Ventilatory Complexity Persists in <i>Phox2b</i> Mutant Mice Lacking the Retrotrapezoid Nucleus/Parafacial Respiratory Group (RTN/pFRG) and in Humans With Congenital Central Hypoventilation Syndrome

Breathing is inherently variable due to the nonlinear dynamics of its brainstem neural control. In amphibians, a gill and a lung oscillator interact to produce breathing but the lung oscillator is necessary and sufficient to produce a mathematically complex behavior. In mammals, where the preBötzinger complex (preBötC) is considered homologous to the amphibian lung oscillator and the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) homologous to the amphibian gill oscillator, the origin of ventilatory complexity is not known. We address this question by characterizing ventilation variability in Phox2b mutant mice lacking the RTN/pFRG and human patients with Phox2b mutation-confirmed congenital central hypoventilation syndrome (CCHS). Ventilatory recordings were obtained from Phox2b²⁷ ^ala/+-dying within hours after birth-and Egr2^cre/+; Phox2b^27ala/+ mice-generally surviving until adulthood-and their wild-type (WT) littermates, during behavioral quiescence at various developmental stages. Human data were collected from CCHS patients and healthy controls during quiet wakefulness. Variability was assessed using the coefficient of variation, complexity using noise titration (noise limit, NL), and sensitivity to initial conditions using the largest Lyapunov exponent (LLE). Mice from both mutant lineages exhibited greater variability at early developmental stages, which decreased with maturation in Egr2^cre ^/+; Phox2b^27ala/+ mice. NL was consistently higher in mutant mice than in WT, indicating preserved or even enhanced ventilatory complexity despite RTN/pFRG dysfunction. CO₂ reduced variability but did not affect complexity. In humans, no differences were observed between patients and controls for variability, NL, or LLE. Ventilatory complexity persists in mice lacking a functional RTN/pFRG and despite Phox2b mutations in humans, suggesting that the pontomedullary rhythm and pattern generators that include the preBötC may be its principal source. This supports the analogy between mammalian and amphibian rhythm generators.