Insights into the dynamic control of breathing revealed through cell-type-specific responses to substance P

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Abstract

The rhythm generating network for breathing must continuously adjust to changing metabolic and behavioral demands. Here, we examined network-based mechanisms in the mouse preBӧtzinger complex using substance P, a potent excitatory modulator of breathing frequency and stability, as a tool to dissect network properties that underlie dynamic breathing. We find that substance P does not alter the balance of excitation and inhibition during breaths or the duration of the resulting refractory period. Instead, mechanisms of recurrent excitation between breaths are enhanced such that the rate that excitation percolates through the network is increased. We propose a conceptual framework in which three distinct phases of inspiration, the burst phase, refractory phase, and percolation phase, can be differentially modulated to control breathing dynamics and stability. Unraveling mechanisms that support this dynamic control may improve our understanding of nervous system disorders that destabilize breathing, many of which involve changes in brainstem neuromodulatory systems.

Data availability

All data generated during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

Nathan A Baertsch

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States

For correspondence
nathan.baertsch@seattlechildrens.org

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-1589-5575
Jan-Marino Ramirez

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States

For correspondence
jan.ramirez@seattlechildrens.org

Competing interests
Jan-Marino Ramirez, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-5626-3999

Funding

National Heart, Lung, and Blood Institute (R01 HL126523)

Jan-Marino Ramirez

National Heart, Lung, and Blood Institute (R01 HL144801)

Jan-Marino Ramirez

National Heart, Lung, and Blood Institute (K99 HL145004)

Nathan A Baertsch

National Heart, Lung, and Blood Institute (F32 HL134207)

Nathan A Baertsch

National Heart, Lung, and Blood Institute (P01 HL090554)

Jan-Marino Ramirez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments and animal procedures were approved by the Seattle Children's Research Institute's Animal Care and Use Committee and conducted in accordance with the National Institutes of Health guidelines. (approved protocol #15981)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.