Normal respiratory control in newborns, as in adults, is dependent on interactions among networks of neurons comprising the brain stem respiratory centers. However, newborns are particularly prone to develop unstable respiratory patterns, suggesting important differences in these interactions during the postnatal period. The long-range goals of this laboratory is to characterize excitatory and inhibitory central neuronal mechanisms which control autonomic nervous function, including respiratory drive, during the newborn period. The major objective of the present study is characterize the cellular development of the neural pathway responsible for integrating peripheral chemosensory input. We will identify mechanisms regulating expression of neurotransmitter genes and electrophysiologic responses of these neurons during development. Further, these studies will determine how development of this system is affected by pre- and postnatal hypoxemia. Regular progression through defined developmental stages is crucial for normal development of the respiratory control system. Disruption of the normal developmental pattern due to an abnormal condition (eg hypoxia) during the perinatal period can lead to system dysfunction possibly resulting in life threatening pathologies including apnea in premature infants, infantile apnea common in older infants, and Sudden Infant Death Syndrome. The initial series of immunohistochemical and in situ hybridization experiments utilize Fos protein expression as a marker for second and higher order neurons comprising the central chemoreflex pathway. Fos protein is expressed in response to afferent synaptically transmitted signals arising from the peripheral chemosensory structures. Previously, we used this approach to identify higher order neurons comprising the central neural chemoreflex pathway in adult rat. The present studies are to be performed in developing rats and include: 1) Identifying the brainstem neuronal populations that comprise the chemoreflex pathway during postnatal development, 2) Determine the effect of pre- and postnatal hypoxemia on development of this pathway, and 3) identify the effect of perinatal hypoxemia on neurotransmitter-related gene expression throughout early postnatal development. A second series of experiments is designed to determine the electrophysiologic properties of hypoxia sensitive neurons in the brainstem regions identified as containing the chemoreflex pathway. In this latter experiments patch-clamp recording of neurons in an ex vivo brainstem slice preparation will be used to determine cellular mechanisms associated with decreased responsiveness following pre- and post natal hypoxemia.
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