Genesis of rhythmic respiratory activity in pons independent of medulla

We hypothesized that rhythmic respiratory-related activity could be generated in pons independent of medullary mechanisms. In decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats, we recorded efferent activities of the phrenic nerve and mylohyoid branch of the trigeminal nerve. Following transections of the brain stem at the pontomedullary junction, the phrenic and trigeminal nerves discharged with independent rhythms. Spontaneous trigeminal discharges eventually ceased but were reestablished after strychnine, doxapram, and/or protriptyline were administered. In some animals having no spontaneous trigeminal discharges after transection, these discharges appeared, with a rhythm different from the phrenic, following administration of these agents. In other cats having no transections between pons and medulla, these pharmacological agents induced trigeminal and phrenic discharges after kainic acid had been injected into the entire dorsal and ventral medullary respiratory nuclei. Phrenic and trigeminal discharges were linked, indicating survival of bulbospinal neurons or presence of pontospinal units. We conclude that rhythms, similar to respiratory rhythm, can occur by mechanisms in isolated pons. Such mechanisms are hypothesized to be within the pneumotaxic center and may underlie the neurogenesis of eupnea.     

Respiratory neural activities after caudal-to-rostral ablation of medullary regions

The purpose is to assess the importance of medullary mechanisms for the neurogenesis of eupnea. Cats that were used were decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated. Activities of the phrenic, facial, and mylohyoid nerves were monitored. Progressive caudal-to-rostral transections of the spinal cord and medulla were performed. Phrenic activity was eliminated by C1 spinal transections. Only modest changes in facial and mylohyoid activities resulted from transections as far rostral as the level of the dorsal respiratory nucleus. Rhythmic discharges ceased on transections at the pontomedullary junction. However, rhythmic mylohyoid discharges were maintained if protriptyline and strychnine were administered before and during the transection. In other studies rhythmic phrenic, facial, and mylohyoid discharges continued, albeit with an altered rhythm, after destruction of neurons in the dorsal respiratory nucleus by kainic acid. We conclude that caudal medullary mechanisms do not play an essential role in the neurogenesis of breathing movements. Rather, structures in rostral medulla and pons appear necessary for sustaining eupneic neural activities. The concept of multiple brain stem sites for ventilatory neurogenesis is discussed.     

Neurogenesis, control, and functional significance of gasping

Gasps are frequently the first and last breaths of life. Gasping, which is generated by intrinsic medullary mechanisms, differs fundamentally from other automatic ventilatory patterns. A region of the lateral tegmental field of the medulla is critical for the neurogenesis of the gasp but has no role in eupnea. Neuronal mechanisms in separate brain stem regions may be responsible for the neurogenesis of different ventilatory patterns. This hypothesis is supported by the recording of independent respiratory rhythms simultaneously from isolated brain stem segments. Data from fetal and neonatal animals also support gasping and eupnea being generated by separate mechanisms. Gasping may represent the output of a simple but rugged pattern generator that functions as a backup system until the control system for eupnea is developed. Pacemaker elements are hypothesized as underlying the onset of inspiratory activity in gasping. Similar elements, in a different brain stem region, may be responsible for the onset of the eupneic inspiration with neural circuits involving the pons, the medulla, and the spinal cord serving to shape efferent respiratory-modulated neural discharges.     

Identification of medullary loci critical for neurogenesis of gasping

We hypothesized that a discrete medullary locus, critical for gasping neurogenesis, could be identified. In decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats, activities of phrenic, hypoglossal, and recurrent laryngeal nerves were monitored. Gasping was induced by freezing the brain stem, via a fork thermode, at the pontomedullary junction. By reversible cooling of the medulla, chemical lesions with kainic acid, and radio-frequency lesions, a critical area for gasping neurogenesis was localized bilaterally 2-3 mm rostral to obex, 2.0-2.5 mm lateral to midline, and 3-4 mm ventral to medullary surface. Electrical stimulation in this area elicited premature gasps, whereas unilateral lesions or lidocaine injections eliminated gasping activities in all nerves. These procedures did not cause similar changes during eupnea. In apneusis, however, lidocaine injections markedly altered the pattern or caused apnea. We conclude that discharge of neurons in a discrete portion of the lateral tegmental field of medulla is required for gasping neurogenesis. Our results are consistent with these neurons comprising the central pattern generator for gasping.     

Characterization by stimulation of medullary mechanisms underlying gasping neurogenesis

Our purpose was to evaluate the hypothesis that neurons in the lateral tegmental field of the medulla comprise a pattern generator for neurogenesis of gasping. Stimulations in this area produced changes characteristic of pattern generators in other systems. These included shifts in gasping rhythm and refractory periods for eliciting gasps; the latter varied inversely with spontaneous gasping frequency. These responses were recorded from activities of phrenic and hypoglossal nerves of decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats. Gasping followed freezing the brain stem between pons and medulla. In addition to lateral tegmental loci, gasps were elicited by stimulating areas extending lateral to the nucleus ambiguus and medial to the contralateral medulla. These areas are envisaged to contain axons to or from the pattern generator of lateral tegmental field. Finally, stimulations in sites approximating nucleus tractus solitarius and nucleus ambiguus delayed spontaneous gasps and terminated ongoing gasps. Current required to terminate gasps fell during neural inspiration. Our data are consistent with the lateral tegmental field of medulla comprising a central pattern generator for gasping and pacemaker elements being a component of this pattern generator.     

Responses of bulbospinal and laryngeal respiratory neurons to hypercapnia and hypoxia

The purpose was to evaluate activities of medullary respiratory neurons during equivalent changes in phrenic discharge resulting from hypercapnia and hypoxia. Decerebrate, cerebellectomized, paralyzed, and ventilated cats were used. Vagi were sectioned at left midcervical and right intrathoracic levels caudal to the origin of right recurrent laryngeal nerve. Activities of phrenic nerve and single respiratory neurons were monitored. Neurons exhibiting antidromic action potentials following stimulations of the spinal cord and recurrent laryngeal nerve were designated, respectively, bulbospinal or laryngeal. The remaining neurons were not antidromically activated. Hypercapnia caused significant augmentations of discharge frequencies for all neuronal groups. Many of these neurons had no change or declines of activity in hypoxia. We conclude that central chemoreceptor afferent influences are ubiquitous, but excitatory influences from carotid chemoreceptors are more limited in distribution among medullary respiratory neurons. Hypoxia will increase activities of neurons that receive sufficient excitatory peripheral chemoreceptor afferents to overcome direct depression by brain stem hypoxia. The possibility that responses of respiratory muscles to hypoxia are programmed within the medulla is discussed.     

Differing activities of medullary respiratory neurons in eupnea and gasping

Our purpose was to compare further eupneic ventilatory activity with that of gasping. Decerebrate, paralyzed, and ventilated cats were used; the vagi were sectioned within the thorax caudal to the laryngeal branches. Activities of the phrenic nerve and medullary respiratory neurons were recorded. Antidromic invasion was used to define bulbospinal, laryngeal, or not antidromically activated units. The ventilatory pattern was reversibly altered to gasping by exposure to 1% carbon monoxide in air. In eupnea, activities of inspiratory neurons commenced at various times during inspiration, and for most the discharge frequency gradually increased. In gasping, the peak discharge frequency of inspiratory neurons was unaltered. However, all commenced activities at the start of the phrenic burst and reached peak discharge almost immediately. The discharge frequencies of all groups of expiratory neurons fell in gasping, with many neurons ceasing activity entirely. These data are consistent with the hypothesis that brain stem mechanisms controlling eupnea and gasping differ fundamentally.     

Adaptation to hypobaric hypoxia involves GABA A receptors in the pons

Survival in low-oxygen environments requires adaptation of sympathorespiratory control networks located in the brain stem. The molecular mechanisms underlying adaptation are unclear. In na?ve animals, acute hypoxia evokes increases in phrenic (respiratory) and splanchnic (sympathetic) nerve activities that persist after repeated challenges (long-term facilitation, LTF). In contrast, our studies show that conditioning rats to chronic hypobaric hypoxia (CHH), an environment characteristic of living at high altitude, diminishes the response to hypoxia and attenuates LTF in a time-dependent manner. Phrenic LTF decreases following 7 days of CHH, and both sympathetic and phrenic LTF disappear following 14 days of CHH. Previous studies demonstrated that GABA is released in the brain stem during hypoxia and depresses respiratory activity. Furthermore, the sensitivity of brain stem neurons to GABA is increased following prolonged hypoxia. In this study, we demonstrate that GABA(A) receptor expression changes along with the CHH-induced physiological changes. Expression of the GABA(A) receptor alpha4 subunit mRNA increases two-fold in animals conditioned to CHH for 7 days. In addition, de novo expression of delta and alpha6, a subunit normally found exclusively in the cerebellum, is observed after 14 days. Consistent with these changes, diazepam-insensitive binding sites, characteristic of GABA(A) receptors containing alpha4 and alpha6 subunits, increase in the pons. Immunohistochemistry revealed that CHH-induced GABA(A) receptor subunit expression is localized in regions of sympathorespiratory control within the pons. Our findings suggest that a GABA(A) receptor mediated-mechanism participates in adaptation of the sympathorespiratory system to hypobaric hypoxia.     

Mechanisms of abdominal muscle activation during vomiting

The possible contribution of spinal reflexes to abdominal muscle activation during vomiting was assessed in decerebrate cats. The activity of these muscles is partly controlled by bulbospinal expiratory neurons in the caudal ventral respiratory group (VRG). In a previous study it was found that the abdominal muscles are still active during vomiting after midsagittal lesion of the axons of these neurons between C1 and the obex (A.D. Miller, L.K. Tan, and I. Suzuki. J. Neurophysiol. 57: 1854-1866, 1987). The present experiments indicate that this postlesion activity was due to spinal stretch reflexes because 1) such midsagittal lesions eliminate abdominal muscle nerve activity during fictive vomiting in paralyzed cats in which there are no abdominal stretch reflexes, 2) the abdominal muscles are activated during vomiting by spinal reflexes after upper thoracic cord transections, and 3) the normal 100-ms delay between diaphragmatic and abdominal activation during vomiting is reduced to approximately 20-25 ms after both types of lesions, which is consistent with postlesion abdominal reflex activation. Our results also suggest that, during normal vomiting, abdominal stretch and tension reflexes have only a minor role if any and abdominal muscle activation is probably mediated primarily or exclusively by expiratory neurons in the caudal ventral respiratory group. However, our finding that phrenic activity is reduced both during vomiting after thoracic transections and during fictive vomiting after paralysis is consistent with a contribution of reflex activity from abdominal and/or intercostal muscles to phrenic discharge during normal vomiting.     

Recurrent laryngeal nerve activity exhibits a 5-HT-mediated long-term facilitation and enhanced response to hypoxia following acute intermittent hypoxia in rat

A progressive and sustained increase in inspiratory-related motor output ("long-term facilitation") and an augmented ventilatory response to hypoxia occur following acute intermittent hypoxia (AIH). To date, acute plasticity in respiratory motor outputs active in the postinspiratory and expiratory phases has not been studied. The recurrent laryngeal nerve (RLN) innervates laryngeal abductor muscles that widen the glottic aperture during inspiration. Other efferent fibers in the RLN innervate adductor muscles that partially narrow the glottic aperture during postinspiration. The aim of this study was to investigate whether or not AIH elicits a serotonin-mediated long-term facilitation of laryngeal abductor muscles, and if recruitment of adductor muscle activity occurs following AIH. Urethane anesthetized, paralyzed, unilaterally vagotomized, and artificially ventilated adult male Sprague-Dawley rats were subjected to 10 exposures of hypoxia (10% O(2) in N(2), 45 s, separated by 5 min, n = 7). At 60 min post-AIH, phrenic nerve activity and inspiratory RLN activity were elevated (39 ± 11 and 23 ± 6% above baseline, respectively). These responses were abolished by pretreatment with the serotonin-receptor antagonist, methysergide (n = 4). No increase occurred in time control animals (n = 7). Animals that did not exhibit postinspiratory RLN activity at baseline did not show recruitment of this activity post-AIH (n = 6). A repeat hypoxia 60 min after AIH produced a significantly greater peak response in both phrenic and RLN activity, accompanied by a prolonged recovery time that was also prevented by pretreatment with methysergide. We conclude that AIH induces neural plasticity in laryngeal motoneurons, via serotonin-mediated mechanisms similar to that observed in phrenic motoneurons: the so-called "Q-pathway". We also provide evidence that the augmented responsiveness to repeat hypoxia following AIH also involves a serotonergic mechanism.     

Expiratory neural activities in gasping

The purpose was to characterize expiratory-related neural activities in eupnea and gasping. In decerebrate and vagotomized cats, activities were recorded from the phrenic nerve, spinal intercostal and abdominal nerves, and recurrent laryngeal nerve and its branches. Neural inspiration was defined by phrenic discharge. The spinal and laryngeal nerves discharged in inspiration, expiration, or during both phases. Gasping was induced by freezing the brain stem at the pontomedullary junction, exposure to asphyxia or anoxia, or ligation of the basilar artery and its branches. In gasping, peak phrenic activity typically increased as did inspiratory-related activities of laryngeal and spinal nerves. Expiratory activities were greatly reduced in gasping, with some activities being completely eliminated. Reductions of expiratory activity were more prominent for spinal than laryngeal nerves. Similar results were obtained in cats having intact vagi that were ventilated with a servo-respirator so that lung inflation paralleled phrenic activity. The concept that gasping differs fundamentally form other ventilatory patterns is discussed.     

Differences in time-dependent hypoxic phrenic responses among inbred rat strains.

Hypoxic ventilatory responses differ between rodent strains, suggesting a genetic contribution to interindividual variability. However, hypoxic ventilatory responses consist of multiple time-dependent mechanisms that can be observed in different respiratory motor outputs. We hypothesized that strain differences would exist in discrete time-dependent mechanisms of the hypoxic response and, furthermore, that there may be differences between hypoglossal and phrenic nerve responses to hypoxia. Hypoglossal and phrenic nerve responses were assessed during and after a 5-min hypoxic episode in anesthetized, vagotomized, and ventilated rats from four inbred strains: Brown Norway (BN), Fischer 344 (FS), Lewis (LW), and Piebald-viral-Glaxo (PVG). During baseline, burst frequency was higher in PVG than LW rats (P < 0.05), phrenic burst amplitude was higher in PVG vs. other strains (P < 0.05), and hypoglossal burst amplitude was higher in PVG and BN vs. FS and LW (P < 0.05). During hypoxia, burst frequency did not change in BN or LW rats, but it increased in PVG and FS rats. The phrenic amplitude response was smallest in PVG vs. other strains (P < 0.05), and the hypoglossal response was similar among strains. Short-term potentiation posthypoxia was slowest in FS and fastest in LW rats (P < 0.05). Posthypoxia frequency decline was absent in PVG, but it was observed in all other strains. Augmented breaths were observed during hypoxia in FS rats only. Thus genetic differences exist in the time domains of the hypoxic response, and these are differentially expressed in hypoglossal and phrenic nerves. Furthermore, genetic diversity observed in hypoxic ventilatory responses in unanesthetized rats may arise from multiple neural mechanisms.     

Influence of lung volume on activities of branches of the recurrent laryngeal nerve

To investigate the influence of inspiratory lung inflation on the respiratory activities of laryngeal motor nerves, vagally intact decerebrate paralyzed cats were ventilated by a servorespirator in accordance with their own phrenic nerve activity. Records were made of the activities of the phrenic nerve, the superior laryngeal nerve (SLN), the recurrent laryngeal nerve (RLN), and the intralaryngeal branches of the RLN serving the thyroarytenoid (TA) and posterior cricoarytenoid (PCA) muscles. Neural activities were assessed in the steady state at different end-tidal O2 and CO2 concentrations. Transient responses to withholding inspiratory lung inflation and to preventing expiratory lung emptying were also studied. Hypercapnia and hypoxia increased the inspiratory activities of the phrenic nerve, SLN, RLN, and its PCA branch. TA inspiratory activity was not changed. Expiratory activities of RLN, PCA, and TA were all increased in hypoxia. When lung inflation was withheld, neural inspiratory duration and the inspiratory activities of all nerves increased. The subsequent period of neural expiration was marked by an exaggerated burst of activity by the TA branch of the RLN. TA expiratory activity was also sharply increased after inspiratory efforts that were reflexly delayed by the prevention of lung emptying. TA activity in expiration was enhanced after vagotomy and was usually more prominent than when lung inflation was withheld before vagal section. The results demonstrate the importance and complexity of the influence of vagal afferents on laryngeal motor activity.     

Medullary CO2 chemoreceptor neuron identification by c-fos immunocytochemistry.

In a search for CO2 chemoreceptor neurons in the brain stem, we used immunocytochemistry to monitor the expression of neuronal c-fos, a marker of increased activity, after 1 h of exposure to CO2 in five groups of Sprague-Dawley rats (294 +/- 20 g): five air breathing controls, three breathing 10% CO2, three breathing 13% CO2, three breathing 15% CO2, and three breathing 15% CO2 and treated with morphine (10 mg/kg sc). After exposure the rats were anesthetized with pentobarbital sodium and perfused intracardially with 4% paraformaldehyde. The brain stem was removed and cryoprotected, and then 50-microns frozen sections were cut and immunostained for the fos protein. Brain stem fos-immunoreactive neurons were plotted and counted in the superficial 0.5 mm of the ventral medullary surface. Thirteen to 15% CO2 evoked fos-like immunoreactivity (FLI) in 321 +/- 146 neurons/rat. Significant CO2-induced labeling was confined within the superficial 150 microns: 67% of identified cells were less than 50 microns below the surface, greater than 90% between 1.0 and 3.0 mm from the midline, and approximately 60% in the rostral half of the medulla. Thirteen to 15% CO2 also evoked FLI in the area of the nucleus tractus solitarius but not in other medullary regions. Morphine (10 mg/kg sc) did not suppress high CO2-evoked FLI in either the ventral medullary surface or the nucleus tractus solitarius, although it eliminated excitement and hyperventilation. We suggest that respiratory CO2 chemoreceptor neurons can be identified in rats by their expression of c-fos after 1 h of hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of ventral medullary surface in respiratory responses induced by 2,4-dinitrophenol

We examined the contribution of the neural elements near the ventral medullary surface (VMS) to the respiratory response caused by 2,4-dinitrophenol (DNP). Two series of experiments were performed on 12 vagotomized and sinoaortic denervated cats. The first series examined the effect of focal cooling of the VMS on the respiratory response to DNP in four spontaneously breathing, anesthetized cats. When the VMS temperature was 37 degrees C, systemic administration of DNP increased minute ventilation under nearly isocapnic conditions, and focal cooling of the intermediate area of VMS to 20 degrees C attenuated the ventilatory augmentation caused by DNP. To eliminate the influence of anesthetics, a second group of experiments was performed on eight decerebrate, artificially ventilated cats while phrenic nerve activity was monitored as an index of respiration. AgNO3 (10%) was topically applied to the VMS until the respiratory response to inhaled CO2 was abolished. Apnea occurred in seven of eight cats after AgNO3, whereas in the remaining one animal, tidal phrenic activity decreased substantially. Systemic administration of DNP produced no respiratory excitation in any of the animals. On the other hand, rhythmic respiratory activity could be provoked by electrical stimulation of the mesencephalic locomotor area and carotid sinus nerve and by excitation of somatic afferents. Histological examination of the brain stem showed that the AgNO3 had penetrated no more than 350 microns from the ventral medullary surface. These results indicate superficial structures of the VMS are of potential importance in mediating the respiratory responses to hypermetabolism.     

Inhibition of inspiratory upper airway motoneuron activity by phasic volume feedback

The effects of phasic volume feedback on efferent hypoglossal, recurrent laryngeal and phrenic nerve activity were studied in decerebrate, paralyzed intubated cats ventilated with a phrenic-driven servo-respirator. The gain of the respirator was altered for single inspirations, and the resulting changes in neural activities were quantified by comparison with respective neural activities without phasic volume feedback. The volume thresholds for suppression of hypoglossal and recurrent laryngeal activities were time independent. Above these two thresholds and extending over a substantial range, volume feedback caused graded inhibition of upper airway motoneuron outputs. At any particular time during inspiration the relationships between hypoglossal or recurrent laryngeal inhibition and volume were concave to the volume axis. Rate of airflow appeared to exert an effect on upper airway motoneuron activity independent of volume. These results indicate that for hypoglossal and recurrent laryngeal efferent activity 1) volume feedback can cause a sustained graded inhibition throughout inspiration; 2) the volume thresholds are time independent; and 3) partial inhibition decreases susceptibility to additional inhibition. These actions of volume feedback on upper airway motoneuron output differ from those on phrenic efferent discharge and show that phasic vagal volume feedback has a marked and differential effect on upper airway motoneuron activity. The vagus, in this preparation, appears to play a critical role in the regulation of upper airway motoneuron activity and therefore maintenance of upper airway patency.     

Characterization of respiratory-modulated activities of hypoglossal motoneurons

In decerebrate, vagotomized, paralyzed, and ventilated cats, activities of the phrenic nerve and single hypoglossal nerve fibers were monitored. The great majority of hypoglossal neuronal activities were inspiratory (I), discharging during a period approximating that of phrenic. Many were not active at normocapnia but were recruited in hypercapnia or hypoxia. Once recruited, discharge frequencies, which rose quickly to near maximal levels in early to midinspiration, significantly increased with further augmentations of drive. Also, the onset of activities became progressively earlier, compared with phrenic discharge, in hypercapnia or hypoxia. Smaller numbers of hypoglossal fiber activities, having inspiratory-expiratory (I-E), expiratory (E), expiratory-inspiratory (E-I), or tonic discharge patterns, were also recorded. Activities of E, I-E, and those I fibers that became I-E in high drive may underlie the early burst of expiratory activity of the hypoglossal nerve. It is concluded that the firing and recruitment patterns of hypoglossal neurons differ from those of phrenic motoneurons. However, responses to chemoreceptor stimuli are similar among the two neuronal groups.     

Neonatal sex steroids affect ventilatory responses to aspartic acid and NMDA receptor subunit 1 in rats.

We hypothesized that administration of estradiol benzoate to males and testosterone propionate to female neonatal rat pups alters sex-specific ventilatory responses to aspartic acid with correspondent changes in N-methyl-D-aspartate receptor subunit 1 (NR1) expression determined by Western blot in specific brain regions. One-day-old rat pups received estradiol benzoate, testosterone propionate, or vehicle and were studied at weanling and adulthood. Different groups had distinct patterns of changes in tidal volume and frequency of breathing after aspartic acid administration. NR1 expression in hypothalamus was altered by age, sex, and treatment. Medullary and pontine NR1 expression correlated with baseline ventilation and magnitude of the ventilatory response to aspartic acid in some groups. Thus 1) tidal volume and breathing frequency patterns in response to aspartic acid are gender, age, and treatment dependent; 2) sex, age, and exogenous steroid hormones affect NR1 expression primarily in the hypothalamus; and 3) there is correlation between NR1 expression in pons and medulla with ventilatory parameters.     

Persistence of eupnea and gasping following blockade of both serotonin type 1 and 2 receptors in the in situ juvenile rat preparation.

In severe hypoxia or ischemia, normal eupneic breathing is replaced by gasping, which can serve as a powerful mechanism for "autoresuscitation." We have proposed that gasping is generated by medullary neurons having intrinsic pacemaker bursting properties dependent on a persistent sodium current. A number of neuromodulators, including serotonin, influence persistent sodium currents. Thus we hypothesized that endogenous serotonin is essential for gasping to be generated. To assess such a critical role for serotonin, a preparation of the perfused, juvenile in situ rat was used. Activities of the phrenic, hypoglossal, and vagal nerves were recorded. We added blockers of type 1 and/or type 2 classes of serotonergic receptors to the perfusate delivered to the preparation. Eupnea continued following additions of any of the blockers. Changes were limited to an increase in the frequency of phrenic bursts and a decline in peak heights of all neural activities. In ischemia, gasping was induced following any of the blockers. Few statistically significant changes in parameters of gasping were found. We thus did not find a differential suppression of gasping, compared with eupnea, following blockers of serotonin receptors. Such a differential suppression had been proposed based on findings using an in vitro preparation. We hypothesize that multiple neurotransmitters/neuromodulators influence medullary mechanisms underlying the neurogenesis of gasping. In greatly reduced in vitro preparations, the importance of any individual neuromodulator, such as serotonin, may be exaggerated compared with its role in more intact preparations.     

Reductions of neural activities to upper airway muscles after elevations in static lung volume.

We evaluated the hypothesis that the tonic discharge of pulmonary stretch receptors significantly influences the respiratory-modulated activities of cranial nerves. Decerebrate and paralyzed cats were ventilated with a servo-respirator, which produced changes in lung volume in parallel with integrated phrenic activity. Activities of the facial, hypoglossal, and recurrent laryngeal nerves and nerves to the thyroarytenoid muscle and triangularis sterni were recorded. After a stereotyped pattern of lung inflation, tracheal pressure was held at 1, 2, 4, or 6 cmH2O during the subsequent ventilatory cycle. Increases in tracheal pressure caused progressive reductions in both inspiratory and expiratory cranial nerve activities and progressive elevations in triangularis sterni discharge; peak levels of phrenic activity declined modestly. Similar changes were observed in normocapnia and hypercapnia. We conclude that the tonic discharge of pulmonary stretch receptors is an important determinant of the presence and magnitude of respiratory-modulated cranial nerve activity. This reflex mechanism may maintain upper airway patency and also regulate expiratory airflow.