Effects of aging and CIH exposure on respiratory function, postsynaptic excitatory muscarinic receptor expression, and cholinergic inputs

Alzheimer’s disease (AD) is an irreversible neurodegenerative process that is often comorbid with several diseases, including Obstructive Sleep Apnea (OSA). An individual with AD is 5 times more likely to have OSA than a non-AD individual of similar age. OSA is characterized by partial or complete occlusion of the upper airways, occurring intermittently throughout sleep, leading to arterial blood desaturation of oxygen and sleep fragmentation. Persistent intermittent airway occlusion during sleep that results in blood oxygen desaturation is termed Chronic Intermittent Hypoxia (CIH). A contributing factor to OSA is insufficient neural control of upper airway muscles, particularly the tongue, innervated by hypoglossal motoneurons (XII MNs). We hypothesize that CIH exposure will change respiratory patterns in adult mice and that these effects will be more pronounced in older adult mice. As an initial test of our hypothesis, we have examined the effects of CIH on respiratory pattern in three-month old adult mice. For each day of the protocol, mice were subjected to 8 hours of intermittent hypoxia with a nadir of 5% oxygen for 15 s and a recovery at 21% oxygen for 4 minutes and 45 seconds. Ramp times to go between 5% and 21% oxygen were just over one minute. Thus, mice were exposed to ~60 hypoxic episodes/8-hour period. Respiratory parameters were collected using whole body plethysmography at day 0 (i.e., before any exposure to intermittent hypoxia) and then after 4 and 7 days of intermittent hypoxia exposure. Respiratory parameters collected include: tidal volume (Vt), respiratory frequency (fR), and minute ventilation (Ve). At the end of the CIH protocol, brain tissue was collected for future immunofluorescence and molecular analysis. Our preliminary data evaluated respiratory function of young mature male CD1 mice (n=3) in response to CIH over 7 days and are reported as mean (range). Our preliminary data indicated a trend for a transient decrease in Vt and Ve and a transient increase in fR after four days of CIH exposure compared to baseline or after seven days of CIH exposure. Vt (mL) for days 0, 4, and 7 was 14.2 (11.96-18.25), 11.6 (8.80-13.01), and 15.3 (12.05-21.52), respectively. fR (breath/min) for days 0, 4, and 7 was 208 (140-253), 217 (133-266), and 207 (152-278) respectively. Ve (mL/min, kg) at days 0, 4, and 7 was 2821.7 (2563.25-3117.28), 2449.2 (1728.48-3413.09), and 3010.9 (2375.00-3370.12), respectively. Further data collection will be needed to determine whether this trend continues and additional data collection to evaluate metabolic rate will be needed to determine the functional effects of CIH on respiratory parameters in adult mice. Finally, we will repeat these experiments in older adult mice to evaluate whether CIH has an age-dependent effect on respiratory function. Funding from the Arizona Alzheimer's Consortium Development Grant (to ALR and GSFS and DBZ) and Midwestern University Kenneth A. Suarez Summer Research Fellowship (to JMH) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.