Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke

Resident neural stem and progenitor cells, collectively termed neural precursor cells (NPCs), reside in a well-defined neurogenic niche in the subventricular zone (SVZ) and contribute to ongoing postnatal neurogenesis. It is well established that the NPC niche can alter the behavior of NPCs. NPC activation is a promising therapeutic strategy for brain repair. The drug metformin has been shown to activate neural stem cells, promote differentiation, and lead to functional motor recovery in a neonatal stroke model. We demonstrate that metformin-induced NPC expansion and functional recovery is sex hormone dependent. Metformin increases the size of the NPC pool in adult females, but not males, and promotes cognitive recovery in a model of brain injury in females, but not males. Our data demonstrate that metformin has age- and sex-dependent effects on NPCs that correlate with functional recovery, which has important implications for neural repair.