The brain is formed during embryonic development, where neural stem/progenitor cells (NSPCs) generate neurons and glial cells. A small population of NSPCs is set aside during development and will remain quiescent until adulthood. Indeed, in the adult brain, NSPCs persist in specific regions, referred to as neurogenic niches, and are able to generate new neurons in a process called adult neurogenesis. In mammalians, there are at least two neurogenic niches in adulthood: the sub­ ventricular zone (SVZ) of the lateral ventricle, where NSPCs generate inhibitory interneurons of the olfactory bulb, and the sub-granular zone (SGZ) of the dentate gyms (DG) of the hippocampus, where NSPCs produce excitatory neurons which integrate in the hippocampal circuitry. Adult NSPCs are mainly quiescent and first need to be activated to eventually produce neurons. Over the last years, metabolism bas been shown to be a patent regulator of NSPC behavior and neurogenesis, yet its role in the transition from quiescence to proliferation is not fully understood. While quiescent stem cells have been considered mainly as glycolytic cells, recent publications (including work from our group), demonstrated that quiescent NSPCs also rely on mitochondrial metabolism. Indeed, mitochondria are abundant in NSPCs and mitochondrial dynamics affect self-renewal and fate choice.
In th is thesis, we investigated the raie of mitochondrial pyruvate carrier (MPC) in NSPCs. MPC is a gatekeeper for pyruvate entry into mitochondria, and therefore links glycolysis with mitochondrial metabolism. We showed that quiescent NSPCs have high levels of MPC, suggesting an active role in the quiescence state. Deletion of MPC l in NSPCs led to a remarkable increase in activation, which resulted in an overall increase in hippocampal neurogenesis.
It remains unknown whether similar metabolic pathways are required for both neurogenic niches. We therefore conducted a comparative analysis of NSPCs extracted from bath regions. Interestingly, we found that DG and SVZ NSPCs retain a distinct gene expression profile in vitro, despite being cultured under the same conditions, and exhibit differences in lipid metabolic pathways, such as in carnitine synthesis and fatty acid P-oxidation. ln addition, DG and SVZ NSPCs seem primed at the chromatin level to differentiate in respectively excitatory and inhibitory neurons.
Taken together, these findings support the idea that metabolism is a central regulator of NSPC function.