Exposure to retinoic acid at the onset of hindbrain segmentation induces episodic breathing in mice.

Hyperpnoeic episodic breathing (HEB), a cyclic waxing and waning of breathing, has been widely reported in pre-term neonates, patients with Joubert syndrome and adults (Cheyne-Stokes respiration) with congestive heart failure and brainstem infarction. We now provide a developmental mouse model of neonatal HEB. We used retinoic acid (RA) (0.5-10 mg/kg of maternal weight) to alter embryonic development of the respiratory neuronal network at the onset of hindbrain segmentation (7.5 days post-coitum). HEB was observed in vivo after RA treatment during post-natal days 1-7 but not in control animals. HEB persisted after reduction of the chemoafferent input by hypocapnic hyperoxia (100% O(2)). A large increase and decrease of the rhythm resembling an HEB episode was induced in vitro by stimulating the parafacial respiratory oscillator in treated but not in control neonates. Post-natal localization of the superior cerebellar peduncle and adjacent dorsal tegmentum was found to be abnormal in the pons of RA-treated juvenile mice. Thus, early developmental specifications in the rostral hindbrain are required for the development of neurones that stabilize the function of the respiratory rhythm generator, thereby preventing HEB during post-natal maturation.

Regional brain response patterns to Cheyne-Stokes breathing.

Cheyne-Stokes breathing (CSB) results from impaired integration of sensory information with respiratory motor output; however, regions mediating the disturbed control are unknown. We examined functional magnetic resonance imaging signals during CSB within sleep to determine affected areas. Two male patients with severe obstructive sleep apnea were scanned while asleep over multiple sessions during which they exhibited CSB. Significant signal increases coincident with apneic periods emerged bilaterally in the cerebellar cortex, hippocampus, mediodorsal thalamus, frontal cortex and precentral gyrus. Signals declined bilaterally in the anterior cingulate cortex and postcentral gyrus. The reduced activation in primary sensory cortex and increased signals prior to breathing onset in the motor cortex are consistent with loss of sensory stimulation by airflow, and with anticipatory action of the motor cortex prior to initiation of breathing. Hippocampal and anterior cingulate cortex participation likely reflect previously-demonstrated roles for initiating inspiratory efforts and resolving sensory information and motor action, respectively.