Brainstem serotonin deficiency in the neonatal period: autonomic dysregulation during mild cold stress

Non-technical summary In adult animals serotonergic neurones contribute to heat production (thermogenesis) in response to severe cold stress, as well as the respiratory response to increasing carbon dioxide. We show that in neonatal life, serotonin in the brainstem is absolutely essential for the thermogenic and heart rate responses to very mild (5°C) environmental cooling, probably by aiding the response of the sympathetic nervous system. In contrast, the respiratory response to increasing carbon dioxide is unaffected by a 90% loss of serotonin. Human infants with brainstem serotonin deficiency may be prone to a variety of homeostatic deficits owing to a reduced sympathetic response to mild cold stress. Abstract Based on previous studies in adult animals, devoid of 5-HT neurones, showing altered thermoregulation in cold stress (4°C) and a reduced ventilatory response to CO2, we hypothesized that neonatal mice lacking 60–70% of their 5-HT neurones (Pet-1−/−) would have: (1) a reduced thermogenic response to a mild drop in ambient temperature (TA), (2) reduced and heart rate (HR) responses to mild cooling that reflect this reduced thermogenic response, and (3) a reduced ventilatory response to CO2 after postnatal day 12 (P12), when 5-HT neurones become chemosensitive in vitro. We first determined that a 60–70% loss of 5-HT-positive neurones results in a ∼90% loss of 5-HT from the brainstems of Pet-1−/− animals. We then subjected Pet-1−/− and wild-type (WT) mice (N= 5) to mild environmental cooling (TA= 29°C) at ∼P12. TA was initially held at 34°C for ∼20 min, reduced to 29°C over 15 min and held for an additional 10 min at steady state, and then returned to 34°C. From 34°C to 29°C, there was a robust increase in in P12 WT, but not Pet-1−/− animals (68 ± 19.9%versus−16 ± 8%, respectively; P= 0.002). On average, body temperature (TB) dropped 1.1°C more in Pet-1−/− compared to WT animals (P= 0.03). HR remained unchanged in WT but dropped 22 ± 2.3% in Pet-1−/− animals (P= 0.01). Genotype had no effect on tail temperature (TT), either at 34°C or 29°C. After cooling, values for and HR of Pet-1−/− animals were no different to values predicted by Q10 effects alone, while values of WT animals were greater than predicted. increased in WT with cooling, while it decreased in Pet-1−/− animals (P= 0.002). Still, Pet-1−/− animals hyperventilated relative to WT (increased ) irrespective of TA (P= 0.002). As tested in a separate group of pups, there was no difference in the ventilatory response to CO2 between WT and Pet-1−/− animals, either at P5 or P15. We conclude that during neonatal life in mouse pups: (1) brainstem 5-HT is critical for the thermogenic response to a mild drop in environmental temperature probably via a sympathetically-mediated increase in brown fat metabolism; (2) reduced thermogenesis probably contributes to the reduced HR and observed with 5-HT deficiency; and (3) the presence of some brainstem 5-HT is sufficient for an appropriate ventilatory response to hypercapnia up until P15. Infants with reduced brainstem 5-HT could be prone to cardiovascular and respiratory abnormalities resulting from compromised thermogenesis.