The effect of brain serotonin deficiency on breathing is magnified by age

Abstract

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,

Revisiting the Role of Serotonin in Sleep-Disordered Breathing

“…We found that, regardless of age, brain-5-HT-deficient mice exhibited suppressed control of breathing during NREM and REM sleep. During wakefulness, 16-18-week-old mice with brain 5-HT deficiency maintained ventilation and hypercapnic ventilatory response during hypercapnia, whereas older 40-44-week-old 5-HT-deficient mice had decreased ventilation and hypercapnic ventilatory responses [119]. These data suggest that 5-HT plays a role in the neural control of breathing during sleep, which is magnified with aging.…”

TRPM7 channels regulate breathing during sleep in obesity by acting peripherally in the carotid bodies

“…Sixth, we only assessed $${\dot V_{{{\rm{O}}_{\rm{2}}}}}$$ and $${\dot V_{{\rm{C}}{{\rm{O}}_{\rm{2}}}}}$$ under normoxia. Metabolic measurements using CLAMS units are only validated under room air conditions (Pho et al., 2021, 2022). Further studies regarding the effects of TRPM7 in the CB on respiratory metabolism in response to hypoxia are warranted.…”

“…Ventilatory response to hypercapnia (HCVR) during wakefulness was assessed at baseline and after 9−10 days of Trpm7 shRNA expression in the CB area as previously reported by our group (Pho et al., 2022). Measurements were performed using a similar design as the HVR protocol.…”

Leptin signaling in the dorsomedial hypothalamus couples breathing and metabolism in obesity

“…We measured apnea index across sleep stages in accordance with our previous study. 96 Apneas were scored as ≥ 90% reduction in airflow for a period corresponding to two or more breath cycles or ≥0.7 s based on average respiratory rate at baseline.…”

“…Metabolic studies were performed as previously described. 47 , 96 Mice were placed in individual Comprehensive Laboratory Animal Monitoring System (CLAMS) units (Oxymax series; Columbus Instruments, Columbus, OH) for a 24-h acclimation period followed by 24 h of continuous recordings starting at 10:00a.m. The CLAMS units were sealed and equipped with O 2 electrochemical sensors, CO 2 infrared sensors and infrared beam movement sensors.…”