Mechanism of Bilirubin-induced Apnea in Preterm Infants

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Elevated free bilirubin (Bf) in preterm newborns is a major global cause of long term neurodevelopmental disability but the mechanisms of injury are still unclear. Bf in preterm infants has been associated with episodic cessation of breathing, which if exceeds 15 sec is called apnea of prematurity. Collectively, these apneic spells lead to intermittent hypoxemia, ultimately resulting in poor neurodevelopmental outcomes. The neurons of the nucleus tractus solitarius (nTS) are an essential part of the neural circuitry governing respiratory drive including CO2 chemosensitive neurons, peripheral chemoreceptors and mediating responses to peripheral hypoxia. In the preterm newborn, the nTS of the brain is undergoing rapid development: Neurons are differentiating and extending neurites, forming synapses and undergoing myelination. These processes depend on dynamic microdomains of the plasma membrane called lipid rafts. Lipid rafts regulate activity of ion channels, signal transduction and protein trafficking. We hypothesize that Bf disrupts lipid rafts leading to perturbations in the nTS, and that choline, a known neuroprotectant, reduces the impact of Bf on both lipid rafts and apnea. With our previously funded R21, we developed an animal model of hyperbilirubinemia of prematurity using the Gunn rat which lacks the ability to conjugate bilirubin to glucuronide and thus excrete it. We discovered that 1) elevated Bf disrupts the function of a lipid raft associated protein both in vitro and ex vivo, and alters cerebellar mediated behaviors, and that 2) choline confers resistance to the effects of Bf on both the lipid raft associated protein and behaviors. These results have put us in a position to accomplish the following novel and clinically relevant goals: 1) explore the effects of Bf on lipid rafts in the nTS and associated nuclei involved in respiration, and their response to choline, 2) determine the impact of elevated Bf with or without choline on neuron excitability in the nTS and 3) measure respiratory drive and how it is impacted by Bf and choline. We predict that lipid raft dysfunction will precede changes in neuronal excitability and respiratory drive, and all changes in outcomes will be lessened by choline. The attainment of these goals will lead to clinical trials using choline to try to reduce the morbidity associated with elevated Bf in human preterm infants.