A brainstem peptide system activated at birth protects postnatal breathing

Among numerous challenges encountered at the beginning of extrauterine life, the most celebrated is the first breath that initiates a life-sustaining motor activity 1. The neural systems that regulate breathing are fragile early in development, and how they adjust to support breathing at the time of birth is not well understood. Here, we identify a neuropeptide system that becomes activated immediately upon birth and supports breathing. Mice lacking pituitary adenylate cyclase-activating peptide (PACAP) selectively in retrotrapezoid nucleus (RTN) neurons displayed increased apneas and blunted CO(2)-stimulated breathing; re-expression of PACAP in RTN neurons corrected these breathing deficits. Deletion of the PACAP receptor, PAC1, from the pre-Bötzinger Complex (preBötC), an RTN target region responsible for respiratory rhythm generation, phenocopied breathing deficits observed with RTN deletion of PACAP, and suppressed PACAP-evoked respiratory stimulation in the preBötC. Notably, a striking 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 apneas 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.