The Effects of Exercise‐Associated Factors on Hippocampal Progenitor Cell Dynamics Are Mediated by Cannabinoid Type 2 Receptors

Neural stem/progenitor cells (NSPCs) operate in specialized niches of the adult mammalian brain, where their proliferative and differentiative potential is modulated by a myriad of factors. Emerging evidence sheds light on the interaction between cannabinoids and neurotrophic factors underlying a major regulatory force of NSPC dynamics. Previous data show that cannabinoid type 2 receptors (CB2Rs) tightly regulate the actions of brain-derived neurotrophic factor (BDNF), a neurotrophic factor highly upregulated during physical exercise. However, further research into the effects of exercise-associated neurotrophic factors in the regulation of NSPCs is still necessary. Therefore, we aimed at exploring the effects of exercise-associated factors in postnatal hippocampal neurogenesis and how CB2Rs regulate this process. By using dentate gyrus-derived neurospheres and treating them with a combination of exercise-associated factors, as an in vitro proxy for exercise, we found that these factors significantly promoted cell proliferation, an action partially reduced when CB2Rs were blocked. Moreover, CB2Rs were shown to be required for the actions of this exercise-mimicking cocktail in early neuronal commitment and differentiation. However, late neuronal differentiation promoted by exercise-associated factors remained unaltered in the presence of CB2R ligands. Together, these data suggest that CB2R actions are preponderant in early stages of hippocampal neurogenesis promoted by exercise. Astroglial late differentiation was also accelerated by a combination of exercise-associated factors, an effect prevented by CB2R blockage. This work provides a deeper understanding of the mechanisms underlying the actions of cannabinoids and exercise on NSPC regulation, highlighting the role of CB2R in modulating exercise-induced hippocampal neurogenesis.