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

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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.

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Acknowledgements

This work was supported by CNR projects DSB.AD004.093 to Felice Tirone.

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    Authors and Affiliations

    1. Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy

      Valentina Mastrorilli, Daniele Saraulli, Marco Costanzi, Stefano Farioli-Vecchioli & Felice Tirone

    2. University Roma 3, Rome, Italy

      Chiara Scopa

    3. European Brain Research Institute (EBRI), Rome, Italy

      Chiara Scopa & Raffaella Scardigli

    4. Institute of Translational Pharmacology, National Research Council, Rome, Italy

      Raffaella Scardigli

    5. Department of Human Sciences, LUMSA University, Rome, Italy

      Daniele Saraulli & Marco Costanzi

    6. Centre Léon Bérard-Université Claude Bernard Lyon I, Lyon, France

      Jean-Pierre Rouault

    7. Dipartimento di Biologia e Biotecnologie Charles Darwin, Sapienza Università di Roma, Rome, Italy

      Valentina Mastrorilli

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    1. Valentina Mastrorilli
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    Stefano Farioli-Vecchioli and Felice Tirone contributed equally.

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    429_2017_1376_MOESM1_ESM.tif

    Supplement figure 1. Volume measurement of the SVZ carried out in 2 month-old (A) and in 15 month-old mice (B) did not show any differences among the experimental conditions analyzed (TIF 238 KB)

    429_2017_1376_MOESM2_ESM.tif

    Supplement figure 2. Quantification of the number per SVZ area of the different markers demonstrated that 5 days of running enhanced SVZ neurogenesis in the KO RUN mice with respect to the KO NO RUN but not when compared with WT NO RUN mice. Graphs indicated a significant increment in the KO RUN mice with respect to the KO NO RUN mice of Ki67-dividing cells (genotype x exercise interaction F1,78= 32.76 p<0.001, followed by the analysis of simple effects, p<0.01 KO RUN vs. KO NO RUN), of total B stem cells (GFAP+, genotype x exercise interaction F1,56= 39.87 p<0.001, followed by the analysis of simple effects p<0.01) and of total A neuroblast cells (Dcx+, genotype x exercise interaction F1,56= 18.87 p<0.001, followed by the analysis of simple effects p<0.01). Moreover, we detected a significant increase of dividing B cells in the KO RUN mice with respect to the KO NO RUN (Ki67+/GFAP+, genotype x exercise interaction F1,23= 31.43 p<0.01, followed by analysis of simple effects p<0.01) and of A neuroblast cells (Ki67+/Dcx+, genotype x exercise interaction F1,23= 12.56 p<0.01, followed by analysis of simple effects, p<0.05). Cell numbers in the SVZ are means ± SEM of the analysis of at least three animals per group. *p<0.05, ***p<0.001 (TIF 334 KB)

    429_2017_1376_MOESM3_ESM.tif

    Supplement figure 3. Graphs illustrating that 5 days of physical activity induced in the KO RUN mice a significant shortening of S-phase in comparison with the KO NO RUN mice (genotype x exercise interaction F1,44= 13.98 p<0.01, followed by the analysis of simple effects, ***p&#x003E;0.001) and a concomitant increase of the fraction of cells exiting from the S-phase (KO RUN vs KO NO RUN genotype x exercise interaction F1,44= 19.56 p&#x003C;0.01, followed by the analysis of simple effects, ***p< 0.001). These events result in a shortening of the whole cell cycle length in the KO RUN with respect to the KO NO RUN mice (genotype x exercise interaction F1,44= 26.97, p<0.01, followed by the analysis of simple effects, *p<0.05). Cell cycle analysis was performed in the SVZ of at least three animals per group. Data obtained through the 12 day running protocol are those shown in Figure 2. * p<0.05, *** p<0.001 (TIF 273 KB)

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    Mastrorilli, V., Scopa, C., Saraulli, D. et al. Physical exercise rescues defective neural stem cells and neurogenesis in the adult subventricular zone of Btg1 knockout mice. Brain Struct Funct 222, 2855–2876 (2017). https://doi.org/10.1007/s00429-017-1376-4

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