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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 and George B. Richerson^1,7

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 (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°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

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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

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