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Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

  1. Jerry Silvera,1
  1. aDepartment of Neurosciences, Case Western Reserve University, Cleveland, OH 44106;
  2. bDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106
  1. Contributed by Lynn T. Landmesser, October 20, 2017 (sent for review June 30, 2017; reviewed by Michael J. O’Donovan and Huda Y. Zoghbi)

Significance

Humans breathe ~20,000 times per day and hundreds of millions of times over the average life span. The neural mechanisms which control respiratory rate are poorly understood. Although it was previously thought that the signal to breathe was solely an excitatory command, we show that selective stimulation of putative CO2-chemosensitive neurons likely initiates inspiration through inhibition. These results argue that the clock which determines respiratory rate operates in two distinct modes: a first mode which is highly modular and allows for flexibility to adapt to everyday behaviors, and a second mode which is specifically recruited in situations of elevated CO2.

Abstract

Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-B?tzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO2-chemosensitive neurons. As a mechanistic explanation for inhibition-dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by expiration. Thus, although it is widely thought that inhibition between inspiration and expiration simply prevents activity in the antagonistic phase, we instead propose a model whereby inhibitory coupling via postinhibitory rebound excitation actually generates fast modes of inspiration.

Footnotes

  • ?1To whom correspondence may be addressed. Email: lynn.landmesser{at}case.edu or jxs10{at}case.edu.
  • Author contributions: J.M.C., L.T.L., and J.S. designed research; J.M.C., K.A.C., and L.T.L. performed research; J.M.C., K.A.C., T.E.D., L.T.L., and J.S. analyzed data; and J.M.C. wrote the paper.

  • Reviewers: M.J.O., National Institutes of Health; and H.Y.Z., Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and Howard Hughes Medical Institute.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1711536114/-/DCSupplemental.

Published under the PNAS license.

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