Neurogenic activation of striatal astrocytes and fate of their neuronal progeny

The stem cell (SC) potential, i.e. the capacity to generate new cells, varies across mammalian organs. While some, like the skin and intestines, maintain high cellular turnover rates, others, such as skeletal muscles, possess dormant SCs that activate on demand in response to injury. The mature mammalian brain lacks regenerative capacity, and for this reason it has long been thought that it may lack a stem cell compartment. Nonetheless, it is now known that neurogenesis extends to postnatal development with some variations across species and brain regions, and in two specialized niches, the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) it persists also during adulthood. In these regions subpopulation of astrocytes acted as neural stem cells (NSCs) actively producing neurons through life. This organization of the adult brain NSC potential is aligned with established models in SC research whereby SCs are rare and anatomically restricted cells. Furthermore, the SVZ and DG progenitors are committed to the production of olfactory bulb (OB) interneurons and dentate gyrus (DG) granule cells, indicating a very limited neurogenic potential in the adult brain. In contrast to this view, comparative studies showed that in some mammalian species, including humans, low levels of neurogenesis can also occur in regions normally non-neurogenic in mice, such as the striatum and neocortex. Further, brain lesions can induce neurogenesis in these same regions also in laboratory rodents. In the striatum, the origin of part of the newly generated neurons could be traced to local parenchymal astrocytes. These results revealed the presence of a latent NSC potential outside of the canonical niches. However, the prevalence, distribution, behavior and cell fate potential of these ectopic NSCs have not been established. Consequently, the extent to which the neurogenic potential of the mature brain parenchyma differs from that of conventional neurogenic niches remains to be determined. To fill these gaps, during my PhD, I focused on a mouse model of striatal neurogenesis obtained through intra-striatal infusion of quinolinic acid (QA) that causes an excitotoxic lesion. In this model a huge number of immature neuroblasts is generated for several months exclusively from local astrocytes. Following excitotoxic injury, striatal astrocytes spontaneously activate their NSC potential at the lesion border, displaying similar spatiotemporal dynamics as observed in canonical niches. Our data indicate that the prevalence of neurogenic astrocytes in the striatal parenchymal is similar to that in the SVZ niche. Striatal astrocytes neurogenic activation leads to the continuous and widespread generation of LGE-class interneurons resembling those produced in the adult V-SVZ and during the perinatal period in various brain regions. Remarkably, despite their transient nature, newly generated striatal neurons functionally integrate into brain circuits, suggesting a potential plastic role in post-lesion circuit reorganization. These findings challenge the notion that NSCs are rare cells confined to specific regions in the adult brain. Additionally, contrary to previous beliefs, the brain parenchyma is largely conducive to the maintenance and activation of NSCs, similarily to canonical niches. Notably, adult V-SVZ NSCs and parenchymal astrocytes share a common cell fate potential. However, whether the neurons generated by parenchymal astrocytes play a role in post-lesion recovery remains uncertain. Overall, the disparity in neurogenic activity between the parenchyma and canonical niches seems to stem not from differences in NSC presence, expansion capacity, or fate potential, but rather from context-dependent regulatory mechanisms.