| Summary: | The loss of neurons throughout aging, due to trauma or neurodegenerative diseases, was considered irreversible until recent discoveries demonstrated the capacity for the postnatal mammalian brain to generate new neurons in discrete niches capable of integrating into existing neural circuitry. Adult neurogenesis is highly dynamic and modulated by numerous factors. However, the temporal patterns of adult neurogenesis, kinetics of cell proliferation, and migration remain poorly understood. Zebrafish, a model used in this investigation, is a diurnal vertebrate with a circadian clock and clock-controlled processes organized similar to humans. Importantly, zebrafish display active neurogenesis.
The studies comprising this dissertation demonstrate for the first time that a diurnal vertebrate displays robust circadian, i.e. near-24-h, patterns of adult neurogenesis. It proceeds as an orderly transition of cells from G1 to S phase of the cell cycle throughout the day, followed by nighttime progression of G2 phase, culminating with M phase in the early morning. While all five neurogenic niches studied reveal a common circadian pattern, each niche demonstrates a distinct S length and timing of the G1-S transition.
Further investigation into kinetics of adult neurogenesis focused on the events occurring in the neurogenic niches over several days. Both experimental and mathematical modeling approaches determined a consistent number of neural stem cells (NSCs) dividing daily. These approaches also elucidated the predominant modes of division for transient amplifying cells, the neural progenitors (NPCs), the pace of migration and survival of their progeny.
Finally, this dissertation addressed age-related changes in adult neurogenesis in zebrafish, supporting its gradual decline with age. Developing a pathological aging model, based on excessive nutrition throughout development and maturation, revealed a major decline in the number of dividing NSCs and extreme modification of the pattern of division and survival of NPCs.
Together the results of the studies presented in this dissertation reveal that adult neurogenesis undergoes predictable dynamic changes over hours, days, and years. Future studies using a high-throughput zebrafish model should provide needed insights into the role of specific factors in adult neurogenesis and help develop therapeutic strategies to benefit human patients.
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