Identification of brainstem neurons responding to hypoxia in fetal and newborn sheep

Abstract

Hypoxia causes a reversible decrease in the level of respiratory, oculomotor and postural muscle activity in fetal sheep, an effect not seen in newborn lambs. We have used Fos immunohistochemistry to identify neurons which are activated by hypoxia and which may mediate this motor inhibition in the fetus. Pregnant sheep of either 117 or 138 days gestation were made hypoxic by allowing them to breathe 8-9% O2 for 2 h. Compared to age-matched control fetuses, hypoxia caused a significant increase in Fos-immunoreactivity in several medullary nuclei including the nucleus tractus solitarius, lateral reticular nucleus and the rostral ventrolateral medulla and also in the lateral parabrachial nucleus, locus coeruleus and subcoeruleus region in the pons. Hypoxia in newborn lambs, 7-18 days old, resulted in Fos staining in the same medullary and pontine nuclei with the exception of the subcoeruleus region which was devoid of Fos-immunoreactivity. In newborn lambs in which the carotid sinus nerves had been sectioned bilaterally, Fos-immunoreactivity was increased in the nucleus tractus solitarius in the medulla and in the locus coeruleus, lateral parabrachial and Kölliker-Fuse nuclei in the pons when compared to intact control newborn lambs. When carotid sinus nerve denervated-lambs were subjected to hypoxia the pattern of Fos-ir was similar to the pattern seen in the denervated control lambs but in addition staining was present in the subcoeruleus. These results suggest that a specific set of pontine neurons are activated by low oxygen levels in the fetus but not in the newborn lamb in the presence of an intact innervation from the carotid sinus. We hypothesise that: (a) in the fetus hypoxia activates neurons in the region of the subcoeruleus and this causes cessation of breathing movements and muscle atonia; and (b) that after birth stimulation of the carotid chemoreceptors by hypoxia normally inhibits activation of these subcoeruleus neurons.