Hypoxia abolishes fetal breathing (FB) through a direct effect of low P02 on the brain. We have recently shown that the parafascicular nuclear complex (Pf) in the thalamus is critically involved in hypoxic depression of FB, leading to a new paradigm regarding the neural substrate mediating hypoxic inhibition. The proposed studies in fetal sheep have four goals: 1) To determine the role of Pf in the second- phase reduction in ventilation in newborns, which undoubtedly involves the same central mechanism that mediates hypoxic inhibition of FB. Hypoxic inhibition of FB will be abolished by selectively destroying fetal Pf neurons with subsequent testing of newborn respiratory responses to hypoxia. The large size of the near-term fetal sheep brain will greatly facilitate the identification of the neural substrate mediating ventilatory """"""""roll off"""""""" during hypoxia in the newborn. 2) To identify the Pf neural pathways involved in inhibition of FB. The lipophilic dye DiI will enable anterograde and retrograde labelling of fiber tracts which will determine the connections of these cells and thus help establish the neural network involved in hypoxic inhibition. Distinct advantages of DiI include its applicability to postmortem tissue and optimum efficiency in perinatal brains. 3) To determine the mechanism of hypoxic inhibition. Increased brain adenosine (ADO) concentrations, derived from hydrolysis of extracellular adenine nucleotides, mediate hypoxic inhibition of FB. Microdialysis with a novel inhibitor of extracellular ATPase will establish whether extracellular ATP is an essential precursor for the hypoxia-induced rise in ADO. 4) To identify the locus of ADO receptors that mediate hypoxic inhibition of FB. ADO receptor agonists and antagonists will be microinjected into Pf to determine whether ADO A1 or A2 receptors in or proximate to this sector inhibit FB during hypoxia. Hypoxic inhibition appears to be part of a survival mechanism whereby O2 that would otherwise be used for breathing is made available to vital organs, especially the heart and brain; thus it has relevance to hypoxia-induced perinatal brain damage. Such injury may predispose infants to Sudden Infant Death Syndrome (SIDS) by increasing the depressing effects of hypoxia on ventilation and by altering sleep state regulation of breathing postnatally. Thus, these studies on hypoxic inhibition should provide insight into mechanisms of SIDS and enhance our understanding of the clinically important transition of neural control of respiration in the perinatal period.
| 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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