Abstract
Parenchymal astrocytes have emerged as a potential reservoir for new neurons in non-neurogenic brain regions. It is currently unclear how astrocyte neurogenesis is controlled molecularly. Here we show that Notch signaling-deficient astrocytes can generate new neurons after injury. Using single-cell RNA sequencing, we found that, when Notch signaling is blocked, astrocytes transition to a neural stem cell-like state. However, only after injury do a few of these primed astrocytes unfold a neurogenic program, including a self-amplifying progenitor-like state. Further, reconstruction of the trajectories of individual cells allowed us to uncouple astrocyte neurogenesis from reactive gliosis, which occur along independent branches. Finally, we show that cortical neurogenesis molecularly recapitulates canonical subventricular zone neurogenesis with remarkable fidelity. Our study supports a widespread potential of parenchymal astrocytes to function as dormant neural stem cells.