Hypoxia and Control of Fetal Breathing Movements

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): Extracellular adenine nucleotides, central adenosine (ADO) A2A receptors, and the parafascicular nuclear complex (Pf) of the thalamus are crucially involved in hypoxic inhibition of fetal breathing (FB). As in hypoxic depression of FB, the roll-off ventilatory response to hypoxia in newborns is abolished by 1) blockade of central A2A receptors, or 2) disruptions of the rostral brainstem. Thus, mechanisms involved in the depressant respiratory effects of hypoxia on FB can now be studied in newborn lambs, where experiments are more easily performed. The proposed studies in lambs have four goals: 1) To determine the source of extracellular adenine nucleotides in the hypoxia-induced rise in brain ADO levels. Inhibitors of ATP degradation and the synaptic release of ATP will be administered locally to Pf via microdialysis while measuring in real time extracellular levels of ADO and ATP in Pf. These studies will establish whether ATP released from synaptic vesicles or glia is the primary precursor for the hypoxia-induced rise in Pf ADO levels. 2) To determine the locus of brain ADO A2A receptors that depresses ventilation. ADO A2A receptor agonists and antagonists will be microinjected into Pf to determine whether the identified A2A receptors in this locus slow or disrupt ventilation. 3) To determine the ontogeny of the distribution and coupling efficiency of brain ADO A2A receptors. These studies will determine whether transient expression and/or changes in coupling efficiency of brain ADO A2A receptors contribute to developmental changes in the impact of hypoxia on respiration. 4) To determine the role of Pf in roll-off ventilatory response to hypoxia. Ventilatory responses to hypoxia will be determined in lambs with bilateral neuronal lesions of Pf to determine whether Pf is a critical part of the neuronal circuitry involved in the roll off. Sleeping infants who experience oxygen deprivation caused by airway obstruction (e.g., due to infection or sleeping in the prone position) associated with prolonged interruptions in breathing (apnea) are particularly vulnerable to hypoxic brain damage and unexplained death. Sleep apnea associated with snoring can also lead to significant oxygen deficiency in children and adults, which can result in stroke, high blood pressure, diabetes, and abnormalities in heart rate. Thus, the proposed studies are directly applicable to the morbidity and mortality of heart and breathing disorders in infants, children, and adults, including prolonged sleep apnea, brain injury, and sudden death.