturation of adult-born DG neurons (Zhao et al 2006; Piatti et al 2011; Steib et al 2014). In particular, retroviral labeling studies (van Praag et al 2002; Zhao et al 2006) have shown that running promotes spine formation in the outer molecular layer of adult-born dentate granule cell dendrites (Zhao et al 2014).…”