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The Journal of Neuroscience, August 1, 1998, 18(15):6048-6056
A Brainstem Network Mediating Apneic Reflexes in the Rat
Nancy L. Chamberlin and Clifford B. Saper Department of Neurology, Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts 02115
ABSTRACT
Top
Abstract
Introduction
Apnea is an important protective response to upper airway irritation, but the central mechanisms responsible for eliciting sensory-induced apnea are not well understood. Recent studies have emphasized the Kölliker-Fuse nucleus in producing apnea and proposed a trigeminoparabrachial pathway for mediating these reflexes. However, in our earlier study of apneic responses produced by glutamate stimulation in the dorsolateral pons, we found that apnea was elicited from the area just ventral to the Kölliker-Fuse nucleus, rather than within it. Because this region was not known to be involved in respiratory control, we combined chemical microstimulation with both anterograde and retrograde axonal tracing to characterize the sites in the pons that produce apneic responses. We found that apneic sites were consistently associated with the intertrigeminal region, between the principal sensory and motor trigeminal nuclei. Injections of anterograde tracer at these sites labeled terminals in the ventral respiratory group, in the ventrolateral medulla. Injection of retrograde tracer into this target region in the ventrolateral medulla disclosed a previously unrecognized population of neurons among the trigeminal motor rootlets. Injection of retrograde tracer into this intertrigeminal region demonstrated inputs from portions of the spinal trigeminal nucleus and the nucleus of the solitary tract that have been associated with producing sensory apnea. Our observations suggest that the intertrigeminal region receives a convergence of sensory inputs capable of driving apneic responses and that it may represent a common link between input from different portions of the airway and the respiratory neurons that mediate apneic reflexes.
Key words: intertrigeminal region; apnea; respiration; chemical microstimulation; tract tracing; trigeminal
INTRODUCTION
Reflexive apnea is critical for protecting the airways and lungs from potentially damaging events such as aspiration of water or food. The sensory input that causes transient cessation of breathing is conveyed by several cranial nerves, including the ethmoidal branch of the trigeminal nerve, which innervates the nasal mucosa (James and De Burgh Daly, 1972
; Yavari et al., 1996
Earlier studies on the trigeminal apneic reflex emphasized a putative relay in the Kölliker-Fuse nucleus. Early studies on the Kölliker-Fuse nucleus demonstrated respiratory suppressive responses to stimulation with electrical current in cats (Cohen, 1971
In contrast, our own earlier microstimulation studies, using much smaller amounts of glutamate, had found only hyperpneic responses or apneusis in the Kölliker-Fuse nucleus, whereas apneic sites were found in the area just ventral to the Kölliker-Fuse nucleus (Chamberlin and Saper, 1994
To test the possibility of the presence of an apneic nucleus in the trigeminal complex, we combined chemical microstimulation with threshold dosages of glutamate with anterograde and retrograde transport to map the distribution of cells and axonal pathways associated with the apneic sites. In doing so, we have identified a previously unrecognized group of cells in the intertrigeminal region that projects to the ventral respiratory group in the medulla. The intertrigeminal region in turn is innervated by sensory subnuclei that receive vagal and glossopharyngeal as well as trigeminal input from the upper airway. The intertrigeminal region may therefore represent a key relay for a wide range of apneic airway protective reflexes.
MATERIALS AND METHODS
Chemical microstimulation and injections of biotinylated dextran amines at apneic sites. Thirteen male Sprague Dawley rats (275-325 gm) were obtained from Taconic (Germantown, NY). To prepare animals for surgery, anesthesia was induced with 7% chloral hydrate (0.8 ml/100 gm, i.p.). An endotracheal tube was inserted through the oropharynx and a catheter (PE-50 tubing) was placed into a femoral vein. Anesthesia was subsequently maintained by a continuous intravenous infusion of
-chloralose. An acceptable level of anesthesia was gauged by the absence of withdrawal movements in response to a noxious foot pinch.
Rats were placed in a stereotaxic apparatus (David Kopf Instruments) with the incisor bar set at the level of ear bar zero, and a burr hole was drilled into the skull to allow access to the left rostral pons. The distal end of the endotracheal tube was attached to a flow of humidified 100% oxygen via a "Y" connector. Breathing caused the rate of gas flow to fluctuate and these changes were measured by a Fleisch pneumograph with a PT5B pressure transducer. The respiratory flow and stimulus timing signals were amplified by a Grass Polygraph and digitized by a computer equipped with A/D hardware and software (TL-2 and Axotape, Axon Instruments, Foster City, CA). These data were analyzed and displayed with an Apple Macintosh computer with Igor Pro software (Wavemetrics, Lake Oswego, OR). Tidal volume was determined by digital integration of the respiratory flow signal.
Glass micropipettes with an outer tip diameter of 10-20 µm were used to pressure-inject glutamate (1 mM in phosphate buffer), a mixture of glutamate (500 µM) and biotinylated dextran amines (BDA) (5%, 3000 molecular weight; Molecular Probes, Eugene, OR), or a mixture of glutamate, BDA, and cholera toxin B subunit (CTB) (0.07%; List Biologic, Campbell, CA). All pipettes were held by a stereotaxic manipulator and fitted with a piece of Tygon tubing that was connected to an air pressure injection apparatus. The injected volume was determined (±1 nl) by measuring the movement of the meniscus within the pipette with an eyepiece reticule in an operating microscope.
The rostral lateral pons was initially explored with 1-3 nl injections of 1 mM glutamate. Specifically, glass micropipettes filled with glutamate (1 mM in phosphate buffer) were positioned by stereotaxic coordinates 4 mm above ear bar zero. At this site, 1-3 nl of glutamate was pressure-injected and the respiratory responses were observed. The pipette was then advanced ventrally in 100 µm intervals as the respiratory responses to glutamate were explored. If no respiratory suppressive response occurred in a given track, the pipette was moved to a different location. When a site was reached where glutamate produced a pause in breathing, the coordinates were noted and the pipette was drawn dorsally out of the brain, but not otherwise moved. Air pressure pulses were applied until the remaining glutamate solution was cleared from the pipette, which was then refilled with a solution of BDA (5-7%) and glutamate (0.5-1 mM) or, in three cases, a mixture of glutamate, BDA, and CTB. The pipette was then reintroduced into the brain at the predetermined dorsoventral coordinate where 6-9 nl of the mixture was injected. The presence of glutamate in the tracer solution allowed respiratory responses to be recorded during tracer injection, thus physiologically characterizing the injection site. The pipette was removed from the brain, intravascular lines were removed, and the wounds were closed. Rats were extubated and allowed to recover from anesthesia.
After a 3-10 d survival period, rats were deeply anesthetized and perfused through the heart as described previously (Chamberlin and Saper, 1994
Biotinylated dextran amine labeling was visualized by incubating the tissue for 1 hr with an avidin-peroxide complex (ABC kit; Vector Laboratories, Burlingame) diluted 1:500 in PBS containing 0.25% Triton X-100 (PBT). The tissue was rinsed three times for 10 min in PBS and then stained with 0.05% diaminobenzidine hydrochloride (DAB; Sigma, St. Louis, MO) and 0.01% H2O2 in PBS containing 0.01-0.02% nickel sulfate and 0.01-0.02% cobalt chloride.
In some cases sections were subsequently immunostained for choline acetyl transferase (ChAT) as follows. The tissue was incubated overnight at room temperature in rabbit anti-ChAT antiserum (UO95, gift of L. Hersh, University of Kentucky) diluted 1:20,000-100,000 in PBS containing 0.25% Triton X-100 and 3% normal goat serum (PGT). Tissue sections were rinsed in PBS three to six times for 10 min each. After successive incubations in biotinylated goat anti-rabbit IgG (Vector; 1:500 in PGT; 2 hr) and then avidin-biotinylated peroxidase complex (Vector elite ABC kit; 1:500 in PBS; 1-2 hr), sections were reacted in 0.05% DAB and 0.01% hydrogen peroxide in PBS.
In cases in which BDA and CTB were injected together, sections were stained for BDA using nickel/cobalt-enhanced DAB as described above and subsequently immunostained for CTB by incubating overnight in goat anti-CTB (List Biological Laboratories) diluted 1:100,000 in PBT. The tissue was then treated with a mouse monoclonal anti-goat antibody (1:1000; Sigma) and the Vector ABC solution (1:500) for 1 hr each with rinses between incubations. DAB staining was accomplished as described above in the absence of Ni or Co ions such that a brown reaction product was formed in CTB-containing neurons. Tissue was mounted on gelatin-coated glass microscope slides, dehydrated in graded alcohols, cleared in xylene, and coverslipped with Permaslip mounting medium. After drawings were made and photographs taken (see below), the slides were replaced in xylene to remove the coverslips, and the tissue was counterstained for Nissl substance with thionin (0.125%).
Retrograde tracing with horseradish peroxidase conjugated to wheat germ agglutinin. Injections of 3-6 nl of a 1% solution of horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP) (Sigma) were pressure-injected into the ventrolateral medulla in eight additional cases. After 30-60 hr survival, the animals were reanesthetized and perfused as described above except that the fixative contained 0.5 or 1% paraformaldehyde and 1.25% glutaraldehyde. The brains were removed and immersed overnight in 20% sucrose, and frozen sections were cut into three series of 50 µm. One series was processed according to the tetramethylbenzidine (TMB) method of de Olmos and coworkers (1978)
Data analysis. The distribution of labeled cells and axon terminals was mapped with a microscope equipped with a camera lucida drawing tube. Line drawings were digitized with a flatbed scanner, and "Canvas" (Deneba) software was used to create the final maps of injection sites, anterogradely labeled axon terminals, and retrogradely labeled cells. Digital photomicrographs were taken with a Kodak 460 DCS camera mounted on a Zeiss microscope and were prepared using Adobe Photoshop on an Apple Macintosh computer. Images were sharpened, brightness and contrast were adjusted, and then images were printed with a Kodak 8600 dye sublimation printer.
RESULTS
Anatomical location of respiratory suppressive effects of pontine stimulation
Microinjection of doses of glutamate as low as 1 pmol caused abrupt, transient inhibition of inspiration, which we term hypopnea or apnea (Fig. 1). In previous studies (Chamberlin and Saper, 1994
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Figure 1. Respiratory suppressive effect of glutamate microinjection. Shown is an example of the effect on breathing of glutamate microinjection in case SPB629. The top trace reflects tidal volume in milliliters. The bottom trace shows the timing of a train of five pressure pulses that ejected ~1.5 nl each of 0.5 mM glutamate. Note that the first breath after glutamate injection is reduced in amplitude and followed by a pause. The baseline drift is artifactual. In this case the injection site was located just medial to the ventral border of the principal sensory trigeminal nucleus (Fig. 2D, vertical arrow), and the distribution of fibers is shown in Figure 3.
The anatomical distribution of injection sites where glutamate caused hypopnea is summarized in Figure 2. In general, nearly all apneic sites were found among the fiber bundles between the motor and principal sensory trigeminal nuclei. These fibers, which primarily represent the motor rootlets of the trigeminal nerve, contain scattered medium- to large-sized multipolar neurons, and the entire area has been termed the intertrigeminal region. Rostrally, apneic sites stretched up to the ventral border of the Kölliker-Fuse nucleus (Fig. 2A,B) but were never found within this nucleus (Chamberlin and Saper, 1994
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Figure 2. Anatomical distribution of hypopneic sites. Each gray diamond represents the location where microinjection of glutamate and BDA produced a decrease in respiratory rate in one rat. A-E, Representative coronal sections through the rat brain at 160 µm intervals. The vertical arrow in D shows the case in which the response is shown in Figure 1. The horizontal arrow in E shows the case that is also presented in Figure 5. DLL, Dorsal nucleus of the lateral lemniscus; Int 5, intertrigeminal nucleus; KF, Kölliker-Fuse nucleus; ll, lateral lemniscus; mcp, middle cerebellar peduncle; Me5, mesencephalic trigeminal nucleus, me5, mesencephalic trigeminal tract; Mo5, motor trigeminal nucleus; Pr5, principal sensory trigeminal nucleus; s5, sensory root of the trigeminal nerve; scp, superior cerebellar peduncle; tr5, motor roots; vsct, ventral spinocerebellar tract.
Projections from apneic sites: anterograde tracing with BDA
In 12 cases in which injection of a mixture of glutamate and BDA produced a hypopneic response, anterogradely labeled fibers were traced from the injection site to their terminal fields. Although these injection sites were widely varied in their location (Fig. 2), all demonstrated a consistent pattern of efferent projections. Labeled fibers descended in the ventrolateral region of the brainstem just medial to the exit of the seventh nerve at pontine levels and medial to the ventromedial edge of the spinal trigeminal nucleus in the medulla. Table 1 summarizes the brain regions in which labeled axon terminals were found in each case. In all cases terminals were seen bilaterally, with a strong ipsilateral preference, in the ventrolateral quadrant of the medulla. In most cases terminals were found in the lateral portions of the facial motor nucleus. The heaviest labeling was always seen just caudal to this area at the level of the compact formation of the nucleus ambiguus in the periambigual region (Figs. 3, 4A). Examination of tissue stained for ChAT as well as anterogradely labeled terminals showed that although axon terminals were located in the vicinity of the nucleus ambiguus, they rarely formed close appositions with cholinergic neurons (Fig. 3). The distribution of medullary terminals in a typical case, SPB629, is shown in Figure 4, where it can be seen that terminals were found in the entire length of the ventrolateral medulla from the periambigual region to the spinomedullary junction. In several cases large BDA injections also produced sparse retrograde labeling. These cells were found in the ventrolateral medulla in the same area as the labeled terminals and in the spinal trigeminal nucleus. In the cases in which BDA injection sites included a few labeled cells in the Kölliker-Fuse nucleus, labeled axon terminals were also found in the nucleus of the solitary tract and in the hypoglossal motor nucleus. Efferent fibers were not found in the dorsal vagal complex or the hypoglossal nucleus in the cases in which injections did not include the Kölliker-Fuse nucleus. In several cases labeled axons were seen in the white matter of the ipsilateral cervical spinal cord; however, no labeled terminals were seen in the phrenic motor nucleus.
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Table 1. Summary of anterograde transport from apneic sites in this study
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Figure 3. Projections of apneic sites to the ventrolateral medulla. Photomicrographs showing BDA-labeled terminals (arrowheads) and ChAT-immunoreactive neurons (arrows). Note that terminals are nearby but not closely apposed to ChAT-immunoreactive neurons.
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Figure 4. Distribution of terminal fields from a hypopneic site. Each dot represents three to eight BDA-labeled axon terminals. Labeled fibers of passage are not shown. Each drawing (A-F, rostral to caudal) is a representative coronal section through the medulla separated by ~160 µm intervals. Note that labeling is heaviest at rostral levels and extends the entire length of the medulla (case SPB629). 10, Dorsal motor vagal nucleus; 12, hypoglossal motor nucleus; AP, area postrema; cu, cuneate fasciculus; Ecu, external cuneate nucleus; Gr, gracile nucleus; icp, inferior cerebellar peduncle; IO, inferior olive; LVe, lateral vestibular nucleus; LRN, lateral reticular nucleus; MVe, medial vestibular nucleus; NAc, compact formation of the nucleus ambiguus; NTS, nucleus of the solitary tract; sp5, spinal trigeminal tract; Sp5, spinal trigeminal nucleus.
Forebrain projections from apneic sites were less consistent and less dense than medullary terminal fields. Fibers were seen to cross the pontine tegmentum between the decussation of the superior cerebellar peduncle and the base of the pons. Many axons turned dorsally near the red nucleus, and in most cases labeled axon terminals were seen in the contralateral oculomotor nucleus. Other axons continued rostrally in the central tegmental tract and in some cases formed terminals in the deep layers of the superior colliculus. Fibers continued rostrally in the central tegmental field and in the medial lemniscus. A few terminals were found in the prerubral field, the zona inserta, and the ventromedial nucleus of the thalamus.
The location of apneic neurons: retrograde tracing with WGA-HRP
To identify the neurons of origin of the observed medullary projections from apneic sites, injections of WGA-HRP were placed into the ventrolateral medulla at different rostrocaudal levels in eight rats. In each of these cases neurons were identified at nonapneic sites in the Kölliker-Fuse nucleus and the lateral crescent parabrachial subnucleus, as described previously (Fig. 5) (Herbert et al., 1990
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Figure 5. Distribution of pontine neurons projecting to the rostral ventrolateral medulla. A-E, Coronal sections (rostral to caudal) through the pons depicting the locations of neurons retrogradely labeled after an injection of WGA-HRP into the rostral ventrolateral medulla just ventral to the compact formation of the nucleus ambiguus (inset: scale bar, 500 µm). The retrogradely labeled neurons in the intertrigeminal region (ITR) are shown as stars. Note that these cells extend from the area just ventral to the Kölliker-Fuse nucleus, stretching ventrally and caudally underneath the motor trigeminal nucleus. Abbreviations are as in Figure 2.
Inputs to apneic sites: retrograde labeling with CTB
In three cases (SPB635, SPB636, and SPB639) CTB was included in the mixture of glutamate and BDA that was injected at an apneic site. In each case retrogradely labeled neurons were found in the spinal trigeminal nucleus and in the nucleus of the solitary tract (Fig. 6). In the spinal trigeminal nucleus, the greatest number of labeled neurons was found in the transition region between its caudalis and interpolaris divisions. In each of these cases, retrogradely labeled neurons were also located in the interstitial (Fig. 6B) and medial (Fig. 6A-C) subnuclei of the nucleus of the solitary tract. Very few retrogradely labeled neurons were seen in the Kölliker-Fuse nucleus, parabrachial complex, or pontomedullary reticular formation.
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Figure 6. Distribution of retrogradely labeled neurons from apneic sites. In this case (SPB639), cholera toxin subunit B (0.07%) was included in the injection mixture. In A-D, (rostral to caudal) coronal sections through the medulla, each dot represents a single retrogradely labeled neuron.
DISCUSSION
We identified a population of neurons in the intertrigeminal region of the pons from which apneic responses can be elicited and which project to the ventral respiratory group. Intertrigeminal apneic sites receive inputs from the nucleus of the solitary tract as well as the spinal trigeminal nucleus. We suggest that the intertrigeminal region may participate in trigeminal, vagal, or glossopharyngeal apneic reflexes. Figure 7 illustrates proposed pathways for these reflexes.
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Figure 7. Summary diagram illustrating the proposed apneic pathways. Sensory information from the upper airway carried by the trigeminal nerve (5) terminates in the spinal trigeminal nucleus, which in turn projects to the intertrigeminal region (ITR). Vagal (10) and glossopharyngeal (9) afferents terminate in the nucleus of the solitary tract, which also projects to the ITR. The ITR causes apnea via a projection to the ventral respiratory group in the ventrolateral medulla (VLM). KF, Kölliker-Fuse nucleus; Mo5, motor trigeminal nucleus; s5, sensory root of the trigeminal nerve.
Technical considerations
Combining glutamate with tracers enabled measurement of respiratory responses at the very sites at which tracing originated, a powerful technique for correlating function with neuronal connectivity. Our use of threshold doses of glutamate provided the finest anatomical resolution possible with microstimulation mapping. Although there is no certainty that the neurons producing the response and those that transport the tracer are identical, the validity of the results requires only an overlap between these two populations. Cells that do not mediate apneic responses may be labeled in some cases, but the labeling of irrelevant terminal fields may vary from case to case, whereas those pathways crucial for the response should be labeled in all cases. Therefore, examination of a number of cases should reveal the relevant projections. Without exception, every injection at an apneic site labeled terminals in the ventral respiratory group in the medulla (Ellenberger and Feldman, 1990
The tracers that we used (BDA, CTB, WGA-HRP) are capable of bidirectional transport, which can complicate the interpretation of results. Our BDA injections were quite small and produced very few retrogradely labeled cells. Hence it is unlikely that axonal transport represented collaterals of retrogradely labeled neurons. WGA-HRP cases were used only to identify retrograde transport. The intertrigeminal region, into which we injected CTB, is crossed by nearly all of the connections of the parabrachial complex with the spinal cord and the medulla. However, CTB is not taken up by uninjured fibers of passage, and our injection method, using fine micropipettes, did not damage this region, as witnessed by the lack of retrograde labeling in the parabrachial complex in these cases. Hence the retrograde label seen represents input to the intertrigeminal region neurons. This conclusion was confirmed by examining material from earlier studies in which we injected PHA-L into these ascending pathways (Herbert et al., 1990
Previous investigations using microinjections of excitatory amino acids or blockers of synaptic transmission implicated the Kölliker-Fuse nucleus as an apneic region (Lara et al., 1994
Anatomical considerations
The area between the principal sensory and motor trigeminal nuclei has been referred to as the intertrigeminal region (Brodal, 1981
Neurons in the intertrigeminal region have been retrogradely labeled by tracer injections into the superior colliculus and the oculomotor nucleus (Guerra-Seijas et al., 1993
All of our cases demonstrated a projection from intertrigeminal apneic sites to the ventrolateral medulla (Fig. 4, Table 1). Because the ventrolateral medulla contains the ventral respiratory group, a complex of neurons that generate respiratory rhythm and drive the respiratory motor neurons, we presume that the intertrigeminal apneic response is produced by alterations in the activity of some of these neurons. Efferent projections from the intertrigeminal region were found along the entire rostrocaudal extent of the ventrolateral medulla in nearly all cases, so it is not clear which subsets of respiratory neurons mediate the pontine apneic response. However, in most cases the densest terminal labeling was seen at rostral levels of the ventrolateral medulla, coextensive with the Bötzinger and pre-Bötzinger complexes (Ellenberger and Feldman, 1990
Physiological role of the intertrigeminal apneic response
Studies in muskrat, rat, and dog have shown that apnea can be evoked by noxious stimulation of the nasal mucosa (James and De Burgh Daly, 1972
We also found that apneic sites in the intertrigeminal region received inputs from the nucleus of the solitary tract, mainly from its medial and interstitial subnuclei (Fig. 6), which receive vagal and glossopharyngeal primary afferents innervating the lungs and upper airway (Kalia and Richter, 1988
The connections between the nucleus of the solitary tract and the intertrigeminal region may mediate the apnea that occurs during swallowing and pulmonary stretch or after mechanical or chemical upper airway stimulation. A projection from neurons in the interstitial subnucleus of the nucleus of the solitary tract that are active during swallowing (Ootani et al., 1995
FOOTNOTES Received April 6, 1998; revised May 18, 1998; accepted May 20, 1998.
This work was supported by National Institutes of Health-U.S. Public Health Service Grant NS22835 and a grant to N.L.C. by the American Lung Association and the Massachusetts Thoracic Society. We thank Dr. L. Hersh for donating the UO95 antisera and Quan Hue Ha and Minh Ha for excellent technical assistance. We thank Dr. Tom Scammell and Amy Malick for helpful comments on this manuscript.
Correspondence should be addressed to Dr. Nancy L. Chamberlin, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Room 823, 77 Avenue Louis Pasteur, Boston, MA 02115.
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