Inspiratory Termination Research Articles

Distributed latent dynamics underlie breathing control in the brainstem during normal breathing, OIRD, and gasping

The neural control of breathing involves the coordinated activity of diverse populations of medullary neurons distributed along the rostrocaudal aspect of the ventrolateral medulla. Here, we use high‐density electrophysiological recordings (Neuropixels) to record spiking activity simultaneously from hundreds of neurons across the ventral respiratory column (VRC, including the Bötzinger and pre‐Bötzinger complexes) in anesthetized, freely breathing mice. Across sequential recordings, we have recorded from over 13,000 medullary neurons. We couple this with an optogenetic tagging approach to identify ChAT, Dbx1, Vgat, and Vglut2 positive neurons; and reconstruct the three dimensional location of each recorded neuron. We find diverse patterns of respiratory‐related neural activity throughout the medulla that tile the breathing phase such that discrete functional cell classes cannot be quantitatively defined. Moreover, while certain genotypes are biased towards particular anatomical locations or functional activity patterns, cells active during all parts of the respiratory phase are found across the VRC, and across all genotypes. We use dimensionality reduction techniques to show that the neural populations governing breathing follow rotational trajectories on low dimensional neural manifolds. Analyses of these trajectories indicate that the termination of inspiration (“inspiratory‐off switch”) may represent an attractor in the low‐dimensional neural space. Further, during opioid induced respiratory depression (OIRD), the network reconfigures, but the low‐dimensional trajectories of the neural population are preserved. Thus, patterns of neural coactivity remain the same, while breathing is slowed. Finally, we expose animals to hypoxia which reconfigures the respiratory network into gasping. The low‐dimensional neural activity no longer follows rotational trajectories. Instead, gasping is a ballistic, non‐rotational dynamic mode strikingly different than eupnea or OIRD. The transition to gasping is represented in the low dimensional trajectories by a gradual sequestering of the neural activity away from normal eupneic rotations. Together these data suggest that the VRC functions as a distributed and well‐coordinated population. The eupneic cycle begins with the inspiratory off‐switch and is maintained by the reciprocal interactions between inspiratory and expiratory neurons. This reciprocity is lost as the network transitions into gasping, a rhythm governed by fundamentally different mechanisms.

Control of breathing by interacting pontine and pulmonary feedback loops

The medullary respiratory network generates respiratory rhythm via sequential phase switching, which in turn is controlled by multiple feedbacks including those from the pons and nucleus tractus solitarii; the latter mediates pulmonary afferent feedback to the medullary circuits. It is hypothesized that both pontine and pulmonary feedback pathways operate via activation of medullary respiratory neurons that are critically involved in phase switching. Moreover, the pontine and pulmonary control loops interact, so that pulmonary afferents control the gain of pontine influence of the respiratory pattern. We used an established computational model of the respiratory network [1] and extended it by incorporating pontine circuits and pulmonary feedback (Figure ​(Figure1).1). In the extended model, the pontine neurons receive phasic excitatory activation from, and provide feedback to, medullary respiratory neurons responsible for the onset and termination of inspiration. The model was used to study the effects of: (1) (removal of pulmonary feedback), (2) suppression of pontine activity attenuating pontine feedback, and (3) these perturbations applied together on the respiratory pattern and durations of inspiration (TI) and expiration (TE). Figure 1 A general schematic diagram representing the system with two interacting feedback loops. In our model: (a) the simulated vagotomy resulted in increases of both TI and TE, (b) the suppression of pontine-medullary interactions led to the prolongation of TI at relatively constant, but variable TE, and (c) these perturbations applied together resulted in apneusis, characterized by a significantly prolonged TI. The results of modeling were compared with, and provided a reasonable explanation for, multiple experimental data. The model was able to reproduce the experimentally demonstrated changes in TI and TE and phrenic pattern following vagotomy and/or pontine suppression by NMDA receptor blockers MK801and AP-5. According to the model these changes reflect the characteristic changes in the balance between the pontine and pulmonary feedback mechanisms involved in control of breathing during various cardio-respiratory disorders and diseases.

Control of breathing by interacting pontine and pulmonary feedback loops

The medullary respiratory network generates respiratory rhythm via sequential phase switching, which in turn is controlled by multiple feedbacks including those from the pons and nucleus tractus solitarii; the latter mediates pulmonary afferent feedback to the medullary circuits. It is hypothesized that both pontine and pulmonary feedback pathways operate via activation of medullary respiratory neurons that are critically involved in phase switching. Moreover, the pontine and pulmonary control loops interact, so that pulmonary afferents control the gain of pontine influence of the respiratory pattern. We used an established computational model of the respiratory network (Smith et al., 2007) and extended it by incorporating pontine circuits and pulmonary feedback. In the extended model, the pontine neurons receive phasic excitatory activation from, and provide feedback to, medullary respiratory neurons responsible for the onset and termination of inspiration. The model was used to study the effects of: (1) “vagotomy” (removal of pulmonary feedback), (2) suppression of pontine activity attenuating pontine feedback, and (3) these perturbations applied together on the respiratory pattern and durations of inspiration (TI) and expiration (TE). In our model: (a) the simulated vagotomy resulted in increases of both TI and TE, (b) the suppression of pontine-medullary interactions led to the prolongation of TI at relatively constant, but variable TE, and (c) these perturbations applied together resulted in “apneusis,” characterized by a significantly prolonged TI. The results of modeling were compared with, and provided a reasonable explanation for, multiple experimental data. The characteristic changes in TI and TE demonstrated with the model may represent characteristic changes in the balance between the pontine and pulmonary feedback control mechanisms that may reflect specific cardio-respiratory disorders and diseases.

Respiration-related control of abdominal motoneurons

The abdominal muscles form part of the expiratory pump in cooperation with the other expiratory muscles, primarily the internal intercostal and triangularis sterni muscles. The discharge of abdominal muscles is divided into four main patterns: augmenting, plateau, spindle and decrementing. The patterns tend to be species-specific and dependent on the state of the central nervous system. Recent studies suggest that the abdominal muscles are more active than classically thought, even under resting conditions. Expiratory bulbospinal neurons (EBSN) in the caudal ventral respiratory group are the final output pathway to abdominal motoneurons in the spinal cord. Electrophysiological and anatomical studies indicated the excitatory monosynaptic inputs from EBSN to the abdominal motoneurons, although inputs from the propriospinal neurons seemed to be necessary to produce useful motor outputs. Respiration-related sensory modulation of expiratory neurons by vagal afferents that monitor the rate of change of lung volume and the end-expiratory lung volume (EELV) play a crucial role in modulating the drive to the abdominal musculature. Studies using in vitro and in situ preparations of neonatal and juvenile rats show bi-phasic abdominal activity, characterized by bursting at the end of expiration, a silent period during the inspiratory period, and another burst that occurs abruptly after inspiratory termination. Since the abdominal muscles rarely show these post-inspiratory bursts in the adult rat, the organization of the expiratory output pathway must undergo significant development alterations.

Termination of inspiration by phase-dependent respiratory vagal feedback in awake normal humans.

Imperceptible levels of proportional assist ventilation applied throughout inspiration reduced inspiratory time (TI) in awake humans. More recently, the reduction in TI was associated with flow assist, but flow assist also reaches a maximum value early during inspiration. To test the separate effects of flow assist and timing of assist, we applied a pseudorandom binary sequence of flow-assisted breaths during early, late, or throughout inspiration in eight normal subjects. We hypothesized that imperceptible flow assist would shorten TI most effectively when applied during early inspiration. Tidal volume, integrated respiratory muscle pressure per breath, TI, and TE were recorded. All stimuli (early, late, or flow assist applied throughout inspiration) resulted in a significant increase in inspiratory flow; however, only when the flow assist was applied during early inspiration was there a significant reduction in TI and the integrated respiratory muscle pressure per breath. These results provide further evidence that vagal feedback modulates breathing on a breath-by-breath basis in conscious humans within a physiological range of breath sizes.

Expiratory Asynchrony in Proportional Assist Ventilation

One of the proposed advantages of proportional assist ventilation (PAV) has been the automatic synchrony between the end of the patient's inspiratory effort and the ventilator cycle (i.e., expiratory synchrony). However, recent clinical studies have shown a prolonged ventilator inspiratory time or even a "runaway" phenomenon with the normal use of PAV. We hypothesize that control-system delay may account for this, because in reality there is always some degree of delays between control-system's input and output in all ventilators. Computer simulation study to date has not taken into account the potential effect of control-system delay on expiratory synchrony. We therefore created a computer model in which the parameter of control-system delay time was introduced. We found that significant expiratory asynchrony may occur with this more realistic model of PAV. The ventilator flow termination may fall behind the completion of the patient inspiration by as long as 0.33 seconds under the selected simulation conditions. The inspiratory termination delay time is in proportion to the control-system delay time, the respiratory time constant, and the assist gain settings. In conclusion, this model indicates that due to the unavoidable control-system delay in the ventilators, expiratory asynchrony may be an inherent shortcoming associated with PAV.

Absence of MK801-induced inspiratory prolongation in chronically hypoxic rats

N-methyl- d-aspartate (NMDA) receptors play important roles in the neural control of respiration. We hypothesized that the brainstem circuit for respiratory control is modulated in response to chronic hypoxia during postnatal maturation, and the modulation may involve changes in the neurotransmission mediated by the NMDA receptors for inspiratory termination. Electrophysiological studies were performed on anesthetized, vagotomized, paralyzed and ventilated rats. Phrenic nerve activity was recorded in normoxic control and chronically hypoxic (CH) rats maintained in normobaric hypoxia (10% O 2) for 4–5 weeks from birth. In normoxic rats, the NMDA receptor antagonist, dizocilpine (MK801, I.P.) irreversibly increased inspiratory time (Ti) by 53% and decreased expiratory time (Te) by 29%. However, MK801 did not change the Ti, Te, respiratory rate and peak phrenic nerve activity in CH rats. Results suggest that brainstem mechanisms underlying inspiratory termination mediated by NMDA receptors are modulated by early chronic hypoxia.

Newer modes of mechanical ventilation for the neonate.

For decades, the overwhelming majority of infants requiring mechanical ventilation for respiratory failure were treated with standard time-cycled, pressure-limited intermittent mandatory ventilation. Technologic advances in the 1990s brought forth sophisticated transducers and microprocessor-based mechanical ventilators that enabled implementation of many newer modes of mechanical ventilation. Some of these are volume-targeted rather than pressure-targeted, and many allow an element of patient control of the ventilator, including initiation and termination of inspiration and control of flow. Some modes are even hybrids, combining the best features of both pressure-targeted and volume-targeted modes. This article reviews the principles and salient clinical features of the newer ventilatory modes for newborns with respiratory failure.

Role of nucleus parabrachialis complex in inspiratory off-switch studied in isolated brainstem-spinal cord preparation from neonatal rat

The nucleus parabrachialis complex (NPB) of the pons is known as a respiratory modulating center. The NPB and the medullary respiratory center are mutually interconnected and vagus nerve afferents from pulmonary stretch receptors project to the NPB [1]. There is much evidence in in vivo preparations from adult mammals [2] that the NPB plays a crucial in the inspiratory off-switch. In the present study, we examined how the NPB participates in the inspiratory off-switch using brainstem-spinal cord preparations obtained from 0–4 days old rats. We hemi-sectioned the pons keeping one side intact. First, we examined the effects of NPB electrical stimulation on C4 ventral nerve inspiratory activity. The electrical stimulation (0.1 ms duration, 1–5 trains, 20 ms interval) applied at various times (100–300 ms after the onset of C4 inspiratory activity) induced a transient depression or termination in C4 inspiratory activity. This depression was stronger when the stimulation was applied near the end of inspiratory activity but less conspicuous when it was applied at around the peak of inspiratory activity. Thus, activation of the NPB neuronal elements could produce termination of inspiratory activity in this in vitro preparation similar to the in vivo preparation. Previous in vivo experiments in adult mammals suggested that an NMDA receptor- mediated off-switch mechanism is present in the inspiratory termination [3]. Then, we examined whether a similar mechanism is involved in the above-observed inspiratory off-switch in the in vitro preparation. It was shown that the inhibition of C4 inspiratory activity induced by the NPB stimulation was greatly reduced by perfusion of NMDA antagonists (MK-801, APV) and that the inhibition was blocked by perfusion of a GABAA-antagonist (Bicuculline). To determine the location of NMDA receptors responsible for this inhibition by the NPB stimulation, an NMDA-antagonist MK-801 (1 mM) was microinjected into the NPB using a glass capillary placed in the vicinity of the stimulation electrode. The injection of MK-801 reduced the inhibition of C4 inspiratory activity by the NPB stimulation, indicating that NMDA receptor-mediated processes take place within the NPB. Since neurons and/or neuron networks responsible for inspiratory off-switch are expected to exist in the NPB, we tried to find respiratory neurons and analyzed their distribution and firing patterns. Neurons were recorded from the cut-surface of the intact half of the pons using whole cell patch clamp method. We found several types of respiratory neurons: inspiratory, tonic inspiratory, expiratory and inspiratory-expiratory (I-E) neurons. The population of I-E neurons was the largest, being more than 50% of the recorded neurons. I-E neurons fired from middle of C4 inspiratory activity through the early expiratory phase and were inhibited at the early part of C4 inspiratory activity. Perfusion of MK-801 (10 M) decreased significantly the driving potential and burst duration of I-E neurons. In addition, this perfusion decreased also the amplitudes of EPSPs induced by vagal nerve stimulation in the I-E neurons. In conclusion, 1) the NPB is involved in the inspiratory off-switch in in vitro preparations, 2) NMDA receptors within the NPB mediate, at least partly, the NPB-related inspiratory off-switch, and 3) a relatively large population of I-E neurons of the NPB could be responsible for the NPB-related inspiratory termination.

Analysis of the mechanisms of expiratory asynchrony in pressure support ventilation: a mathematical approach.

A mathematical model was developed to analyze the mechanisms of expiratory asynchrony during pressure support ventilation (PSV). Solving the model revealed several results. 1) Ratio of the flow at the end of patient neural inspiration to peak inspiratory flow (VTI/V(peak)) during PSV is determined by the ratio of time constant of the respiratory system (tau) to patient neural inspiratory time (TI) and the ratio of the set pressure support (Pps) level to maximal inspiratory muscle pressure (Pmus max). 2) VTI/V(peak) is affected more by tau/TI than by Pps/Pmus max. VTI/V(peak) increases in a sigmoidal relationship to tau/TI. An increase in Pps/Pmus max slightly shifts the VTI/V(peak)-tau/TI curve to the right, i.e., VTI/V(peak) becomes lower as Pps/Pmus max increases at the same tau/TI. 3) Under the selected adult respiratory mechanics, VTI/V(peak) ranges from 1 to 85% and has an excellent linear correlation with tau/TI. 4) In mechanical ventilators, single fixed levels of the flow termination criterion will always have chances of both synchronized termination and asynchronized termination, depending on patient mechanics. An increase in tau/TI causes more delayed and less premature termination opportunities. An increase in Pps/Pmus max narrows the synchronized zone, making inspiratory termination predisposed to be in asynchrony. Increasing the expiratory trigger sensitivity of a ventilator shifts the synchronized zone to the right, causing less delayed and more premature termination. Automation of expiratory trigger sensitivity in future mechanical ventilators may also be possible. In conclusion, our model provides a useful tool to analyze the mechanisms of expiratory asynchrony in PSV.

Bladder contractions alter inspiratory termination by superior laryngeal and intercostal nerve stimulation

Gradual distension of the urinary bladder evokes spontaneous bladder contractions (SBCs), which are associated with reduced inspiratory activity in the phrenic and other inspiratory motor nerves. We examined the influence of isovolumetric SBCs on the threshold for termination of phrenic inspiration by electrical stimulation of superior laryngeal and/or mid-thoracic intercostal nerves (ICN) in decerebrate, vagotomized, paralyzed, ventilated cats. Although SBCs reduced phrenic inspiratory activity, the threshold for inspiratory termination by nerve stimulation was increased. The results emphasize the complexity of the synaptic connections among brain stem neurons governing micturition and breathing.

GABA A receptor-mediated inspiratory termination evoked by vagal stimulation in decerebrate cats

To identify the GABAergic inhibitory mechanisms involved in inspiratory termination or off-switching (IOS), the effects of a specific enhancer of GABA A receptors, midazolam, and an antagonist, bicuculline, on vagally evoked inspiratory inhibitions and IOS were investigated in decerebrate cats. Stimulation of vagal afferents at late inspiration provoked either reversible inspiratory inhibition or IOS, depending on the stimulus intensity. Each response occurred at a constant latency (phase 1). The reversible response was triphasic, consisting of an early (phase 2) inhibition, a brief (phase 3) excitation and a late (phase 4) inhibition in the phrenic neurogram, and early (phase 2) IPSPs, brief (phase 3) EPSPs and late (phase 4) IPSPs in bulbar inspiratory (I) neurones. With an increasing stimulus intensity, phase 4 inhibitions were increased in amplitude and duration, leading to IOS. Midazolam (0.1 mg/kg i.v.) increased more selectively phase 4 IPSPs than phase 2 IPSPs in I neurones, and decreased the threshold for evoking IOS by producing an earlier and larger phase 4 IPSPs. Bicuculline (1.0 mg/kg i.v.) had an opposite effect. These results suggest that the late inhibitory response evoked by vagal stimulation in the I neuronal pool organizes an initial phase of IOS which is mediated by GABA A receptors.

Evidence for medullary projections of the intercostal nerve-elicited inspiratory termination

This study hypothesized that the ICN-elicited inspiratory termination reflex required synaptic activation in two distinct regions of the ventral respiratory group (VRG): (1) transitional (tVRG), and (2) pre-Bötzinger complex (pre-BötC). Data from adult cats indicate that axons of passage associated with the ICN-elicited termination reflex traverse tVRG, but that relevant synaptic processing does not occur in this region. Furthermore, data indicate that neither synaptic nor axonal transmission within the pre-BötC is required for the SLN- or ICN-elicted termination reflex.

Vagal stimulation induces expiratory lengthening in the in vitro neonate rat

Respiration is modulated by lung mechanoreceptor feedback in vivo on a cycle-to-cycle basis. We replicated this modulation in vitro and tested four stimulus protocols to identify which of these most closely replicated in vivo responses to lung mechanoreceptor activation in mammals. We activated pulmonary vagal afferent pathways by electrical stimulation or by lung inflation, applied during expiration, which produces expiratory lengthening in vivo. In each modality, transient and tonic stimuli were applied. Stimuli were applied over a range of delays following inspiratory termination. Tonic stimuli were maintained until subsequent inspiratory onset. All stimulus modalities prolonged expiration (P < 0.05). These results indicate that the neural circuitry mediating pulmonary afferent modulation of expiratory duration is retained in vitro.

Involvement of the motor trigeminal nucleus in respiratory phase-switching in the cat.

We investigated the hypothesis that the motor trigeminal nucleus, consisting of expiratory motoneurons, might be influential in termination of inspiration. We addressed the issue by comparing the effects on neural respiration of a reversible, unilateral, pharmacologic blockade of the motor trigeminal nucleus (5M), the medial parabrachial nucleus (PB), and of other nearby structures that are neutral for respiration in anesthetized, vagotomized, paralyzed, and ventilated cats. The blockade was achieved by microinjections of 2% xylocaine, laced with Pontamine Sky Blue to identify sites of injections, from the tip of a penetrating microelectrode. Integrated phrenic neurograms were recorded to quantify the time of neural inspiration (TI), expiration (TE), and the peak phrenic amplitude. We found that blockade of the 5M caused a pattern of apneustic respiration, consisting of a selective prolongation of inspiratory phases that were interrupted by short expiratory pauses. In contrast, blockade of the PB resulted in a prolongation of both TI and TE, which corresponds to a mere slowing of respiration. The results confirmed important functions of the rostral pons in ventilatory control but pointed to the 5M rather than PB as a structure underlying the inspiratory off-switch. We conclude that the motor trigeminal nucleus may have a part in the pontine pneumotaxic mechanism.

Respiratory Neurons Mediating the Breuer–Hering Reflex Prolongation of Expiration in Rat

Afferent input from pulmonary stretch receptors is important in the control of the timing of inspiratory and expiratory phases of the respiratory cycle. The current study was undertaken to identify neurons within a column of respiratory neurons in the ventrolateral medulla (termed the ventral respiratory group, VRG) that, when activated by lung inflation, produce the Breuer-Hering (BH) reflex in which lung inflation causes inspiratory termination and expiratory prolongation. Intracellular recordings of VRG neurons revealed three groups of inspiratory (I) and two groups of expiratory (E) neurons similar to previous descriptions: I-augmenting (I-Aug), I-decrementing (I-Dec), I-plateau (I-All), E-augmenting (E-Aug), and E-decrementing (E-Dec) neurons. Low-intensity, low-frequency stimulation of a vagus nerve elicited paucisynaptic EPSPs in E-Dec, I-Aug, and I-All neurons that could be divided into two groups on the basis of latency (2.8 +/- 0.1 msec, n = 10; 4.0 +/- 0.1 msec, n = 17). IPSPs were elicited in I-Aug and I-All neurons (4.8 +/- 0.1 msec, n = 12). However, only E-Dec neurons were depolarized when the BH reflex was activated by lung inflation (7.5 cm H2O) or mimicked by vagus nerve stimulation (50 Hz). All other neurons were hyperpolarized and ceased firing during BH reflex-mediated expiratory prolongation. A subset of E-Dec neurons (termed E-Decearly) discharged before inspiratory termination and could contribute to inspiratory termination. The findings are consistent with the hypothesis that a group of E-Dec neurons receives a paucisynaptic (probably disynaptic) input from pulmonary afferents and, in turn, inhibits inspiratory neurons, thereby lengthening expiration.

Involvement of NMDA receptors in the respiratory phase transition is different in the adult guinea pig in vivo and in the isolated brain stem preparation.

1. We investigated the involvement of N-methyl-D-aspartate (NMDA) receptors in the respiratory pattern in an in vitro preparation of adult brain stem compared with in vivo conditions in the guinea pig. 2. In vivo, combining administration of the NMDA channel blocker dizocilpine (MK-801) (3 mg/kg) with a surgical section of the vagus nerves induced an apneustic type of respiration characterized by long inspiratory "holds," as has been shown in other species. The same effect was observed in hypothermic animals (30 degrees C). 3. The isolated in vitro brain stems from these apneustic animals did not present a prolonged inspiratory phase. A second dose of dizocilpine (100 microM perfused vascularly did not induce apneusis, even after increasing brain stem temperature to 35.5 degrees C. 4. In another group of isolated brain stems of adult guinea pigs anesthetized with pentobarbital sodium before decapitation, we perfused dizocilpine and NMDA through the basilar artery. The duration of periodic inspiratory motor activity recorded from the hypoglossal nerve was unaffected by dizocilpine (1-100 microM) or the competitive NMDA antagonist D- or DL-2-amino-5-phosphonopentanoic acid (100 microM and 1 mM), although respiratory frequency decreased. The increase in respiratory activity produced by vascularly perfused NMDA (25-100 microM) was blocked by dizocilpine (100 microM). 5. We conclude that the central mechanism of inspiratory termination in the vagotomized adult guinea pig requires the activation of NMDA receptors in vivo but not in vitro. This difference is not due to the hypothermic environment in vitro. Possible mechanisms for phase switching in vitro are discussed.

Involvement of NMDA receptors in inspiratory termination in rodents: effects of wakefulness

We investigated the role of N-methyl- d-aspartate (NMDA) receptors in the off-switching of inspiration in rodents. Respiratory activity was measured by the plethysmographic method in Swiss and Balb c mice, Hartley guinea pigs, Wistar and Sprague-Dawley rats. The NMDA channel blocker dizocilpine (MK-801) administered systemically, had little effect on the timing of respiratory phases in intact animals. When dizocilpine was associated with a vagotomy performed under anesthesia, an apneustic respiratory pattern was obtained in all species and strains. As the anesthetic dissipated, the inspiratory pauses disappeared and the apneustic respiratory pattern was replaced by an eupneic respiratory pattern. Apneuses were re-instated by small doses of anesthetic (halothane, pentobarbital, alphaxolone-alphadolone or chloral hydrate) and suppressed by larger doses. We conclude that (i) the central NMDA-receptor dependent inspiratory off-switching mechanism previously described in cats and primates, also exists in rodents; (ii) wakefulness maintains a normal respiratory pattern after suppression of both the NMDA-receptor mediated and the vagally-mediated off-switching mechanisms; (iii) deep anesthesia suppresses inspiratory pauses in rodents.

Neuronal activities underlying inspiratory termination by pneumotaxic mechanisms

The purpose was to identify and characterize the discharge patterns of pontile neurons which are responsible for the termination of inspiratory activity. Phrenic discharge is prolonged following destruction of neurons at the junction of mesencephalon and pons by neurotoxins. Neuronal activities were recorded in this region in decebrate, vagotomized, paralyzed and ventilated cats. At normocapnia, neurons had tonic discharge patterns, most of which were linked to phasic periods of phrenic activity. Peak activities occurred in late neural inspiration or early expiration. In hypercapnia, neuronal discharge frequencies did not increase, rather activity became more concentrated during one portion of the respiratory cycle. In severe hypoxia, neuronal activities diminished in parallel with prolongations of phrenic discharge and establishment of apneusis. During recovery, some neurons transiently acquired phasic, respiratory-modulated discharge patterns. Neuronal activities from neighboring regions did not exhibit comparable changes in hypercapnia or hypoxia. We conclude that rostral pontile neuronal activities are a primary determinant of teh reversible and irreversible terminations of eupneic inspiratory activity.

Involvement of pontile NMDA receptors in inspiratory termination in rat

We evaluated the hypothesis that N- methyl- d-aspartate (NMDA) receptors in the rostal pons mediate the off-switch of inspiration in the adult rat. Experiments were performed on decebrate, vagotomized, paralyzed and ventilated animals. Activity of phrenic nerve was recorded. Small volumes (10 nl) of NMDA antagonists, MK-801 and Ap-5, or non-NMDA antagonists, CNQX and DNQX, were injected nto the rostral pons. We found that injections of MK-801 reversibly increased the duration of neural inspiration (T i), and the increase was dose-dependent. Injections of AP-5 also increased T i. Injections of the DNQx and CNQX in these same loci resulted in no significant chagnes in the duration of neural inspiration, expiration or peak phrenic activity (PNA). However, injections of kainic acid (KA, 4.7 mM) in the loci increased T i and decreased PNA. We conclude that neurons regulating the off-switch mechanism are located in the rostral pons. Further, the binding of NMDA receptors in the rostral pons is involved in this off-switch mechanism.