Although the specific pathogenetic mechanisms that lead to demise in the Sudden Infant Death Syndrome (SIDS) are still obscure, data so far indicate that the fetal intra-uterine environment may not be optimal for the development of postnatal regulatory mechanisms. For example, there is a large number of SIDS infants who are growth-retarded and that this retardation is due to exposure of the fetus to an abnormal intrauterine environment including smoking. However, it is not known whether this abnormality is due to limitation in O2 or to ischemia and limitation of nutrients to the fetus. For a number of years, we have been interested in SIDS and in abnormalities in cardiorespiratory control in early life. Recently, we have developed an animal model which allows us to either impose graded and specific levels of hypoxia or reduced placental blood flow prenatally. We have also developed the methodologies to examine brain growth, structure and function at the cellular and subcellular level, and determine the integrity of regulatory mechanisms responsible for brainstem control of cardiorespiratory function in early life. Based on preliminary results from our laboratory we have formulated the following Specific Hypotheses: 1. Graded prenatal stress (i.e. placental ischemia or fetal hypoxia) leads to graded changes in the morphology and membrane structural integrity of brainstem neurons examined postnatally and 2. Graded prenatal stress alters the electrophysiologic properties of brainstem neurons and renders them more susceptible (or less resistant) to acute postnatal hypoxia in a graded manner. To address these hypotheses, we will use rats and subject them to either prenatal hypoxia or intrauterine artery ligation and examine their postnatal brainstem development and neuronal responsiveness to acute hypoxia. Our methods will include light and confocal microscopy to examine overall neuronal morphology and membrane integrity, autoradiographic and electrophysiologic techniques (brain slice) to study ion channel function and Magnetic Resonance Spectroscopy on whole animal central nervous system and brain extracts to examine intermediary metabolic profiles. We believed that these proposed studies are crucial for determining the effect of prenatal hypoxia or placental insufficiently on brainstem neuronal development, tolerance or susceptibility to O2 deprivation and the structural and functional alterations in the growing postnatal animal.
