Control of ventilation occurs at different levels of the respiratory system through a negative feedback system that allows precise regulation of levels of arterial carbon dioxide and oxygen. Mechanisms for ventilatory instability leading to sleep-disordered breathing include changes in the genesis of respiratory rhythm and chemoresponsiveness to hypoxia and hypercapnia, cerebrovascular reactivity, abnormal chest wall and airway reflexes, and sleep state oscillations. One can potentially stabilize breathing during sleep and treat sleep-disordered breathing by identifying one or more of these pathophysiological mechanisms. This review describes the current concepts in ventilatory control that pertain to breathing instability during wakefulness and sleep, delineates potential avenues for alternative therapies to stabilize breathing during sleep, and proposes recommendations for future research.

The Hering-Breuer (HBR) reflex is considered a major regulatory feedback for the generation and patterning of respiratory activity. While HBR is important in neonates, its significance in adults is controversial. Previous experiments that investigated the plasticity of entrainment of the respiratory rhythm by vagal input demonstrated postnatal changes in HBR plasticity. Here we analyzed postnatal changes in the plasticity of HBR by mimicking the classic lung inflation tests with repetitive tonic vagal stimulation across different postnatal stages in an in situ perfused brainstem preparation of rat. The study shows that neonates stereotypically exhibit HBR stimulus-dependent prolongation of expiration while juvenile preparations (>postnatal day 16) showed significant habituation of HBR following repetitive stimulation. Subsequent experiments employing physiological lung inflation tests in situ confirmed HBR habituation in juveniles. We conclude that postnatal emergence of HBR habituation explains the weak contribution and high activation threshold of HBR in the regulation of eupnea.

Pontine respiratory nuclei provide synaptic input to medullary rhythmogenic circuits to shape and adapt the breathing pattern. An understanding of this statement depends on appreciating breathing as a behavior, rather than a stereotypic rhythm. In this review, we focus on the pontine-mediated inspiratory off-switch (IOS) associated with postinspiratory glottal constriction. Further, IOS is examined in the context of pontine regulation of glottal resistance in response to multimodal sensory inputs and higher commands, which in turn rules timing, duration, and patterning of respiratory airflow. In addition, network plasticity in respiratory control emerges during the development of the pons. Synaptic plasticity is required for dynamic and efficient modulation of the expiratory breathing pattern to cope with rapid changes from eupneic to adaptive breathing linked to exploratory (foraging and sniffing) and expulsive (vocalizing, coughing, sneezing, and retching) behaviors, as well as conveyance of basic emotions. The speed and complexity of changes in the breathing pattern of behaving animals implies that "learning to breathe" is necessary to adjust to changing internal and external states to maintain homeostasis and survival.

The hallmark of the dynamic regulation of the transitions between inspiration and expiration is the timing of the inspiratory off-switch (IOS) mechanisms. IOS is mediated by pulmonary vagal afferent feedback (Breuer-Hering reflex) and by central interactions involving the Kölliker-Fuse nuclei (KFn). We hypothesized that the balance between these two mechanisms controlling IOS may change during postnatal development. We tested this hypothesis by comparing neural responses to repetitive rhythmic vagal stimulation, at a stimulation frequency that paces baseline breathing, using in situ perfused brainstem preparations of rats at different postnatal ages. At ages < P15 (P, postnatal days), phrenic nerve activity (PNA) was immediately paced and entrained to the afferent input and this pattern remained unchanged by repetitive stimulations, indicating that vagal input stereotypically dominated the control of IOS. In contrast, PNA entrainment at > P15 was initially insignificant, but increased after repetitive vagal stimulation or lung inflation. This progressive adaption of PNA to the pattern of the sensory input was accompanied by the emergence of anticipatory centrally mediated IOS preceding the stimulus trains. The anticipatory IOS was blocked by bilateral microinjections of NMDA receptor antagonists into the KFn and PNA was immediately paced and entrained, as it was seen at ages < P15. We conclude that as postnatal maturation advances, synaptic mechanisms involving NMDA receptors in the KFn can override the vagally evoked IOS after 'training' using repetitive stimulation trials. The anticipatory IOS may imply a hitherto undescribed form of pattern learning and recall in convergent sensory and central synaptic pathways that mediate IOS.

The aim of this study was to determine the effect of positioning on the Hering-Breuer inflation reflex (HBIR) in the preterm infant. Seven, non-intubated, premature infants, ranging in birthweight from 732 to 1450 g with post-conceptual ages of 32-36 weeks were studied. In each infant, pulmonary function testing, including the HBIR was obtained using the SensorMedics 2600 during quiet sleep in the supine and prone position. The strength of the HBIR was quantified by the measurement of the percent prolongation of expiration after an occluded breath. Sleep states were categorized by the criteria of Prechtl. There was a significant difference in Hering-Breuer activity in the prone position versus the supine position with a consistently stronger reflex in the prone position. The mean percent prolongation of expiration was 237 +/- 108% in the prone position versus 95 +/- 32% in the supine position. Analysis of the data, using paired t-testing revealed a mean difference of 142 +/- 119% between prone and supine positions (P=0.028). Significant differences in the strength of the HBIR occur in relation to positioning in the preterm infant. Newborn positioning may affect pulmonary reflexes and may play a role in control of breathing.

Lung sensory receptors with afferent fibers coursing in the vagus nerves are broadly divided into three groups: slowly (SAR) and rapidly (RAR) adapting stretch receptors and bronchopulmonary C fibers. Central terminations of each group are found in largely nonoverlapping regions of the caudal half of the nucleus of the solitary tract (NTS). Second order neurons in the pathways from these receptors innervate neurons located in respiratory-related regions of the medulla, pons, and spinal cord. The relative ease of selective activation of SARs, and to a lesser extent RARs, has allowed for more complete physiological and morphological characterization of the second and higher order neurons in these pathways than for C fibers. A subset of NTS neurons receiving afferent input from SARs (termed pump or P-cells) mediates the Breuer-Hering reflex and inhibits neurons receiving afferent input from RARs. P-cells and second order neurons in the RAR pathway also provide inputs to regions of the ventrolateral medulla involved in control of respiratory motor pattern, i.e., regions containing a predominance of bulbospinal premotor neurons, as well as regions containing respiratory rhythm-generating neurons. Axon collaterals from both P-cells and RAR interneurons, and likely from NTS interneurons in the C-fiber pathway, project to the parabrachial pontine region where they may contribute to plasticity in respiratory control and integration of respiratory control with other systems, including those that provide for voluntary control of breathing, sleep-wake behavior, and emotions.

Breathing is constantly modulated by afferent sensory inputs in order to adapt to changes in behaviour and environment. The pontine respiratory group, in particular the Kolliker-Fuse nucleus, might be a key structure for adaptive behaviours of the respiratory network. Here, we review the anatomical connectivity of the Kolliker-Fuse nucleus with primary sensory structures and with the medullary respiratory centres and focus on the importance of pontine and medullary postinspiratory neurones in the mediation of respiratory reflexes. Furthermore, we will summarise recent findings from our group regarding ontogenetic changes of respiratory reflexes (e.g., the diving response) and provide evidence that immaturity of the Kolliker-Fuse nucleus might account in neonates for a lack of plasticity in sensory evoked modulations of respiratory activity. We propose that a subpopulation of neurones within the Kolliker-Fuse nucleus represent command neurones for sensory processing which are capable of initiating adaptive behaviour in the respiratory network. Recent data from our laboratory suggest that these command neurones undergo substantial postnatal maturation.

The aim of this study was to determine the effect of sleep state on the Hering-Breuer inflation reflex in the preterm infant. Seventeen nonintubated, premature infants, ranging in birth weight from 980-2,440 g with postconceptual ages of 30-36 weeks, were studied. In each infant, pulmonary function testing, including the Hering-Breuer inflation reflex, was obtained using the SensorMedics 2600 during active and quiet sleep states in supine position. The strength of the Hering-Breuer inflation reflex was quantified by the measurement of the percent prolongation of expiration after an occluded breath. Sleep states were categorized by the criteria of Prechtl. There was a significant difference in Hering-Breuer activity in active (REM) vs. quiet (non-REM) sleep, with a consistently stronger reflex in the active sleep state. The mean percent prolongation of expiration was 419% in active sleep vs. 87% in quiet sleep. Analysis of the data, using a paired t-test, revealed a mean difference of 331 +/- 185% between active and quiet sleep (P = 0.000). In conclusion, significant differences in the strength of the Hering-Breuer inflation reflex occur in relation to sleep state, and may explain the variability of the reflex described in previous studies. Measurement of the Hering-Breuer inflation reflex may be affected by pulmonary stretch receptors as well as chest wall afferents in the preterm infant.

The history of our understanding of the respiratory system has been long and progressive, probably starting with Galenus who did experimental spinal cord sections, and progressed through the poorly known work of Leonardo da Vinci on the structure-function relation of chest wall components.

Despite numerous experiments in the past, the respiratory control system remains complex and poorly integrated because of the diversity of the afferent pathways and of the interacting respiratory centres.

Here we show a dual role of N-methyl-d-aspartate receptor (NMDAR) activation in controlling polysialylated neural cell adhesion molecule (PSA-NCAM) dynamic expression in the dorsal vagal complex (DVC), a gateway for many primary afferent fibres. In this structure the overall expression of PSA-NCAM decreases during the first 2 weeks after birth to persist only at synapses in the adult. Electrical stimulation of the vagal afferents causes a rapid increase of PSA-NCAM expression both in vivo and in acute slices before postnatal day (P) 14 whereas a similar stimulation induces a decrease after P15. Inhibition of NMDAR activity in vitro completely prevented these changes. These regulations depend on calmodulin activation and cGMP production at all stages. By contrast, blockade of neuronal nitric oxide synthase (nNOS) prevented these changes only after P10 in agreement with its late expression in the DVC. The pivotal role of NMDAR is also supported by the observation that chronic blockade induces a dramatic decrease in PSA-NCAM expression.

A membrane bound cytochrome b(558) (NADPH oxidase) is a candidate for the oxygen sensor in pulmonary neuroepithelial bodies (NEBs) - putative airway chemoreceptors. Recent electrophysiological studies on NEB from mice with NADPH oxidase deficiency (OD; gp(91phox) knock-out) have shown lack of response of O(2) sensitive K(+) current to hypoxia challenge compared with wild-type (WT) control mice. To assess the effects of oxidase deficiency on the control of ventilation at the whole animal level, respiratory measurements were conducted under normoxic and hypoxic conditions in neonatal OD mice and compared that with the WT control group. Five-day-old OD mice were faster and shallower breathers during normoxia as well as hypoxia. In addition, the maximum hypoxic ventilatory response of the OD mice was lower than that of the WT control group and the peak increase in minute ventilation (.V(max)-.V(normoxia)) was greater in WT control than the OD mice (P=0.02). Since the lung development and NEB morphology in OD mice were comparable to the WT control mice, the observed differences implicate NADPH oxidase as an O(2) sensor involved in neonatal ventilatory control, possibly modulated via pulmonary NEBs.

The control of breathing results from a complex interaction involving the respiratory centers, which feed signals to a central control mechanism that, in turn, provides output to the effector muscles. In this review, we describe the individual elements of this system, and what is known about their function in man. We outline clinically relevant aspects of the integration of human ventilatory control system, and describe altered function in response to special circumstances, disorders, and medications. We emphasize the clinical relevance of this topic by employing case presentations of active patients from our practice.

Postnatal development of neurons in the caudal nucleus tractus solitarii of rats was studied using the Golgi-Cox technique and whole-cell recordings. Two cell classes were defined on the basis of somatic and dendritic morphology. Elongated neurons have two thick primary dendrites originating from the long axis of the soma. The primary dendrites, tapering distally, give rise to one to four secondary dendrites. Multipolar neurons have pyramidal somas. Extending from each apex of the cell body was a long primary dendrite, which gave rise to a variable number of secondary dendrites. The relative proportion of the two classes was rather constant from birth to adulthood. During the first two postnatal weeks, dendritic length and area of influence increase, but neuronal geometry is not altered in either class. Dendritic appendages appear by postnatal day 5, reach a peak at postnatal day P12 and then almost disappear in adult neurons. Combined intracellular injection of neurobiotin and whole-cell recordings indicate that morphological alteration of caudal nucleus tractus solitarius neurons occurs in parallel with changes in passive properties and spike characteristics. However, the firing pattern of discharge is not correlated with morphology. The physiological significance of these results is discussed.

Effects of saphenous nerve stimulation (SNS) on the Hering-Breuer expiratory-promoting reflex evoked by a positive tracheal pressure (PTR; 5 cmH2O) and on the diaphragmatic EMG (EMG(DI)), inspiratory (TI) and expiratory (TE) time, were studied in 16 urethane-anesthetized (1.2-1.6 g/kg, i.p.) spontaneously breathing 2-week-old rabbits. Positive P(TR) applied at the end of T(I) increased the subsequent TE to 255+/-29% (+/-S.E.; P < 0.0001) of control. SNS (1 sec train, 2 msec pulse, 6 Hz) applied at the onset of TE, shortened this TE by 42+/-3% (P < 0.0001). When SNS preceded positive PTR or positive PTR preceded SNS, the TE increased to 163+/-20 and 184+/-21% of control, respectively. These responses were not different, and smaller than that provoked by the PTR test alone (P < 0.003 and 0.05, respectively). The results show that in newborns somatic afferent stimulation attenuates the vagally mediated respiratory inhibition, whether immediately before or during the vagal stimulation.

Both end-inspiratory (EIO) and end-expiratory (EEO) occlusions have been used to measure the strength of the Hering-Breuer inflation reflex (HBIR) in infants. The purpose of this study was to compare both techniques in anesthetized infants. In each infant, HBIR activity was calculated as the relative prolongation of expiratory and inspiratory time during EIO and EEO, respectively. Respiratory drive was assessed from the change in airway pressure during inspiratory effort against the occlusion, both at a fixed time interval of 100 ms (P0.1) and a fixed proportion (10%) of the occluded inspiratory time (P10%). Twenty-two infants [age 14.3 +/- 6. 4 (SD) mo] were studied. No HBIR activity was present during EIO [-11.8 +/- 15.9 (SD) %]. By contrast, there was significant, albeit weak, reflex activity during EEO [HBIR: 27.2 +/- 17.4%]. A strong HBIR (up to 310%) was elicited in six of seven infants in whom EIO was repeated after lung inflation. P0.1 was similar during both types of occlusions, whereas mean +/- SD P10% was lower during EEO than during EIO: 0.198 +/- 0.09 vs. 0.367 +/- 0.15 kPa, respectively (P < 0.01). These data suggest a difference in the central integration of stretch receptor activity in infants during anesthesia compared with during sleep.

Various aspects of the postnatal development of intrapulmonary neuroepithelial bodies (NEB) were quantified in guinea-pigs, rabbits, cats, rats and hamsters. The highest densities of NEB were found at birth, especially in species with very immature neonates. Postnatally this density decreased, most probably by lung expansion and growth. The number of corpuscular cells per NEB generally did not change during postnatal development. Likewise, the volume density of their secretory dense cored vesicles remained unchanged. On the other hand, in most species and especially in those with very immature neonates, the number of intracorpuscular NEB nerve endings increased during postnatal development. At the same time, the number of afferent nerve endings increased at the expense of the efferent ones. We argue that NEB serve a dual function: endocrine and chemoreceptor. The endocrine function, dependent on the number of cells and their content of secretory vesicles, is already well developed at birth and does not mature further. The chemoreceptor function, dependent on the innervation, shows considerable maturation in the postnatal period.