Duration Dependent Effects of Intermittent Hypoxia (IH) on Adult Hippocampal Neurogenesis

Abstract

Patients with sleep apnea commonly exhibit cognitive decline and injury to the hippocampal formation. Rodents exposed to IH, a primary consequence of the condition, also show impaired hippocampal based learning and memory. While these impairments correlate with suppressed long‐term potentiation, synaptic plasticity is only one process that supports normal function in this brain structure. Adult neurogenesis is also important for maintaining normal hippocampal physiology. Although Hypoxia Inducible Factor 1a (HIF1a) signaling is to important cellular development and homeostatic responses to hypoxia, chronic IH‐dependent HIF1a activity can promote pathophysiology. In this ongoing study, we test the hypothesis that IH causes HIF1a dependent signaling in neural stem cells (NSCs) to disrupt the adult neurogenesis. To follow the fate of wildtype NSCs and NSCs heterozygous for HIF1a (HIF1a+/−), we used a birth labeling strategy in transgenic mice. After labeling NSCs, we exposed mice to 0 (control), 10, or 30 days of IH. Tissue was harvested for immunohistochemical study at the 33 to 35 day time point. Relative to control, 10 days of IH increased the proportion of GCs generated from wildtype NSCs (by 23% ± 1% SEM, n=3); whereas, 30 days IH suppressed this proportion (−9% ± 2% SEM, n=2). Sholl analysis showed dendritic complexity was similar across all wildtype GCs. 30 days IH exaggerated the loss of GCs generated from HIF1a+/− NSCs (by −30% ± 5%, n=3). These findings indicate that IH has duration‐dependent effects on adult neurogenesis that impact the terminal differentiation of NSCs to GCs and involves IH‐dependent HIF1a signaling in NSCs. These findings suggest that IH‐dependent HIF1a signaling has both positive and negative effects on adult neurogenesis. This mechanism could be a contributor to the negative effects on learning and memory commonly seen in sleep apnea patients.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.