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The Journal of Neuroscience, April 18, 2007, 27(16):4359-4365; doi:10.1523/JNEUROSCI.4131-06.2007

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Brief Communications
Vagal Regulation of Respiratory Clocks in Mice

Hideki Bando,^1,2 Takeshi Nishio,^1,2 Gijsbertus T. J. van der Horst,³ Satoru Masubuchi,¹ Yasuo Hisa,² and Hitoshi Okamura¹

¹Division of Molecular Brain Science, Department of Brain Sciences, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan, ²Department of Otolaryngology, Kyoto Prefectural University of Medicine, Kamikyo-ku, Kyoto 602-8566, Japan, and ³Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

Correspondence should be addressed to Dr. Hitoshi Okamura, Division of Molecular Brain Science, Department of Brain Sciences, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Email: okamurah{at}med.kobe-u.ac.jp

The present study addresses the role of the circadian system in day–night changes of respiratory functions in the mouse. In all airway tissues investigated (i.e., larynx, trachea, bronchus, and lung), we observed clear rhythmic expression of the Per1, Per2, Bmal1, and Clock core oscillator genes (the latter two genes oscillating in antiphase with the Per genes), as well as the clock-regulated Dbp gene. Oscillations were abolished in arrhythmic Cry1^–/–Cry2^–/– knock-out mice and after lesioning of the master clock in the suprachiasmatic nucleus (SCN) in wild-type animals. These findings indicate that respiratory system cells contain a functional peripheral oscillator that is controlled by the SCN. Furthermore, we found that the muscarinic acetylcholine receptor genes Chm2, Chm3, and Chm4 are expressed in a circadian manner, and that mucin secretion (rather than synthesis) by the airway submucosal glands is under circadian control. Signals from the SCN are mainly transmitted by the vagal nerve because unilateral vagotomy completely abolished rhythms in mucin and PER2 protein levels in the (operated) ipsilateral side of the submucosal glands, but not in the (intact) contralateral side. Thus, peripheral clock mediated circadian expression of muscarinic acetylcholine receptor proteins, and parasympathetic signaling between SCN and respiratory tissues are essential gears in conferring circadian "time" information to airway glands.

Key words: circadian; vagal nerve; clock genes; mucin; PER2; muscarinic receptor

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Received Sept. 21, 2006; revised March 10, 2007; accepted March 10, 2007.

Correspondence should be addressed to Dr. Hitoshi Okamura, Division of Molecular Brain Science, Department of Brain Sciences, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Email: okamurah{at}med.kobe-u.ac.jp

This article has been cited by other articles:

				J. E. Gibbs, S. Beesley, J. Plumb, D. Singh, S. Farrow, D. W. Ray, and A. S. I. Loudon Circadian Timing in the Lung; A Specific Role for Bronchiolar Epithelial Cells Endocrinology, January 1, 2009; 150(1): 268 - 276. [Abstract] [Full Text] [PDF]

				E. Kowalska and S. A. Brown Peripheral Clocks: Keeping Up with the Master Clock Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 301 - 305. [Abstract] [PDF]

				H. Okamura Suprachiasmatic Nucleus Clock Time in the Mammalian Circadian System Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 551 - 556. [Abstract] [PDF]

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