The neuronal and musculoskeletal components of the respiratory system mature postnatally, whereas the systems governing respiratory control in general, and more specifically rhythmogenesis, must be mature and functional by birth to enable the successful transition from fetus to infant. In newborn infants, whose chest wall is highly compliant, rhythmical respiration must be coordinated with other behaviors including sucking, swallowing, crying, and other vocalizations. Premature infants display deficiencies of central respiratory rhythmogenesis or of activation of respiratory musculature. However, such problems are not restricted to this particular stage of life, and alterations in the control of breathing may play a role in many conditions that become apparent throughout childhood and adolescence, particularly during sleep. During sleep, the clinical manifestations of many diseases of respiratory control as well as other conditions affecting the respiratory system in general are more likely to emerge. Thus, understanding the pathogenesis of breathing problems is an important component of the clinical evaluation of any child with respiratory symptoms.
DEVELOPMENT OF RESPIRATORY CONTROL AND NORMAL FUNCTION
Current understanding of the mechanisms governing the control of respiration has evolved significantly over the last century. Breathing is an important and vital function, and as such should be prioritized during evolution, it has become apparent that at least in mammals, and more particularly in humans, the control of respiration undergoes substantial maturation during the first few years of life. There is, however, substantial uncertainty regarding the exact anatomic locations and functions of specific neural respiratory pathways. Furthermore, the complexities of neuronal firing activities, the multitude of neurotransmitters within each brainstem nucleus, and the frequently nucleus-dependent opposing roles played by these neurotransmitters on respiratory function make integration of all these elements a difficult and sometimes confusing task. The progress in our understanding of the intricate neural networks of respiration has been tremendous, and the identity of several of the genes that control the development and maturation of multiple neurally controlled respiratory functions is now emerging.
THE RESPIRATORY RHYTHM GENERATOR
The presumed neural region underlying the generation of respiratory rhythmic activity has now been identified, and specific markers such as neurokinin and opioid receptors in these neurons have revealed that this uniquely important neural center consists of a small cluster of only 150 to 200 neurons in the brainstem region designated as pre-Bötzinger complex. These relatively few rhythmically firing neurons appear both necessary and sufficient to generate most of the complex normal respiratory behaviors that we currently recognize, such as eupnea, sigh, and gasping. The development of several elegant models, ranging from highly reductionistic (brainstem slice) to less reductionistic approaches (whole brainstem-heart-lung preparation), has now permitted extensive characterization of the network connectivity and responses and the functional neurotransmitters involved in generation of respiratory rhythm, thus enabling a comprehensive understanding of the electrophysiologic properties of these unique cells during development, sleep, or exercise, as well as in the context of specific ...