A Widespread Neurogenic Potential of Neocortical Astrocytes Is Induced by Injury

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. [Display omitted] •Cortical astrocytes generate interneurons after Notch signaling ablation and injury•Silencing of Notch elicits a neural stem cell program irrespective of injury•Neurogenesis by astrocytes unfolds independent of reactive gliosis•Cortical and subventricular zone neurogeneses display similar molecular programs Zamboni et al. show that cortical astrocytes can generate interneurons following Notch signaling depletion and injury. Transcriptional analysis reveals early activation of a neural stem cell program that arises irrespective of injury condition. Neurogenesis by cortical astrocytes recapitulates canonical neurogenic programs and unfolds independent of reactive gliosis.