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. ? ?
| Koos, Brian J; Rajaee, Arezoo; Ibe, Basil et al. (2016) Thalamic mediation of hypoxic respiratory depression in lambs. Am J Physiol Regul Integr Comp Physiol 310:R586-95 |
| Koos, Brian J; Rajaee, Arezoo (2014) Fetal breathing movements and changes at birth. Adv Exp Med Biol 814:89-101 |
| Koos, Brian J (2011) Adenosine Aýýýa receptors and Oýýý sensing in development. Am J Physiol Regul Integr Comp Physiol 301:R601-22 |
| Maeda, Takatsugu; Koos, Brian J (2009) Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep. Am J Physiol Regul Integr Comp Physiol 296:R693-701 |
| Yan, X; Koos, B J; Kruger, L et al. (2006) Characterization of [125I]ZM 241385 binding to adenosine A2A receptors in the pineal of sheep brain. Brain Res 1096:30-9 |
| Koos, Brian J; Kawasaki, Yoshikazu; Kim, Young-Han et al. (2005) Adenosine A2A-receptor blockade abolishes the roll-off respiratory response to hypoxia in awake lambs. Am J Physiol Regul Integr Comp Physiol 288:R1185-94 |
| Shi, Lijun; Yao, Jiaming; Koos, Brian J et al. (2004) Induced fetal depressor or pressor responses associated with c-fos by intravenous or intracerebroventricular losartan. Brain Res Dev Brain Res 153:53-60 |
| Koos, Brian J; Kawasaki, Yoshikazu; Hari, Ashwinii et al. (2004) Electrical stimulation of the posteromedial thalamus modulates breathing in unanesthetized fetal sheep. J Appl Physiol 96:115-23 |
| Koos, Brian J; Maeda, Takatsugu; Jan, Calvin et al. (2002) Adenosine A(2A) receptors mediate hypoxic inhibition of fetal breathing in sheep. Am J Obstet Gynecol 186:663-8 |
| Koos, B J; Maeda, T; Jan, C (2001) Adenosine A(1) and A(2A) receptors modulate sleep state and breathing in fetal sheep. J Appl Physiol 91:343-50 |
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