Depression- and exercise-associated stimuli exert contrasting effects on neural stem cell activity and paracrine...

Adult neurogenesis is dysregulated in neurological disorders, including depression. Adult neural stem cells (NSCs) are close to the vasculature and the cerebrospinal fluid, placing them in an ideal position to receive extrinsic signals and transmit these cues to the neurogenic niche. Herein, we aimed to explore how different systemic cues influence the regenerative properties of NSC secretome on recipient differentiating cells and microglia, key neurogenic components. To mimic signals that NSCs may sense in pathological conditions, we used the secretome of oxidative damaged cells (acute oxidative damage), and the serum from depressed mice (depression-associated chronic signals). Alternatively, NSCs were conditioned with different mitochondrial metabolic regulators to mimic a pro-metabolic NSC environment. Results showed that both injury and metabolic stimuli triggered the increase of NSC proliferation and mitochondrial fragmentation, along with the delivery of a neuroprotective secretome toward injured recipient cells. However, premature differentiation was only observed in NSCs sensing depression-associated chronic signals. The secretome from metabolic-stimulated NSCs favored neurogenesis of target cells, being enriched in regenerative metabolites. Depression-associated signals promoted a NSC secretome with reduced regenerative metabolites and microRNAs that repressed microglial phagocytosis and differentiation in target NSCs. At last, the reduction of oxidative phosphorylation-related proteins in the neurogenic niche of depressed mice was rescued by physical exercise. Our data indicate a central role of external metabolic and injury signals in regulating the neurogenic niche through NSC paracrine activity, unveiling distinct NSC regenerative responses upon transient acute and chronic injuries, and new cues for physical exercise-induced alleviation of depression.