The role of serotonin in central sleep apnea, sympathoexcitation, and heart failure in spinalcord injured mice.

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Project Summary Sleep apnea, which affects 2-4% of the general population and 8-10% in the veteran population, is 15 times more prevalent in patients with spinal cord injury (SCI). Sleep apnea is linked to cardiovascular co-morbidities, including hypertension, coronary artery disease (CAD), stroke, and atrial fibrillation, along with autonomic, metabolic, and cognitive co-morbidities. There are three neurally regulated mechanisms that determine the frequency and duration of apneic events: upper airway collapsibility and the arousal and chemoreflex response to hypoxia and hypercapnia. Our work revealed that the arousal and chemoreflex response to hypoxia and hypercapnia are blunted in mice with a deficiency of serotonin (5-HT) in the central nervous system (TPH2-/-). Additionally, we also uncovered that SCI leads to depletion of 5-HT in the central nervous system in wild-type mice (TPH2+/+), coupled to blunting of the arousal and chemoreflex response to hypoxia and hypercapnia. We hypothesize that blunting of the arousal and chemoreflex response to hypoxia and hypercapnia leads to increases in apnea frequency and duration. In addition to these modifications, we propose that the depletion of 5-HT in the central nervous system is accompanied by alterations in left ventricular geometry in TPH2-/- mice and increases in sympathetic nervous system activity (SNSA) that could lead to heart failure. Our preliminary work revealed left ventricular hypertrophy was evident in TPH2-/- mice, as evidenced by a conserved ejection fraction and an increase in left ventricular mass. Likewise, increased SNSA was evident in the TPH2-/- mice. We hypothesize that these changes observed in TPH2-/- mice will also be evident in TPH2+/+ mice following SCI. We propose that our results provide an underlying unifying mechanism that could explain the link between central sleep and heart failure in SCI mammals. The results will also provide the rationale to therapeutically modulates 5-HT levels and its receptor sub-types to mitigate centrally modulated apneic events and cardiac dysfunction in Veterans with intact or injured spinal cord.