Physical exercise rescues defective neural stem cells and neurogenesis in the adult subventricular zone of Btg1 knockout mice

Abstract

Adult neurogenesis occurs throughout life in the dentate gyrus (DG) and the subventricular zone (SVZ), where glia-like stem cells generate new neurons. Voluntary running is a powerful neurogenic stimulus triggering the proliferation of progenitor cells in the DG but, apparently, not in the SVZ. The antiproliferative gene Btg1 maintains the quiescence of DG and SVZ stem cells. Its ablation causes intense proliferation of DG and SVZ stem/progenitor cells in young mice, followed, during adulthood, by progressive decrease of the proliferative capacity. We have previously observed that running can rescue the deficit of DG Btg1-null neurogenesis. Here, we show that in adult Btg1-null SVZ stem and neuroblast cells, the reduction of proliferation is associated with a longer cell cycle and a more frequent entry into quiescence. Notably, running increases proliferation in Btg1-null SVZ stem cells highly above the levels of sedentary wild-type mice and restores normal values of cell cycle length and quiescence in stem and neuroblast cells, without affecting wild-type cells. Btg1-null SVZ neuroblasts show also increased migration throughout the rostral migratory stream and a deficiency of differentiated neurons in the olfactory bulb, possibly a consequence of premature exit from the cycle; running, however, normalizes migration and differentiation, increasing newborn neurons recruited to the olfactory circuitry. Furthermore, running increases the self-renewal of Btg1-null SVZ-derived neurospheres and, remarkably, in aged Btg1-null mice almost doubles the proliferating SVZ stem cells. Altogether, this reveals that SVZ stem cells are endowed with a hidden supply of self-renewal capacity, coupled to cell cycle acceleration and emerging after ablation of the quiescence-maintaining Btg1 gene and following exercise.

Interaction Between Neurogenic Stimuli and the Gene Network Controlling the Activation of Stem Cells of the Adult Neurogenic Niches, in Physiological and Pathological Conditions

“…In the SVZ, as mentioned above, running is able to activate stem cells in aged but not in adult mice (Brown et al, 2003;Blackmore et al, 2009;Mastrorilli et al, 2017; Table 2). Moreover, the deletion of p21Cip1 or Btg1 enables running to activate adult as well as aged SVZ stem and progenitor cells, with improvement of olfactory circuits and threshold (Mastrorilli et al, 2017;Nicolis di Robilant et al, 2019 ; Table 3).…”

“…In the SVZ of adult mice, running is not effective as an activator of stem cells (B cells; Brown et al, 2003;Mastrorilli et al, 2017), although prolonged running activates the proliferation of neuroblasts (A cells; Bednarczyk et al, 2009). In aged mice, however, running activates SVZ stem cells (neurospheres) as well as neuroblasts (Blackmore et al, 2009; Table 2).…”

Pathways of Prevention: A Scoping Review of Dietary and Exercise Interventions for Neurocognition

“…Several other neuropathological features of adult neurogenesis may explain their importance to the lifestyle and neurocognitive decline association. It is notable that the two primary areas of adult neurogenesis in mammals are in close proximity and have interconnections to neurocircuitry critical for learning/memory and executive functions: the dentate gyrus (proximal to the hippocampal gyrus) [259,328] and the subventricular zone (proximal to the caudate nucleus) [329][330][331][332][333]. As noted earlier, these are also the two primary brain circuits implicated in AD and vascular cognitive impairment, respectively.…”

Reduction of Movement in Neurological Diseases: Effects on Neural Stem Cells Characteristics

“…Despite this evidence, there are limited hints about the role of exercise on neurogenesis in SVZ which impact remains debated (Brown et al, 2003 ; Bednarczyk et al, 2009 ; Blackmore et al, 2012 ; Chae et al, 2014 ). On the contrary, the positive role of exercise, especially in the case of previous brain impairment, is well assured (Lee et al, 2016 ; Mastrorilli et al, 2017 ). Finally, the impact on the hippocampus is more extensive and established (Lee et al, 2016 ; Mastrorilli et al, 2017 ; Snyder et al, 2017 ; Bouchard-Cannon et al, 2018 ; Firth et al, 2018 ; Masrour et al, 2018 ).…”

“…On the contrary, the positive role of exercise, especially in the case of previous brain impairment, is well assured (Lee et al, 2016 ; Mastrorilli et al, 2017 ). Finally, the impact on the hippocampus is more extensive and established (Lee et al, 2016 ; Mastrorilli et al, 2017 ; Snyder et al, 2017 ; Bouchard-Cannon et al, 2018 ; Firth et al, 2018 ; Masrour et al, 2018 ).…”