Substance P (SubP) is Sufficient to Induce Frequency Plasticity in Neonatal Rat Isolated Brainstem‐spinal cord Preparations in the Absence of Hypoxia

Abstract

The capacity for expressing respiratory neuroplasticity in neonates is poorly understood. One example is frequency plasticity, which is a persistent increase in breath frequency following a perturbation. Intermittent hypoxic exposures induce frequency plasticity in P14–P15 intact rats and in rhythmic medullary slices from neonatal P0–P7 mice. However, mutant mice lacking neurokinin‐1 receptors for which SubP is the endogenous ligand, do not express frequency plasticity following intermittent hypoxia, suggesting that SubP may be necessary for intermittent hypoxia‐induced frequency plasticity. Thus, we hypothesized that intermittent bath‐application of SubP is sufficient to induce frequency plasticity in isolated neonatal rat (P0–P3) brainstem‐spinal cord preparations. Intermittent SubP application (100 nM; 3 min on/7 min off; ×3 applications; n=13) to the entire brainstem‐spinal cord preparation increased burst frequency from 11.6 bursts/min (baseline) to 14.3 bursts/min (peak response). Burst frequency was still elevated to 12.7 and 12.1 bursts/min at 30 and 60 min following intermittent SubP exposure, indicating that acute SubP application induces a persistent effect. Respiratory burst frequency in time control experiments (n=13) was 11.5 bursts/min (baseline) and decreased by 25% over an equivalent time period. One bout of sustained SubP application (100 nM; 9 min; n=6) did not induce a persistent increase in respiratory burst frequency, suggesting a pattern sensitivity to this form of frequency plasticity. Likewise, intermittent SubP application at 10 (n=11) or 1.0 nM (n=7) did not induce frequency plasticity. Thus, intermittent SubP application is sufficient to induce frequency plasticity in a dose‐ and pattern‐dependent manner in the absence of hypoxia. Current studies are aimed at identifying if sexual dimorphisms exist, and understanding the role of inflammation in abrogating this form of frequency plasticity.Support or Funding InformationSupported by R01 HL111598, the Vilas Family Foundation and a private donation.