Sunday, November 24, 2024
11/24/2024
Abstract Obstructive sleep apnea (OSA) is a growing sleep-related breathing disorder with the prevalence rate of 10-15% in the middle-age adults and of 32%-62% in elderly. OSA patients undergo recurrent upper airway collapse due to suppression of upper airway dilator muscle activity during sleep, and thus suffer from repeated hypoxia, frequent stressful arousals and sleep deprivation. OSA has a major health impact due to its cardiovascular, metabolic and neurocognitive sequelae, including a significant risk factor for developing Alzheimer’s disease and increased mortality in older adults. Brainstem noradrenergic (NA) neurons, specifically A1 and A7, are suggested to play an important role in maintaining the tonus of upper airway (UA) muscles to keep airway open. The sleep-related decrease in NA drive may results in a loss of the UA muscle tone leading to UA collapse in many OSA patients. However, there is no information regarding age-related changes in functional relationship between brainstem NA neurons and UA muscles. In the proposed project, we will use a novel molecular-genetic technology that will allow a cell-type- specific activation of NA neurons in the A1/C1 and A7 nuclei while recording activity of the genioglossus (GG), a major UA dilator muscle, during sleep and wakefulness in young (3-4 months), middle-aged (10-12 months) and old (18-20 months) behaving DBH-Cre mice. We will determine the age-related changes in 1) the ability of A1 and A7 NA neurons to activate the GG muscle; 2) the number of NA neurons in these and other brainstem NA nuclei; and 3) the density of axons and their terminals that originate from A1 and A7 neurons and project to hypoglossal and other UA motoneurons. The proposed work will reveal the neural basis of the reduction in effectiveness of UA muscles to protect UA from collapse during sleep in older individuals. The results of this study will fill a major gap in our understanding of underlying mechanisms of OSA pathogenesis in elderly and lay the groundwork for translational research of OSA pathology in aging to develop preventive and/or therapeutic strategies for clinical management of OSA in older patients.
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