Investigating the neurogenic potential of neocortical astrocytes

SNIC 2018/8-47


SNAC Small

Principal Investigator:

Margherita Zamboni


Karolinska Institutet

Start Date:


End Date:


Primary Classification:

30105: Neurosciences




Endogenous neural stem cells may represent a source for replacing neurons lost to injury. Their contribution to self-repair is, however, limited by their restricted population size. Our lab has demonstrated that astrocytes, which are abundant support cells found throughout the brain, can generate new neurons in an experimental model of ischemic injury. Activation of a neurogenic program after stroke is mediated by Notch signalling inhibition and seems to be restricted to the mouse striatum. The current aim of our project is to investigate whether astrocyte-mediated neurogenesis can be achieved in yet other regions of the mammalian brain, thus supporting the idea that astrocytes may be considered as a widespread source of potential neural stem cells. Recently, we discovered that a small portion of astrocytes retains neurogenic capabilities in the injured cortex, which is believed to be a hostile environment, not prone to regeneration. Using the mouse cortex as a model for investigating lineage fate transitions of astrocytes, we aim to unveil molecular mechanisms that allow activation of the neurogenic process, and that could be tackled to promote regeneration across the damaged adult brain. Using single cell RNA sequencing, we aim to understand how traumatic injury shapes the cortical microenvironment and what molecular mechanisms allow parenchymal astrocytes to mount a neurogenic response. With this project, we hope to identify astroglial subpopulations that transcriptionally segregate and are heterogeneous in their neurogenic potential. We plan to characterize molecular dynamics and cell state checkpoints that describe lineage fate modifications as cortical astrocytes transition to neural progenitors. Additionally, we plan to adapt an ATACseq protocol to single cell sequencing experiments that will be used on similar samples to produce information about changes in chromatin accessibility as astrocyte transition to neurogenic lineages. Ultimately, we hope to gain useful insight into the transcriptional and epigenetic mechanisms that may be tackled to promote regeneration in regions of the mammalian brain that are, otherwise, incapable of replenishing neuronal populations lost to injury.