The fundamental goal of this proposal is to investigate cellular mechanisms associated with plasticity in the carotid body (CB) chemoreceptors. Specifically, we propose to investigate cellular mechanisms which underlie putative hypoxia-induced functional recovery of impaired CBs in rats treated with perinatal hyperoxia. In rats, perinatal hyperoxia (60 percent O2 for the first month post-partum) impairs the ventilatory response to hypoxia, an effect that persists into adulthood. This is due to impaired CB function and includes a reduction in CB size and number of chemoafferent axons from the petrosal ganglion (PG). It is postulated that perinatal hyperoxia suppresses normal maturation of the CB and PG chemoafferent neurons within a critical developmental window. Once this developmental window has ended, normal mechanisms of developmental plasticity cannot proceed. Recent studies indicate that 1 week of sustained hypoxia (SH) induces significant recovery of the hypoxic ventilatory response, and preliminary data suggest that this recovery may be CB-mediated. Our central hypothesis is that SH-induced recovery of ventilatory function arises from plasticity in the CB and its chemoafferent neurons. To test this hypothesis, adult rats subjected to perinatal hyperoxia, will be exposed to SH for up to 4 weeks. Predictable outcomes should determine if SH-induced recovery of CB function is permanent. Measurements in SH-treated and control groups will include assessment of CB function by carotid sinus nerve recording, immunocytochemical analysis and/or mRNA analysis of functional proteins (phosphorylated cyclic-AMP response element-binding protein, tyrosine hydroxylase, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, vascular endothelial growth factor) and evidence of morphological recovery in the CB and PG. This project should provide new information on SH-induced neuroplasticity of the CB and PG in both perinatal hyperoxia treated and normal animals and may suggest methods to treat children with impaired arterial chemosensitivity due to perinatal hyperoxia.
