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The Journal of Neuroscience, March 25, 2009, 29(12):3720-3737; doi:10.1523/JNEUROSCI.5271-08.2009

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Behavioral/Systems/Cognitive
Raphé Neurons Stimulate Respiratory Circuit Activity by Multiple Mechanisms via Endogenously Released Serotonin and Substance P

Krzysztof Ptak,^1 * Tadashi Yamanishi,^1 * Jason Aungst,^1 * Lorin S. Milescu,¹ Ruli Zhang,¹ George B. Richerson,^2,3,4 and Jeffrey C. Smith¹

¹Cellular and Systems Neurobiology Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, Maryland 20892, Departments of ²Neurology and ³Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, and ⁴Department of Neurology, Veterans Affairs Medical Center, West Haven, Connecticut 06516

Correspondence should be addressed to Dr. Jeffrey C. Smith, Porter Neuroscience Research Center, Building 35, Room 3C-917, 35 Convent Drive, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, MD 20892. Email: jsmith{at}helix.nih.gov

Brainstem serotonin (5-HT) neurons modulate activity of many neural circuits in the mammalian brain, but in many cases endogenous mechanisms have not been resolved. Here, we analyzed actions of raphé 5-HT neurons on respiratory network activity including at the level of the pre-Bötzinger complex (pre-BötC) in neonatal rat medullary slices in vitro, and in the more intact nervous system of juvenile rats in arterially perfused brainstem–spinal cord preparations in situ. At basal levels of activity, excitation of the respiratory network via simultaneous release of 5-HT and substance P (SP), acting at 5-HT_2A/2C, 5-HT₄, and/or neurokinin-1 receptors, was required to maintain inspiratory motor output in both the neonatal and juvenile systems. The midline raphé obscurus contained spontaneously active 5-HT neurons, some of which projected to the pre-BötC and hypoglossal motoneurons, colocalized 5-HT and SP, and received reciprocal excitatory connections from the pre-BötC. Experimentally augmenting raphé obscurus activity increased motor output by simultaneously exciting pre-BötC and motor neurons. Biophysical analyses in vitro demonstrated that 5-HT and SP modulated background cation conductances in pre-BötC and motor neurons, including a nonselective cation leak current that contributed to the resting potential, which explains the neuronal depolarization that augmented motor output. Furthermore, we found that 5-HT, but not SP, can transform the electrophysiological phenotype of some pre-BötC neurons to intrinsic bursters, providing 5-HT with an additional role in promoting rhythm generation. We conclude that raphé 5-HT neurons excite key circuit components required for generation of respiratory motor output.

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Received Nov. 1, 2008; revised Dec. 15, 2008; accepted Feb. 13, 2009.

Correspondence should be addressed to Dr. Jeffrey C. Smith, Porter Neuroscience Research Center, Building 35, Room 3C-917, 35 Convent Drive, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, MD 20892. Email: jsmith{at}helix.nih.gov

This article has been cited by other articles:

				H. J. Yu and A. Yamaguchi Endogenous Serotonin Acts on 5-HT2C-Like Receptors in Key Vocal Areas of the Brain Stem to Initiate Vocalizations in Xenopus laevis J Neurophysiol, February 1, 2010; 103(2): 648 - 658. [Abstract] [Full Text] [PDF]

				J. C. Smith, A. P. L. Abdala, I. A. Rybak, and J. F. R. Paton Structural and functional architecture of respiratory networks in the mammalian brainstem Phil Trans R Soc B, September 12, 2009; 364(1529): 2577 - 2587. [Abstract] [Full Text] [PDF]

				M. R. Hodges, M. Wehner, J. Aungst, J. C. Smith, and G. B. Richerson Transgenic Mice Lacking Serotonin Neurons Have Severe Apnea and High Mortality during Development J. Neurosci., August 19, 2009; 29(33): 10341 - 10349. [Abstract] [Full Text] [PDF]

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