RT Journal Article SR Electronic T1 Cell kinetics in the adult neurogenic niche and impact of diet-induced accelerated aging JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 2730-18 DO 10.1523/JNEUROSCI.2730-18.2019 A1 Alexander J. Stankiewicz A1 Farzad Mortazavi A1 Peter V. Kharchenko A1 Erin M. McGowan A1 Vasili Kharchenko A1 Irina V. Zhdanova YR 2019 UL http://www.jneurosci.org/content/early/2019/02/07/JNEUROSCI.2730-18.2019.abstract AB Neurogenesis in 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 of DNA replication, 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 in 3D whole brain images (Clarity). We then reveal complex alterations in cell kinetics associated with accelerated aging due to chronic high caloric intake (HCI). Low activity of neuronal stem cells in this condition persists two months after reverting to normal diet, and is accompanied by overproduction of transient amplifying cells, their accelerated cell death, and slow migration of post-mitotic 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.SIGNIFICANCE STATEMENTUnderstanding normal cell kinetics of adult neurogenesis and the type of cells affected by a pathological process is needed to develop effective prophylactic and therapeutic measures directed at specific cell targets. Complex time-dependent mechanisms involved in the kinetics of multiple cell types require a combination of experimental and mathematical modeling approaches. This study demonstrates such a combined approach by comparing normal neurogenesis to that altered by diet-induced accelerated aging in adult zebrafish.