Abstract
Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer’s disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.
Highlights
Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health
Since enhanced hypoxia inducible factor 1-alpha (HIF1a) signaling in the hippocampus has been shown to contribute to the pro-oxidant condition caused by IH22 and T-box brain protein 2 (Tbr2)+ intermediate neural progenitors (INPs) are susceptible to oxidative s tress[34], we examined how intermittent hypoxia (IH) affected HIF1a expression among early neural precursors and the potential role that an IH-dependent pro-oxidant state has on T br2+ cells
In contrast to the improvement of neurogenesis using intermittent hypoxia designed for therapeutic p urposes[53,54,55,56], the paradigm of IH used in this study reflects the fast-recurrent oscillations in oxygen homeostasis that is associated with sleep apnea
Summary
Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while suppressing terminal differentiation of adult born neurons during late adult neurogenesis. Paradigms of IH used to model sleep apnea report that thirty or more days of IH enhances the neural precursor pool[18,38] while suppressing the generation of adult-born n eurons[18]. Exposure to IH can promote a pro-oxidant state (i.e., increased oxidative stress) and has differential effects on early neural precursors and adult-born neurons[18]. These differences raise the question of whether IH experienced during different stages of adult neurogenesis have distinct outcomes on the generation of adult-born neurons.
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