Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

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Abstract
Serotonergic neurons project widely throughout the CNS and modulate many different brain functions. Particularly important, but controversial, are the contributions of serotonin (5-HT) neurons to respiratory and thermoregulatory control. To better define the roles of 5-HT neurons in breathing and thermoregulation, we took advantage of a unique conditional knock-out mouse in whichLmx1bis genetically deleted inPet1-expressing cells (Lmx1bf/f/p), resulting in near-complete absence of central 5-HT neurons. Here, we show that the hypercapnic ventilatory response in adultLmx1bf/f/pmice was decreased by 50% compared with wild-type mice, whereas baseline ventilation and the hypoxic ventilatory response were normal. In addition,Lmx1bf/f/pmice rapidly became hypothermic when exposed to an ambient temperature of 4°C, decreasing core temperature to 30°C within 120 min. This failure of thermoregulation was caused by impaired shivering and nonshivering thermogenesis, whereas thermosensory perception and heat conservation were normal. Finally, intracerebroventricular infusion of 5-HT stimulated baseline ventilation, and rescued the blunted hypercapnic ventilatory response. These data identify a previously unrecognized role of 5-HT neurons in the CO2chemoreflex, whereby they enhance the response of the rest of the respiratory network to CO2. We conclude that the proper function of the 5-HT system is particularly important under conditions of environmental stress and contributes significantly to the hypercapnic ventilatory response and thermoregulatory cold defense.