Impaired spatio-temporal coordination of subventricular neurogenesis is restored by physical exercise

A major aim of neural stem cells field is to harness endogenous neurogenesis to replace neurons damaged as a consequence of brain damage and neurodegeneration. Olfactory interneurons arise throughout life from neural stem cells residing in the subventricular zone (SVZ) of the lateral ventricle. Post mitotic neuroblast then migrate along the rostral migratory stream (RMS) to the olfactory bulb where undergone to fully maturation and functional integration in the olfactory circuitry. To ensure a continuous source of newly-generated adult interneurons, stem and progenitor cell proliferation, neuroblast migration, and terminal differentiation must be tightly coordinated. In this study we analyzed the effect of physical exercise in orchestrating the different steps of subventricular neurogenesis in a mouse lacking the antiproliferative gene Btg1 which displays an impaired subventricular neurogenesis. As previously demonstrated Btg1 loss-of-function mice exhibit a strong reduction of proliferation associated with a premature exit from the cell cycle and an anticipated migration toward the olfactory bulb where the neuroblast fail to fully differentiate and consequently to be specifically recruited in olfactory-dependent memory circuitry. In the study we demonstrate that running fully reverses the profound reduction of proliferation within the SVZ of the lateral ventricle in the Btg1-deficient mice, mainly through a recruitment and expansion of the quiescent neural stem cells (NSCs) . Moreover, cell cycle analysis reveals that 12 days of running induces a shortening of the S-phase and consequently of the whole cell cycle length in both neural stem (GFAP+, type C) and progenitor (DCX+, type A) cells of Btg1 knockout mice, allowing the restoring of a proper coordination between the cell cycle exit and the initial phase of post-mitotic neuroblasts migration. These events result in a increased rate of terminal maturation and integration in the olfactory- dependent memory circuits. Finally, as previously stated by others, we does not detect any beneficial effect of running in the subventricular zone wild type mice . All together these in vivo data suggest that a) the quiescent state of neural stem cells lacking the cell cycle inhibitory control can be reactivated by running; b) the cell cycle kinetics in the adult SVZ plays a pivotal role not only for proliferation but also for the tight coordination of cell cycle exit, migration and terminal differentiation. In vitro analysis demonstrates that running induces a great expansion of primary neurospheres isolated by Btg1 ko subvrenticular zone, supporting the in vivo observation about the increase of neural stem pool in this neurogenic niche. However the running-dependent hyperproliferation of the neural stem cells leads to a rapid depletion of the stem cell pool and /or to its ability to further expand in vitro. This fact suggest that the effect of running on the Btg1 knock out neural stem cell proliferation is not cell-autonomous but strictly dependent on niche environment. We can hypothesized that the presence of still unknown factors triggered by physical activity in the subventricular niche promotes and maintains in vivo the hyperproliferative state of neural stem cells in the Btg1 knockout mice.