Circadian regulation of adult neurogenesis in zebrafish and its modulation by nutrition
McGowan, Erin M.
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The recently accepted phenomenon of adult neurogenesis is important for basic biological research and, potentially, can have major implications for the treatment of age-related cognitive decline and disease. Investigation into the mechanisms of adult neurogenesis and its ability to replenish brain circuits with new functional neurons requires whole animal models. Zebrafish, a diurnal vertebrate, has robust cell proliferation in several neurogenic niches, including the cerebellum and dorsal telencephalon, the latter bearing homology to mammalian hippocampus. Because zebrafish demonstrate rapid regeneration in all tissues, including successful repair following brain traumas, they are promising as a model for designing therapies for human brain traumas or stroke. Their long lifespan and gradual aging also makes them an interesting model for the role of neurogenesis in counteracting human neurodegenerative disorders of aging. In different models, it has been found that cell proliferation in adult brain can be significantly affected by behavioral and environmental factors. Among those is nutrition, impacting adult neurogenesis through the amount of caloric intake, meal frequency, and meal content. The study presented here addressed the effects of nutritional factors on adult neurogenesis in a zebrafish model of premature aging due to excessive caloric food intake since early development. Fish were exposed to fasting, different diets and feeding schedules, with the rate of cell proliferation documented in two largest neurogenic niches of the zebrafish brain, the cerebellum and dorsal telencephalon. Here we show that, under normal conditions, fish with premature aging demonstrate dramatic decline in adult neurogenesis in both niches, when compared to age-matched control. The present findings establish an effect of nutrition on neurogenesis in the cerebellum and dorsal telencephalon of adult zebrafish. Zebrafish maintained on HFD, subjected to fasting, or fed only in the evenings showed significant changes in neurogenesis in two distinct neurogenic niches from that of control fish. Remarkably, the two brain regions under investigation displayed partially different responses to nutrition related factors. This was reflected in the cerebellar niche in which neurogenesis was significantly increased by 24h fast/24h refeed, high fat diet, and evening feeding conditions. Neurogenesis of the cerebellum was significantly decreased in 24h fast, 42h fast/refeed conditions. In the dorsal telencephalon, neurogenesis was significantly amplified by high protein, and similar to the cerebellum, high fat diet and evening feeding conditions. In contrast, neurogenesis of the dorsal telencephalon was significantly attenuated only in the 72h fasting condition. This study provides evidence that nutrition plays important role in the modulation of adult neurogenesis in zebrafish, and presence of niche-specific responses to nutritional factors. This further suggests that zebrafish can serve as a model for studying the effects of specific diets, metabolic factors and drugs that affect metabolism in search for prophylactic and therapeutic measures for age-related cognitive decline or neurodegenerative disorders.