Sleep and circadian organization as regulators of adult hippocampal neurogenesis

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Thesis type
(Thesis) Ph.D.
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The functions of sleep and hippocampal neurogenesis are topics of current research and remain unresolved. Both are suggested to play a role in hippocampus-dependent memory processes and in the development and symptoms of stress and depression. Total sleep deprivation, sleep fragmentation and rapid-eye-movement sleep deprivation (RSD) have been shown to reduce hippocampal neurogenesis, suggesting a functional link between sleep and neurogenesis, but the underlying mechanism remains unknown. To shed light on this issue, we subjected adult, male rodents to long-term RSD, using the platform-over-water method. In addition, we provided adrenalectomized (ADX) rats with a subcutaneous osmotic minipump, resulting in a constant low dose of corticosterone (CORT) supplementation to prevent elevated levels of CORT, a known inhibitor of cell proliferation. A side effect of the RSD procedure is the suppression of daily behavioural rhythms. To test a role for this in the antineurogenic effect of RSD we disrupted behavioural circadian organization by constant bright light exposure. In a final set of experiments, we examined the role of the pro-inflammatory cytokine interleukin-1-beta (IL-1β), using two approaches. First, we assessed the effect of elevated IL-1β by lateral ventricle injections. Second, we inhibited IL-1β signalling using IL-1RI receptor knockout mice and subjected intact and ADX animals to the RSD procedure. Immunohistochemical analysis of 5-bromo-2’-deoxyuridine, Ki67 and doublecortin provided information on hippocampal cell proliferation, differentiation and survival. Here we show that RSD consistently reduced hippocampal cell proliferation, independent of adrenal stress hormones and that the CORT supplementation technique is critical to detect this effect. Furthermore, the data suggest that RSD is antineurogenic independent of species, strain, social interaction, proliferation marker and activity level. The results show in addition that neither disrupted circadian organization nor melatonin suppression reduces hippocampal neurogenesis. Studies in IL-1RIKO mice demonstrate that eliminating IL-1β signalling alone is not sufficient to suppress the inhibitory effect of RSD on cell proliferation. However, the data suggest that eliminating both non-specific stress responses (CORT and IL-1β) together can eliminate the antineurogenic effect of RSD. Thus RSD might reduce hippocampal neurogenesis via multiple secondary mechanisms as part of a stress response.
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Thesis advisor: Mistlberger, Ralph E.
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