464 Review D.W. Richter Dept of Physiology II, Georg August Universität Göttingen, 37073 Göttingen, Germany. e-mail: d.richter@ gwdg.de K.M. Spyer Dept of Physiology, Royal Free, University College London, London, UK. e-mail: k.spyer@ucl.ac.uk In mammals breathing depends on periodic contractions of respiratory muscles that are innervated by spinal motoneurons to produce ventilation of the lungs. Such rhythmic neural activity is generated by a respiratory network within the ventrolateral region of the lower brainstem. Respiratory rhythm The respiratory rhythm is not just a periodicity of inspiratory bursts, but a coordinated alternation of inspiratory, post-inspiratory and expiratory burst activities1. Coordination of these activities is important, not only for breathing, but also for vocalization, swallowing and motor control. There is no fundamental change to this three-phased process during postnatal development. Respiratory activity is actively controlled by specific classes of medullary neuron that interact synaptically. Various studies have shown that at least two antagonistic phasic activities are necessary, for example, inspiratory and post-inspiratory (stage 1 expiratory) activities during rapid shallow breathing. These phases are usually supplemented by a third, (stage 2) expiratory activity, which is either weak or absent during quiet breathing2. Respiratory center The respiratory nervous outflow in spinal motoneurons that supplies respiratory muscles originates from bilaterally organized dorsal (DRG) and ventral groups of respiratory neurons (VRG) within the lower brainstem3 (Fig. 1a). Only the VRG is essential for rhythm generation. It extends rostro-caudally in close proximity to the nucleus ambiguus and forms a ‘distributed’ network, which means that assemblies of different classes of respiratory neurons are located in close proximity (Fig. 1a). Some classes of neuron are additionally aggregated in other brainstem and upper spinal cord regions, such as expiratory neurons in the Bötzinger complex, which is in the rostral part of the VRG. A dominating ‘kernel’ is localized in the pre-Bötzinger complex (PBC) within the VRG just caudal to the compact division of the rostral nucleus ambiguus, which contains all classes of respiratory neuron that are necessary for respiratory rhythm generation4,5. The vital role of the PBC is demonstrated by the evidence that the rhythmic respiratory output from the brainstem disappears when the PBC is deleted6,7. The PBC can be visualized by labeling the neurons with antibodies against neurokinin-1 and μ-opioid receptors, which are suggested to be specific for