A brainstem peptide system activated at birth protects postnatal breathing

Yingtang Shi, Daniel S. Stornetta, Robert J. Reklow, Alisha Sahu, Yvonne Wabara, Ashley Nguyen, Keyong Li, Yong Zhang, Edward Perez-Reyes, Rachel A. Ross, Bradford B. Lowell, Ruth L. Stornetta, Gregory D. Funk, Patrice G. Guyenet and Douglas A. Bayliss ()
Additional contact information
Yingtang Shi: University of Virginia
Daniel S. Stornetta: University of Virginia
Robert J. Reklow: University of Alberta
Alisha Sahu: University of Virginia
Yvonne Wabara: University of Virginia
Ashley Nguyen: University of Virginia
Keyong Li: University of Virginia
Yong Zhang: University of Alberta
Edward Perez-Reyes: University of Virginia
Rachel A. Ross: Harvard University
Bradford B. Lowell: Harvard University
Ruth L. Stornetta: University of Virginia
Gregory D. Funk: University of Alberta
Patrice G. Guyenet: University of Virginia
Douglas A. Bayliss: University of Virginia

Nature, 2021, vol. 589, issue 7842, 426-430

Abstract: Abstract Among numerous challenges encountered at the beginning of extrauterine life, the most celebrated is the first breath that initiates a life-sustaining motor activity1. The neural systems that regulate breathing are fragile early in development, and it is not clear how they adjust to support breathing at birth. Here we identify a neuropeptide system that becomes activated immediately after birth and supports breathing. Mice that lack PACAP selectively in neurons of the retrotrapezoid nucleus (RTN) displayed increased apnoeas and blunted CO2-stimulated breathing; re-expression of PACAP in RTN neurons corrected these breathing deficits. Deletion of the PACAP receptor PAC1 from the pre-Bötzinger complex—an RTN target region responsible for generating the respiratory rhythm—phenocopied the breathing deficits observed after RTN deletion of PACAP, and suppressed PACAP-evoked respiratory stimulation in the pre-Bötzinger complex. Notably, a postnatal burst of PACAP expression occurred in RTN neurons precisely at the time of birth, coinciding with exposure to the external environment. Neonatal mice with deletion of PACAP in RTN neurons displayed increased apnoeas that were further exacerbated by changes in ambient temperature. Our findings demonstrate that well-timed PACAP expression by RTN neurons provides an important supplementary respiratory drive immediately after birth and reveal key molecular components of a peptidergic neural circuit that supports breathing at a particularly vulnerable period in life.

Date: 2021
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DOI: 10.1038/s41586-020-2991-4

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