Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 333 (6042): 637-642

Copyright © 2011 by the American Association for the Advancement of Science

Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition

Russell S. Ray,1,* Andrea E. Corcoran,2,* Rachael D. Brust,1,* Jun Chul Kim,3 George B. Richerson,4 Eugene Nattie,2 Susan M. Dymecki1,{dagger}

Abstract: Physiological homeostasis is essential for organism survival. Highly responsive neuronal networks are involved, but their constituent neurons are just beginning to be resolved. To query brain serotonergic neurons in homeostasis, we used a neuronal silencing tool, mouse RC::FPDi (based on the synthetic G protein–coupled receptor Di), designed for cell type–specific, ligand-inducible, and reversible suppression of action potential firing. In mice harboring Di-expressing serotonergic neurons, administration of the ligand clozapine-N-oxide (CNO) by systemic injection attenuated the chemoreflex that normally increases respiration in response to tissue carbon dioxide (CO2) elevation and acidosis. At the cellular level, CNO suppressed firing rate increases evoked by CO2 acidosis. Body thermoregulation at room temperature was also disrupted after CNO triggering of Di; core temperatures plummeted, then recovered. This work establishes that serotonergic neurons regulate life-sustaining respiratory and thermoregulatory networks, and demonstrates a noninvasive tool for mapping neuron function.

1 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Physiology and Neurobiology, Dartmouth Medical School, Lebanon, NH 03756, USA.
3 Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada.
4 Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 2007 RCP, Iowa City, IA 52242, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dymecki{at}

Purinergic signalling contributes to chemoreception in the retrotrapezoid nucleus but not the nucleus of the solitary tract or medullary raphe.
C. R. Sobrinho, I. C. Wenker, E. M. Poss, A. C. Takakura, T. S. Moreira, and D. K. Mulkey (2014)
J. Physiol. 592, 1309-1323
   Abstract »    Full Text »    PDF »
Medullary serotonin neurons are CO2 sensitive in situ.
K. E. Iceman, G. B. Richerson, and M. B. Harris (2013)
J Neurophysiol 110, 2536-2544
   Abstract »    Full Text »    PDF »
Genome-Wide Expression Analysis of Ptf1a- and Ascl1-Deficient Mice Reveals New Markers for Distinct Dorsal Horn Interneuron Populations Contributing to Nociceptive Reflex Plasticity.
H. Wildner, R. Das Gupta, D. Brohl, P. A. Heppenstall, H. U. Zeilhofer, and C. Birchmeier (2013)
J. Neurosci. 33, 7299-7307
   Abstract »    Full Text »    PDF »
Increasing brain serotonin corrects CO2 chemosensitivity in methyl-CpG-binding protein 2 (Mecp2)-deficient mice.
M. A. Toward, A. P. Abdala, S. J. Knopp, J. F. R. Paton, and J. M. Bissonnette (2013)
Exp Physiol 98, 842-849
   Abstract »    Full Text »    PDF »
HTR2 Receptors in a Songbird Premotor Cortical-Like Area Modulate Spectral Characteristics of Zebra Finch Song.
W. E. Wood, T. K. Roseberry, and D. J. Perkel (2013)
J. Neurosci. 33, 2908-2915
   Abstract »    Full Text »    PDF »
The Inhibition of Neurons in the Central Nervous Pathways for Thermoregulatory Cold Defense Induces a Suspended Animation State in the Rat.
M. Cerri, M. Mastrotto, D. Tupone, D. Martelli, M. Luppi, E. Perez, G. Zamboni, and R. Amici (2013)
J. Neurosci. 33, 2984-2993
   Abstract »    Full Text »    PDF »
Allosteric Modulation of a Chemogenetically Modified G Protein-Coupled Receptor.
A. Abdul-Ridha, J. R. Lane, P. M. Sexton, M. Canals, and A. Christopoulos (2013)
Mol. Pharmacol. 83, 521-530
   Abstract »    Full Text »    PDF »
CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits.
L. Meigh, S. A. Greenhalgh, T. L. Rodgers, M. J. Cann, D. I. Roper, and N. Dale (2013)
eLife Sci 2, e01213
   Abstract »    Full Text »    PDF »
KCNQ Channels Determine Serotonergic Modulation of Ventral Surface Chemoreceptors and Respiratory Drive.
J. M. Hawryluk, T. S. Moreira, A. C. Takakura, I. C. Wenker, A. V. Tzingounis, and D. K. Mulkey (2012)
J. Neurosci. 32, 16943-16952
   Abstract »    Full Text »    PDF »
The vesicular glutamate transporter VGLUT3 contributes to protection against neonatal hypoxic stress.
S. Miot, N. Voituron, A. Sterlin, E. Vigneault, L. Morel, B. Matrot, N. Ramanantsoa, B. Amilhon, O. Poirel, E. Lepicard, et al. (2012)
J. Physiol. 590, 5183-5198
   Abstract »    Full Text »    PDF »
Autonomous and nonautonomous roles of Hedgehog signaling in regulating limb muscle formation.
J. K.-H. Hu, E. McGlinn, B. D. Harfe, G. Kardon, and C. J. Tabin (2012)
Genes & Dev. 26, 2088-2102
   Abstract »    Full Text »    PDF »
Comment on "Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition".
S. Loffler, J. Korber, U. Nubbemeyer, and K. Fehsel (2012)
Science 337, 646
   Abstract »    Full Text »    PDF »
Response to Comment on "Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition".
S. M. Dymecki, R. R. Ray, R. D. Brust, A. E. Corcoran, J. C. Kim, G. B. Richerson, and E. Nattie (2012)
Science 337, 646-647
   Abstract »    Full Text »    PDF »
Acute and chronic effects of carotid body denervation on ventilation and chemoreflexes in three rat strains.
G. C. Mouradian, H. V. Forster, and M. R. Hodges (2012)
J. Physiol. 590, 3335-3347
   Abstract »    Full Text »    PDF »
Brainstem Deficiency of the 14-3-3 Regulator of Serotonin Synthesis: A Proteomics Analysis in the Sudden Infant Death Syndrome.
K. G. Broadbelt, K. D. Rivera, D. S. Paterson, J. R. Duncan, F. L. Trachtenberg, J. A. Paulo, M. D. Stapels, N. S. Borenstein, R. A. Belliveau, E. A. Haas, et al. (2012)
Mol. Cell. Proteomics 11, M111.009530
   Abstract »    Full Text »    PDF »
Redefining the components of central CO2 chemosensitivity - towards a better understanding of mechanism.
R. T. R. Huckstepp and N. Dale (2011)
J. Physiol. 589, 5561-5579
   Abstract »    Full Text »    PDF »
Central circuitries for body temperature regulation and fever.
K. Nakamura (2011)
Am J Physiol Regulatory Integrative Comp Physiol 301, R1207-R1228
   Abstract »    Full Text »    PDF »
Serotonergic neurons in regulating homeostasis.
Dis. Model. Mech. 4, 558
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882