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Nurr1, a transcription factor belonging to the family of nuclear receptors, is expressed at high levels immediately after birth. Gene-targeted mice lacking Nurr1 fail to develop midbrain dopaminergic neurones and do not survive beyond 24 h after birth. Dopamine (DA) levels may be regulated by Nurr1, and as DA is involved in both central and peripheral respiratory control, we hypothesized that lack of Nurr1 may impair breathing and cause death by respiratory failure. We demonstrate herein that Nurr1 newborn knockout mice have a severely disturbed breathing pattern characterized by hypoventilation, numerous apnoeas and failure to increase breathing when challenged with hypoxia. In heterozygote Nurr1 mice the response to hypoxia is also altered. Furthermore, the central respiratory rhythm, generated from isolated brainstem-spinal cord preparations, exhibits impaired response to hypoxia in mice lacking Nurr1. Moreover, Nurr1 is expressed in several respiratory-related regions of the nervous system, including the nucleus of the solitary tract, the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve, and in the carotid bodies. The prominent Nurr1 expression in these areas, involved in respiratory control, along with the severe respiratory phenotype, indicates that Nurr1 plays a major role in the extrauterine adaption of respiratory control and the response to hypoxia.

1. To define the effects of prenatal hypoxia on the postnatal development of the chemoafferent pathway, ventilation and metabolism, pregnant rats were exposed to normobaric hypoxia (10 % oxygen) from embryonic day 5 to embryonic day 20. Offspring were studied at 1, 3 and 9 weeks of age in three separate protocols. 2. Prenatal hypoxia decreased the dopamine content in the carotid bodies at all ages, and decreased the utilisation rate of noradrenaline in the caudal part of the A2 (A2c), A1 and A5 noradrenergic brainstem cell groups at 3 weeks after birth. At 9 weeks of age, the level of dopamine in the carotid bodies was still reduced but the utilisation rate of noradrenaline was enhanced in A1. 3. Rats from dams subjected to hypoxia during pregnancy hyperventilated until 3 weeks after birth. In these rats, the biphasic hypoxic ventilatory response was absent at 1 week and the increase in minute ventilation was amplified at 3 weeks. 4. Prenatal hypoxia disturbed the metabolism of offspring until 3 weeks after birth. A weak or absent hypometabolism in response to hypoxia was observed in these rats in contrast to control animals. 5. Prenatal hypoxia impairs the postnatal development of the chemoafferent pathway, as well as the ventilatory and metabolic responses to hypoxia. These alterations were mostly evident until 3 weeks after birth.

1. The first step of this study was to determine the early time course and pattern of hypoxic ventilatory response (HVR) recovery following irreversible bilateral carotid sinus nerve transection (CSNT). The second step was to find out if HVR recovery was associated with changes in the neurochemical activity of the medullary catecholaminergic cell groups involved in the O2 chemoreflex pathway. 2. The breathing response to acute hypoxia (10% O2) was measured in awake rats 2, 6, 10, 45 and 90 days after CSNT. In a control group of sham-operated rats, the ventilatory response to hypoxia was principally due to increased respiratory frequency. There was a large reduction in HVR in the CSNT compared to the sham-operated rats (-65%, 2 days after surgery). Within the weeks following denervation, the CSNT rats progressively recovered a HVR level similar to the sham-operated rats (-37% at 6 days, -27% at 10 days, and no difference at 45 or 90 days). After recovery, the CSNT rats exhibited a higher tidal volume (+38%) than the sham-operated rats in response to hypoxia, but not a complete recovery of respiratory frequency. 3. Fifteen days after CSNT, in vivo tyrosine hydroxylase (TH) activity had decreased in caudal A2C2 (-35%) and A6 cells (-35%). After 90 days, the CSNT rats displayed higher TH activity than the sham-operated animals in caudal A1C1 (+51%), caudal A2C2 (+129%), A5 (+216%) and A6 cells (+79%). 4. It is concluded that HVR following CSNT is associated with a profound functional reorganisation of the central O2 chemoreflex pathway, including changes in ventilatory pattern and medullary catecholaminergic activity.