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. 2002 May 1;540(Pt 3):1047–1060. doi: 10.1113/jphysiol.2001.014985

Swallowing-related activities of respiratory and non-respiratory neurons in the nucleus of solitary tract in the rat

Yoshiaki Saito *,†, Kazuhisa Ezure *, Ikuko Tanaka *
PMCID: PMC2290262  PMID: 11986389

Abstract

Swallowing-related activity was examined in respiratory (n = 60) and non-respiratory (n = 82) neurons that were located in and around the nucleus of the solitary tract (NTS) in decerebrated, neuromuscularly blocked and artificially ventilated rats. Neurons that were orthodromically activated by electrical stimulation of the superior laryngeal nerve (SLN) were identified, and fictive swallowing was evoked by SLN stimulation. The pharyngeal phase of swallowing was monitored by hypoglossal nerve activity. Two types of non-respiratory neurons with swallowing-related bursts were identified: ‘early’ swallowing neurons (n = 24) fired during periods of hypoglossal bursts, and ‘late’ swallowing neurons (n = 8) fired after the end of hypoglossal bursts. The remaining non-respiratory neurons were either suppressed (n = 21) or showed no change in activity (n = 29) during swallowing. On the other hand, respiratory neurons with SLN inputs included 56 inspiratory and four expiratory neurons. Inspiratory neurons were classified into two major types: a group of neurons discharged simultaneously with hypoglossal bursts (type 1 neurons, n = 19), while others were silent during bursts but were active during inter-hypoglossal bursts when swallowing was provoked repetitively (type 2 neurons, n = 34). Three of the expiratory neurons fired during hypoglossal bursts. Many of the swallowing-related non-respiratory neurons and the majority of the inspiratory neurons received presumed monosynaptic inputs from the SLN. Details of the distribution and firing patterns of these NTS neurons, which have been revealed for the first time in a fictive swallowing preparation in the rat, suggest their participation in the initiation, pattern formation and mutual inhibition between swallowing and respiration.

Swallowing is a co-ordinated motor sequence of muscles in the alimentary tract and consists of the orofacial, pharyngeal and oesophageal phases. Electrical stimulation of the trigeminal, glossopharyngeal and vagal nerves induces swallowing starting from the pharyngeal phase and skipping the orofacial phase (Jean, 2001). Stimulation of the superior laryngeal nerve (SLN) is the most effective manner in inducing swallowing. Since the stereotyped motor sequence of once-started swallowing is accomplished automatically without any further input, the presence of the central-pattern generator (CPG) for swallowing has been widely accepted (Doty et al. 1967; Miller, 1982, 1986; Jean, 1990). At present, however, the neuronal mechanisms of the swallowing CPG, thought to be located in the medulla oblongata, are not well clarified. Two groups of swallowing-related neurons which have been identified in the areas of the nucleus of solitary tract (NTS) and the nucleus ambiguus (NA) (Jean, 1972; Kessler & Jean, 1985; Umezaki et al. 1998), are called the dorsal and ventral swallowing groups (DSG and VSG), respectively (Jean, 2001). The neurons in the DSG discharge during pharyngeal or oesophageal phases, and are assumed to provide the temporal sequence for pharyngo-oesophageal co-ordination. The VSG includes motoneurons to the pharynx, larynx and oesophagus as well as interneurons that may participate in the co-ordination of motoneurons in the hypoglossal, ambiguus and facial nuclei (Amri et al. 1990; Ezure et al. 1993) during swallowing. Based on these observations, Jean (2001) has presented an intriguing model of the swallowing CPG in which the pattern generation is completed within the DSG, and the VSG neurons are passively driven by the DSG activity. The DSG includes, as its main constituents, NTS neurons which receive input from SLN afferents. In order to analyse the role of these NTS neurons in the swallowing CPG, it is important to know how they behave during swallowing without phasic feedback input from the periphery. The previous studies (Jean, 1972; Kessler & Jean, 1985; Umezaki et al. 1998) analysed this issue by neuromuscularly blocking the animals during the middle of unit recording in exchange for swallowing monitors of EMG activity, but the information obtained was limited.

Anatomical studies using horse radish peroxidase (HRP) (Bieger & Hopkins, 1987; Altschuler et al. 1989; Hayakawa et al. 1998) or viral tracers (Bao et al. 1995) have shown many aspects of swallowing-related neural pathways. In particular, the following viscerotopic neuronal representation is relevant. The afferent fibres from the pharynx and oesophagus project to the interstitial and central subnuclei of the NTS. The neurons in these subnuclei then send viscerotopic projections to the NA where motoneurons projecting to the corresponding parts of the alimentary tract are located rostrocaudally. The SLN afferents primarily project to the interstitial and the central subnuclei and projections from the former to the latter subnucleus are also found (Broussard et al. 1998). These neuronal connections may support the DSG-driven swallowing model. However, the relevant data of DSG neuronal activities have not been studied precisely in relation to the cytoarchitectonic subdivisions of the NTS.

Swallowing is closely related to respiration. Breathing is arrested during swallowing, and this arrest is followed by expiration in most cases (Selley et al. 1989; Paydarfar et al. 1995; Hadjikoutis et al. 2000). In turn, swallowing is easily evoked at certain phases of the respiratory cycle (Dick et al. 1993; McFarland & Lund, 1993) and is modulated by the lung volume changes (Kijima et al. 2000). The influence of swallowing on individual respiratory neurons in the dorsal respiratory group (Gestreau et al. 1996) and the ventral respiratory group (Oku et al. 1994) has been studied in cats. Although it has been shown that many of the inspiratory and expiratory neurons are involved in swallowing in various ways, their significance in the mutual influence remains obscure. On the other hand, many studies on the swallowing-related neurons have paid little attention to the participation of respiratory neurons in swallowing (Jean, 1972; Umezaki et al. 1998).

To elucidate these issues we aimed, in the present study, to clarify details of electrophysiological and anatomical properties of NTS neurons with SLN inputs in a fictive swallowing preparation, under the hypothesis that respiratory and non-respiratory neurons of the NTS are both involved in the pattern generation through their local network. Indeed, we found a type of respiratory neurons that may function in co-ordination between swallowing and respiration.

METHODS

Surgical procedure

Experiments were conducted on 19 adult male rats (385–580 g). The animals were initially anaesthetized with sodium barbiturate (Nembutal, 60 mg kg−1; i.p.). When necessary, supplementary doses (about 5 mg kg−1 h−1; i.v) were given throughout surgery before decerebration (see below). The trachea was intubated, and cannulae were placed in the femoral artery and vein for blood pressure monitoring and drug administration, respectively. The rats were placed in a stereotaxic frame, initially in the supine position. The hypoglossal nerve on one side was cut distally and mounted in a bipolar cuff electrode for recording. Similar bipolar cuff electrodes were attached to the cut SLN on both sides for stimulation. The exposed hypoglossal and SLN nerves were covered with Vaseline jelly, thin plastic films and skin flaps. The animals were then rotated to the prone position and supported by hip pins and a clamp placed on an upper thoracic vertebra. Precollicular decerebration was performed after craniotomy. The brain rostral to the transection was removed by suction. During experiments no further anaesthetics were given after decerebration, since this rendered the animal insentient. The decerebration was normally completed within 3 h after the anaesthetic induction. The dorsal surface of the medulla was exposed for recording by partial cerebellectomy. In four experiments, three stainless needle electrodes were fixed in the C2/C3 spinal cord for stimulation after laminectomy, two in the ventrolateral quadrant bilaterally and one ventral to the central canal. The C4/C5 phrenic nerve was cut distally, mounted on a bipolar recording electrode, and immersed in oil pools. The animals were injected with the neuromuscular blocker pancronium bromide (Mioblock, Sankyo, Tokyo; 0.15 mg kg−1 h−1) and artificially ventilated. A bilateral pneumothorax was made and a positive end-expiratory pressure (1–3 cmH2O) was applied. In two experiments, the animals were not initially neuromuscularly blocked, and a balloon attached to a polyethylene tube was inserted orally into the upper oesophagus to detect the oesophageal pressure accompanying swallowing. Blood pressure was monitored and kept above 80 mmHg; pressor agents (10 % dextran, 1–2 ml kg−1; phenylephrine hydrochloride, Neo-Synesin, Kowa, Tokyo, 2–3 mg kg−1) were intravenously administered when necessary. Tracheal pressure, end-tidal CO2 (kept at 4–6 %), and rectal temperature (kept at 36–37 °C) were monitored. All the experimental procedures were performed in accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Science (Physiological Society of Japan, 1988). The experiments were reviewed and approved by the Animal Experiment Committee of the Tokyo Metropolitan Institute for Neuroscience.

Recording and stimulation

Activities from the phrenic and hypoglossal nerves were amplified, full-wave rectified and low-pass filtered (τ = 10 ms). Brainstem neuronal activity was recorded extracellularly with glass micropipettes filled with 3 m kclsollution saturated with Fast Green FCF dye (DC impedance, 1–1.2 MΩ). For later histological reconstruction, a number of recording sites in each experiment were marked with dye.

Fictive swallowing could be evoked by electrical stimulation of the SLN with either single rectangular pulses, trains of 5 to 11 pulses at 200 to 300 Hz, or continuous trains of constant current pulses (0.15 ms duration) between 35 and 55 Hz. The intensity of stimulation was between 15 and 50 μA and was less than two-fold of the threshold current for phrenic inhibition, which was defined as the current above which the repetitive stimulation of SLN inhibited the central respiratory activity. Responses to single-shock stimulation of the SLN were studied by applying stimuli during control respiration at 2 Hz. For the spinal cord, stimulation of 100–500 μA intensity was applied.

At the end of each experiment, the rat was killed by i.v. injection of anaesthetic (Nembutal, 50 mg kg−1) followed by cessation of ventilation. The brainstem was removed and fixed in 4 % paraformaldehyde for at least 3 days. After fixation, serial frozen sections of the brainstem (100 μm thick in the frontal plane) were made. All the recording sites were reconstructed on the basis of the dye marks. The anatomical structures were identified using the atlas by Paxinos (Paxinos et al. 1999). All signals were monitored on a thermal array recorder (8M15, NEC-Sanei, Tokyo, Japan) and oscilloscopes. In addition, most data were stored on magnetic tape (PCM recorder; PC-216A, Sony Precision Technology, Tokyo, Japan; sampling rate 50 μs) for subsequent off-line analysis.

RESULTS

Characteristics of fictive swallowing

Fictive swallowing could be evoked by single or train pulse stimulation and by continuous repetitive stimulation of the SLN. The corresponding hypoglossal nerve activity was characterized by its brief burst (400 to 500 ms) with a decrementing discharge pattern (Fig. 1). Single swallows were evoked at various latencies after single shock or train stimulation of the SLN. SLN stimulation of sufficient intensity resulted in the provocation of swallowing within 50 ms (Fig. 1A). Continuous stimulation often evoked swallowing composed of a number of rhythmic, repetitive swallows (Fig. 1C and D).

Figure 1. Fictive and active swallowing evoked by SLN stimulation.

Figure 1

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Timing of stimulation • (single or train stimulation) and horizontal bar (continuous stimulation at 30–50 Hz) over the traces. Arrowheads indicate individual swallows. A, isolated swallows just after train stimulation. B, single stimuli during mid-inspiration evoked swallows after the end of inspiration (post-I swallow). C and D, rhythmic swallowing evoked by continuous SLN stimulation. E and F, rhythmic swallowing under non-neuromuscularly blocked condition (E) and subsequent neuromuscularly blocked condition (F). Each hypoglossal burst is followed by a peak (indicated by arrow) in the oesophageal pressure under non-neuromuscularly blocked condition. After neuromuscular blockade, the hypoglossal and phrenic nerve activities show the same pattern of temporal sequence as that in E. XII, hypoglossal nerve activity; Eso, oesophageal pressure; Phr, integrated phrenic nerve activity; TP, tracheal pressure.

During swallowing the inspiratory phrenic activity was consistently suppressed, or swallowing occurred in the absence of inspiratory phrenic activity. Single or train SLN stimulation applied during the mid-inspiratory phase did not evoke immediate swallows, rather it evoked swallows just after the end of the inspiratory phase (Fig. 1B and D). We tentatively termed this pattern, ‘post-inspiratory (post-I) swallow’, and the pattern not coupled with phrenic inspiratory activity was termed ‘isolated swallow’. During rhythmic swallowing evoked by continuous SLN stimulation, these two patterns appeared in various proportions. The post-I swallows often predominated over the isolated swallows, when continuous SLN stimulation did not completely suppress the phrenic activity (Fig. 1D). Small phrenic nerve activity, possibly corresponding to ‘swallow-breath’ (Grélot et al. 1992; Oku et al. 1994), was often observed simultaneously with swallowing (Fig. 1A–C). In particular, during periods of post-I swallows, this phrenic activity was noticeably superimposed by post-inspiratory phrenic activity (Fig. 1B and D).

The occurrence of swallows often coincided with periods of lung inflation (Fig. 1A to D). We occasionally stopped the artificial ventilation during repetitive SLN stimulation to examine the effect of lung inflation. Post-I swallows and repetitive swallows were similarly evoked without phasic lung inflation (see Fig. 5B and Fig. 9Aa).

Figure 5. Neurons without swallowing-related bursts.

Figure 5

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Aa, inhibited neurons. SLN-evoked spikes disappeared at the onset of each swallowing. Responses (a, b in Aa) are expanded in Ab (i and ii correspond to a and b in Ab, respectively; ten superimposed traces). B, indifferent neuron. SLN-evoked spikes were not influenced by swallowing.

Figure 9. Activity of respiratory neurons during swallowing.

Figure 9

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A, three type 1 inspiratory neurons. Aa-c, ipsilateral SLN stimulation. Ad, activity of the neuron shown in Ac during contralateral SLN stimulation. B, two type 2 inspiratory neurons. During rhythmic swallowing, these neurons discharged between the hypoglossal bursts (Bb-d). Ba and Bb, same neuron during train and continuous stimulation. Bc and Bd, same neuron during partial (Bc) and complete (Bd) phrenic suppression. In Bd, the intensity of SLN stimulation is 1.5 times of that in Bc. C, two expiratory neurons that fired during swallowing.

In non-neuromuscularly blocked and spontaneously breathing rats, electrical stimulation of the SLN also provoked both isolated and post-I swallows, which were confirmed by the presence of increased oesophageal pressure that was preceded by hypoglossal burst activity (Fig. 1E). After subsequent neuromuscular blockade and artificial ventilation, the pattern of hypoglossal and phrenic activity during swallowing remained unchanged (Fig. 1F).

Identification of SLN-activated neurons

We searched for neurons that responded orthodromically to electrical stimulation of the SLN at short latencies of less than 10 ms (Fig. 2). A total of 142 neurons were recorded from the region between 0.6 and 1.5 mm lateral to the midline, between 0.2 caudal and 1.7 mm rostral to the obex, and between 0.4 and 1.1 mm below the dorsal surface. Sixty of the 142 neurons were respiratory neurons, their firing being modulated by central respiratory activity. The other 82 neurons were non-respiratory neurons, the firing of which showed no apparent respiratory modulation.

Figure 2. Orthodromic activation of NTS neurons by SLN stimulation.

Figure 2

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A, a neuron with fixed latency at 2.0 ms, identified as receiving putative monosynaptic inputs from SLN afferents. B-D, neurons judged not to have the monosynaptic activation from SLN afferents. B, the spike latency is short but varies between 2 and 3 ms. C, the latency is fixed but as late as 5.9 ms. D, the latency varies between 4 and 6 ms. •, SLN stimulation. Ten sweeps are superimposed in each trace.

The threshold for orthodromic activation in each neuron varied between 3 and 40 μA. In most of the neurons which responded to the SLN stimulation with latency at, or shorter than 3 ms, the orthodromic spikes were evoked at fixed latencies (Fig. 2A). On the other hand, in most neurons with latency longer than 3 ms, the spike latencies were varied (Fig. 2D). Accordingly, if a neuron fulfilled the two criteria of: (1) latency to single SLN stimulation was shorter than 3 ms, and (2) variability of latency of less than 0.3 ms (see Bellingham & Lipski, 1992, and Umezaki et al. 1998), we considered it to be a neuron with a high possibility of monosynaptic SLN inputs (called mSLN neuron). Otherwise we assumed it to be a probable polysynaptically activated neuron (pSLN neuron, Fig. 2B and C). Forty-one of the 60 respiratory neurons and 47/82 non-respiratory neurons were mSLN neurons. The orthodromic latencies and properties of each neuronal population are summarized in Fig. 3 and Table 1, respectively. Detailed behaviour and location of each neuron are described below.

Figure 3. Latency distribution for spikes elicited by SLN stimulation.

Figure 3

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A, non-respiratory neurons. B, respiratory neurons. C, entire population of NTS neurons.

Table 1.

Properties of each neuronal population

SLN latency (ms) Number of mSLN neurons Location (NTS subnuclei) Rostrocaudal level to obex (μm)
Non-respiratory neuron
 Early
  Pre-sw(−) (n = 20) 3.2 ± 1.2 7 c, int, is, v +0∼+1500
  Pre-sw(+) (n = 4) 4.7 ± 2.9 0 int, is, m +500∼+1300
 Late (n = 8) 3.0 ± 0.3 3 c +1000∼+1300
 Inhibited (n = 21) 3.0 ± 1.0 11 c, int, is, v +0∼+1500
 Indifferent (n = 29) 2.5 ± 0.8 26 c, d, int, is, l, m, v, vl +200∼+1600
Inspiratory neuron
 Type 1 (n = 19) 2.6 ± 1.5 12 int, is, v −200∼+1700
 Type 2 (n = 34) 2.3 ± 0.8 28 l, v, vl −200∼+1350
Expiratory neuron (n = 4) 3.8 ± 1.3 1 int, v +400∼+1300
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Abbreviations are as follows: c, central;d, dorsal; int, intermediate; is, interstitial; l, lateral; m, medial; NTS, nucleus of solitary tract; Pre-sw, pre-swallowing activity; SLN, superior laryngeal nerve; v, ventral and vl, ventrolateral.

Behaviour of non-respiratory neurons

Out of the 82 non-respiratory neurons, 53 neurons showed swallowing-related activities. Twenty-four of the 53 neurons were activated during periods of hypoglossal swallowing bursts (Fig. 4A) and eight neurons were activated after the hypoglossal bursts (Fig. 4B). These two groups were named ‘early’ and ‘late’ neurons after Jean (1972). In the other 21/53 neurons, the SLN-evoked spikes disappeared or were delayed in latency during swallowing, suggesting that they were inhibited during swallowing (‘inhibited’ neurons; Fig. 5A). The remaining 29 non-respiratory neurons showed no swallowing-related activities (‘indifferent’ neurons; Fig. 5B). Their SLN evoked spikes were not modulated with swallowing. Early, late and inhibited neurons included a smaller number of mSLN neurons than the indifferent neurons (Fig. 3A, Table 1).

Figure 4. Non-respiratory neurons with various patterns of swallowing-related burst activity.

Figure 4

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A, four early neurons are shown. Aa-c, this neuron fires during hypoglossal bursts. Swallowing was evoked by ipsilateral train (Aa), ipsilateral continuous (Ab) and contralateral continuous (Ac) SLN stimulation. Ad, this neuron fired briefly at the onset of hypoglossal bursts. Ae and Af, neurons with pre-swallowing activity (arrows). B, two late neurons. Contralateral SLN stimulation was applied. N, extracellular neuronal activity; XII, hypoglossal nerve activity; Phr, integrated phrenic nerve activity and TP, tracheal pressure.

The behaviour of each neuron during swallowing was the same whether the swallowing was evoked by single or continuous SLN stimulation (Fig. 4Aa, b and Bb), or whether it was evoked by ipsilateral or contralateral SLN stimulation (Figs 4Ab, c; 6C and D), although the ipsilateral stimulation evoked additional spikes responding to each shock SLN stimulus (Fig. 4Ab and Fig. 6C). There was no difference in each neuronal activity between the conditions with, or without, preceding inspiration (Fig. 4Ab and d).

Figure 6. Firing characteristics of early swallowing neurons during SLN stimulation.

Figure 6

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A, this neuron showed sporadic spontaneous spikes at rest. B, when single stimuli were applied to the ipsilateral SLN, discharge frequency increased. C and D, repetitive stimulation of ipsilateral (C) and contralateral (D) SLN evoked isolated swallows. Note the brief burst activity at the onset of each swallow (arrow) and the preceding augmented discharges. E and F, another example of early swallowing neuron with a similar discharge pattern during single (E) and repetitive (F) swallows.

We noted some features in the activity of early swallowing neurons. First, four neurons were characterized by the ‘pre-swallowing activity’ (Jean, 1972). These neurons showed a burst of firing after a single shock or a train of SLN stimulation. This activity decayed rapidly when no swallowing followed, or it was replaced by a burst of discharge if a swallow was provoked (Fig. 4Ae). In one neuron, its discharge disappeared in the late phase of hypoglossal swallowing activity (Fig. 4Af). These pre-swallowing activities could be evoked even during the inspiratory phase (Fig. 4Af). Second, the early swallowing neurons varied in duration of firing; some fired during the entire hypoglossal swallowing activity, and others showed a brief burst at the onset of swallowing (Fig. 4A). In the latter cases, slight augmentation of discharge was often observed before the onset of swallowing when we applied continuous SLN stimulation (Figs 4Ad; 6C and D). This augmentation differed from the pre-swallowing activity in that it occurred only in continuous stimulation and was only observed when swallowing was provoked. Third, in some ‘early’ swallowing neurons, recruitment of background discharge was apparent during the course of SLN stimulations (Fig. 6). When the stimulation was stopped, the background discharges were then decreased and even disappeared completely. These features could not be found in the other types of neurons, including the ‘inhibited’ and ‘indifferent’ ones.

Location of non-respiratory neurons

The early neurons were concentrated in areas medial and ventral to the solitary tract. These areas included the interstitial, intermediate, ventral and central subnuclei of the NTS. Of these, mSLN neurons were largely confined to the interstitial subnucleus. The late neurons were concentrated in the areas medial to the solitary tract, which corresponded to the central subnucleus (Fig. 7). The inhibited and indifferent neurons distributed diffusely around the solitary tract (Fig. 8). As a whole, mSLN type non-respiratory neurons were located rostolaterally as compared with pSLN type neurons (Fig. 7 and Fig. 8).

Figure 7. Distribution of non-respiratory neurons with swallowing-related bursts.

Figure 7

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Levels indicated as a, b and c in the horizontal plane (A) correspond to a, b and c in the transverse plane (B). ▴, early neuron with pre-swallowing activity. ○ and •, early neurons without pre-swallowing activity. □ and ▪, late neurons. mSLN neurons are indicated by open symbols, and pSLN neurons are indicated by filled symbols. Amb, nucleus ambiguus; AP, area postrema; CU, cuneate nucleus; GR, gracilis nucleus; Li, linear nucleus; VN, spinal vestibular nucleus; Sp5, spinal trigeminal nucleus; ts, solitary tract; 10, vagal motor nucleus; 12, hypoglossal nucleus.

Figure 8. Distribution of non-respiratory neurons without swallowing-related bursts.

Figure 8

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Levels indicated as a, b and c in the horizontal plane (A) correspond to a, b and c in the transverse plane (B). ▵ and ▴, inhibited neurons. ○ and •, indifferent neurons. Open symbols, mSLN neurons and filled symbols, pSLN neurons.

Behaviour of respiratory neurons

The respiratory neurons with SLN inputs exhibited various patterns of respiratory activity. The majority of these neurons were inspiratory neurons with a clear and strong inspiratory activity phase locked to phrenic activity (Fig. 9B). Some neurons did not exhibit strong burst activity but showed sparse discharges locked to certain phases of the respiratory cycle (Fig. 9Ab–d and 9C). We tentatively classified a few phase-spanning neurons with discharges at periods from inspiratory to early expiratory phases as ‘inspiratory neurons’, because their inspiratory activity predominated the expiratory activity (Fig. 9Ac and d). Similarly, those respiratory neurons with faint expiratory rhythm were classified as ‘expiratory neurons’ (Fig. 9C). Fifty-six/sixty respiratory neurons were inspiratory and four neurons were expiratory.

Fifty-six (53 inspiratory and 3 expiratory) of the 60 respiratory neurons showed swallowing-related activity. Based on the behaviour during swallowing, the 53 inspiratory neurons were classified into two types. Many (n = 19) inspiratory neurons were activated simultaneously with the hypoglossal bursts (type 1 neurons, Fig. 9A). Whereas, other neurons (n = 34) were inactive during hypoglossal bursts; however these neurons fired characteristically between hypoglossal bursts of repetitive swallows (type 2 neurons, Fig. 9B). The remaining three inspiratory neurons did not show any apparent swallowing-related activities (not shown). Three of the expiratory neurons (n = 4) showed swallowing-related burst activity (Fig. 9C). The remaining one was unresponsive to swallowing.

The behaviour of each respiratory neuron was not changed whether the swallowing was evoked by ipsilateral SLN stimulation or by contralateral stimulation (Fig. 9Ac and d). It was not changed whether or not the phrenic activity was completely inhibited during repetitive SLN stimulation (Fig. 9Bc and d), either.

The swallowing-related bursts of type 1 neurons were similar to those of early swallowing neurons in that their duration varied from a brief one at the onset of swallowing to one corresponding to the entire period of hypoglossal burst. It is important to note that the burst activity of type 2 neurons between the repetitive hypoglossal bursts appeared even when phrenic inspiratory activity was absent (Fig. 9Bb–d). When we applied continuous SLN stimulation, this activity occurred at first in advance of the first swallowing (Fig. 9Bd) or after the initiation of first swallow (Fig. 9Bb). Type 1 inspiratory and expiratory neurons included many neurons with weak respiratory activity; whereas, the majority of type 2 inspiratory neurons had a distinct burst rhythm (Fig. 9). The majority of both type 1 and type 2 neurons were mSLN neurons (Fig. 3B).

Location of respiratory neurons

Type 1 inspiratory neurons were located in the areas ventral and medial to the solitary tract, corresponding to the interstitial, intermediate and ventral subnuclei of the NTS. Type 2 neurons showed a more widespread distribution but were primarily located ventrolateral to the solitary tract. The other three unclassified inspiratory neurons were located dorsal to the solitary tract (not shown). Expiratory neurons were located medial and ventral to the solitary tract (Fig. 10).

Figure 10. Distribution of respiratory neurons.

Figure 10

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Levels indicated as a, b and c in the horizontal plane (A) correspond to a, b and c in the transverse plane (B). ▵ and ▴, type 1 neurons, ○ and •, type 2 neurons, □ and ▪ expiratory neurons. Open symbols, mSLN neurons and filled symbols, pSLN neurons.

Absent spinal projections of inspiratory neurons

To investigate the bulbospinal projection of the NTS inspiratory neurons with SLN inputs, we examined 14 inspiratory neurons (four type 1, nine type 2 and one unclassified; 12 mSLN neurons and two type 2 neurons of pSLN type) using spinal cord stimulation in four animals. None of them was antidromically activated.

DISCUSSION

The present fictive swallowing preparation, which was used in the rat for the first time, has shown that both respiratory and non-respiratory NTS neurons receiving SLN inputs are involved in the central pattern formation of swallowing. Importantly, many of these NTS neurons receive presumably monosynaptic inputs from SLN afferents. Details of their distribution and firing patterns reinforce the idea that the NTS area is not a simple relay station but is largely involved in initiation and pattern formation of swallowing (Jean, 1972). In particular, the identification of a new type of inspiratory neurons with SLN inputs might provide a clue for the study of the interaction between swallowing and respiration.

SLN-activated NTS neurons and their distribution

The NTS neurons analysed in the present study were orthodromically activated by SLN stimulation at short latencies. Our primary interest is to determine whether or not these neurons receive monosynaptic inputs from SLN afferents. Although the orthodromatic latency of NTS neurons at monosynaptic SLN activation is suggested to be shorter than 3.2 ms (Bellingham & Lipski, 1992; Jiang & Lispki, 1992) or 5.0 ms (Mifflin, 1993) in cats, none of the preceding studies in rats provides sufficient details on the latency of NTS neurons. Swallowing-related neurons identified in the rat NTS area by Kessler & Jean (1985) also exhibited short orthodromic latencies (range from 1 to 4 ms; mean 2.7 ± 1.17 ms). Of these, some showing very short latencies were considered to be monosynaptic (Kessler & Jean, 1985). The latency distribution (Fig. 3) of the present mSLN neurons shows that they form a group of the shortest latencies: with the peak around 2 ms. This, together with their fixed latencies, strongly suggests that the mSLN neurons are monosynaptically activated from the SLN. This latency distribution is comparable with that of NTS neurons that receive monosynaptic input from lung stretch afferents, the thickest vagal afferents (Miyazaki et al. 1999). This notion is further supported by the distribution of the mSLN neurons, which is consistent with the anatomical data that afferent fibres of the SLN project mainly to the interstitial and intermediate subnuclei and the rostral part of the central subnucleus of the NTS (Altschuler et al. 1989; Furusawa et al. 1996), as well as to the subnuclei lateral to the solitary tract (Lucier et al. 1986). In particular, early swallowing neurons of the mSLN type were confined to the area corresponding to the interstitial subnucleus, which agrees with the distribution of cat NTS neurons that burst during swallowing and have monosynaptic SLN inputs (Umezaki et al. 1998).

In addition, we also found other types of non-respiratory and respiratory mSLN neurons in the areas where SLN afferents are concentrated. It is of interest that we found mSLN type late swallowing neurons in the area corresponding to the central subnucleus of the NTS, which is consistent with the anatomical findings (Altschuler et al. 1989). The origin of SLN afferents to this area is unidentified, but this mSLN type late neurons may be related to the activity of the lower pharyngeal constrictor muscle that contracts in the later phase of swallowing (Doty & Bosma, 1956; Kawasaki et al. 1964) and is innervated with SLN (Furusawa et al. 1996).

Reciprocal inhibition between inspiration and swallowing

Jean (1972, 2001) postulated that the neurons with pre-swallowing activity are the trigger neurons that initiate swallowing. Pre-swallowing activity may play an important role under conditions when swallowing is initiated with some delay after the stimulation, like post-I swallow. The phenomenon of post-I swallow, frequently found in this study, has not been explicitly described in previous studies. Here, when brief trains of SLN stimuli were applied during the inspiratory phase, swallowing could be evoked only after the completion, and without interruption, of inspiration. On that occasion, pre-swallowing activity that could be provoked in some early swallowing neurons during inspiration may participate in the initiation of post-I swallows, by storing the ‘memory’ of afferent excitation. On the other hand, when single or a train of SLN stimulation of sufficient intensity immediately provokes swallowing, the entire population of early swallowing neurons including those with pre-swallowing activity may be activated. Participation of some early swallowing neurons in the initiation of swallowing is also suggested by their augmenting discharges preceding each swallow during continuous SLN stimulation, as well as by the recruitment of background spikes during low frequency SLN stimulation. The functional difference of mSLN and pSLN types remains unclear, but the former may act in the earlier stages of swallowing initiation.

As suggested above by the post-I swallow, swallowing initiation and swallowing-related neurons seem to be inhibited by inspiratory neurons. This inhibition may modulate the background firing of swallowing-related neurons. In fact, it is quite possible that the subtle rhythm in the four expiratory neurons was produced by such an inhibition. Frequent provocation of swallowing (including post-I swallow) during the inflation phase of the ventilator may not mean that activation of pulmonary stretch receptors directly facilitates swallowing. Rather, it may result indirectly from the inhibition of inspiratory neurons in response to phasic afferent inputs from these stretch receptors (Bonham & McCrimmon, 1990; Hayashi et al. 1996) and the resultant decreased inhibition of swallowing neurons by these inspiratory neurons. Since tonic lung inflation inhibits swallowing in humans (Kijima et al. 2000), such tonic inflation may act differently on the swallowing pattern generation.

The presence of excitatory inputs from SLN afferents to type 2 inspiratory neurons is of particular interest because these neurons are inactive during hypoglossal bursts of swallowing evoked by SLN activation. On the contrary, these inspiratory neurons fire between rhythmic hypoglossal bursts (Fig. 9B). These phenomena can be explained by possible reciprocal inhibition between these inspiratory neurons and early swallowing neurons. Such inhibitory connections may play a role in the arrest of respiration during swallowing, and in the inhibition of swallowing during inspiration. When repetitive SLN inputs co-activate these two populations of neurons, the reciprocal inhibition may provide the basis for rhythmogenesis of repetitive swallows, in the same way as the central respiratory rhythm produced by inspiratory and expiratory neurons (Richter et al. 1986; Ezure, 1990; Blessing, 1997). From this point of view, the SLN inputs to the inspiratory neurons can be regarded as a switch (Hooper & Moulins, 1989) that changes the participation of these neurons from respiration to swallowing. It is also possible that these inspiratory neurons have nothing to do with respiratory movements but merely interact with the swallowing system.

The fact that none of the inspiratory NTS neurons examined in this study had projections to the spinal cord is compatible with the rarity of bulbospinal neurons in the rat dorsal respiratory group (Onai et al. 1987; Yamada et al. 1988; Portillo & Núñez-Abades, 1992; de Castro et al. 1994) as compared with those in cats (Berger, 1977; Otake et al. 1989). These inspiratory neurons with SLN inputs may have intramedullary projections and act as an interface between respiratory and swallowing networks.

Functional correlations with other central components of swallowing

The present study has revealed various types of firing patterns in swallowing-related NTS neurons. These neurons may project to swallowing-related motoneurons, as suggested previously (Jean, 2001). In fact, anatomical studies have shown the direct projection from the NTS to the hypoglossal nucleus (Norgren, 1978; Amri et al. 1990), particularly from the ventrolateral, interstitial, intermediate and commissural subnuclei (Cunnigham & Swachenko, 2000). Therefore, it is possible that early neurons and types 1 and 2 inspiratory neurons in these areas may act directly on hypoglossal motoneurons, as well as indirectly through premotor neurons in the dorsomedial reticular formation (Cunningham & Swachenko, 2000) or ventrolateral reticular formation that corresponds to the VSG (Amri & Car, 1988; Ezure et al. 1993). Some ambiguus motoneurons, including oesophageal motoneurons, receive inhibitory post synaptic potentials during periods of hypoglossal bursts, i.e. the pharyngeal phase of swallowing (Zoungrana et al. 1997). Early swallowing neurons in the DSG may be the origin of the inhibition, as suggested by Jean (2001). On the other hand, the anatomically shown viscerotopic representation between the NTS and the NA (Broussard et al. 1998) indicates that early swallowing neurons in the interstitial, intermediate and ventral subnuclei may not send direct inhibition to the above-mentioned oesophageal motoneurons. We found a few early swallowing neurons medial to the solitary tract corresponding to the central subnucleus of the NTS, the area where projections to the oesophageal motoneurons have been shown (Barrett et al. 1994; Broussard, et al. 1998). These early swallowing neurons in the central subnucleus are possible inhibitory premotor neurons of the oesophageal motoneurons.

Conclusion

The present results suggest that the NTS area is intimately involved in the establishment of the pharyngo-oesophageal co-ordination and the reciprocal inhibition between swallowing and inspiration. We think that synaptic interactions within the local network in the NTS are essential in the swallowing CPG, in addition to the intrinsic cellular properties (Tell et al. 1990; Tell & Jean, 1991).

Acknowledgments

We express our thanks to Ms Y. Kishimoto for her technical assistance. This work was partly supported by a Grant-in-Aid for Scientific Research (No. 12680805. for K. E.) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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