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The peptidergic control circuit for sighing

Nature volume 530, pages 293297 (18 February 2016) | Download Citation


Sighs are long, deep breaths expressing sadness, relief or exhaustion. Sighs also occur spontaneously every few minutes to reinflate alveoli, and sighing increases under hypoxia, stress, and certain psychiatric conditions. Here we use molecular, genetic, and pharmacologic approaches to identify a peptidergic sigh control circuit in murine brain. Small neural subpopulations in a key breathing control centre, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), express bombesin-like neuropeptide genes neuromedin B (Nmb) or gastrin-releasing peptide (Grp). These project to the preBötzinger Complex (preBötC), the respiratory rhythm generator, which expresses NMB and GRP receptors in overlapping subsets of ~200 neurons. Introducing either neuropeptide into preBötC or onto preBötC slices, induced sighing or in vitro sigh activity, whereas elimination or inhibition of either receptor reduced basal sighing, and inhibition of both abolished it. Ablating receptor-expressing neurons eliminated basal and hypoxia-induced sighing, but left breathing otherwise intact initially. We propose that these overlapping peptidergic pathways comprise the core of a sigh control circuit that integrates physiological and perhaps emotional input to transform normal breaths into sighs.

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We thank M. Sunday for providing the Nmbr−/− and Grpr−/− mice, Y. Zhang for providing rat tissues, and K. Wada and E. Wada for plasmid constructs for in situ hybridization probes. We also thank members of the Krasnow and Feldman laboratories for comments. This work was supported by the Howard Hughes Medical Institute (M.A.K.), NIH grants HL70029, HL40959 and NS72211 (J.L.F.), a Walter V. and Idun Berry postdoctoral fellowship (P.L.), the NIH Medical Scientist Training Program (K.Y.), and CIHR and AIHS postdoctoral fellowships (S.P.). M.A.K. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Peng Li
    • , Wiktor A. Janczewski
    •  & Kevin Yackle

    These authors contributed equally to this work.

    • Kaiwen Kam
    •  & Silvia Pagliardini

    Present addresses: Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA (K.K.); Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada (S.P.).

    • Mark A. Krasnow
    •  & Jack L. Feldman

    These authors jointly supervised this project.


  1. Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA

    • Peng Li
    • , Kevin Yackle
    •  & Mark A. Krasnow
  2. Systems Neurobiology Laboratory, Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA

    • Wiktor A. Janczewski
    • , Kaiwen Kam
    • , Silvia Pagliardini
    •  & Jack L. Feldman


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W.A.J. and S.P. performed experiments showing the effects on sighing of bombesin injection into the preBötC and ablation of receptor-expressing neurons with bombesin–saporin. K.Y. performed the screen that discovered Nmb expression in the respiratory centres. P.L. performed experiments identifying and characterizing expression of Nmb, Grp and their receptors. W.A.J., P.L., and K.Y. performed genetic and pharmacology experiments on Nmb and Grp pathways. K.K. performed in vitro slice experiments. W.A.J., K.K., P.L., S.P., and K.Y. analysed data. J.L.F., W.A.J., K.K., M.A.K., P.L., and K.Y. conceived experiments, interpreted data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mark A. Krasnow or Jack L. Feldman.

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  1. 1.

    Video 1: 3-D view of Nmb-GFP neurons in RTN/pFRG region of CLARITY-processed P14 brainstem

    Nmb-GFP neurons surround the lateral half of the facial nucleus, as shown in Figure 1d, e.

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