activation of xii motoneurons and premotor neurons during various oropharyngeal behaviors

Respiratory Physiology & Neurobiology 147 (2005) 159–176

Activation of XII motoneurons and premotor neurons duringvarious oropharyngeal behaviors

Christian Gestreaua,∗, Mathias Dutschmannb, Stephane Obleda,Armand Louis Bianchia

a Laboratoire de Physiologie Neurovégetative, UMR CNRS 6153 INRA 1147, Université Paul Cezanne Aix-Marseille III, Av.Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France

b Department of Physiology, University of Göttingen, Humboldstallee 23, 37073 Göttingen, Germany

Received 2 December 2004; received in revised form 11 March 2005; accepted 13 March 2005

Abstract

Neural control of tongue muscles plays a crucial role in a broad range of oropharyngeal behaviors. Tongue movements mustbe rapidly and accurately adjusted in response to the demands of multiple complex motor tasks including licking/mastication,swallowing, vocalization, breathing and protective reflexes such as coughing. Yet, central mechanisms responsible for motorand premotor control of hypoglossal (XII) activity during these behaviors are still largely unknown. The aim of this article is toreview the functional organization of the XII motor nucleus with particular emphasis on breathing, coughing and swallowing.Anatomical localization of XII premotor neurons is also considered. We discuss results concerned with multifunctional activityo o produced geminal)m teda©

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f medullary and pontine populations of XII premotor neurons, representing a single network that can be reconfigured tifferent oromotor response patterns. In this context, we introduce new data on swallowing-related activity of XII (and triotoneurons, and finally suggest a prominent role for the pontine Kolliker-Fuse nucleus in the control of inspiratory-relactivity of XII motoneurons supplying tongue protrusor and retrusor muscles.2005 Elsevier B.V. All rights reserved.

eywords:Brainstem networks; Central pattern generator; Breathing; Swallowing; Coughing

. Introduction

Central mechanisms that drive upper airway mo-oneurons in response to sensory stimuli are still not

∗ Corresponding author. Tel.: +33 491 28 2724;ax: +33 491 28 8885.

E-mail address:[email protected]. Gestreau).

sufficiently investigated. In particular, little is knownhow the central nervous system generates and conates different motor programs involving overlappgroups of muscles. This problem of integrated phology has been preferentially addressed with celanalyses of fictive oromotor behavior using variouvivo animal models (Gestreau et al., 1996, 2000; Oet al., 1994, 1998a,b; Peever et al., 2002; Roda e2002; Sahara et al., 1996; Saito et al., 2003; Sha

569-9048/$ – see front matter © 2005 Elsevier B.V. All rights reserved.doi:10.1016/j.resp.2005.03.015

160 C. Gestreau et al. / Respiratory Physiology & Neurobiology 147 (2005) 159–176

et al., 2004; Shiba et al., 1999), and studies in humans(for review, seeRemmers, 2001).

The rich sensory modalities of the oral cavity areable to trigger a broad range of reflexes that ultimatelyinfluence hypoglossal (XII) muscle activity (Miller,2002). This diversity of oropharyngeal behaviors inwhich tongue muscles are involved constitutes a goodframework to (i) analyze changes in XII motor output,(ii) delineate neural substrates related to these func-tions, and (iii) improve the understanding of neuralmechanisms orchestrating specific motor programs re-quired for the coordination of complex oropharyngealbehaviors. Indeed, motor programs related to breath-ing, swallowing, licking, mastication, gaping, gagging,coughing, sneezing, vocalization, and vomiting arecontrolled by brainstem neural networks that all impacton XII motoneurons (Bianchi et al., 1995; Ertekin andAydogdu, 2003; Jean, 2001; Lund et al., 1998; Traverset al., 1997; Chen et al., 2001; Chen and Travers,2003).

Excellent reviews exist on the neural control oftongue movements with respect to breathing, swallow-ing, licking, mastication and/or vomiting (Lowe, 1981;Miller, 2002; Sawczuk and Mosier, 2001; Traverset al., 1997), but new results have been publishedthat highlight our understanding of central organiza-tion of oropharyngeal behaviors at the level of XII mo-tor and premotor neurons. Therefore, the aim of thisreview is to discuss available literature on motor andpremotor control of XII activity with a special em-p atac ingl lsoc

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rse,a apea insicm caus-ig thes s them leva-t the

geniohyoid produces protrusion of the hyoid bone, andhence pharyngeal dilatation. However, present knowl-edge favors a co-contraction of both intrinsic andextrinsic muscles during various tongue movements(Bailey and Fregosi, 2004; McClung and Goldberg,2000; Mu and Sanders, 1999). Indeed, tongue protru-sion/elongation is mediated by the activity of the ge-nioglossus in combination with intrinsic vertical andtransversal tongue muscles. Tongue retrusion is pro-duced by contraction of the styloglossus, hyoglossus,and intrinsic longitudinal tongue muscles.

The complexity and diversity of the tongue musclesare represented by a myotopic organization of the XIImotor nucleus (Aldes, 1995; Dobbins and Feldman,1995; Fay and Norgren, 1997; McClung andGoldberg, 1999, 2002; Travers et al., 1995; Traversand Rinaman, 2002). Extrinsic and intrinsic tongueprotrusors are innervated via the medial branch ofthe XII nerve. The somata of protrusor motoneuronsare located in the ventral compartment of the motornucleus. In contrast, extrinsic and intrinsic tongueretrusors are supplied by the lateral branch of the XIInerve, and corresponding motoneurons have their cellbodies in the dorsal compartment of the motor nucleus.Distinctions also exist within the dorsal and/or the ven-tral compartment of the XII motor nucleus with respectto the location, size, and other morphological featuresof subgroups of motoneurons such as orientation andextention of their dendritic arborization outside theXII nucleus (Aldes, 1995; Altschuler et al., 1994;M ers,1 andR o-h leusi Re-cp eusa theh los-s alli ons( 88a n oft pre-s arem tralm -r us.

hasis on breathing, swallowing and coughing. Doncerning activities of XII premotor neurons dur

icking, mastication, and rejection (gaping) are aonsidered.

. Tongue muscles, movements, and myotopicrganization of XII nucleus

The tongue is composed of longitudinal, transvend vertical intrinsic muscles that determine its shnd have no bony attachment. In contrast, the extruscles have bony attachment and are capable of

ng tongue protrusion and retrusion (Lowe, 1981). Theenioglossus is the main tongue protrusor whiletyloglossus and the hyoglossus are considered aain retrusors. The thyrohyoid serves as tongue e

or. Contraction of muscles of the buccal floor like

cClung and Goldberg, 1999, 2002; Mu and Sand999; Sawczuk and Mosier, 2001; Traversinaman, 2002). Motoneurons controlling the geniyoid muscle are located outside the main XII nuc

n the so-called lateral accessory compartment.ently, McClung and Goldberg (2002)identified twoopulations of motoneurons in the ventral XII nuclfter small injections of retrograde tracer intoorizontal or oblique compartments of the geniogus muscle. Identification of a population of smnterneurons intermingled among the XII motoneurPopratiloff et al., 2001; Takasu and Hashimoto, 19)dds even more complexity to central organizatio

he XII nucleus. These intranuclear interneurons reent about 5% of the neurons in the XII nucleus, andainly restricted to its dorsolateral, lateral and venargins (Sawczuk and Mosier, 2001). Fig. 1 summa

izes the myotopic organization within the XII nucle

C. Gestreau et al. / Respiratory Physiology & Neurobiology 147 (2005) 159–176 161

Fig. 1. Myotopic organization of the rat XII motor nucleus.Schematic drawings of the dorsomedial medulla at five distinct lev-els (top to bottom: rostral to caudal) expressed in mm relative to theobex (or calamus scriptorius). They represent approximate locationof XII motoneurons supplying both the intrinsic (left side) and ex-trinsic (right side) tongue muscles based on references cited in thetext. Abbreviations: X, dorsal motor nucleus of the vagus; sol, trac-tus solitarius; AP, area postrema; CC, central canal. Modified fromPaxinos and Watson (1998).

Fig. 1. (Continued).

3. Activity of XII motoneurons duringbreathing, swallowing and coughing

Depending on the required movement, extrinsictongue muscles contract in various combinations, ei-ther synergistically or antagonistically. During quietbreathing, the characteristic discharge patterns of XIImotoneurons have been described in several studies(Hwang et al., 1983; Withington-Wray et al., 1988; seealso references inPeever et al., 2002). The XII motorpattern during inspiration leads to enhanced activity ofthe genioglossus muscle to increase airway patency,and the co-contraction of retrusor muscles contributeto the stiffening of the pharyngeal wall. The multiax-ial activity of the intrinsic tongue muscles also con-tributes to lingual stiffness, and can affect the actionsof the extrinsinc muscles during inspiration (Baileyand Fregosi, 2004). In contrast, inspiration is inhib-ited during swallowing to prevent aspiration of food,while tongue retrusor muscles propel the bolus of foodtowards the pharyngeal cavity. In addition, the genio-hyoid and thyrohyoid muscles act in synergy to closethe laryngeal vestibule and elevate the entire larynx,thus facilitating the upper esophageal sphincter open-ing (see references inUmezaki et al., 1998a). The com-plex discharge patterns of XII motoneurons required tocoordinate muscle contractions during swallowing aredocumented as well (Amri et al., 1991; Tomomune andTakata, 1988). Compared to swallowing and breathing,


the roles of the various tongue muscles and activity ofXII motoneurons during cough were only investigatedin few studies (Roda et al., 2002; Satoh et al., 1998).

Other studies examined the activity of XII motoneu-rons in various combinations of behaviors (Dick et al.,1993; Dinardo and Travers, 1994; Hayashi andMcCrimmon, 1996; Ono et al., 1998a; Satoh et al.,1998; Tomomune and Takata, 1988; Travers andJackson, 1992; Umezaki et al., 1998b). The results ofthese studies underline that XII motoneurons are not ahomogeneous population, but rather represent distinctfunctional pools. Roda and collaborators (Roda et al.,2002) analyzed the discharge patterns of XII motoneu-rons, and changes in their membrane potentials dur-ing (fictive) breathing, swallowing and coughing. Thisstudy was performed in non-vagotomized cats decer-ebrated at the mid-collicular level (n= 19), and usedthe intracellular recording technique. Antidromic ac-tivation and collision test were used to identify mo-toneurons (n= 58). Fictive swallowing and coughingwere evoked by electrical stimulation of the superiorlaryngeal nerves. In agreement with previous observa-tions (Tomomune and Takata, 1988; Ono et al., 1998a;Umezaki et al., 1998b), the results revealed that com-mon subsets of XII motoneurons are activated duringmultiple behaviors. Indeed, 15% of the recorded cellsshowed no change in their membrane potential, 20%were concerned with only one behavior (swallowing),while 30% received a synaptic drive during breathingand swallowing, and 35% exhibited membrane poten-t iors.Aw dr rgef tialsw mo-t eda rives.T lvedi ameX adei esis( in asd -i edt dur-i ted

Fig. 2. Schematic drawings showing nerve activities (bottom traces)and changes in membrane potentials (upper traces) of subsets ofXII motoneurons (XII Mn) during breathing, coughing and swal-lowing in non-vagotomized, artificially ventilated decerebrate cats.One group of XII Mn was activated only during swallowing (SwXII). Three groups of inspiratory XII Mn (Insp XII) had differentmembrane trajectories during coughing and swallowing (see text fordetailed patterns). Expiratory XII Mn (Exp XII) were not involvedin coughing but were depolarized during swallowing. Abbreviations:XII, hypoglossal nerve; Abd, abdominal nerve; Phr, phrenic nerve.Adapted fromRoda et al. (2002).

motoneurons which activation may rely on a separateXII premotor pathway selective for swallowing (Rodaet al., 2002).

In the study byRoda et al. (2002)it was foundthat membrane trajectories and activities of XII mo-toneurons can be correlated with distinct behaviors.A schematic summary of the specific synaptic activ-ity during breathing, swallowing and coughing is il-lustrated inFig. 2. Eighty percent of the cells withmembrane potential changes in response to swallow-ing and coughing were inspiratory XII motoneurons.Nevertheless, subpopulations of inspiratory motoneu-rons can be distinguished via pattern analysis. One spe-cific subset of motoneurons exhibited a “type 1 pattern”during cough (seeFig. 2). The “type 1 pattern” is char-acterized by hyperpolarization during the inspiratoryand expiratory phases of cough, followed by a rebound

ial changes in relation to the three tested behavll motoneurons recorded byRoda et al. (2002)whichere activated during coughing (n= 20) also displaye

espiratory-related activity. Remarkably the discharequencies and the amplitudes of synaptic potenere similar during breathing and coughing. Thus,

oneurons contributing to these two behaviors formcommon subset and received equal synaptic dhese results suggest that neural networks invo

n breathing and coughing potentially share the sII premotor neurons. Comparable observations m

n laryngeal motoneurons led to a similar hypothGestreau et al., 2000) that has been demonstratedubsequent study (Baekey et al., 2001). Interestingly, aistinct subset of XII motoneurons (n= 11) was specif

cally recruited only during swallowing. We proposhat the stereotyped activity of tongue musclesng swallowing requires at least one pool of dedica


excitation. The same motoneurons are depolarized dur-ing swallowing (D pattern). In contrast, inspiratory XIImotoneurons with a “type 2 pattern” during cough wereeither hyperpolarized (H pattern) or showed a bi-phasicresponse (HD pattern) during swallowing (Fig. 2). The“type 2 pattern” corresponded to hyperpolarization dur-ing the inspiratory phase followed by depolarizationduring the expiratory phase of cough. Thus, distinctsynaptic drives and discharge patterns were observedin specific subsets of XII motoneurons.

Based on these observations, and the known activ-ity of particular tongue muscles in breathing and swal-lowing (Bailey and Fregosi, 2004; Fregosi and Fuller,1997; Fuller et al., 1998; Tomomune and Takata, 1988)or during cough (Satoh et al., 1998), the type of tonguemuscle innervated by the distinct subsets of motoneu-rons can be proposed (Roda et al., 2002). Inspiratorymotoneurons with D pattern during swallowing and“type 1 pattern” during cough probably innervate thestyloglossus, whereas inspiratory motoneurons with Hor HD pattern during swallowing and “type 2 pattern”during cough likely innervate the genioglossus (Fig. 2).

Interestingly, numerous inspiratory XII motoneu-rons activated in coughing switch their phasic activ-ity pattern in relation to the phrenic nerve. Indeed, 10out of 20 motoneurons having an inspiratory patternduring breathing were activated during the expiratorybut not the inspiratory phase of cough. Similar changeshave been also reported in external intercostal musclesin the transition from breathing to coughing (Iscoe andG

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oligosynaptic connections to the XII motoneurons (seereferences inFay and Norgren, 1997; Pinganaud et al.,1999), and the associated reflex responses serve primar-ily to protect and maintain upper airway patency. Forexample, narrowing of the pharynx produces negativepressure across the wall of the extra-thoracic airway,which in turn distorts mechanoreceptors and elicits areflex increase in both protrusor and retrusor tonguemuscle activities (Ryan et al., 2001).

Numerous anatomical studies have shown that cen-tral projections to XII motoneurons arise from sev-eral brainstem structures. These studies were basedon retrograde tracer injections into the XII nucleus(Cunningham and Sawchenko, 2000; see referencesin Roda et al., 2004). Other studies took advantageof trans-synaptic neurotropic viruses which can be in-jected into defined tongue muscles (see references inTravers and Rinaman, 2002). These anatomical stud-ies revealed that premotor neurons with monosynap-tic connection to XII motoneurons exhibit bilateralprojections with an ipsilateral preponderance. Theyare segregated in the dorsal medullary reticular fieldsclose to the XII nucleus, including the parvocellular(PCRt), intermediate (IRt), and dorsomedial (MdD)nuclei. Other pools of premotor neurons are distributedin the Probst’s region, the spinal trigeminal nucleuscaudalis, the dorsal aspect of the ventral reticular for-mation above the nucleus ambiguous. Pontine premo-tor neurons were found in the supratrigeminal, inter-trigeminal and principal sensory trigeminal nuclei, aswF ysi-o o-t itaryt 04;O upo al.,2 omt ellu-l cu-l ablyc eu-r y XIIpt ltedi larys theX tor

relot, 1992).

. Distributed brainstem projections to XIIotoneurons

.1. Peripheral and central processing ofnformation

Orofacial and upper airway afferents convey sory information from the jaws, teeth, lips, tonguealate, as well as from the nasal, pharyngeal, and laeal cavities. This information exerts a powerful efn XII motoneurons (Lowe, 1981; Miller, 2002). The

ingual, trigeminal, glossopharyngeal and in partiche superior laryngeal nerves (SLN) have been sho play an important role in mediating these informion. Most of these peripheral inputs are processe

ell as in the subcoeruleus region and the Kolliker-use (KF) nucleus. Both anatomical and electrophlogical results suggest that relatively few XII prem

or neurons are located in the nucleus of the solract (NTS) (Fay and Norgren, 1997; Roda et al., 20no et al., 1998a), or near the ventral respiratory grof the rat (Dobbins and Feldman, 1995; Peever et002). In contrast, NTS neurons as well as cells fr

he ventrolateral aspect of the medulla, gigantocar (Gi) and lateral paragigantocellular (LPGi) retiar nuclei, and the raphe pallidus and magnus probonstitute main afferent sources to XII premotor nons, and thus may be considered as secondarremotor neurons (Fay and Norgren, 1997). Alterna-

ively, since injections of neurotropic viruses resun more labeled cells in ventral (and medial) medultructures than after retrograde tracer injections inII nucleus, these cells may be primary XII premo


neurons with distal dendritic inputs to XII motoneu-rons, possibly outside the XII nucleus (Travers andRinaman, 2002).

Interestingly, viral tracing studies investigating thebrainstem distribution of premotor neurons for tongueprotrusor and retrusor muscles revealed extensive over-lapping fields of XII premotor neuron populations forboth muscle groups in the dorsal and lateral com-partments of the reticular formation (Dobbins andFeldman, 1995; Fay and Norgren, 1997; Travers andRinaman, 2002). Simultaneous synaptic inputs ontodistinct subsets of XII motoneurons (Roda et al., 2002)may have a pivotal role in orchestrating the neural con-trol of tongue movements during breathing, swallowingand/or other oropharyngeal behaviors. Bilateral coor-dination of the XII motor nucleus is not fully described(Peever and Duffin, 2001). Intranuclear XII interneu-rons (Popratiloff et al., 2001), thought to inhibit XIImotoneurons (see references inTakasu and Hashimoto,1988; Peever et al., 2002), may play an important role inlateral tongue movement during chewing/mastication,grooming and licking.

4.2. Divergence from XII premotor neurons toseveral motor nuclei

XII premotor neurons have divergent projections tothe facial, trigeminal and possibly also phrenic mo-tor nuclei (Amri et al., 1990; Dauvergne et al., 2001;Pinganaud et al., 1999; Ono et al., 1998a; Popratiloffeo cat

F stinctl ve tot rons.C theX s, re-s oupso neu-r withd bate( theirr nu-c ellarp ellart KF,K chialn tic-u

t al., 2001; Zerari-Mailly et al., 2001). The proportionf dual projecting XII premotor neurons found in

ig. 3. Schematic drawings of the medulla and pons at three dievels (top to bottom: rostral to caudal) expressed in mm relatihe obex. Black somata represent groups of XII premotor neuells in the dorsal (XIId) and ventral (XIIv) compartments ofII nucleus show groups of retrusor and protrusor motoneuronpectively. Regions outlined in gray depict dorsal and ventral grf neurons involved in swallowing and breathing. Premotorons in the intermediate nucleus of the reticular formation (IRt)ual projections to XII and phrenic motor nuclei are under dequestion mark). Axonal trajectories are not representative ofeal anatomical pathways. Abbreviations: V, trigeminal motorleus; 7n, facial nerve; py, pyramidal tract; scp, superior cerebeduncle; sp5, spinal trigeminal tract; vsc, ventral spinocereb

ract; AMB, ambiguous nucleus; Int5, intertrigeminal nucleus;olliker-Fuse nucleus; LPB/MPB, lateral and medial parabrauclei; NTS, nucleus of the solitary tract; PCRtA, parvocellular relar nucleus, pars�, SubC, sub-coeruleus nucleus.


or sheep is about 20% of the population of premotorneurons (Amri et al., 1990; Ono et al., 1998a). These di-vergent projections are likely involved in co-activationof different cranial or spinal nuclei during masticationor rejection behavior.Fig. 3 summarizes the anatomi-cal location of major groups of brainstem XII premotorneurons and depicts their dual projections.

5. Activity of XII premotor neurons

Several methodological approaches can be used toassign a functional role to XII premotor neurons. Acombination of immunohistochemical detection of Fosproteins (an indirect marker of neuronal activation)with retrograde-labeling method has proven to be help-ful to gauge the level of activation of premotor neuronsduring a given behavior (DiNardo and Travers, 1997;Roda et al., 2004). Alternatively, electrophysiologicaltechniques based on extracellular recordings of neu-rons with antidromic activation of their axons in oneor several motor nuclei (Donga and Lund, 1991; Onoet al., 1994, 1998a; Sahara et al., 1996; Saito et al.,2003; Woch et al., 2000) have been used. Finally, cross-correlation analyses between the neurons spike dis-charges and nerve activities (Ono et al., 1998a; Peeveret al., 2002), or combined extracellular and intracellu-lar recordings and spike-triggered averaging analyses(Ono et al., 1998b) can help to elucidate this issue.Hereby, it has to be mentioned that only the latter elec-t erized nsi

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bym ate.Oi XIIm neu-r TS,v nu-c ofX tingb rel of

neurons exerted a facilitation of XII and phrenic nerveactivities. Thus, two types of XII premotor neuronshave been described in the cat. In a follow up study, Onoand collaborators (Ono et al., 1998a) recorded from in-spiratory XII premotor neurons during fictive rejection(large opening of the mouth associated with phrenicnerve activity, or gaping) and ingestion. The dual pro-jecting neurons were activated during inspiration andrejection but not swallowing, while the majority (76%)of neurons projecting only to the XII nucleus displayedbursts of action potentials during inspiration, swallow-ing and rejection. However, recent cross-correlationstudies made in rats found no evidence for the pres-ence of dual-projection cells, and thus yielded a dif-ferent conclusion (Peever et al., 2001, 2002). Althoughco-activation of protrusor and retrusor motoneurons bythe same premotor neurons was demonstrated in the rat,XII motoneurons were not monosynaptically excitedby inspiratory phrenic premotor neurons. Therefore,separate respiratory control pathways may exist for XIIand phrenic motoneurons in rats (Peever et al., 2002).Although there is no satisfactory explanation for thediscrepancy between results obtained in cats and rats,these species may have a different organization in theneural control of XII motoneurons (see question markin Fig. 3).

5.2. Activity of pontine respiratory-related XIIpremotor neurons

ofX ro-s os-t them ity( lda eryl ver,h es ina im-u of ani en-h eses eralX t la-r nica DAa II

rophysiological techniques are suitable to charactynamic changes in activity of XII premotor neuro

n relation to one or several behaviors.

.1. Activity of medullary respiratory-related XIIremotor neurons

Respiratory control of XII motoneuronsedullary premotor neurons is still subject to debno and collaborators (Ono et al., 1994) first described

nspiratory neurons monosynaptically projecting tootoneurons in the cat brainstem. These premotor

ons were found in the regions ventrolateral to the Nentrolateral to the XII, and dorsomedial to theleus ambiguous (dm-AMB). Approximately 20%II premotor neurons had bifurcating axons projecoth to the XII and phrenic motor nuclei. Most we

ocated in the dm-AMB, and spikes from this type

Very few studies examined pontine controlII motoneurons during breathing. Electrical mictimulation and chemical stimulation of the cat’s rral pons have been shown to induce changes inedial (protrusive) branch of the XII nerve activ

Kuna and Remmers, 1999). Selective low threshoctivation of XII motoneurons were obtained in a v

ocalized site associated with the KF nucleus. Howeigher voltage stimulation at this site caused changctivity of phrenic motoneurons. Tonic electrical stlation of the KF was associated with appearance

psilateral increase of XII nerve discharge, due toanced tonic and phasic (inspiratory) activities. Thtimulation had only a small effect on the controlatII nerve, and showed no effect on the recurren

yngeal and phrenic nerves. Microinjection of kaicid, or the excitatory amino acid agonists NMnd AMPA into the KF yielded variable results. X


discharge showed tonic increase, ipsilateral excitationand controlateral suppression, or bilateral increase ordecrease in inspiratory-related activity. From these re-sults,Kuna and Remmers (1999)concluded that a se-lective premotor input to XII motoneurons innervatingtongue protrusors arises from the KF.

A recent study from our laboratory (Roda et al.,2004) confirmed and extended the results ofKuna andRemmers (1999). In this study, changes in Fos expres-sion in responses to anesthetics were used to gaugethe level of activity of XII premotor neurons identifiedafter iontophoretic injection of the retrograde tracerFluorogold in the right XII motor nucleus (for a de-tailed description, seeRoda et al., 2004). In paral-lel, the effects of four distinct anesthetics on the XIInerve activity, amplitude and frequency of chest move-ments, cardiac rate, and changes in CO2/O2 levels werecompared in spontaneously breathing rats. Strikingly,halothane inhalation but not the other three tested anes-thetics was associated with a clear respiratory-related(inspiratory) activity in the XII nerve (Fig. 4A). Nosignificant changes in CO2/O2 levels could explain theselective effect of halothane. Although halothane in-duced significantly less cardio-respiratory depressionthan the other anesthetics, no difference was observedin amplitude or frequency of chest movements duringanesthesia with one or another anesthetic. A clear in-crease in Fos expression was elicited in anesthetizedrats in agreement with previous findings (Clement et al.,1998; Rocha and Herbert, 1997). However, less than1 ose otorn ionc cesi do -t andI salc ren-

tial projection onto tongue retrusor muscles (Dobbinsand Feldman, 1995). Altogether, the results byRodaet al. (2004)showed that changes in XII respiratory-related activity were associated with an increase in ac-tivity of KF-Int5 premotor neurons. Since halothaneis known to hyperpolarize neurons (see references inRoda et al., 2004), activation of KF-Int5 premotor neu-rons resulted more likely from disinhibition, rather thanfrom a direct excitatory effect of the anesthetic. Conse-quently, we hypothesize that KF-Int5 premotor neuronsare controlled by inhibitory neurons (seeFig. 8B). Fur-ther studies are needed to identify precisely the func-tional connectivity within the KF and between KF-Int5premotor neurons and XII motoneurons.

In a recent series of experiments (unpublished obser-vations), we used the in situ perfused working heart-brainstem preparation (WHBP) of rat (n= 6) to elu-cidate the role of this KF-XII premotor pathway incontrolling retrusor XII motoneurons during breath-ing. General methods used were rigorously similar toprevious studies using this preparation (see for exam-ples,Dutschmann and Paton, 2002; St-John and Paton,2000). Chemical activation of neurons was achievedafter injection of glutamate (40 nl, 40 nmol) into theright KF using one compartment of a multi-barrel glassmicropipette, while discharge activities were recordedfrom the phrenic nerve and the lateral (retrusive) branchof the ipsilateral XII nerve. The other two compart-ments of the micropipette were filled with artificialcerebrospinal fluid (ACSF for vehicle injections) orp ri-fi ed,p e int ac-t n,2 ,2 -j KF( tion

F activit rons (B).( iratory ) activitya ital (pe hlo-ureth)( (AUC)e hosph uced Fose tral Klliker-F ion;( tine (K lothane.A

% of medullary XII premotor neurons exhibited Fxpression. In contrast, more than 70% of XII premeurons in the KF and in a more ventral pontine regalled the intertrigeminal region (Int5, see referenn Chamberlin and Saper, 1998), were double-labelenly after halothane inhalation (Fig. 4B). More premo

or neurons were observed bilaterally in the KFnt5 regions after injection of Fluorogold in the dorompartment of the XII nucleus, suggesting a prefe

ig. 4. Anesthesia-induced changes in respiratory-modulatedA1) Strong inspiratory activity of XII motoneurons, weak respfter halothane inhalation (halo), as compared with pentobarbA2) halothane increased (p< 0.001) the area under the curvexample of iontophoretic injection of fluorogold (2% diluted in pxpression in retrograde-labeled cells (open arrows) of the venoB4) significant increase (p< 0.001) in numbers of activated ponbbreviations: seeFig. 2. Adapted fromRoda et al. (2004).

ontamine sky blue (2% in ACSF for histological vecations of injection sites). As previously describhrenic and XII nerves are spontaneously activ

he WHBP and exhibit phasic inspiratory-relatedivities with in vivo-like patterns (St-John and Pato000). In accordance to previous studies (Chamberlin004; Dutschmann and Herbert, 1998), glutamate in

ections placed into the intermediate portion of then= 5) produced an immediate inspiratory termina

y of the XII nerve (A) and Fos expression in XII premotor neudepression, and no significant change in diaphragmatic (DIAnto), ketamine-xylazine (keta-xyla) or chloralose-urethane (c;measured from the integrated activity of the XII nerve (ʃXII); (B1)ate-buffer saline) in the right XII motor nucleus. Halothane induse (KF) nucleus; (B2) low magnification; (B3) high magnificatF and Int5) XII premotor neurons in rats anesthetized with ha


Fig. 5. Changes in respiratory-related activity after chemical stimulation of the Kolliker-Fuse nucleus (KF). The raw phrenic nerve (PNA) andlateral (retrusive) branch of the XII nerve (XII) activities, and respective integrated signals (ʃPNA, ʃXII) were recorded in the in situ perfusedworking-heart brainstem preparation of rat. Microinjection of small amounts of glutamate (Glu, 40 nl) into the intermediate part (A) of the rostralpart (B) of the KF. (A) Glutamate induced a transient apnea and a long lasting suppression of phasic inspiratory XII nerve discharge and minimalchange in PNA. (B) Transient increase in PNA and tonic XII activity, followed by a mild decrease in inspiratory-related discharge of retrusormotoneurons without obvious change in PNA. A2 and B2 are schematic drawings illustrating the precise location of the according injection siteswith respect to the parabrachial complex. Abbreviations: Dll, dorsal nucleus of the lateral lemniscus; scp, superior cerebellar peduncle; nucleiof the parabrachial complex: c, central nucleus; d, dorsal nucleus; el, external lateral nucleus; exl, extreme lateral nucleus; v, ventral nucleus;s,superior nucleus.

and a transient prolongation of the expiratory inter-val (apnea). The transient apnea was accompanied bya complete suppression of the phasic inspiratory dis-charges recorded from the retrusive branch of the XIInerve. Strikingly, in contrast to the phrenic nerve ac-tivity which showed almost complete recovery afterthe initial effect, the XII activity remained absent orsuppressed for more than 30 s (Fig. 5A). When gluta-mate was injected in caudal or rostral aspects of the KF(n= 4), we observed a transient increase by 40–50% inthe frequency of the phrenic nerve discharge. The XIIinitially displayed tonic activity lasting for 2–3 respira-tory cycles recorded from the phrenic nerve, followedby a long-lasting (more than 30 s) decrease in XII burstamplitude (Fig. 5B). Vehicle injection of ACSF never

produced changes in XII and phrenic discharge patterns(n= 6, data not shown). Previous studies have describeddifferent, even opposite, respiratory effects depend-ing on the stimulated pontine region (Chamberlinand Saper, 1994, 1998; see also references inKuna andRemmers, 1999). The parabrachial complex includingthe KF is heterogeneous with regard to the cellular com-position, i.e. it contains different types of respiratoryneurons, and to the anatomical connections with otherbrainstem nuclei (Chamberlin, 2004). Changes in res-piratory phase-switching observed in the present studyis likely due to stimulation of neurons located at theventral border of the KF and in the adjacent Int5 regionsince these regions have been proposed to represent akey relay for a wide range of apneic airway protective


reflexes (Chamberlin and Saper, 1998; Dutschmannet al., 2004). Overall, our results strengthen the viewthat the KF nucleus is an important structure in con-trolling the inspiratory activity of XII motoneurons,including protrusors (Kuna and Remmers, 1999; Rodaet al., 2004) and retrusors (present results). We sug-gest that this control is mediated by the KF-XII premo-tor pathway recently localized in the ventral KF anddorsal Int5 region (Fig. 4B) (Roda et al., 2004). Sev-eral populations of pontine XII premotor neurons mayproduce opposite changes in tongue muscles activity.However, we favor the hypothesis that glutamate in-hibits XII motor activity by stimulating local inhibitoryinterneurons connected with KF-Int5 premotor neurons(seeFig. 8B).

Since inspiratory activity in tongue protrusor andretrusor muscles is crucial for upper airway patency,this pontine premotor pathway may selectively con-tribute to the control of oropharyngeal caliber in normalbreathing and during reflex modulation. This pathwaymight be also of importance under pathophysiologi-cal condition like sleep associated respiratory disor-ders (Kubin and Fenik, 2004; Radulovacki et al., 2004;Remmers, 2001; Woch et al., 2000). However, moreelectrophysiological investigations are needed to deter-mine the discharge patterns of the pontine XII premotorneurons (tonic or phasic, inspiratory or expiratory).

5.3. Activity during coughing

at’sX rentr rk re-l ized.I eens enicne onst lly,n ns int redd ir in-v at-t u-r XIIp thers nec-

tions, and patterns of activity of neurons projecting onXII motoneurons during the cough reflex.

5.4. Activity during swallowing

Only few studies described the activity of XIIpremotor neurons during swallowing (Amri et al.,1990; Ono et al., 1998b). In the study ofOno et al.(1998b)peri-hypoglossal neurons activated during (fic-tive) swallowing have monosynaptic inhibitory in-puts to XII motoneurons. Such premotor neurons maybe responsible for both the SLN-evoked inhibitorypost-synaptic potentials and chloride-dependent inhi-bition observed in subsets of respiratory-modulated XIImotoneurons during swallowing (Roda et al., 2002).Double-labeling experiments using combined analy-sis of Fos expression and tract tracing have failed todemonstrate an activation of XII premotor neurons dur-ing swallowing. Less than 1% of double-labeled neu-rons were observed in response to sucrose ingestion inawake rats (Dinardo and Travers, 1997), or after swal-lowing elicited by electrical stimulation of the SLNin anesthetized rats (see introduction inRoda et al.,2004). This may be due to a limitation of this technique,although medullary or pontine (KF-Int5) XII premo-tor neurons do express Fos in response to quinine-induced rejections (Dinardo and Travers, 1997) or afterhalothane inhalation (Roda et al., 2004). Thus, the lo-cation and electrophysiological characterization of ex-citatory XII premotor neurons activated during swal-l

eda res-p rtifi-c ofi weda oryn ndedw rged oryn butfi thisr igha inga tingb , itw pre-m

As stated above, intracellular recordings of cII motoneurons demonstrated at least two diffe

esponses during coughing (Fig. 2). However, to ounowledge, the activity of XII premotor neurons ination to the cough reflex has not been characternspiratory neurons in the ventrolateral NTS have bhown to mediate the increase in activity of the phrerve during both breathing and coughing (Gestreaut al., 1996), but potential projections of these neur

o the XII motor nucleus were not tested. Additionaumerous respiratory (and non-respiratory) neuro

he medial parabrachial and KF nuclei display alteischarge patterns during cough, suggesting theolvement in the configuration of the cough motor pern (Shannon et al., 2004). Some of these pontine neons, including KF neurons, could correspond toremotor neurons activated during cough. Thus, furtudies should examine the location, nature of con

owing remains to be established.Saito et al. (2003)examined the swallowing-relat

ctivity of respiratory neurons in the ventrolateraliratory groups in decerebrate, paralyzed and aially ventilated rats. During fictive swallowing 36%nspiratory-modulated laryngeal motoneurons sho

late synaptic activation. The majority of expirateurons with decrementing pattern (E-Dec) respoith either an early (68%) or a late (15%) dischauring swallowing. In contrast, augmenting expirateurons (E-Aug) were inactive during swallowing,red between and after the pharyngeal phase ofeflex. Saito and collaborators interpreted this hmount of E-Dec neurons activated during swallows an evidence for their contribution in coordinareathing and swallowing networks. Unfortunatelyas not investigated if some E-Dec neurons wereotor to XII motoneurons.


We performed similar experiments in decerebrate(pre-collicular level), non-vagotomized, spontaneouslybreathing rats (n= 11) (unpublished observations). Wefocused on the swallowing-related activity of neu-rons in a specific portion of the reticular formationlocated between the NTS and the nucleus ambigu-ous, i.e. the IRt. This region contains numerous XIIpremotor neurons (Fig. 3; see references inRodaet al., 2004), and we studied respiratory (n= 108) andnon-respiratory (n= 28) neurons in this area. Generalmethods for decerebration, electromyographic (EMG)recordings from muscles, and SLN-induced swallow-ing have been detailed elsewhere (Roda et al., 2004;Zheng et al., 1993). The cells recorded were locatedfrom the obex to +0.5 mm rostral, 0.8–2.1 mm lateralfrom the midline, and 0.3–2.9 mm below the dorsalsurface. Glass microelectrodes with tip diameters of5�m or less (impedances typically less than 10 M�

at 100 Hz) were filled with 2 M NaCl. Extracellularpotentials were amplified and filtered (0.10–10 kHz)through a high impedance circuit. EMG signals wereamplified and filtered (0.01–10 kHz), discharge activi-ties were fed to leaky integrators (time constant 100 ms)

giving a moving average of both digastric EMG (ʃDIG)and diaphragm EMG (ʃDIA) muscle activities. How-ever, no attempt was made to identify the axonal pro-jections of these neurons. We found that 27% of in-spiratory, 43% of E-Dec, and 18% of E-Aug neuronswere activated during swallowing, and 50% of the non-respiratory modulated neurons discharged in responseto this reflex. Examples of recordings of these neuronsare illustrated inFig. 6. The data indicate that numer-ous neurons of the rat reticular formation contribute tothe pattern generation of swallowing. This is supportedby several investigations. Putative XII premotor neu-rons in the lateral reticular formation that fired in cor-relation with licking display enhanced activity duringswallowing (Travers et al., 1997, 2000). Microinjectionof lidocaine into this region inhibits both licking andgaping (Chen et al., 1999). Also, activation of GABAAreceptors (Chen et al., 2001), or selective blockade ofNMDA or AMPA/kainate receptors (Chen and Travers,2003) in this region reversibly suppressed ingestion.The latter study also provided evidence that pharmaco-logical manipulations of the lateral reticular formationcould switch ingestion to a rejection response. This

F urons i ng elicitb 10 Hz, spiked ities of piratory-r ere act d neuronsw owing-r with thed on exh

ig. 6. Examples of extracellular recordings from respiratory ney electrical stimulation of the right superior laryngeal nerve (ischarges; Middle and lower traces: electromyographic activelated neurons with a decrementing discharge rate (E-Dec) with augmenting discharge rate (I-Aug) also displayed swalliaphragm activity during swallowing. Note that this I-Aug neur

n the intermediate reticular nucleus (IRt) during actual swallowied1 V, 250�s duration) in a decerebrate rat. Upper traces: neuronaldigastric (EMG DIG) and diaphragm (EMG DIA) muscles. Exivated during swallowing (burst in EMG DIG). Inspiratory-relateelated activity, indicating changes in their phase-relationshipibits a decrementing pattern during swallowing.


Fig. 7. Effect of an electrolytic lesion (cathodal current, 100�A, 25 s) of the intermediate KF (A) on swallowing-related activity of the XIInerve (B) in a decerebrate rat. Microphotograph of the dorsolateral pons (A1) and schematic anatomical landmarks at the same section level(A2) showing a unilateral KF lesion (black area). Mechanical probing of the pharyngeal mucosa elicited swallowing bursts in both ipsilateral(XIIi) and controlateral (XIIc) XII nerves before (B1) and after (B2) destruction of the left KF. Note that coordination between breathingand swallowing is unchanged since in both cases swallowing-related activity of the XII occurred in expiration, as evidenced by silent periodsof external intercostals (EI) muscles activity. Unilateral KF lesion produced bilateral enhancement in XII burst duration and amplitude duringswallowing (see enlarged view in insets showing increases by 110 and 150% in areas under the curve). Phasic inspiratory activity of upper airway(more visible in XIIc) and thoracic muscle (EI) was also increased. Differences in respiratory-modulation between XIIi and XIIc are probablydue to different placement of the electrodes around the nerves. Abbreviations: Int5: intertrigeminal region; seeFig. 3for other abbreviations.


suggests that medullary XII premotor neurons consti-tute the central pattern generator (CPG) for at least twodifferent oromotor behaviors. Whether several pools ofmultimodal XII premotor neurons are segregated in thereticular formation is not known. However, our resultsshow that neurons located in caudal part (around theobex) of the rat IRt may form a pool of XII premotorneurons involved in breathing and swallowing.

Recently, we investigated whether pontine XII pre-motor neurons play a role in the neural control duringswallowing. These experiments were performed in de-cerebrate rats (n= 8) using similar methods than thosedescribed above. Recordings were also made from theright and left XII nerves and anterior digastric bellies.Series of ten bursts of swallowing were induced bymechanical stimulation of the pharyngeal mucosa be-fore and after electrolytic lesions of the dorsolateralpons. Cathodal currents (50–200�A, 15–45 s) were ap-plied through platinum–iridium monopolar electrodes.As described inRoda et al. (2004), changes in areaunder the curve measured from the integrated nerveand muscle activities were used to evaluate the effectsof lesions on swallowing (and breathing). Lesions ofthe intermediate portion of the KF nucleus (n= 5) re-vealed significant unilateral (n= 2) or bilateral increase(n= 3) in hypoglossal (and digastric, data not shown)bursts associated with the pharyngeal phase of swal-lowing (Fig. 7). These results suggest that KF neu-rons inhibit XII (and anterior digastric) motoneuronsduring swallowing. Again, if inhibitory interneuronsc theK thatt ineX uldb l le-s ow-i s oft als)m

5

ntsd (forr att me-d larn tory

premotor neurons for masseter (jaw closer) and digas-tric (jaw opener) motoneurons. Other premotor neuronshave been suggested to contribute to this rhythmic ac-tivity, and location of these cells partially overlaps thatof the XII premotor neurons: sensory trigeminal nuclei,oral division of the nucleus reticularis, dorsal reticularformation adjacent to the XII nucleus, supratrigeminaland Int5 regions (see references inDonga and Lund,1991). One-third of trigeminal premotor neurons arerythmically active during fictive mastication inducedby cortical stimulation (Donga and Lund, 1991). Fur-thermore, activation of XII premotor neurons of thedorsal medullary reticular formation during mastica-tion has been demonstrated. Twenty-five percent ofthem were phasically active and likely contribute toexcitation of protrusors and retrusors during corticallyinduced rhythmical tongue movements (Sahara et al.,1996). However, whether these neurons also displayrespiratory- or swallowing-related activity remains tobe determined.

6. Summary and conclusions

Schematic diagrams summarizing the findings andhypotheses are depicted inFig. 8. Motoneurons do notparticipate to the generation of motor programs butcontribute through their endogeneous properties to thepatterning of motor outputs during breathing (Berger,2000) and swallowing (discussed inRoda et al., 2002).T ingv canh XIIm canr pticd ands to-r eu-r theX at-t guei ing.S de-s lm 99

unc-t bys m

onnected to KF-Int5 premotor neurons exist inF (previous hypothesis), then it is conceivable

heir destruction results in disinhibition of the pontII premotor neurons spared by the lesion. It shoe noted that the excitatory effects of a unilateraion of the KF nucleus were not restricted to swallng bursts, but also concerned inspiratory activitiehe XII nerve and thoracic pump (external intercostuscles (Figs. 7B2 and 8B).

.5. Activity during mastication

Mechanisms governing rhythmic jaw movemeuring mastication have been extensively studiedeview,Lund et al., 1998). Early models proposed thhe CPG for mastication is located in the ventroial part of the rostral medulla (Gi and LPGi reticuuclei). These areas contain excitatory and inhibi

hey represent the “final common pathway” servarious oropharyngeal behaviors. A single CPGave divergent synaptic inputs on distinct pools ofotoneurons. Also, one subset of XII motoneurons

eceive convergent excitatory and inhibitory synarives arising from CPGs dedicated to breathingwallowing. In addition, distinct membrane trajecies are observed in different subsets of XII motonons. This suggests a functional segregation withinII motor nucleus in relation to both timing and p

ern of contraction of the target-muscle of the tonn response to breathing, coughing and/or swallowimilar principles of neural organization have beencribed for phrenic (Grelot et al., 1992) and laryngeaotoneurons (Gestreau et al., 2000; Shiba et al., 19).Several results suggest the existence of multif

ional XII premotor neurons, i.e. neurons sharedeveral CPGs (Fig. 8). These were obtained fro


Fig. 8. (A) Output patterns of lingual muscles are achieved by activation of various subsets of XII motoneurons. Brainstem neural networks (orcentral pattern generators, CPGs) producing breathing, swallowing and coughing motor activities form neural ensembles including XII premotorneurons (black circles). The latter send convergent and divergent projections onto the subsets of motoneurons. Several results suggest the existenceof multifunctional (or shared) premotor neurons (see overlapping CPGs). The cough motor pattern is likely generated by reconfiguration of thebreathing CPG. (B) Medullary and pontine XII premotor neurons may form multiple entities involved in several behaviors. A segregation mayexist in the reticular formation (RF), with premotor neurons involved in breathing and swallowing located in the intermediate nucleus (IRt), andthose involved in licking, mastication, and rejection within the rostrolateral part of the RF (PCRt). Functional activity of intranuclear inhibitoryneurons (white circle with a minus sign) remains to be determined. At the level of the KF, we propose a mechanism by which halothane mayfacilitate excitatory KF-Int5 premotor neurons via inhibition (minus sign) of local inhibitory interneurons, and thus increase inspiratory activityof XII motoneurons. This mechanism could also explain decreases or increases in XII motor activity observed respectively after glutamate (Glu)injection in the KF or electrolytic lesion of this nucleus.

detailed analysis of changes in membrane potentialsand discharge frequencies of XII motoneurons (Rodaet al., 2002), and from recordings of respiratory- andswallowing-related activities in neurons located in theintermediate nucleus (IRt) of the reticular formation(RF) (Ono et al., 1998a; present results). Furthermore,physiological studies focusing on the role of the rostro-

lateral part of the RF (PCRt) have provided the best ev-idence for a multifunctional substrate in ingestion andrejection behaviors (Chen et al., 1999, 2001; Chen andTravers, 2003; Travers et al., 2000). In parallel, a pon-tine XII premotor pathway located in the ventral KFand Int5 region contributes to XII motoneurons activ-ity during various oropharyngeal behaviors (Kuna and


Remmers, 1999; Roda et al., 2004; present results).Several pools of multimodal XII premotor neurons(Fig. 8B) could be involved in switching from res-piration to ingestion and rejection. Alteration of thecoupling between functional modules (shared premo-tor neurons) may represent a way to generate highlyorganized and complex tongue movements required formastication, licking, swallowing, coughing and breath-ing. Thus, as demonstrated in invertebrates (Weimannand Marder, 1994), a single network in mammals func-tioning in different chemically controlled configura-tions may underlie various lingual movements. Furtherexperiments are required to understand how, and un-der which conditions the functional modules are acti-vated or synchronized to produce complex oromotorpatterns. The exact anatomical location and the degreeof overlap for the specific subpopulation of premotorneurons including their connections to specific pools ofhypoglossal motoneurons are important aims for futureexperiments. Especially needed are multi-unit record-ings from various types of XII premotor neurons toelucidate their functions and interactions.

Acknowledgments

We are extremely grateful to Laurent Grelot, FabriceRoda, and Yu Zheng for their respective contributionsto part of the experiments and interpretation of data.This work was supported by grants from CNRS (UMR6

R

A ntralat. J.

A ec-gue

A larylos-flu-

384–

A rveingleus.

Baekey, D.M., Morris, K.F., Gestreau, C., Li, Z., Lindsey, B.G., Shan-non, R., 2001. Medullary respiratory neurones and control of la-ryngeal motoneurones during fictive eupnoea and cough in thecat. J. Physiol. (London) 534, 565–581.

Bailey, E.F., Fregosi, R.F., 2004. Coordination of intrinsic and ex-trinsic tongue muscles during spontaneous breathing in the rat.J. Appl. Physiol. 96, 440–449.

Berger, A.J., 2000. Determinants of respiratory motoneuron output.Respir. Physiol. 122, 259–269.

Bianchi, A.L., Denavit-Saubie, M., Champagnat, J., 1995. Centralcontrol of breathing in mammals: neuronal circuitry, membraneproperties, and neurotransmitters. Physiol. Rev. 75, 1–45.

Clement, C.I., Keay, K.A., Bandler, R., 1998. Medullary cate-cholaminergic projections to the ventrolateral periaqueductalgray region activated by halothane anaesthesia. Neuroscience 86,1273–1284.

Chamberlin, N.L., 2004. Functional organization of the parabrachialcomplex and intertrigeminal region in the control of breathing.Respir. Physiol. Neurobiol. 143, 115–125.

Chamberlin, N.L., Saper, C.B., 1994. Topographic organiza-tion of respiratory responses to glutamate microinjection ofthe parabrachial nucleus in the rat. J. Neurosci. 18, 6048–6056.

Chamberlin, N.L., Saper, C.B., 1998. Brainstem neural network me-diating apneic reflexes in the rat. J. Neurosci. 18, 371–387.

Chen, Z., Travers, J.B., 2003. Inactivation of amino acid receptorsin medullary reticular formation modulates and suppresses in-gestion and rejection responses in the awake rat. Am. J. Physiol.Regul. Integr. Comp. Physiol. 285, 68–83.

Chen, Z., Travers, S.P., Travers, J.B., 1999. Inhibition of licking andthe oral phase of rejection by microinjection of lidocaine in themedullary reticular formation. Appetite 33, 259.

Chen, Z., Travers, S.P., Travers, J.B., 2001. Muscimol infusions inthe brain stem reticular formation reversibly block ingestion inthe awake rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280,

C llarytionsrol.

D s, C.,g tots in

D rac-swal-

D dur-l. 72,

D m-ratNeu-

D pro-urol.

153) and INRA (USC 1147).

eferences

ldes, L.D., 1995. Subcompartimental organization of the ve(protrusor) compartment in the hypoglossal nucleus of the rComp. Neurol. 353, 89–108.

ltschuler, S.M., Bao, X., Miselis, R.R., 1994. Dendritic architture of hypoglossal motoneurons projecting to extrinsic tonmusculature in the rat. J. Comp. Neurol. 342, 538–550.

mri, M., Car, A., Roman, C., 1990. Axonal branching of medulswallowing neurons projecting on the trigeminal and hypogsal motor nuclei: demonstration by electrophysiological andorescent double labeling techniques. Exp. Brain Res. 81,390.

mri, M., Lamkadem, M., Car, A., 1991. Effects of lingual neand chewing cortex stimulation upon activity of the swallowneurons located in the region of the hypoglossal motor nucBrain Res. 548, 149–155.

1085–1094.unningham Jr., E.T., Sawchenko, P.E., 2000. Dorsal medu

pathways subserving oromotor reflexes in the rat: implicafor the central neural control of swallowing. J. Comp. Neu417, 448–466.

auvergne, C., Pinganaud, G., Buisseret, P., Buisseret-DelmaZerari-Mailly, F., 2001. Reticular premotor neurons projectinboth facial and hypoglossal nuclei receive trigeminal afferenrats. Neurosci. Lett. 311, 109–112.

ick, T.E., Oku, Y., Romaniuk, J.R., Cherniack, N.S., 1993. Intetion between central pattern generators for breathing andlowing in the cat. J. Physiol. (London) 465, 715–730.

inardo, L.A., Travers, J.B., 1994. Hypoglossal neural activitying ingestion and rejection in the awake rat. J. Neurophysio1181–1191.

inardo, L.A., Travers, J.B., 1997. Distribution of fos-like imunoreactivity in the medullary reticular formation of theafter gustatory elicited ingestion and rejection behaviors. J.rosci. 17, 3826–3839.

obbins, E.G., Feldman, J.L., 1995. Differential innervation oftruder and retractor muscles of the tongue in rat. J. Comp. Ne357, 376–394.


Donga, R., Lund, J.P., 1991. Discharge patterns of trigeminal com-missural last-order interneurons during fictive mastication in therabbit. J. Neurophysiol. 66, 1564–1578.

Dutschmann, M., Herbert, H., 1998. NMDA and GABAA receptorsin the rat Kolliker-Fuse area control cardiorespiratory responsesevoked by trigeminal ethmoidal nerve stimulation. J. Physiol.(London) 543, 643–653.

Dutschmann, M., Paton, J.F., 2002. Glycinergic inhibition is es-sential for co-ordinating cranial and spinal respiratory motoroutputs in the neonatal rat. J. Physiol. (London) 543, 643–653.

Dutschmann, M., Morschel, M., Kron, M., Herbert, H., 2004. De-velopment of adaptative behaviour of the respiratory network:implication for the pontine Kolliker-Fuse nucleus. Respir. Phys-iol. Neurobiol. 143, 155–165.

Ertekin, C., Aydogdu, I., 2003. Neurophysiology of swallowing.Clin. Neurophysiol. 114, 2226–2244.

Fay, R.A., Norgren, R., 1997. Identification of rat brainstem multi-synaptic connections to the oral motor nuclei using pseudorabiesvirus. III. Lingual muscle motor systems. Brain Res. Rev. 25,291–311.

Fregosi, R.F., Fuller, D.D., 1997. Respiratory-related control ofextrinsic tongue muscle activity. Respir. Physiol. 110, 295–306.

Fuller, D., Mateika, J.H., Fregosi, R.F., 1998. Co-activation of tongueprotrudor and retractor muscles during chemoreceptor stimula-tion in the rat. J. Physiol. (London) 507, 265–276.

Gestreau, C., Milano, S., Bianchi, A.L., Grelot, L., 1996. Activity ofdorsal respiratory group inspiratory neurons during laryngeal-induced fictive coughing and swallowing in decerebrate cats.Exp. Brain Res. 108, 247–256.

Gestreau, C., Grelot, L., Bianchi, A.L., 2000. Activity of respiratorylaryngeal motoneurons during fictive coughing and swallowing.Exp. Brain Res. 130, 27–34.

Grelot, L., Milano, S., Portillo, F., Miller, A.D., Bianchi, A.L., 1992.g fic-cat.

H nsesgul.

H ationons.

I gh-acol.

J ork

K their143,

K ossalcats.

L rog.

Lund, J.P., Kolta, A., Westberg, K.G., Scott, G., 1998. Brainstemmechanisms underlying feeding behaviors. Curr. Opin. Neuro-biol. 8, 718–724.

McClung, J.R., Goldberg, S.J., 1999. Organization of motoneurons inthe dorsal hypoglossal nucleus that innervate the retrusor musclesof the tongue in the rat. Anat. Rec. 254, 222–230.

McClung, J.R., Goldberg, S.J., 2000. Functional anatomy of the hy-poglossal innervated muscles of the rat tongue: a model for elon-gation and protrusion of the mammalian tongue. Anat. Rec. 260,378–386.

McClung, J.R., Goldberg, S.J., 2002. Organization of the hypoglos-sal motoneurons that innervate the horizontal and oblique com-ponents of the genioglossus muscle in the rat. Brain Res. 950,321–324.

Miller, A.J., 2002. Oral and pharyngeal reflexes in the mammaliannervous system: their diverse range in complexity and the pivotalrole of the tongue. Crit. Rev. Oral. Biol. Med. 13, 409–425.

Mu, L., Sanders, I., 1999. Neuromuscular organization of the caninetongue. Anat. Rec. 256, 412–424.

Ono, T., Ishiwata, Y., Inaba, N., Kuroda, T., Nakamura, Y., 1994. Hy-poglossal premotor neurons with rhythmical inspiratory-relatedactivity in the cat: localization and projection to the phrenic nu-cleus. Exp. Brain Res. 98, 1–12.

Ono, T., Ishiwata, Y., Inaba, N., Kuroda, T., Nakamura, Y., 1998a.Modulation of the inspiratory-related activity of hypoglossal pre-motor neurons during ingestion and rejection in the decerebratecat. J. Neurophysiol. 80, 48–58.

Ono, T., Ishiwata, Y., Kuroda, T., Nakamura, Y., 1998b. Swallowingrelated perihypoglossal neurons projecting to hypoglossal mo-toneurons in the cat. J. Dent. Res. 77, 351–360.

Paxinos, G., Watson, C., 1998. The Rat Brain in Stereotaxic Coordi-nates. Academic Press, San Diego.

Peever, J.H., Duffin, J., 2001. Bilateral synchronization of respiratorymotor output in rats: adult versus neonatal in vitro preparations.Pflugers Arch. 442, 943–951.

P ol of.

P con-110,

P 1999.ei in

P O.,.F.,

oro-9.

R od-ntineuro-

R irway.ed.

R roteincular

Membrane potential changes of phrenic motoneurons durintive vomiting, coughing, and swallowing in the decerebrateJ. Neurophysiol. 68, 2110–2119.

ayashi, F., McCrimmon, D.R., 1996. Respiratory motor respoto cranial nerve afferent stimulation in rats. Am. J. Physiol. ReIntegr. Comp. Physiol. 271, 1054–1062.

wang, J.-C., Bartlett Jr., D., St-John, W.M., 1983. Characterizof respiratory-modulated activity of hypoglossal motoneurJ. Appl. Physiol. 55, 793–798.

scoe, S., Grelot, L., 1992. Regional intercostal activity during couing and vomiting in decerebrate cats. Can. J. Physiol. Pharm70, 1195–1199.

ean, A., 2001. Brain stem control of swallowing: neuronal netwand cellular mechanisms. Physiol. Rev. 81, 929–969.

ubin, L., Fenik, V., 2004. Pontine cholinergic mechanims andimpact on respiratory regulation. Respir. Physiol. Neurobiol.235–249.

una, S.T., Remmers, J.E., 1999. Premotor input to hypoglmotoneurons from Kolliker-Fuse neurons in decerebrateRespir. Physiol. 117, 85–95.

owe, A.A., 1981. The neural regulation of tongue movements. PNeurobiol. 15, 295–344.

eever, J.H., Mateika, J.H., Duffin, J., 2001. Respiratory contrhypoglossal motoneurons in the rat. Pflugers Arch. 442, 78–86

eever, J.H., Shen, L., Duffin, J., 2002. Respiratory pre-motortrol of hypoglossal motoneurons in the rat. Neuroscience711–722.

inganaud, G., Bernat, I., Buisseret, P., Buisseret-Delmas, C.,Trigeminal projections to hypoglossal and facial motor nuclthe rat. J. Comp. Neurol. 415, 91–104.

opratiloff, A.S., Streppel, M., Gruart, A., Guntinas-Lichius,Angelov, D.N., Stennert, E., Delgado-Garcia, J.M., Neiss, W2001. Hypoglossal and reticular interneurons involved infacial coordination in the rat. J. Comp. Neurol. 433, 364–37

adulovacki, M., Pavlovic, S., Saponjic, J., Carley, D.W., 2004. Mulation of reflex and sleep related apnea by pedonculopotegmental and intertrigeminal neurons. Respir. Physiol. Nebiol. 143, 293–306.

emmers, J.E., 2001. Wagging the tongue and guarding the aReflex control of the genioglossus. Am. J. Respir. Crit. Care M164, 2013–2014.

ocha, M.J., Herbert, H., 1997. Effects of anesthetics on Fos pexpression in autonomic brain nuclei related to cardiovasregulation. Neuropharmacology 36, 1779–1781.


Roda, F., Gestreau, C., Bianchi, A.L., 2002. Discharge patterns ofhypoglossal motoneurons during fictive breathing, coughing, andswallowing. J. Neurophysiol. 87, 1703–1711.

Roda, F., Pio, J., Bianchi, A.L., Gestreau, C., 2004. Effects of anes-thetics on hypoglossal nerve discharge and c-Fos expression inbrainstem hypoglossal premotor neurons. J. Comp. Neurol. 468,571–586.

Ryan, S., McNicholas, W.T., O’Regan, R., Nolan, P., 2001. Reflexrespiratory response to changes in upper airway pressure in theanaesthetized rat. J. Physiol. (London) 537, 251–265.

Sahara, Y., Hashimoto, N., Nakamura, Y., 1996. Hypoglossal premo-tor neurons in the rostral medullary parvocellular reticular for-mation participate in cortically-induced rhythmical tongue move-ments. Neurosci. Res. 26, 119–131.

Saito, Y., Ezure, K., Tanaka, I., Osawa, M., 2003. Activity of neuronsin ventrolateral respiratory groups during swallowing in decere-brate rats. Brain Dev. 25, 338–345.

Satoh, I., Shiba, K., Kobayashi, N., Nakajima, Y., Konno, A., 1998.Upper airway motor outputs during sneezing and coughing indecerebrate cats. Neurosci. Res. 32, 131–135.

Sawczuk, A., Mosier, K.M., 2001. Neural control of tongue move-ment with respect to respiration and swallowing. Crit. Rev. OralBiol. Med. 12, 18–37.

Shannon, R., Baekey, D.M., Morris, K.F., Nuding, S.C., Segers, L.S.,Lindsey, B.G., 2004. Pontine respiratory group neuron dischargeis altered during fictive cough in the decerebrate cat. J. Appl.Physiol. 84, 2020–2035.

Shiba, K., Satoh, I., Kobayashi, N., Hayashi, F., 1999. Multifunc-tional laryngeal motoneurons: an intracellular study in the cat. J.Neurosci. 19, 2717–2727.

St-John, W.M., Paton, J.F., 2000. Characterizations of eupnea, ap-neusis and gasping in a perfused rat preparation. Respir. Physiol.123, 201–213.

Takasu, N., Hashimoto, P.H., 1988. Morphological identification ofan interneurons in the hypoglossal nucleus of the rat: a com-

271,

T tsy-wal-

Travers, J.B., Jackson, L.M., 1992. Hypoglossal neural activity dur-ing licking and swallowing in the awake rat. J. Neurophysiol. 67,1171–1184.

Travers, J.B., Montgomery, N., Sheridan, J., 1995. Transneu-ronal labeling in hamster brainstem following lingual injec-tions with herpes simplex virus-1. Neuroscience 68, 1277–1293.

Travers, J.B., Dinardo, L.A., Karimnamazi, H., 1997. Motor andpremotor mechanisms of licking. Neurosci. Biobehav. Rev. 21,631–647.

Travers, J.B., Dinardo, L.A., Karimnamazi, H., 2000. Medullaryreticular formation activity during ingestion and rejection in theawake rat. Exp. Brain Res. 130, 78–92.

Travers, J.B., Rinaman, L., 2002. Identification of lingual motor con-trol circuits using two strains of pseudorabies virus. Neuroscience115, 1139–1151.

Umezaki, T., Nakazawa, K., Miller, A.D., 1998a. Upper airway motoroutputs during vomiting versus swallowing in the decerebrate cat.Brain Res. 781, 25–36.

Umezaki, T., Shiba, K., Zheng, Y., Miller, A.D., 1998b. Behaviorsof hypoglossal hyoid motoneurons in laryngeal and vestibularreflexes and in deglutition and emesis. Am. J. Physiol. Regul.Integr. Comp. Physiol. 274, 950–955.

Weimann, J.M., Marder, E., 1994. Switching neurons are inte-gral members of multiple oscillatory networks. Curr. Biol. 4,896–902.

Withington-Wray, D.J., Mifflin, S.W., Spyer, K.M., 1988. Intracellu-lar analysis of respiratory modulated hypoglossal motoneuronsin the cat. Neuroscience 25, 1041–1051.

Woch, G., Ogawa, H., Davies, R.O., Kubin, L., 2000. Behavior ofhypoglossal inspiratory premotor neurons during the carbachol-induced, REM sleep-like suppression of upper airway motoneu-rons. Exp. Brain Res. 130, 508–520.

Zerari-Mailly, F., Pinganaud, G., Dauvergne, C., Buisseret, P.,Buisseret-Delmas, C., 2001. Trigemino-reticulo-facial and

mp.

Z im-ue

bined Golgi-electron microscopic study. J. Comp. Neurol.461–471.

omomune, N., Takata, M., 1988. Excitatory and inhibitory posnaptic potentials in cat hypoglossal motoneurons during slowing. Exp. Brain Res. 71, 262–272.

trigemino-reticulo-hypoglossal pathways in the rat. J. CoNeurol. 429, 80–93.

heng, Y., Barillot, J.C., Kessler, J.P., Bianchi, A.L., 1993. A splified technique for decerebrating rats. Hua Xi Yi Ke Da XXue Bao 24, 343–345.

activation of xii motoneurons and premotor neurons during various oropharyngeal behaviors

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