Abstract
We have identified a critical period of respiratory development in rats at postnatal days P12‐13, when inhibitory influence dominates and when the response to hypoxia is at its weakest. This critical period has significant implications for Sudden Infant Death Syndrome (SIDS), the cause of which remains elusive. One of the known risk factors for SIDS is prematurity. A common intervention used in premature infants is hyperoxic therapy, which, if prolonged, can alter the ventilatory response to hypoxia and induce sustained inhibition of lung alveolar growth and pulmonary remodeling. The goal of this study was to test our hypothesis that neonatal hyperoxia from postnatal day (P) 0 to P10 in rat pups perturbs the critical period by altering the normal progression of neurochemical development in brain stem respiratory‐related nuclei. An in‐depth, semiquantitative immunohistochemical study was undertaken at P10 (immediately after hyperoxia and before the critical period), P12 (during the critical period), P14 (immediately after the critical period), and P17 (a week after the cessation of hyperoxia). In agreement with our previous findings, levels of cytochrome oxidase, brain‐derived neurotrophic factor (BDNF), TrkB (BDNF receptor), and several serotonergic proteins (5‐HT1A and 2A receptors, 5‐HT synthesizing enzyme tryptophan hydroxylase [TPH], and serotonin transporter [SERT]) all fell in several brain stem respiratory‐related nuclei during the critical period (P12) in control animals. However, in hyperoxic animals, these neurochemicals exhibited a significant fall at P14 instead. Thus, neonatal hyperoxia delayed but did not eliminate the critical period of postnatal development in multiple brain stem respiratory‐related nuclei, with little effect on the nonrespiratory cuneate nucleus.
Highlights
The respiratory system in rats is not fully mature at birth
This study found that the downregulation of cytochrome oxidase (CO) occurred at P12 in normoxic animals, but was delayed until P14 in hyperoxia-exposed animals in the respiratory-related nuclei XII, pre-Bo€tzinger complex (PBC), and NTSVL, but not in the cuneate nucleus (CN)
This study showed that severe hyperoxia for the first ten postnatal days clearly caused a disruption in the development of several neurochemicals important for neuronal functioning within a number of brain stem respiratory-related nuclei
Summary
The respiratory system in rats is not fully mature at birth. The alveoli are not fully formed in the lung (Thurlbeck 1975) and the neural control of breathing is still immature (Carroll 2003). The system passes through a brief, transient period of synaptic imbalance toward the end of the second postnatal week (P12-13), during which excitatory synaptic activity and neurochemicals are significantly downregulated, and inhibitory neurotransmission is increased (Liu and WongRiley 2002, 2005; Wong-Riley and Liu 2005; Gao et al 2011). At this time, the ventilatory response to acute hypoxia (10% O2, 5–7 min) is at its weakest (Liu et al 2006, 2009).
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