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 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. 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. SIGNIFICANCE STATEMENT Understanding 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 with that altered by diet-induced accelerated aging in adult zebrafish.

Acute and long-term metabolic consequences of early developmental Bisphenol A exposure in zebrafish (Danio rerio)

“…Finally, in case of the estrogen-related receptor gamma b (ESRRγb), the predicted binding affinity for EE2 is again higher compared to BPA with eight and three main identified amino acid residue interactions, respectively. Leu 42 , Ala 46 and Leu 83 were the amino acid residues predicted to interacted with both ligands, Glu 49 , Val 87 , Phe 100 , Leu 116 and Leu 119 were predicted to additionally interact with EE2 only (Supplemental File SF10).…”

“…Interestingly, recent evidence does indeed suggest that developmental BPA exposure differentially affects methylated target genes with potential function in neurogenesis (Olsvik et al, 2019), and further longitudinal studies in zebrafish probing epigenetic mechanisms (Best et al, 2018) will likely provide additional insight into molecular underpinnings of the observed long-term effects following developmental BPA exposure on locomotion. In addition to these effects of BPA on zebrafish neurogenesis, high caloric intake in zebrafish has recently been demonstrated to impair neurogenesis in the adult zebrafish brain (Stankiewicz et al, 2019), raising the intriguing possibility that developmental BPA exposure interacts with caloric intake modulation at later life stages to alter neuronal plasticity and subsequent locomotion behaviour. This emerging hypothesis warrants additional rigorous testing in the zebrafish model.…”

Looking through Brains with Fast Passive CLARITY: Zebrafish, Rodents, Non-human Primates and Humans

“…Zebrafish represents an excellent model to study the kinetics of adult neurogenesis and its changes in normal and pathological aging (Stankiewicz et al, 2019). To follow the kinetics of stem cells, neural progenitors and their progeny, we use a pulse-chase technique, with BrdU pulse followed by EdU chase.…”

“…While studying neurogenesis in mammalian embryo and in neurogenic niches of adult brain, lack of tissue transparency is the major obstacle(Stankiewicz et al, 2019). CLARITY allows for deep tissue fluorescent imaging of numerous cells in whole brain specimens.…”

Effects of nutraceutical intervention on serum proteins in aged rats

“…Aging is a complex and multifactorial physiological process associated with decreased stem cell proliferation in stem cell niches throughout the body, leading to reduced tissue rejuvenation and loss of organ function (Murshid et al 2013;Bickford et al 2015). The decline in stem cell regeneration is global, occurring both in the periphery (Ning et al 2019;Jung et al 2019;Chambers et al 2007) and in the central nervous system (CNS) (Villeda et al 2011;Lazarov et al 2010;Kozareva et al 2019;Ayaz et al 2019;Kase et al 2019;Stankiewicz et al 2019;Bickford et al 2015;Flowers et al 2015;Acosta et al 2010). While the exact biological mechanisms underlying dampened stem cell proliferation with age remain unclear, two areas of investigation are being explored: cellautonomous changes and cell non-autonomous changes.…”