The aim of the proposed research is to define the role of neurotrophic factors in the functional maturation of key elements in the brainstem respiratory network, including primary chemoafferent neurons, secondary relay neurons in the nucleus tractus solitarius and rhythmically active neurons in the preBotzinger complex (pBC), a vital site for respiratory rhythm generation. Gene mutations affecting neurotrophic factor expression and signaling, including Brain-Derived Neurotrophic Factor (BDNF), Glial Cell Line-Derived Neurotrophic Factor (GDNF), the GDNF receptor, RET, and MeCP2, a transcriptional represser of BDNF, have all been associated with developmental disorders of breathing. However, little is known about how these genes regulate the functional maturation of brainstem neurons and circuits that control ventilation. Based on recent discoveries in my laboratory, we hypothesize that genetic or environmental perturbations of BDNF and GDNF function can derange maturation of the brainstem respiratory network by disrupting maturation of 1) transynaptic signaling between first- and second-order chemoafferent neurons and 2) the pBC rhythm. To test this hypothesis, the proposed research will use fetal and newborn mice, including mutant animals in which growth factor expression or signaling are perturbed, to define the role of BDNF and GDNF in the functional maturation of these critical respiratory cell groups. We will use a multidisciplinary approach, including patch clamp recording from isolated cells and brainstem slice preparations, mRNA expression profiling of identified neurons by single cell RT-PCR and anatomic mapping of neuronal projections in fetuses and neonates. By defining growth factor regulation of respiratory neural development, the proposed research aims to shed light on cellular and molecular mechanisms relevant to understanding and improved management of hypoventilation and apnea syndromes in neonates and infants. Moreover, it is hoped that defining developmental mechanisms in this system will, in turn, create a model of growth factor function and regulation that is applicable to the nervous system as a whole. ? ?
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