Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons.
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 which Lmx1b is genetically deleted in Pet1-expressing cells (Lmx1b(f/f/p)), resulting in near-complete absence of central 5-HT neurons. Here, we show that the hypercapnic ventilatory response in adult Lmx1b(f/f/p) mice was decreased by 50% compared with wild-type mice, whereas baseline ventilation and the hypoxic ventilatory response were normal. In addition, Lmx1b(f/f/p) mice rapidly became hypothermic when exposed to an ambient temperature of 4 degrees C, decreasing core temperature to 30 degrees 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 CO(2) chemoreflex, whereby they enhance the response of the rest of the respiratory network to CO(2). 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.
Hodges
Matthew R
MR
Department of Neurology, Yale University, New Haven, Connecticut 06520, USA. matthew.hodges@yale.edu
Tattersall
Glenn J
GJ
Harris
Michael B
MB
McEvoy
Sean D
SD
Richerson
Diana N
DN
Deneris
Evan S
ES
Johnson
Randy L
RL
Chen
Zhou-Feng
ZF
Richerson
George B
GB
D000818:Animals; D001833:Body Temperature Regulation / Q000235:genetics*; D002490:Central Nervous System / Q000502:physiology; D002628:Chemoreceptor Cells / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D012119:Respiration / Q000235:genetics*; D012701:Serotonin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
D012701:Serotonin