Increasing Neural Stem Cell Division Asymmetry and Quiescence Are Predicted to Contribute to the Age-Related Decline in Neurogenesis

Abstract

Summary: Adult murine neural stem cells (NSCs) generate neurons in drastically declining numbers with age. How cellular dynamics sustain neurogenesis and how alterations with age may result in this decline are unresolved issues. We therefore clonally traced NSC lineages using confetti reporters in young and middle-aged adult mice. To understand the underlying mechanisms, we derived mathematical models that explain observed clonal cell type abundances. The best models consistently show self-renewal of transit-amplifying progenitors and rapid neuroblast cell cycle exit. In middle-aged mice, we identified an increased probability of asymmetric stem cell divisions at the expense of symmetric differentiation, accompanied by an extended persistence of quiescence between activation phases. Our model explains existing longitudinal population data and identifies particular cellular properties underlying adult NSC homeostasis and the aging of this stem cell compartment. : Bast and colleagues traced the lineages of single neural stem cells in the brains of young and aged adult mice to shed light on the age-related decline in neurogenesis. Mathematical modeling of lineage dynamics revealed changes in the behavior of neural stem cells with age. Keywords: adult neurogenesis, lineage tracing, computational model, moment equations, model averaging, lineage tree simulation