Activation of PACAP expression in mouse RTN neurons at birth protects postnatal breathing

The brainstem systems that regulate breathing are established prenatally but they remain immature and vulnerable to failure at the time of birth; this reflects, in part, underdevelopment of the respiratory chemosensory systems that typically monitor blood gases (O2, CO2) to regulate breathing. In the mouse retrotrapezoid nucleus (RTN), Phox2b‐expressing respiratory chemoreceptor neurons are a nexus for integration of multiple respiratory‐related inputs, homeostatically regulating blood gases by providing CO2‐modulated drive to brainstem respiratory rhythm generator and pre‐motor circuits. In this work, we demonstrate that postnatal expression of a neuropeptide in chemosensitive RTN neurons is precisely tuned to influence breathing at the time of birth. First, by using single cell qRT‐PCR and multiplex in situ hybridization, we define a striking postnatal burst of pituitary adenylate cyclase‐activating peptide (PACAP) expression in RTN neurons that is activated in neonates within minutes of exposure to the external environment. Further, by using whole body plethysmography, we show that mouse pups (P2‐P12) lacking PACAP in Phox2b neurons (Phox2b::Cre;PACAP fl/fl ) have severely blunted CO2‐stimulated ventilation (reduced by >50%) and a striking ~3‐fold greater incidence of apneic episodes. PACAP expression in RTN neurons persists into adulthood, albeit at apparently lower levels. PACAP deletion/depletion in adult RTN neurons (in Phox2b::Cre;PACAP fl/fl mice or by shRNA‐mediated knockdown) also depresses CO2‐regulated breathing (by ~30–40%) and increases apneas (~3‐fold), while viral‐mediated re‐expression of PACAP in RTN neurons corrects these deficits. After PACAP knockdown in RTN, CO2‐dependent Fos expression was retained in RTN neurons but decreased in cells of the preBötzinger complex (preBötC), which contains respiratory rhythm‐generating neurons targeted by the RTN. Consistent with the preBötC as a site of action for RTN‐derived PACAP, we show that: 1) the PACAP receptor, PAC1, is expressed in preBötC; 2) PACAP injection directly into the preBötC stimulated central respiratory output, both in vitro and in vivo; and 3) shRNA‐mediated depletion of PAC1 in the preBötC phenocopied breathing deficits observed with RTN deletion of PACAP. Notably, PACAP variants are associated with sudden infant death syndrome (SIDS), and with a SIDS‐like phenotype in PACAP‐null mice. Collectively, these data demonstrate that well‐timed PACAP expression by RTN neurons protects the developmentally immature respiratory control system from hypoventilation and potentially dangerous apneas at birth, and identifies key molecular components of a circuit that supports breathing at this particularly vulnerable period in life. Support or Funding Information R01 HL108609; R01 HL074011

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