Cell kinetics in the adult neurogenic niche and impact of diet-induced accelerated aging

Abstract

Neurogenesis in the adult brain, a powerful mechanism for neuronal plasticity and brain repair, is altered by aging and pathological conditions, including metabolic disorders. The search for mechanisms and therapeutic solutions to alter neurogenesis requires understanding of cell kinetics within neurogenic niches using a high-throughput quantitative approach. The challenge is in the dynamic nature of the process and multiple cell types involved, each having several potential modes of division or cell fate. Here we show that cell kinetics can be revealed through a combination of the BrdU/EdU pulse-chase, based on the circadian pattern ofDNAreplication, and a differential equations model that describes time-dependent cell densities. The model is validated through the analysis of cell kinetics in the cerebellar neurogenic niche of normal young adult male zebrafish, with cells quantified in 2D (sections), and with neuronal fate and reactivation of stem cells confirmed in3Dwhole-brain images (CLARITY).Wethen reveal complex alterations in cell kinetics associated with accelerated aging due to chronic high caloric intake. Low activity of neuronal stem cells in this condition persists 2 months after reverting to normal diet, and is accompanied by overproduction of transient amplifying cells, their accelerated cell death, and slow migration of postmitotic progeny. This combined experimental and mathematical approach should allow for relatively high-throughput analysis of early signs of pathological and age-related changes in neurogenesis, evaluation of specific therapeutic targets, and drug efficacy.