The proposed research seeks to define growth factor regulation of neuronal development in chemoafferent cell groups in the rat petrosal ganglion (PG) and nucleus tractus solitarius (nTS). PG and nTS neurons comprise the sensory pathway between carotid (CB) body chemoreceptors and central respiratory neurons and thereby play a pivotal role in mediating peripheral chemoreflexes. However, CB reflexes change markedly between fetal and adult life, and mechanisms that underlie this development are poorly understood. This continuation proposal is based on our recent discovery that the CB, in addition to its known chemosensory functions, plays a critical role in trophic regulation of chemoreceptor afferent development. Specifically, CB removal in newborn rats leads to death of CB afferents in the PG, whereas afferent survival in vitro is supported by the CB. Moreover, trophic influences of the CB are mimicked by the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), in vivo and in vitro, and we have recently discovered that BDNF mRNA is expressed in the newborn CB. On the basis of these findings we hypothesize that the CB plays an integral role in regulating chemosensory pathway development in vivo, and that this effect is mediated, at least in part, by BDNF. Furthermore, we hypothesize that growth factors are similarly important for maturation of second-order neurons in nTS. In the proposed studies, therefore, the rat PG and nTS will be used as model systems to further define trophic mechanisms of neuronal maturation in the CB afferent (CBA) pathway, in vivo and in vitro. Studies in vitro will elucidate cellular mechanisms of neurotrophin action on CBA neurons, including the time course of BDNF dependence and regulation of transmitter expression. Studies with intact animals will characterize the ability of CBA neurons to respond to BDNF in via by examining neuronal survival, growth and transmitter expression in the presence and absence of exogenous growth factor in fetuses and neonates. Additional studies will examine whether local BDNF application can substitute for target-derived trophic support following removal of the CB at different stages of postnatal development. Molecular biologic techniques will be used to analyze the time course of expression of BDNF and other potentially important growth factors in the CB and nTS, in neonatal animals and in response to chronic hypoxia. Finally, dissociate cell cultures will be used to define growth factor requirements of neurons in the commissural nTS, a principal target of chemoreceptor inputs to the brainstem. Such definition of growth factor regulation of chemosensory pathway development may shed light on cellular and molecular mechanisms relevant to understanding and improved management of hypoventilation and apnea syndromes in infants and neonates. Moreover, it is hoped that elucidating development of this system will create a model of trophic regulation, applicable to sensory networks as a whole.
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