Central nervous system 5‐HT plays a role in ventilatory and arousal responses to hypoxia and hypercapnia in spinal cord injured mice

Abstract

PurposeThe present investigation was designed to explore the impact of serotonin (5HT) on the arousal and ventilatory response to hypercapnia and hypoxia following spinal cord injury (SCI) in mice.MethodsTelemetry transmitters were surgically implanted in wild type mice (Tph2+/+) (n =7 for SCI, n=7 for Sham) and tryptophan hydroxylase 2 knockout mice (Tph2‐/‐) (n=6 for SCI, n=6 for Sham) to measure electroencephalography, electromyography (EMG) of the genioglossus (GG) muscle, core body temperature and gross motor activity. Following recovery, the Tph2+/+ and Tph2‐/‐ mice were placed in whole body plethysmographs and measures of the ventilatory and arousal response to hypoxia and hypercapnia during non‐rapid eye movement sleep were obtained. Following these measures, a C2 hemi‐section of the spinal cord was completed and the physiological measurements were repeated 4 and 21 days following SCI. The ventilatory data is presented as a fraction of baseline.ResultsThe breathing frequency, tidal volume, and minute ventilation response to hypercapnia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (Breathing frequency: 1.37 ± 0.12 vs. 1.02 ± 0.10, p = 0.036, Tidal volume: 1.70 ± 0.21 vs. 0.91 ± 0.09, p = 0.002, Minute Ventilation: 2.87 ± 0.48 vs. 0.93 ± 0.12, p = 0.001). In addition, the tidal volume and minute ventilation response to hypoxia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (Tidal Volume: 1.27 ± 0.09 vs. 0.94 ± 0.08, p = 0.009, Minute Ventilation: 1.45 ± 0.14 vs. 0.98 ± 0.09, p = 0.012). The arousal latency to hypercapnia was reduced in Tph2+/+ compared to Tph2‐/‐ mice at 4 days post SCI (16.22 ± 4.15 vs. 73.83 ± 15.78 s, p = 0.013). The number of arousals during exposure to hypercapnia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (5.31 ± 0.50 vs. 3.40 ± 0.51, p = 0.021). The magnitude of the GG response to hypercapnia and hypoxia was greater in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (Hypercapnia: 47.42 ± 10.17 vs. 0.73 ± 0.18, p = 0.012, Hypoxia: 43.82 ± 11.25 vs. 3.30 ± 1.65, p = 0.019). The fraction of episodes in which there was no EMG response to hypercapnia and hypoxia was lower in Tph2+/+ compared to Tph2‐/‐mice at 4 days post SCI (Hypercapnia: 0.43 ± 0.10 vs. 0.92 ± 0.08, p = 0.001 Hypoxia: 0.19 ± 0.12 vs. 0.85 ± 0.15, p = 0.008). The fraction of episodes in which there was no EMG response to hypercapnia was lower in Tph2+/+ compared to Tph2‐/‐ mice at 21 days post SCI (0.19 ± 0.06 vs. 0.79 ± 0.10, p = 0.001).ConclusionThe ventilatory, arousal and GG response to hypercapnia and hypoxia is greater in Tph2+/+ compared to Tph2‐/‐ mice following SCI. Our results suggest that deficiencies in serotonin have a role in regulating respiratory and arousal responses to hypercapnia and hypoxia following SCI.