Single-cell dissection of neural stem cell heterogeneity in vivo

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 DESCRIPTION (provided by applicant): Adult neural stem cells (NSC) continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. Significnt clusters of NSCs can be found in the ventricular-subventricular zone (V/SVZ), the largest germinal region in the adult brain, which generates different subtypes of olfactory bulb neurons, as well as oligodendrocytes. Recent work has also suggested that adult neural stem cells exhibit regional heterogeneity in terms of their progeny. However, the current understanding of NSCs has relied on population-level studies that average diverse single-cell behaviors. Therefore, little is known about the molecular programs and diversity of individual neural stem cells in vivo. Recently, the Doetsch lab has defined a combination of markers that allows the prospective purification of quiescent and activated adult NSCs directly from the in vivo niche. I will combine this purification strategy with single cell transcriptional profiling of NSCs from distinct regions of the V/SVZ. Ultimately, I propose to: 1) define the heterogeneity of adult NSCs by clustering single-cell transcriptional profiles of individual purified quiescent and activated adult neural stem cells isolated from different regions of the V/SVZ, and 2) validate the in vivo distribution of the novel adult NSC subpopulations and infer cellular regulatory networks underlying different NSC identities. The NSC classification based on single-cell gene expression profiles will serve as a tremendous resource for future efforts to harness these cells for cellular reprogramming and for functional comparisons with NSCs or astrocytes from other brain regions. The single cell resolution provided by this approach will yield much needed key insight into the molecular and functional heterogeneity of adult neural stem cells.