The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology

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Abstract

Respiratory activities are produced by medullary respiratory rhythm generators and are modulated from various sites in the lower brainstem, and which are then output as motor activities through premotor efferent networks in the brainstem and spinal cord. Over the past few decades, new knowledge has been accumulated on the anatomical and physiological mechanisms underlying the generation and regulation of respiratory rhythm. In this review, we focus on the recent findings and attempt to elucidate the anatomical and functional mechanisms underlying respiratory control in the lower brainstem and spinal cord.

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Most cited references 114

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Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Jeanne Amiel, Béatrice Laudier, Tania Attie-Bitach … (2003)

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

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Functional regeneration of respiratory pathways after spinal cord injury

Warren Alilain, Kevin Horn, Hongmei Hu … (2011)

Spinal cord injuries (SCI) often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. Unfortunately, the untoward effects of impaired breathing are a leading cause of SCI-related death, underscoring the importance of developing strategies to restore respiratory activity. Here we show that after cervical SCI, there is upregulation of the perineuronal net (PNN) associated chondroitin sulfate proteoglycans (CSPGs) around phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with Chondroitinase ABC (ChABC) can, by itself, promote plasticity of spared tracts and restore limited activity to the paralyzed diaphragm. However, when combined with application of a peripheral nerve autograft, ChABC treatment results in lengthy regeneration of serotonergic axons and other bulbospinal fibers with remarkable recovery of diaphragm function. Following recovery and initial transection of the bridge, there occurs an unusual, overall increased tonic diaphragmatic EMG activity, suggesting considerable remodeling of spinal cord circuitry after regeneration. This is followed by complete elimination of the restored activity proving that regeneration is critical for the return of function. Overall, these experiments present a way to profoundly restore function of a single muscle following debilitating CNS trauma, through both plasticity of spared tracts and regeneration of essential pathways.

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Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms.

Robin A J Smith, A P L Abdala, Ilya Rybak … (2007)

Mammalian central pattern generators (CPGs) producing rhythmic movements exhibit extremely robust and flexible behavior. Network architectures that enable these features are not well understood. Here we studied organization of the brain stem respiratory CPG. By sequential rostral to caudal transections through the pontine-medullary respiratory network within an in situ perfused rat brain stem-spinal cord preparation, we showed that network dynamics reorganized and new rhythmogenic mechanisms emerged. The normal three-phase respiratory rhythm transformed to a two-phase and then to a one-phase rhythm as the network was reduced. Expression of the three-phase rhythm required the presence of the pons, generation of the two-phase rhythm depended on the integrity of Bötzinger and pre-Bötzinger complexes and interactions between them, and the one-phase rhythm was generated within the pre-Bötzinger complex. Transformation from the three-phase to a two-phase pattern also occurred in intact preparations when chloride-mediated synaptic inhibition was reduced. In contrast to the three-phase and two-phase rhythms, the one-phase rhythm was abolished by blockade of persistent sodium current (I(NaP)). A model of the respiratory network was developed to reproduce and explain these observations. The model incorporated interacting populations of respiratory neurons within spatially organized brain stem compartments. Our simulations reproduced the respiratory patterns recorded from intact and sequentially reduced preparations. Our results suggest that the three-phase and two-phase rhythms involve inhibitory network interactions, whereas the one-phase rhythm depends on I(NaP). We conclude that the respiratory network has rhythmogenic capabilities at multiple levels of network organization, allowing expression of motor patterns specific for various physiological and pathophysiological respiratory behaviors.

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Author and article information

Contributors

Keiko Ikeda: kiikeda@hyo-med.ac.jp

Hiroshi Onimaru: oni@med.showa-u.ac.jp

Yasumasa Okada: yasumasaokada@1979.jukuin.keio.ac.jp

Naohiro Koshiya: nk@mail.nih.gov

Yoshitaka Oku: yoku@hyo-med.ac.jp

Makito Iizuka: iizukam@med.showa-u.ac.jp

Journal

Journal ID (nlm-ta): J Physiol Sci

Journal ID (iso-abbrev): J Physiol Sci

Title: The Journal of Physiological Sciences

Publisher: Springer Japan (Tokyo )

ISSN (Print): 1880-6546

ISSN (Electronic): 1880-6562

Publication date (Electronic): 17 August 2016

Publication date PMC-release: 17 August 2016

Publication date (Print): 2017

Volume: 67

Issue: 1

Pages: 45-62

Affiliations

[1 ]GRID grid.272264.7, ISNI 000000009142153X, Division of Biology, , Hyogo College of Medicine, ; Nishinomiya, Hyogo 663-8501 Japan

[2 ]GRID grid.410804.9, ISNI 0000000123090000, Division of Biology, Center for Molecular Medicine, , Jichi Medical University, ; Shimotsuke, Tochigi 329-0498 Japan

[3 ]GRID grid.410714.7, ISNI 0000000088643422, Department of Physiology, , Showa University School of Medicine, ; Shinagawa, Tokyo 142-8555 Japan

[4 ]GRID grid.415635.0, , Clinical Research Center, Murayama Medical Center, ; Musashimurayama, Tokyo 208-0011 Japan

[5 ]GRID grid.411621.1, ISNI 0000000086611590, Department of Anatomy and Morphological Neuroscience, , Shimane University School of Medicine, ; Izumo, Shimane 693-8501 Japan

[6 ]GRID grid.416870.c, ISNI 000000012177357X, Cellular and Systems Neurobiology Section, , NINDS, NIH, ; Bethesda, MD 20892 USA

[7 ]GRID grid.272264.7, ISNI 000000009142153X, Department of Physiology, , Hyogo College of Medicine, ; Nishinomiya, Hyogo 663-8501 Japan

Article

Publisher ID: 475

DOI: 10.1007/s12576-016-0475-y

PMC ID: 5368202

PubMed ID: 27535569

SO-VID: ce86ff4c-932f-46c9-ade0-9686752cbe81

History

Date received : 15 March 2016

Date accepted : 22 July 2016

Funding

Funded by: JSPS KAKENHI Grant Numbers 25540130, 26460311, 26670676 and 15K00417

Funded by: FundRef http://dx.doi.org/10.13039/100007428, Naito Foundation;

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ScienceOpen disciplines: Anatomy & Physiology

Keywords: respiratory rhythm,pons,medulla,spinal cord,parafacial respiratory group (pfrg),pre-bötzinger complex (prebötc)

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ScienceOpen disciplines: Anatomy & Physiology

Keywords: respiratory rhythm, pons, medulla, spinal cord, parafacial respiratory group (pfrg), pre-bötzinger complex (prebötc)

The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology

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Most cited references 114

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Functional regeneration of respiratory pathways after spinal cord injury

Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms.

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