Koos BJ, Rajaee A, Ibe B, Guerra C, Kruger L. Thalamic mediation of hypoxic respiratory depression in lambs. Am J Physiol Regul Integr Comp Physiol 310: R586 -R595, 2016. First published January 28, 2016 doi:10.1152/ajpregu.00412.2015.-Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53-80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development. brain; biphasic ventilation; hypoxia; respiratory inhibition; thalamus; sheep THE CRITICAL TRANSITION FROM fetus to newborn depends upon timely transfer of respiratory gas exchange from the placenta to lung and an essential change in respiratory control. In contrast to postnatal respiration, fetal breathing involves fluid-filled lungs, minimal pulmonary expansion, prolonged apneas, modulation by glycemia, independence of normal fluctuations in respiratory gases, expression limited to specific behavioral states, and inhibition by moderate hypoxia (47). Thus, parturitional changes critical for survival involve the onset of continuous breathing and hypoxic hyperpnea. Pioneering studies at Cambridge (5) and Oxford (20,21,39) revealed the uniqueness of the control of respiratory muscles in fetal sheep. The ovine model had considerable advantages in resistance to surgery-induced labor, and the large fetus facilitated instrumentation and measurement of blood gases and pH. This work and subsequent discoveries in sheep (e.g., Refs. 10,12,13,40,41,42,43,44,45,46,71,92) were instrumental in establishing the foundation for perinatal medicine.Immaturity of central respiratory controllers dispose newborns to recurrent apnea and thus O 2 deprivation. Respiratory responses to hypoxic stress include a rapid-onset stimulation (augmentation) followed by a gradual decline (depression). Putative O 2 sensors in the supramedullary brain stem (9, 52, 58, 81, 82, 90) mediate the depressant ...