HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free All Versions of this Article: 105/2/404    most recent 90452.2008v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Guyenet, P. G. Search for Related Content PubMed PubMed Citation Articles by Guyenet, P. G.

INVITED REVIEW

The 2008 Carl Ludwig Lecture: retrotrapezoid nucleus, CO₂ homeostasis, and breathing automaticity

Department of Pharmacology, University of Virginia, Charlottesville, Virginia

The retrotrapezoid nucleus (RTN) contains 2,000 glutamatergic neurons that innervate selectively the respiratory centers of the pontomedullary region. These cells are at the ventral medullary surface in a previously identified chemosensitive region. RTN neurons are highly sensitive to acid in vitro and vigorously activated by inputs from the carotid body and from the hypothalamus in vivo. Mutations of the transcription factor Phox2b cause the congenital hypoventilation syndrome (CCHS), a disease characterized by extremely reduced chemoreflexes and the loss of breathing automaticity during sleep. RTN neurons express Phox2b and develop poorly in a mouse model of CCHS, which lacks chemoreflexes. Based on these and other data, I propose that the RTN is a critical nodal point for the homeostatic regulation of arterial PCO₂ and that the nucleus operates as follows. RTN always contributes a major fraction of the tonic excitatory drive to the respiratory centers. RTN neurons derive their activity from two sources: a chemosensory drive (intrinsic chemosensitivity and inputs from the carotid bodies) and synaptic inputs from higher brain centers (non-chemosensory drive). Under anesthesia or non-rapid eye movement sleep, the chemosensory drive to RTN neurons dominates, and, under these circumstances, the excitatory input from RTN to the respiratory controller is required for breathing automaticity. During waking and exercise, RTN contributes a reduced fraction of the total excitatory drive to the respiratory controller, but this fraction remains essential for CO₂ homeostasis because of its exquisite chemosensitivity. The working hypothesis could explain the breathing deficits experienced by CCHS patients.

respiration; retrotrapezoid nucleus; central respiratory chemoreceptors; central chemoreflex; congenital central hypoventilation syndrome; Phox2b; medulla oblongata

This article has been cited by other articles:

				M. G. Fortuna, R. L. Stornetta, G. H. West, and P. G. Guyenet Activation of the retrotrapezoid nucleus by posterior hypothalamic stimulation J. Physiol., November 1, 2009; 587(21): 5121 - 5138. [Abstract] [Full Text] [PDF]

				V. Dubreuil, J. Barhanin, C. Goridis, and J.-F. Brunet Breathing with Phox2b Phil Trans R Soc B, September 12, 2009; 364(1529): 2477 - 2483. [Abstract] [Full Text] [PDF]

				P. M. Pilowsky, M. S. Y. Lung, D. Spirovski, and S. McMullan Differential regulation of the central neural cardiorespiratory system by metabotropic neurotransmitters Phil Trans R Soc B, September 12, 2009; 364(1529): 2537 - 2552. [Abstract] [Full Text] [PDF]

				K. M. Spyer and A. V. Gourine Chemosensory pathways in the brainstem controlling cardiorespiratory activity Phil Trans R Soc B, September 12, 2009; 364(1529): 2603 - 2610. [Abstract] [Full Text] [PDF]

				S. B. G. Abbott, R. L. Stornetta, M. G. Fortuna, S. D. Depuy, G. H. West, T. E. Harris, and P. G. Guyenet Photostimulation of Retrotrapezoid Nucleus Phox2b-Expressing Neurons In Vivo Produces Long-Lasting Activation of Breathing in Rats J. Neurosci., May 6, 2009; 29(18): 5806 - 5819. [Abstract] [Full Text] [PDF]

				G. M. Blain, C. A. Smith, K. S. Henderson, and J. A. Dempsey Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog J Appl Physiol, May 1, 2009; 106(5): 1564 - 1573. [Abstract] [Full Text] [PDF]

				L. G. S. Branco, T. S. Moreira, P. G. Guyenet, P. M. Lalley, A. Kawai, R. W. Putnam, N. L. Chamberlin, C. B. Saper, A. V. Gourine, M. Kanamaru, et al. Commentaries on Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites J Appl Physiol, April 1, 2009; 106(4): 1467 - 1470. [Full Text] [PDF]

				S. B. G. Abbott and P. M. Pilowsky Galanin microinjection into rostral ventrolateral medulla of the rat is hypotensive and attenuates sympathetic chemoreflex Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1019 - R1026. [Abstract] [Full Text] [PDF]

				P. Haouzi and H. J. Bell Control of breathing and volitional respiratory rhythm in humans J Appl Physiol, March 1, 2009; 106(3): 904 - 910. [Abstract] [Full Text] [PDF]

				T. A. Day and R. J. A. Wilson A negative interaction between brainstem and peripheral respiratory chemoreceptors modulates peripheral chemoreflex magnitude J. Physiol., February 15, 2009; 587(4): 883 - 896. [Abstract] [Full Text] [PDF]