Serotonin is an important mediator modulating behavior, metabolism, sleep, control of breathing, and upper airway function, but the role of aging in serotoninmediated effects has not been previously defined. Our study aimed to examine the effect of brain serotonin deficiency on breathing during sleep and metabolism in younger and older mice. We measured breathing during sleep, hypercapnic ventilatory response (HCVR), CO 2 production (VCO 2 ), and O 2 consumption (VO 2 ) in 16-18-week old and 40-44-week old mice with deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, compared to Tph2 +/+ mice. As expected, aging decreased VCO 2 and VO 2 .Tph2 knockout resulted in an increase in both metabolic indexes and no interaction between age and the genotype was observed. During wakefulness, neither age nor genotype had an effect on minute ventilation. The genotype did not affect hypercapnic sensitivity in younger mice. During sleep, Tph2 −/− mice showed significant decreases in maximal inspiratory flow in NREM sleep, respiratory rate, and oxyhemoglobin saturation in REM sleep, compared to wildtype, regardless of age. Neither serotonin deficiency nor aging affected the frequency of flow limited breaths (a marker of upper airway closure) or apneas. Serotonin deficiency increased the amount and efficiency of sleep only in older animals. In conclusion,
The following review is designed to explore the pathophysiology of sleep apnea in aging women. The review initially introduces four endotypes (i.e., a more collapsible airway, upper airway muscle responsiveness, arousal threshold, and loop gain) that may have a role in the initiation of obstructive sleep apnea. Thereafter, sex differences in the prevalence of sleep apnea are considered along with differences in the prevalence that exist between younger and older women. Following this discussion, we consider how each endotype might contribute to the increase in prevalence of sleep apnea in aging women. Lastly, we address how modifications in one form of respiratory plasticity, long-term facilitation, that might serve to mitigate apneic events in younger women may be modified in aging women with obstructive sleep apnea. Overall, the published literature indicates that the prevalence of sleep apnea is increased in aging women. This increase is linked primarily to a more collapsible airway and possibly to reduced responsiveness of upper airway muscle activity. In contrast, modifications in loop gain or the arousal threshold do not appear to have a role in the increased prevalence of sleep apnea in aging women. Moreover, we suggest that mitigation of long-term facilitation could contribute to the increased prevalence of sleep apnea in aging women.
Purpose The 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. Methods Telemetry 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. Results The 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). Conclusion The 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.
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