We have had a long standing interest in the maturation of respiratory control in early life. In particular, we have focussed on the study of mechanisms that can lead to apnea, hypoventilation and hypoxia, conditions that contribute in major ways to morbidity and mortality in infants and children. Although we and others have previously described the ventilatory response to hypoxia in newborns and with maturation, to date, little is known about the cellular and subcellular mechanisms by which graded hypoxia act in the CNS and more specifically in the brainstem. Using intracellular techniques and a brainstem slice preparation, we specifically intent to 1) study the postnatal maturation of the electrophysiologic response to medullary neurons (ventral Nucleus Tractus Solitarius, V-NTS, and Hypoglossal, HYP) to hypoxia in the first several weeks of life in the rat, 2) determine the basic ionic mechanisms that underlie the neuronal excitability during hypoxia and 3) determine whether the electrophysiologic changes seen with hypoxia are mediated by neurotransmitters released by hypoxia. The variables studies will include active and passive cellular properties and membrane properties using current and voltage clamp techniques. In addition, we will use pharmacologic manipulations (e.g., blockers such as TEA, apamin, Cobolt, TTX) ion substitutions (e.g. choline) and ion-selective electrodes to measure changes in ion fluxes (K+, H+) in both intracellular and extracellular compartments. A number of neurotransmitter blockers including Aminophosphonovalerate, Bicuculline, Naloxone and Theophylline will also be used to see whether the electrophysiologic changes seen during hypoxia are neurotransmitter-regulated. Our preliminary results, showing major differences in hypoxic responsiveness between newborns and adults, are very encouraging. We believe that these studies are essential for our understanding of 1) the effects of hypoxia on the function of medullary respiratory-related neurons and 2) neuronal resistance or susceptibility to hypoxic injury in newborns and adults.
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