Sleep apnea is associated with autonomic, cardiovascular, metabolic and cognitive co‐morbidities. The incidence of sleep apnea in the United States ranges from 2‐4 % in the general population, and is up to 15 times greater in individuals with spinal cord injury (SCI). 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 will explore the role of 5HT in modulating the critical factors that exacerbate sleep apnea in intact and SCI mice. Aim 1 of our proposal will examine the impact of 5HT on the AT and CS to ultimately determine the impact on sleep disordered breathing. Aim 2 will explore whether modifications in 5HT levels and/or receptor sub‐types following SCI, are coupled to modifications in the AT and CS leading to hypoventilation, blunting of upper airway muscle function and increases in the frequency and duration of apnea events. Aim 3 will determine whether modifications in 5HT levels and/or receptor sub‐types following SCI, are coupled to increases in upper airway collapsibility. To explore these relationships unanesthetized, spontaneously breathing intact and SCI tryptophan hydroxylase 2 knockout (TPH2‐/‐) and wild type (TPH2+/+) mice will be employed. The absence of TPH2 results in the depletion of central nervous system 5HT, while the raphe neurons remain intact. We will measure ventilatory parameters, the AT and CS before and after SCI in TPH2+/+ and TPH2‐/‐ mice. Breathing events will be detected during sleep via electroencephalograms. Apneic events will be uncovered by monitoring ventilation and diaphragmatic electromyography, while monitoring of genioglossus muscle activity will be used to detect modifications in upper airway muscle function before and after SCI. Our results will establish if modifications in 5HT modulation, either via genetic depletion or SCI, leads to alterations in the AT, CS, upper airway muscle function and ultimately breathing stability.