TY - JOUR
T1 - The effect of brain serotonin deficiency on breathing is magnified by age
AU - Pho, Huy
AU - Amorim, Mateus R.
AU - Qiu, Qingchao
AU - Shin, Mi Kyung
AU - Kim, Lenise J.
AU - Anokye-Danso, Frederick
AU - Jun, Jonathan J.
AU - Ahima, Rexford S.
AU - Branco, Luiz G.S.
AU - Kuhn, Donald M.
AU - Mateika, Jason H.
AU - Polotsky, Vsevolod Y.
N1 - Funding Information:
This research was funded by grants from the National Institutes of Health (R01 HL128970, R01 HL133100, R01 HL13892, R61 HL156240—VYP), (R01HL142757 and R56HL142757—JHM); Office of Research and Development, Veterans Health Administration, Department of Veterans Affairs (I01BX003946, I01CX000125, IK6CX002287—JHM) (IK6RX002419, I01RX000458—DMK); São Paulo Research Foundation (FAPESP #2019/13249‐3‐MRA); American Heart Association funded Postdoctoral Fellowship Award (#828142—LJK) and Career Development Award (19CDA34700025—MS).
Publisher Copyright:
© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
PY - 2022/5
Y1 - 2022/5
N2 - 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 deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, compared to Tph2+/+ mice. As expected, aging decreased VCO2 and VO2. 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, younger Tph2−/− mice were able to defend their ventilation and phenotypically did not differ from wildtype during wakefulness. In contrast, both young and old Tph2−/− mice showed sleep-related hypoventilation, which was manifested by hypoxemia during REM sleep.
AB - 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 deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, compared to Tph2+/+ mice. As expected, aging decreased VCO2 and VO2. 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, younger Tph2−/− mice were able to defend their ventilation and phenotypically did not differ from wildtype during wakefulness. In contrast, both young and old Tph2−/− mice showed sleep-related hypoventilation, which was manifested by hypoxemia during REM sleep.
KW - aging
KW - breathing
KW - serotonin
KW - sleep
UR - http://www.scopus.com/inward/record.url?scp=85130787048&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130787048&partnerID=8YFLogxK
U2 - 10.14814/phy2.15245
DO - 10.14814/phy2.15245
M3 - Article
C2 - 35581741
AN - SCOPUS:85130787048
SN - 2051-817X
VL - 10
JO - Physiological Reports
JF - Physiological Reports
IS - 10
M1 - e15245
ER -