The effect of brain serotonin deficiency on breathing during sleep 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 serotonin‐mediated 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), CO2 production (VCO2), and O2 consumption (VO2) in 16‐18 week old and 40‐44 week old mice with genetic deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, and Tph2+/+ controls.In younger mice, Tph2knockout resulted in an increase in VCO2 and VO2 as a result of an increase in motor activity without any effect on HCVR and breathing during sleep. In contrast, in older mice, Tph2knockout caused not only increases in metabolic rate and motor activity but also weight loss, suppression of the HCVR, a decrease in maximal inspiratory flow during non‐rapid eye movement (NREM) sleep, and oxyhemoglobin desaturation during rapid eye movement (REM) sleep. 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 older mice, brain serotonin deficiency decreases hypercapnic sensitivity leading to hypoventilation and hypoxemia during REM sleep, which were absent at younger age. The serotonin pathway may play a role in the prevention of sleep‐disordered breathing in older individuals.