Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons

Matthew R. Hodges, Glenn J. Tattersall, Michael B. Harris, Sean D. McEvoy, Diana N. Richerson, Evan S. Deneris, Randy L. Johnson, Zhou Feng Chen, George B. Richerson

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278 Scopus citations


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, Lmx1bf/f/p mice 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 CO2 chemoreflex, 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.

Original languageEnglish
Pages (from-to)2495-2505
Number of pages11
JournalJournal of Neuroscience
Issue number10
StatePublished - Mar 5 2008


  • 5-HT
  • Carbon dioxide
  • Chemoreception
  • Respiratory control
  • Temperature
  • Thermogenesis


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