Deciphering the molecular networks that govern the neurogenic potential of astrocytes in the adult mouse brain

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The adult mammalian brain contains specialized astrocytes that act as neural stem cells capable of generating functional neurons throughout life. However, due to the anatomical restriction of constitutive adult neurogenesis to a few neurogenic regions, the brain has only a limited capacity to regenerate. It was recently discovered that astrocytes in the striatum of adult mice possess an intrinsic capacity to generate new neurons in vivo after stroke or attenuation of Notch signaling. While the induction of neurogenesis from striatal astrocytes could provide new avenues for brain repair on the long term, the molecular and cellular mechanisms that govern the process need to be explored first. Here, I propose to use innovative molecular tools to investigate the cell-intrinsic and extracellular networks that govern fate decisions of striatal astrocytes in vivo. First, I will provide an innovative solution to combine CRISPR-based endogenous barcode generation with in situ single cell RNA-seq readout. Second, I will use this approach to reconstruct astrocyte lineages and to identify the underlying transcriptional networks within an anatomical context. Third, based on the obtained insights, I will employ in vivo CRISPR gene editing in adult mice to manipulate the molecular logic underlying fate decisions in striatal astrocytes in order to generate a cell lineage of desire. My approach will yield a comprehensive view on the molecular and cellular networks that govern in vivo neurogenesis from striatal astrocytes and intends to provide new routes for neuronal repair strategies.