CSRD Research Career Scientist Award Application

The prevalence of obstructive sleep apnea (OSA) is higher in Veterans compared to the general populace and the occurrence is increased further in Veterans with spinal cord injury. Thus, OSA is a major health concern in the Veteran population. Adjustments in the neural modulation of the arousal threshold (AT), chemoreflex sensitivity to hypoxia and hypercapnia (CS) and upper airway patency are three critical factors that contribute to exacerbation of sleep apnea. The exact neuromodulators that control these variables are enigmatic, but one possibility is serotonin (5HT) and its target receptors. Thus, plasticity of 5HT neurons may account for modifications in the AT, CS, upper airway patency and ultimately breathing stability in intact and spinal cord injured (SCI) animals. We are exploring the role of 5HT in modulating those factors that exacerbate sleep apnea in intact and SCI mice. If not treated promptly, OSA may result in autonomic, cardiovascular, neurocognitive and metabolic abnormalities. Treatment of OSA in many cases does not lead to significant improvements in outcome measures. This inadequacy may be a consequence of reduced treatment compliance with continuous positive airway pressure (CPAP) and/or because factors other than those directly linked to sleep apnea contribute to the presence of coincident co- morbidities. Consequently, innovative therapies that increase CPAP compliance and/or directly impact those co-morbidities typically associated with OSA independent of CPAP treatment could improve outcomes linked to sleep apnea. My laboratory has established that mild intermittent hypoxia (MIH) initiates sustained increases in chest wall and upper airway muscle activity in humans. This sustained increase is a form of respiratory plasticity known as long-term facilitation (LTF). Repeated daily exposure to MIH that leads to the initiation of LTF of upper airway muscle activity could lead to increased stability of the upper airway. In line with my laboratory's mandate to develop innovative therapies to treat sleep apnea, this increased stability could ultimately reduce the CPAP required to treat OSA. This reduction, coupled with our published findings which showed that exposure to MIH increases the arousal threshold, could lead to improved compliance with CPAP. Improved compliance could ultimately serve to mitigate those co-morbidities linked to sleep apnea. Moreover, in addition to improving CPAP compliance, numerous studies indicate that MIH has many direct beneficial cardiovascular, neurocognitive and metabolic effects. Thus, we are presently exploring if MIH can be used to both directly and indirectly (via improved CPAP compliance) target and mitigate those co- morbidities linked to sleep apnea.