The proposed research seeks to define cellular and molecular mechanisms that regulate the perinatal maturation of carotid body afferent neurons in the rat. These cells, localized to the petrosal ganglion (PG), constitute the sensory pathway between the carotid body chemoreceptor and the brainstem, and thereby play a pivotal role in mediating ventilatory responses to such life- threatening stimuli as hypoxia. However, carotid body reflexes change between fetal, neonatal and adult life, and mechanisms that underlie this development are poorly understood. Carotid chemoreceptor are relatively ineffective, for example in increasing ventilatory responses during hypoxia in the fetus; after birth, hypoxic stimulation produces transient, and eventually sustained increases in respiration. Recent studies in our laboratory indicate that catecholaminergic (CA) properties expressed by carotid body afferents in the PG increase markedly in the perinatal period, indicating a temporal, and possibly causal relationship to chemoreflex development. Therefore, to elucidate the perinatal regulation of carotid body afferent development, the proposal is designed to further define CA maturation in the PG and to investigate underlying physiological, cellular and molecular mechanisms. Biochemical, immunocytochemical and histochemical methods will be used to delineate the pre- and postnatal development of the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) and catecholamine fluorescence. Physiologic studies will explore the possibility that the increase in inspired O2 that occurs after birth, as well as birth process itself, are involved in CA maturation by examining the effects of chronic hypoxia and Cesarean delivery on TH and catecholamine development in the PG. Moreover, tissue culture methods will be used to examine molecular mechanisms, such as trophic interactions and depolarizing stimuli, that may influence the perinatal maturation of carotid body afferent neurons. These studies are part of a long-range effort aimed at defining cardiopulmonary afferent development at the molecular level. It is hoped that this work will help elucidate the molecular pathogenesis of hypoventilation syndromes in infants and adults and lead to new therapeutic approaches. The proposed research may also shed light on basic mechanisms of neuronal development, applicable to the nervous system as a whole.
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