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The Journal of Neuroscience, March 5, 2008, 28(10):2495-2505; doi:10.1523/JNEUROSCI.4729-07.2008
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Behavioral/Systems/Cognitive
Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons
Matthew R. Hodges,1 Glenn J. Tattersall,2 Michael B. Harris,3 Sean D. McEvoy,1 Diana N. Richerson,1 Evan S. Deneris,4 Randy L. Johnson,5 Zhou-Feng Chen,6 andGeorge B. Richerson1,7 1Departments of Neurology and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520, 2Department of Biological Sciences, Brock University, St. Catharines, Ontario, Canada L2S 3A1, 3Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska 99775, 4Department of Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106, 5Department of Biochemistry and Molecular Biology, University of Texas, Houston, Texas 77030, 6Departments of Anesthesiology, Psychiatry, Molecular Biology and Pharmacology, Washington University School of Medicine Pain Center, St. Louis, Missouri 63110, and 7Veterans Affairs Medical Center, West Haven, Connecticut 06516
Correspondence should be addressed to Dr. Matthew R. Hodges, Department of Neurology, LCI-704, Yale University School of Medicine, 15 York Street, P.O. Box 208018, New Haven, CT 06520-8018. Email: matthew.hodges{at}yale.edu
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 (Lmx1bf/f/p), resulting in near-complete absence of central 5-HT neurons. Here, we show that the hypercapnic ventilatory response in adult Lmx1bf/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.
Key words: 5-HT; chemoreception; carbon dioxide; thermogenesis; respiratory control; temperature
Received Oct. 18, 2007; revised Jan. 21, 2008; accepted Jan. 21, 2008.
Correspondence should be addressed to Dr. Matthew R. Hodges, Department of Neurology, LCI-704, Yale University School of Medicine, 15 York Street, P.O. Box 208018, New Haven, CT 06520-8018. Email: matthew.hodges{at}yale.edu
This article has been cited by other articles:
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[Abstract] [Full Text] [PDF]
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