Characteristics in the Vulnerability of the Respiratory Neural Control System During a Critical Window of Postnatal Development

Prior studies have demonstrated the existence of a critical window of neurochemical expression that occurs in the brainstem at approximately 12 days of postnatal (P12) age in the rat. The critical window is characterized by changes in the expression of various neurotransmitters, receptors, trophic factors, and metabolic enzymes in various brainstem respiratory control regions. Presumably these changes represent important neurodevelopmental events necessary for appropriate maturation of the cardio‐respiratory control system. However, studies from our lab have begun to demonstrate the critical window is a period of development during which the respiratory control system exhibits a heightened vulnerability to environmental challenges. For example, five days of sustained hypoxia exposure (SH: 11% O2) between P11–15 days, which encompasses the P12 critical window, abolished the ventilatory response to acute hypoxia (HVR (delta baseline): 0.63 ± 0.31 ml/g/min) compared to age‐matched rats raised in normoxia (0.12 ± 0.45 ml/g/min). The absence of a HVR in these rats was associated with an unexpected and substantial degree of mortality that occurred ~3 days later. These effects were unique to the critical window as neither younger (P1–5) or older (P21–25) rats were affected by the same exposure to SH. We have also shown the critical window appears to be an important stage of brainstem neurodevelopment because it is represented by a transient surge in constitutive expression of brainstem mRNA for NeuroD1 and CyclinB2. However, SH between P11–15 reduced their expression (NeuroD1: 0.66 ± 0.11; CyclinB2: 0.74 ± 0.14 fold‐change from normoxia control rats), indicating a major and potentially fatal disturbance in brainstem mechanisms of neurodevelopment. The critical window of development was also characterized by a transient increase in the constitutive expression of brainstem TNFα mRNA, which was further increased by SH exposure (1.47 ± 0.09 fold‐change from control). Further, SH also decreased serotonin (5‐HT) levels specifically within the dorsal motor nucleus of the vagus (DMNV) and nucleus of the solitary tract (nTS). We speculate that SH exposure interferes with key neurodevelopmental events, ultimately leading to a lethal disturbance in brainstem neurochemistry within distinct (cardio)–respiratory control regions and may involve a mechanism associated with an aberrant cytokine response. These data could contribute to our understanding of the pathways involved in the brainstem neurochemical abnormalities observed in Sudden Infant Death Syndrome (SIDS). Support or Funding Information Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University