Dissertation

Sleep Apnea Impairs Hippocampal Function and Adult Neurogenesis

Pagan, Chelsea M

2018

Overview

Sleep apnea is a respiratory disorder characterized by periods of sleep during which no effective breaths are taken. Recurrent episodes of apnea caused by upper airway obstruction and/or cessation of central respiratory signaling results in repeated bouts of hypoxemia. Sleep apnea is quite common, affecting approximately 10% of adults in western nations, but a large proportion of patients remain undiagnosed and untreated. Continuous positive air pressure devices, or CPAP therapy, are effective therapeutics to maintain upper airway patency and prevent apneas, but are not universally available nor tolerated by sleep apnea patients. Obesity, the single biggest risk factor for the development of sleep apnea, is even more common and its prevalence is expected to rise. Therefore, sleep apnea represents a considerable health burden for the world population. Patients with sleep apnea have a greater risk of developing cardiovascular complications, such as hypertension and stroke, and as a result, much research has focused on the mechanisms of damage to the cardiovascular system. However, OSA is also known to impact the central nervous system. Some proportion of sleep apneas are generated by a failure of the central respiratory network to signal properly. Furthermore, patients with untreated sleep apnea experience mild cognitive impairments and are reported to have alterations in the activity of a number of brain regions. Even so, the mechanisms by which sleep apnea affects the central nervous system remain largely unknown. As both a critical regulator of learning and memory and one of only two structures in the mammalian brain capable of adult neurogenesis, the hippocampus may be particularly at risk in untreated sleep apnea. Indeed, individuals with sleep apnea experience mild cognitive impairment associated with changes to the hippocampus. Although oxygen homeostasis is a well-recognized factor that can influence multiple hippocampal processes, the impact of intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal neurophysiology remains unclear. I hypothesized that intermittent hypoxia would cause dysfunction in multiple stages of adult neural development to impair circuit function of the dentate gyrus (DG), thus contributing to injury of the hippocampus. The studies related in this dissertation utilize behavioral, electrophysiological, and immunohistological techniques to describe the effects of chronic intermittent hypoxia (IH) exposure on the neurophysiology of the murine hippocampus. IH impaired spatial memory in the Barnes maze apparatus and correlated with attenuated long-term potentiation (LTP) in the DG. Immunohistological analyses revealed that IH differentially perturbs adult neurogenesis by decreasing the number of new-born neurons, while simultaneously increasing neuroprogenitor cell proliferation. Although administration of the superoxide anion scavenger antioxidant, MnTMPyP, mitigated LTP suppression and prevented adult born neuron loss, IH-dependent proliferation of neuroprogenitor cells was unaffected. These data demonstrate that IH disrupts multiple processes in the DG that are both dependent on, and independent of, reactive oxygen species (ROS). These novel findings identify IH-induced changes in cellular and functional correlates of hippocampal learning and memory that likely contribute to cognitive deficits in sleep apnea. Further work is required to determine the non-ROS-mediated mechanisms that affect the neural progenitor pool of the hippocampus and whether either mechanism could serve as a future target for sleep apnea therapeutics.

• Publisher: ProQuest Dissertations & Theses
• Subject: Neurosciences / Pathology
• ISBN: 9780355849721, 0355849720