control of locomotion in the decerebrate cat · electroneurogram flexor reflexafferents golgitendon...

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Progressin Neurobiology V 49, 481 515,1996C ~ 1 ElsevierS Ltd.Allrightsr

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PII: S0301-0082(%)00028-7

CONTROL OF LOCOMOTION IN THE DECEREBRATE CAT

PATRICK J. WHELAN*Departmentof Physiologyand Divisionof Neuroscience,Facultyof Medicine, Universityof Alberta,

Edmonton,Canada

(Reuised10 April 1996)

Abstract-Many of the general concepts regardingthe control of walkingwere describedyears ago by:Sherrington (1906)IntegrativeActions of the NervousSystem. Yale UniversityPress: New Haven, CT;Sherrington(1910a)Remarks on the reflexmechanismof the step, Brain33, 1-25;Sherrington(1910b)Flexor-reflex of the limb, crossed extension reflex, and reflex stepping and standing (cat and dog), J.Physiol. (Lend.) 40, 28–121;Sherrington(1931)Quantitative managementof contraction in lowest levelcoordination, BrainS4, 1–28;Graham-Brown(1912)The intrinsicfactors in the act of progressionin themammal, Proc. R. Soc. Lend. 84, 308–319;Graham-Brown (1914)On the nature of the fundamentalactivity of the nervous centres; together with an analysis of the conditioning of rhythmic activity inprogression, and a theory of the evolution of function in the nervous system, J. Physiol. 49, 18-46;Graham-Brown(1915)On the activities of the central nervous system of the unborn foetus of the cat,with a discussionof the questionwhetherprogression(walking,etc.) is a learnt’ complex,J. Physiol.49,208-215;Graham-Brown (1922)The physiologyof stepping,J. Neur. Psychopathol.3, 112-116.

Only in recent years, however, have the mechanismsbeen analyzed in detail. Quite a few of thesemechanismshave been deseribed using the decerebrate cat. Locomotion is initiated in decerebrate catsby activation of the mesencephaliclocomotor region(MLR) that activates the medialmedullaryreticularformation (MRF) whichin turn projeets axons to the spinal cord whichdeseendwithin the ventrolateralfunicuhss(VLF). The MRF region regulates as well as initiates the stepping pattern and is thought tobe involved in interlimb coordination. Afferent feedback from proprioceptors and exteroeeptors canmodifythe ongoinglocomotorpattern. Recently,the typesof afferentsresponsiblefor signalingthe stanceto swingtransition have been identified.A general rule states that if the limb is unloaded and the leg isextended, then swing will occur. The afferents that detect unloading of the limb are the Golgi tendonorgans and stimulationof theseafferents(at group I strengths)prolongsthe stance phase in walkingcats.The afferents that detect the extensionof the leg have been found to be the length-and vebeity-sensitivemuscleafferentslocatedin flexorm P l s d b in this article.Decerebrate animals can adapt locomotor behaviors to respond to new environmental conditions.Oligosynapticreflexpathways that control locomotioncan be recalibrated after injury in a manner thatappears to be functionallyrelated to the recoveryof the animal. Copyright~ 1996ElsevierSeieneeLtd.

CONTENTS1. Introduction

1.1. Definitionof decerebrate preparations2. The control of locomotion by regions of the brainstem

2.1. Introduction2.2. The subthalamic locomotor region (SLR)2.3. The mesencephaliclocomotor region (MLR)

2.3.1. Inputs to the MLR2.3.2. The pontomedullary locomotor strip (PLS)

2.4. The medial medullary reticular formation (MRF)2.4.1. Regulation of ongoing locomotion

2.5. The ventrolateral funiculus(VLF)2.6. htterneurons activated within the spinal cord

2.6.1. Location of rhythmicallyactive interneurons2.6.2. Neurotransmitters involvedin activating the CPG

2.7. Interaction of posture and locomotion2.8. Summary

3. Afferent control of locomotion3.1. Introduction3.2. Reinforcementof the ongoingstep cycle3.3. The control of the stance to swingtransition

3.3.1. Extensor muscle afferents3.3.2. Flexor muscle afferents3.3.3. Cutaneous afferents

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*Presentaddress:755MedicalSciencesBuilding,Universityof Alberta, Edmonton,Alberta, Canada T6G 2H7.Tel: (403)492-1230;Fax: (403)492-8915;email: pwhelan(dgpu.srv.ualberta.ca.

481

482 P. J. Whelan

3.4. A model circuit3.5. Summary

4. Plasticity of locomotor pathways involvedin the production of locomotion4.1. The ability of the decerebrate animal to learn new behaviors4.2. Plasticity of the extensor group I pathway4.3. Summary

5. ConcludingremarksAcknowledgementsReferences

AChAPVCNQXCPGDLFDSCTDTFEAAEDLEMGENENGFRAGTO1P

Acetylcholine2-amino-5-phosphonovalericacid6-cyano-7-nitroquinoxaline-2,3-dioneCentral pattern generatorDorsolateral funiculusDorsal spinocerebellartractDorsal segmentalfieldExcitatory amino acidsExtensor digitorum longusElectromyographicEntopeduncularnucleusElectroneurogramFlexor reflexafferentsGolgi tendon organIliopsoas

ABBREVIATIONS

1. INTRODUCTION

It is evident that the reflex, as well as olher,phenomena of the mammalian spinal cord prescmtalarge field of inquiry, being much more varied andextensive than previous experience had led us tosuppose (Foster, 1879, as cited in Liddell, 1960).

The most astonishing thing about walking is howeasy it seems. This apparent ease, however, is theresult of complex interactions between spinalinterneurons, afferent input from the limbs,supraspinal influences from the cortex and thelocomotor centers within the brainstem. A great dealof knowledge regarding the control of locomotionhas been gathered using the decerebrate cat, whichhas proved useful because, with appropriate stimu-Iation, fully coordinated stepping can beevoked fromall four limbs. In ideal situations, this steppingpattern can be altered by the experimenter fromwalking to trotting to galloping, simply by increasingthe electrical stimulus to the brainstem. Obviously,one would prefer to use the intact animal at all timesto study locomotion, but this is not always possible.For example, stimulation of the brainstem can evokelocomotion in a paralyzed animal that allowsintracellular recordings to be made in the spinal cord.For ethical reasons, these types of experiments canonly be done in reduced preparations such as thedecerebrate cat. Thus, the decerebrate locomotinganimal enables the testing of some hypotheses in amore rigorous fashion than is possible in intactanimals. Naturally, there are disadvantages to thedecerebrate cat, the main one being that thelocomotor pattern is artificial and constrained whencompared to the intact animal. Also, care must betaken when extrapolating the results from decere-brate to intact cats, as the locomotor system may becalibrated differently in the intact animal.

LGSMGMLRmMLRMRFNANMDAPLSPPNSLRSTNTAVLFVSCTVTF

Lateral gastrocnemiusand soleusMedial gastrocnemiusMesencephaliclocomotor regionMedial mesencephaliclocomotor regionMedial medullary reticular formationNucleus accumbensN-methyl-D-aspartatePontomedullarylocomotor stripPedunculopontinenucleusSubthalamic locomotor regionSubthalamicnucleusTibialis anteriorVentrolateral funiculusVentral spinocerebellartractVentral tegmental field

502504504505505507508509509

This review will concentrate on locomotion inthe decerebrate mammal, in particular the cat. Itdoes not address the problem in a historicalcontext, because many recent reviews have done soalready (see Table 1 for reviews). Instead, selectedtopics in the control of locomotion will be reviewedthat have, in the author’s opinion, progressedsignificantly in the last 15 years. Most of theprogress has been made in three areas: (1) theinitiation of walking; (2) the afferent regulation oflocomotion; and (3) the plasticity of locomotorsystems. The organization of the review reflects thisprogress and a section is devoted to each areamentioned above.

1.1. Definition of Decerebrate Preparations

Different types of locomoting decerebrate cats canbe prepared, depending on the level of transection ofthe neuraxis. In this review, reference will be made todecorticate, premammillary, and postmammillarypreparations. The decorticate preparation wascharacterized initially by Goltz (1869) (as cited byLiddell, 1960). The latest description of decorticatepreparations can be found in the methodology ofPerret (1976) (cf Bard and Macht, 1958). These areconsidered generally to be preparations in which thecortex is removed without any particular damage tothe thalamus or basal ganglia. The locomotormovements of these preparations are nearly normaland the cats can indeed run and walk without anyexternal assistance.

The second decerebrate preparation encountered inthis review is referred to as the premammillarypreparation — see slice ‘a’ in Fig. I(A). Apremammillary cat is prepared by making atransection immediately rostral to the superior

Control of Locomotion 483

Table 1. Reviewsof the control of locomotion

Type of review References

General Grinner (1981);Rossignol(1996);Wetzel and Stuart (1976)Interneuronal circuitry Jankowska (1992);Jankowska and Edgley(1993);McCrea (1992)Spinal cord (CPG) Baev and Shimansky(1992);Delcomyn(1980);Eidelberg(1981);Grinner and Wallen

(1985);Loeb (1987);Sillar (1991);Pearson (1987)The role of afferent Baev et al. (1991);Duysensand Tax (1993);Gossard and Hultborn (1991);Loeb

information (1981);Murphy and Martin (1993);Pearson (1995a, 1995b,1993);Pearson andRamirez (1996);Prochazka (1989, 1996,1993);Rossignoler al. (1981, 1988);Rossignoland Drew (1986)

Cerebellum Armstrong (1986);Arshavskyet al. (1986);Arshavskyand Odovsky (1986)Brainstem regions Armstrong (1986);Garcia-Rill (1986, 1991);Inglis and Winn (1995);Jordan er al.

(MLR/SLR/MRF) (1992);Jordan (1991, 1986);Mogenson(1987, 1990);Mori (1987);Mori e[ al.(1992);Mori and Ohta (1986);Reese et al. (1995);Shik and Orlovsky(1976);Sinnamon(1993);Skinner and Garcia-Rill (1990)

Motor cortex Drew (1991a);Armstrong (1986, 1988)Kinematics and Grinner (1981);Halbertsma (1983);Rossignol(1996);Rossignolet al. (1993);Wetzel

interlimb coordination and Stuart (1976)History Adrian (1966);Hall (1837);Hinsey et al. (1930);Liddell (1960);Wetzel and Stuart (1976)

colliculus and continuing rostroventrally to therostral tip of the mammillary bodies. These animalscan walk spontaneously in response to a movingtreadmill, and show righting reflexes.

The postmammillary preparation [also referred toas the mesencephalic preparation — see slice ‘b’ inFig. l(A)] is made by making a cut just rostral to thesuperior colliculi and continuing rostroventrally to apoint caudal to the mammillary bodies. These cats, incontrast to the previously described preparation,rarely walk spontaneously and usually require eitherelectrical or chemical stimulation of the mesen-cephalic locomotor region (MLR) of the brainstem togenerate stepping movements.

Finally, the last class of decerebrate animal isproduced when the transection of the neuraxis ismade between the two colliculi [slice ‘c’ in Fig. I(A)].This type of cut produces the “classic” decerebratepreparation described in detail by Sherrington (1906).These preparations rarely locomote, due to the highlevel of extensor tone [termed decerebrate rigidity bySherrington (1906)] that is produced after thetransection is made.

2. THE CONTROL OF LOCOMOTION BYREGIONS OF THE BRAINSTEM

A single wire electrode is applied to the crosssectionof the bulb at calamus scriporiusafter removalof the head. Weak faradization, when applied inthe region of the funiculus gracilis evokes reflexstepping in the ipsilateral hindlimb; this steppingcommenceswith the flexionof the limb includinghipflexion.If the stimulusis weakthe [reflexstepping]maybe confined to the ipsilateral hindlimb; if strong,stepping of the contralateral hindlimb commencingwith extension, occurs also

(Sherrington, 1910b, as cited by Jordan, 1986).

2.1. Introduction

While the central pattern generator containedwithin the spinal cord can produce the basiclocomotor rhythm (Forssberg and Grinner, 1973;

Forssberg et al., 1980a, 1980b), brainstem structuresare necessary to activate and regulate the rhythm inthe intact and decerebrate animal. Since these regionswere discovered initially using electrophysiologicalmethods, they were labeled as locomotor regions(Shik et al., 1966a, 1966b). However, it is now knownthat “locomotor regions” located within the brain-stem encompass nuclei that are responsible for thecontrol of many diverse processes (Reese e~al., 1995).Thus, the term “locomotor region” is somewhatmisleading, although it will be used in this reviewsince it is used widely in the literature. Locomotorregions within the brainstem are classified as such ifthey contain neurons that, when activated chemicallyor electrically, lead to the production of locomotion.There are at least four regions of the brainstem thatmeet these criteria. The first one is the mesencephaliclocomotor region (MLR) discovered by Shik et al.1966a), 1966b), which projects to neurons located inthe medial medtdlary reticular formation (M RF) andthen on to interneurons in the spinal cord. Thesecond area is the medial MLR (mMLR) whichprojects axons along an area of the brainstem knownas the pontomedullary locomotor strip (PLS) to theMRF, and forms part of a sensorial activating systemthat travels along the dorsolateraI funiculus (DLF).Finally, stimulation of the PLS and MRF can elicitbouts of locomotion, although the bouts tend to beuncoordinated and, at times, spastic.

The MRF and MLR receive inputs from manyforebrain regions that lead to the production ofcomplex locomotor behaviors. The following arethree forebrain pathways that have been described:(1) a projection from the hippocampus and amygdalato the nucleus accumbens (NA) and onwards to thesub-pallidal region and the MLR (Mogenson, 1987);(2) inputs from basal ganglia structures to the MLR(Garcia-Rill, 1986); and (3) inputs from the lateralhypothalamic area to the MLR (Sinnamon, 1993).

While the emphasis in this section is on locomotorareas that initiate locomotion, it is also well knownthat descending inputs to the spinal cord canmodulate the ongoing pattern. For example, inputsfrom the vestibulospinal, reticulospinal and ru-

484 P, J, Whelan

A

B

spinal cord

a .A15n0 5 0 s 10 15 20

Fig, 1. (A) A sagittal diagram of the brain illmtrating the important locomotor areas of the cat (shadedin gray). The lines labeled ‘a’ and ‘b’ reftr to the transections which produce a tbalamic and apostmammillarywalkingpreparation, respectively.The premammillarypreparation includesthe SLRandextendsfrom the rostral superiorcolliculirostloventrallyto the rostral tip of the mammillarybodies.Thispreparation can walk spontaneously.The postmammillarypreparation usuallyrequiresstimulationof thebrainstem to evokea walkingpattern. (B) Tr.msverseslicesof the brain indicatingthe major locomotorareas of the brainstem(shadedin gray).The SIR is locateddorsallyto the subthalamicnucleus.The MLRregion is situated in close proximity to the cuneiform nucleus, the PPN nucleus and the brachiumconjunctivum.Finally, the DTF and VTF arc areas that mediate postural adjustments that accompanylocomotion.Figure modifiedfrom Mori ef al. (1992),with permission.Abbreviations:SLR, subthalamiclocomotor region;MLR, mesencephaliclocomotor region;SC, superiorcolliculus;[C, inferiorcolhculus;PPN, pedunculopontine nucleus; DTF, do,sal tegmental field; VTF, ventral tegmental field; CN,cuneiformnucleus;MLF, medial longitudinalfasciculus;LC, locuscoeruleus;NRPo, nucleusreticularis

pontis oralis: Mm, mammillarybodies.

brospinal tracts can modulate the amplitude oi’ the the brainstem such as the locus coeruleus, rapheelectromyographic activity in muscles in a phase nucleus (Noga et al., 1992)and the cuneiform nucleusdependent manner during walking and in some cases (Noga et al., 1995b; Perreault et al., 1994a) cancan affect the timing of the rhythm (Russel and Z~jac, modulate the amplitude of group I an 11 field1979). Furthermore, electrical stimulation of areiis of potentials. These findings suggest that regions of the


brainstem not only provide the tonic descending drivenecessary to activate the locomotor pattern genera-tor, they can also optimize reflex pathways.

2.2. The Subthalamic Locomotor Region (SLR)

A cat that is decerebrated with a transectionstarting just rostral to the superior colliculus andextending rostroventrally to the rostral tip of themammillary bodies produces a premammillarypreparation that can spontaneously elicit bouts oflocomotion lasting from minutes to hours. Duringtimes when these animals are not spontaneouslylocomoting, electrical stimulation of an area knownas the subthalamic locomotor region (SLR) canevoke locomotion in the premammillary cat. TheSLR region was described by Orlovsky (1969) asbeing centered on stereotaxic coordinates A9, L1-2and H3, with a spherical diameter of 1 mm in theregion of the H, and Hq fields of Forel (Fig. 1) (cfGrossman, 1958). If a thin sliver of tissueapproximately 3 mm thick, containing the SLRregion, is shaved off the brainstem, locomotion ceasesto occur spontaneously and stimulation of the MLRregion is required. Lesion studies in intact cats haveindicated that the SLR is important for the initiationof goal directed locomotion. After a lesion of an areaof the diencephalon corresponding to the SLR, theanimals initially are unable to commence voluntarylocomotion, although they do respond to noxiousstimuli. Within 2–3 weeks after Iesioning, theseanimals eventually recover the ability to initiategoal-directed locomotion, demonstrating that otherstructures eventually compensate for the lesion(Sirota and Shik, 1973; cited by Shik and Orlovsky,1976; cf Bard and Macht, 1958). Further support forthe role of the SLR in initiating goal-directedlocomotion was obtained by stimulating the SLRregion in intact cats (Mori et al., 1989). When theSLR was stimulated, the cat typically was arousedand orientated itself to the surroundings by raising itshead and looking around [Fig. 8(D)]. A few secondsafter the beginning of SLR stimulation, the catstarted to walk slowly and looked around repeatedly.According to Mori et al. (1989), SLR-inducedlocomotion was indistinguishable from spontaneouslocomotion. It is not known what connections fromthe SLR may produce this complex behavior. It islikely to be due to the activation of other rostral andcaudal areas, since stimulation of the SLR typicallyrequires some time before it produces locomotion,suggesting that reverberating circuits are activated.Garcia-Rill (1986) raised the possibility that stimu-lation of the SLR may be activating fibers of passagearising from the entopeduncular nucleus (EN) andsubstantial nigra which project to the thalamus anddirectly to the MLR. Stimulation of the SLR in thedecerebrate cat is thought to cause a disinhibition ofthe MLR. However, while the SLR may project tothe MLR region, the integrity of the MLR is notnecessary for SLR-evoked locomotion to occur inpremammillary cats (Sirota and Shik, 1973, as citedby Shik and Orlovsky, 1976). This suggests thatdescending projections from the SLR may activateother locomotor areas in the brainstem in addition tothe MLR, such as the MRF. Furthermore, this

observation supports the proposal that activation ofmultiple sites within the brainstem are necessary forlocomotion to occur (Garcia-Rill, 1991).

2.3, The Mesencephalic Locomotor Region (MLR)

Locomotion can be initiated in the decerebrate catby electrically stimulating an area of the brainstem[Fig. l(B)] close to the cuneiform nucleus known asthe mesencephalic locomotor region (MLR) (Shiket al., 1966a, 1966b). The MLR region is animportant integrative centre in the brainstem. Itreceives information from many areas of the brain,including the basal ganglia (Mogenson, 1990), theIimbic system (Garcia-Rill, 1986), and the frontalcortex (Divac et al., 1978). Graded electricalstimulation of the MLR in the decerebrate cat isfollowed by an increase in extensor tone and steppingthat often takes a number of seconds to appear. Thelocomotion produced by stimulation of the MLR canbe quite realistic. Many different gait patterns areproduced (walking, trotting, galloping) depending onthe strength of the stimulus. The optimal region in thebrainstem for eliciting locomotion is a 2 mmz arealocated just beneath the inferior colliculus (Fig. IB)and encompassing the pedunculopontine nucleus(PPN), the caudal end of the cuneiform nucleus, andthe brachium conjunctivum (Horsley-Clarke coordi-nates P2: L4: H6). It is controversial whether theanatomical location of the MLR is within thecuneiform nucleus or the PPN (Inglis and Winn,1995; Reese et al., 1995). This issue is still notresolved, although evidence using activity-dependentdyes and electrophysiological techniques points to thecuneiform nucleus as being a more likely candidatethan the PPN in the initiation of locomotion (Inglisand Winn, 1995; Shojania et al., 1992; Moon-Edleyand Gray biel, 1983; Jordan personal communi-cation). However, the PPN may be involved in theinitiation of locomotion under certain conditionssuch as when an intact animal is startled by anauditory stimulus (Garcia-Rill, 1991). One potentialproblem in establishing the anatomical location ofthe MLR is that there are direct connections fromneurons in lamina I of the spinal cord to this area(Hylden e? al., 1985). Thus it is not known whetherelectrical stimulation of the MLR may antidromicallyactivate ceUs in Iamina I and indirectly affect theoperation of the locomotor pattern generator (Reeseetal., 1995).

In addition to the MLR region, there are at leasttwo other areas in close proximity that can elicitlocomotion. The first area lies medial to the MLRand is located close to the spinal trigeminal nucleus(Shefchyk et al., 1984). It is thought that this area iscontinuous with Probst’s tract and forms thepontomedullary locomotor strip [Fig. 2(A); seeSection 2.3.2]. The second region is located dorsal tothe classic MLR in the inferior collicuhrs (Skinnerand Garcia-Rill, 1990). In comparison with the othertwo areas very little is known about its function or itsanatomical connections.

Interestingly, similar locomotor areas have beendescribed in different vertebrate species such as therat (Garcia-Rill et al., 1990; Bedford et al., 1992;Coles er al., 1989; Parker and Sinnamon, 1983),

486 1’.J. Whelan

guinea pig (Mar-linskii and Voitenko, 1992), stingray(Bernau et al., 1991), lamprey (McClellan, 1988;McClellan and Grinner, 1984), rabbit (Corio et al.,1993), monkey (Eidelberg et a/., 1981a; Hultb,xnet al., 1993) and the bird (Steeves et al,, 1987;Sholomenko et al., 1991). There are also clinicalstudies suggesting the existence of similar areas in theadult human (Caplan and Goodwin, 1982; Masdeuet al., 1994; Zweig et al., 1987; Hanna and Frank,1995) and the anencephalic infant (Peiper, 196! ascited by Forssberg, 1985). These and other common-alities amongst disparate vertebrates raise the h.)pethat advances currently being made on simple in t~trw

A Medial Pathway

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preparations such as the lamprey (Grinner et aI.,1995) can be extrapolated to higher vertebrates.

2.3,1. Inputs to the A4LR

Until recently it was not known whether cell bodieswithin the MLR were being activated to producelocomotion, or if the electrical stimulation wasactivating fibers that passed through the MLR region.Evidence suggesting that neurons within the MLRare stimulated has been obtained by chemicallyactivating the MLR/PPN region using agents that actpostsynaptically and which lead to the activation or

B Lateral Pathway

(pontomedullaryLocomotor Strip)

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Fig. 2. (A) The pathway from the MLR regiotipassesmainlyto the MRF regionof the brainstem. Aftersynapsing in the MRF area, the axons travel caudally through the ventrolateral funiculus (VLF) andsynapse with interneurons in the lumbar spin.d cord. (B) The medial MLR has been discovered onlyrelativelyrecentlyand is consideredto be distinct from the classicalMLR. It is located in closeproximityto the trigeminalsystemand nucleusand is th ~ughtto form part of a general sensoryactivating system.It travels through an area of the brainstem ctdled the pontomedullarylocomotor strip (PLS) (Probst’stract) and descendsvia the dorsolateral funiculus(DLF) to the dorsal horn of the spinal cord. The PLSis thought also to send collaterals to the MRI’ region. Figure reproduced from Mori et al. (1992)withpermission.Abbreviations:SLR, subthalamicocomotor region;MLR, mesencephaliclocomotor region;mMLR, medialmesencephaliclocomotorregion;PPN, pedunctdopontinenucleus;DTF, dorsal tegmentalfield; VTF, ventral tegmental field; CNF, cmeiform nucleus; LC, locus coeruleus; NRPo, nucleusreticularis pontis oralis; NRPc, nucleus reticularis pontis centralis; NRGc, nucleus reticularis

gigantocellularis;NRMc, nucleus reticularis magnocellularis;th., thoracic; Iumb., lumbar.


z

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Fig. 3. A diagram illustrating the effects of applyingneurotransmitters, their agonists and antagonists ontolocomotor regionsof the brainstem,The ‘ + ‘ symbolsreferto chemicals that evoked locomotion, while the ‘ – ‘symbols refer to chemicals that blocked locomotion. Thechemicals printed in italics lowered the threshold forevokinglocomotionbut could not, in isolation,evokeit. Seetext for more details. Abbreviations:MLR, mesencephaliclocomotor region; PPN, pedunculopontinenucleus; MRF,medialmedullaryreticular formation;PLS,pontomedullary

locomotor strip.

depression of locomotor activity. Chemical acti-vation of the MLR in the postmammillary cat(Fig. 3) by NMDA (Garcia-Rill et al., 1990) andGABA antagonists such as bicucttlline and picro-toxin (Garcia-Rill et al., 1985) can evoke locomotionthat is similar to that evoked by electricalstimulation. Locomotion evoked by infusion ofpicrotoxin or bicucr.dline will cease if either GABAor muscimol is infused onto the MLR (Garcia-Rillet al., 1985; cf Brudzynski et al., 1986). Thus,activation of the MLR is controlled by a mixture ofinhibitory and excitatory inputs. The origin of theseinputs to the MLR is diffuse, and locomotion maybe controlled by an activation of many systems inparallel (Reese et al., 1995; Inglis and Winn, 1995).In this review, two forebrain regions that projectonto the MLR, the basal ganglia and the NA, willbe discussed. Stimulation of the lateral hypothalamicarea (LHA) which projects to the MLR and onto thereticular formation also can evoke locomotion(Sinnamon, 1993). While the LHA is located in closeproximity to the SLR (Section 2.2), it has beensuggested that the more lateral regions of thehypothalamus may be involved in mediating appeti-tive responses while the area surrounding the zonaincerta (encompassing the SLR) may be responsible

for the control of exploratory locomotion (Sinna-mon, 1993).

The basal ganglia are involved intimately in theproduction of movement. This is evident in patientswho suffer from Parkinson’s disease, characterized byakinesia and abnormalities of gait. Classically, thebasal ganglia have been thought to influencelocomotion by a pathway that travels from the cortexthrough the striatum and pallidum and finally backto the cortex via the thalamus. However, the basalganglia do have direct connections to the MLR andthus could affect locomotion in a more direct way.Garcia-Rill and colleagues have described some ofthe connections between the basal ganglia nuclei andthe MLR (for a review, see Garcia-Rill, 1986). Asmentioned earlier, a premammillary preparation canspontaneously initiate locomotion, while a postmam-millary cat loses this ability and usually requireschemical or electrical stimulation to walk. The onlystructure rostral to the MLR in a postmammillarypreparation that is known to project afferents to theMLR is the substantial nigra pars reticulate (SNpr)which is part of the basal ganglia. Since neuronswithin the MLR can be activated by GABAergicantagonists, it has been suggested that the MLR inthe premammillary cat is under a strong inhibitoryinfluence from the SNpr [Fig. 4(B)]. Indeed,retrogradely labeled neurons have been found in theSNpr after a fluorescent dye was applied to the MLRregion (Garcia-Rill ef al., 1983a, 1983b) andintracelh.dar recordings from cells in the SNpr haveshown that they can be activated antidromically uponstimulation of the MLR (Garcia-Rill, 1983). Apuzzling question is that of whether structure iscontained within the small wedge of tissue [betweenslices ‘a’ and ‘b’ in Fig. l(A)] that allows spontaneouswalking to occur in the premammillary cat. The onlyknown structure that has connections with the SNprand is located within this wedge of tissue is thesubthalamic nucleus (STN). Preliminary evidence hasdemonstrated that the SNpr contains GABAreceptors and that GABA antagonists applied to theSN can block locomotion (Garcia-Rill and Skinner,1986). So this has led to the idea that the subthalamicnucleus inhibits the SNpr, which allows the MLR tobecome active [Fig. 4(B)]. While this hypothesis isvery appealing, it is unclear how this inhibition of theSNpr could occur, since Hammond et al. (1983) hasdocumented that there is a substantial excitatoryconnection to the substantial nigra pars reticulate.Furthermore, although Garcia-Rill et al., 1983a)found a projection from the SNpr to the MLRregion, less than 10°/0of SN neurons were activatedantidromically by stimulation of the MLR,suggesting that the projection is very sparse.

Another area of the basal ganglia that has beenproposed to affect the activity of the MLR is the EN,equivalent to the globus pallidus internis in primates.The EN has excitatory and inhibitory projections tothe STN, SN and the MLR (Garcia-Rill, 1983). Someof the EN axons travel through a region of thediencephalon known as the zona incerta whichcontains the SLR (Garcia-Rill, 1986; Grossman,1958; Wailer, 1970). If electrical stimulation wereprimarily activating the EN fibers, locomotion couldbe produced either by direct activation of the MLR

488 l’. J. Whelan

(possibly by a release of substance P) or indirectl! by that this pathway integrates food procurement,inhibition of the SN (Garcia-Rill et LI1., 1085; predatorescape, and other adaptive behaviors intoGarcia-Rill, 1983). the locomotor behavior of the animal (all studies

Another major input to the MLR arises from the performed using the rat). The projection from thelimbic system (Mogenson, 1987, 1990). It is believed Iimbic system to the MLR is indirect and is mediated

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I

1111

0’~~~,pp~t___-:Fig. 4. Simplifieddiagrams indicating the in mts from the Iimbicsystem (A) and the basal ganglia (B)onto the MLR region.Activationof the nuclms accumbensmainlyoccurs from excitatory activity fromthe hippocampusand amygdala. The nucleu~accumbenshas been shown to project to the MLR bothindirectly(heavylines)and directly(dashedline) The main pathwayis the indirectpathway.(B)The MLRis affected by activity in the basal ganglia. The MLR receives tonic GABAergic inhibition from thesubstantialnigra which, in turn, receivesGABAergicprojections from the subthalamic nucleus (STN).Activity of the STN causes a disinhibitionoi’the MLR, which presumably leads to the production oflocomotion.The entopedulcularnucleusw?i~cts both excitaw and inhibitw aff~retrtsto the sN andMLR, Thedotted linesindicatethe hypothesizedfunctionof the EN. Activityof the EN modulatesactivityin the SN and MLR whichenable the productionof locomotionby the MLR (see text for more details).Abbreviations: EN, entopeduncular nucleu:: SN, substantial nigra; MLR, mesencephalic locomotor

region; PPN, pedunculoponline nucleus;VTF, ventral tegmental field.


by the NA, which is part of the ventral striatum.Under normal situations, tonic inhibition of the NAby mesolimbic dopaminergic afferents from theventral tegmental area (VTA) results in the initiationof movement in the rat by an indirect activation ofthe MLR [Fig. 4(A)] (Mogenson and Wu, 1986;Brudzynski et al., 1993). When the amygdala orhippocampus is active, glutaminergic projectionsonto the NA cause an increase in locomotor behaviorin freely moving rats (Wu et al., 1993). Theseprojections synapse on D, receptors located interminals of the mesolimbic system within the NAand cause an increase in the inhibitory dopaminergicoutput from the terminals, allowing the MLR tobecome active. The NA exerts its effects on the MLRindirectly via an inhibitory GABAergic connection tothe ventral globus pallidus (sub-pallidal region).Finally, excitatory connections from the sub-pallidalregion pass through the zona incerta (the SLR) andwhich terminates onto the MLR (Brudzynski et aZ.,1993). Evidence suggesting this pathway exists isbased on these findings when locomotion is elicitedby NA or limbic system activation: (1) locomotioncan be attenuated by cooling of the zona incertaregion (Mogenson, 1987); (2) application of GABAto the ventral globus pallidus (subpallidal) (Jones andMogenson, 1980) or the MLR region results in areduction in locomotor behavior; (3) picrotoxin(GABA antagonist), when applied to the subpallidalregion, causes locomotion to increase (Mogenson andNielson, 1983); and (4) application of procaine(activity blocker) or cobalt chloride to the MLRregion causes locomotion evoked by limbic systemactivation to be reduced (Brudzynski et al., 1993).

It is important to realize that connections to andbetween nuclei of the brainstem are diverse and oftendiffuse. In light of this, Garcia-Rill (1991) hassuggested that stepping movements produced byactivation of “locomotor regions” occur by recruit-ment of many sites within the brainstem. Thisproposal is supported by these observations: (1)trains of stimuli need to be used when stimulatinglocomotor regions; (2) it usually takes 2–3 sec forlocomotion to occur; (3) while the MLR regionreceives many diverse inputs, locomotion can beproduced if this area is lesioned; and (4) stimulationof other areas of the brainstem, such as the mMLR,the MRF, PLS and SLR can elicit locomotion.

2.3.2. The Pontomedullary Locomolor Strip (PLS)

The PLS consists of a continuous strip of tissuethat extends from an area close to the spinaltrigeminal nucleus, continues caudally to the medullaand projects to the dorsolateral funiculus (DLF). Itis considered to be anatomically equivalent toProbst’s tract, which carries spinal and trigeminalafferents (Garcia-Rill, 1986). Stimulation of the PLSin a decerebrate cat can evoke bouts of locomotionsimilar to MLR-evoked stepping. It was proposedinitially that the PLS carried fibers from the MLRregion through to the DLF (Kazennikov et al., 1979,1983, 1988), It now appears that the PLS receivesafferent input from the medial MLR (mMLR) andprojects mainly to the MRF (Shefchyk et al., 1984)[Fig. 2(B)], because cooling of the MRF blocks

PLS-evoked locomotion while lesions of the DLF donot (Noga et al., 1991). However, since the PLS canbe activated chemically by glutamic acid orpicrotoxin (Fig. 3), it must contain neurons as well asaxons (Noga et al., 1988). It has been proposed thatthe medial MLR and PLS form part of a sensorialactivating system that is similar to the activation ofthe spinal central pattern generator (CPG) by tonicstimulation of dorsal roots or by pinching of the tail(Jordan, 1986; Noga er al., 1988; Garcia-Rill, 1986).This has been suggested in light of the followingobservations: (1) the effective drug-inducing siteswithin the PLS were located within the trigeminalnucleus; and (2) infusion of picrotoxin into the PLSregion allowed mild stimulation of regions innervatedby the trigeminal nerve (Pinna, Mandibulum) toevoke treadmill locomotion in the decerebrate cat(Noga et al., 1988).

2.4. The Medial Medullary Reticular Formation(MRF)

One of the main questions that arose from pastMLR experiments was that of which pathway in thebrainstem was being activated that led to thetriggering of the locomotor pattern generator in thespinal cord. By using a combination of chemical,cooling, lesion and electrophysiological techniques ithas been demonstrated that the MLR projects to anarea of the medial medullary reticular formation(MRF) [Fig. 2A)]. The MRF neurons project axonsto the intermediate and ventral areas of the spinalcord gray matter and descend within the ventrolateralfunicuhrs (VLF). The MRF receives a vast amount ofinformation from the cerebellum, cortex, basalganglia and the MLR (Armstrong, 1986). It is alsothe last integrative point before the descendinglocomotor command signal is relayed via the VLF tothe interneurons in the spinal cord (Noga et al.,1991). The region of the MRF in the cat that canevoke locomotion (PLGP14and LO-L2, Noga et al.,1988) includes the nucleus gigantocelhdaris andnucleus tegmenti reticularis. Electrical (Mori et al.,1978; Garcia-Rill and Skinner, 1987a, 1987b) orchemical (Noga et al., 1988; Garcia-Rill et al., 1985)stimulation of the MRF can induce locomotion indecerebrate cats, but the ensuing rhythm is lessregular and reliable than that evoked from the MLRregion (Jordan, 1986). Cooling or chemical stimu-lation of the MRF has indicated that it is animportant region for the initiation of locomotion.Cooling of the MRF region in postmammillary catscauses stepping to cease during both MLR-evokedand spontaneous stepping (Shefchyk et al., 1984).Furthermore, the effective sites within the MRF forevoking locomotion happen to receive inputs fromthe MLR (Garcia-Rill and Skinner, 1987a, 1987b;Steeves and Jordan, 1984) as well as from areasinvolved in the control of posture (Mori et al., 1992;Mori, 1987; Section 2.7). Pharmacological methodsdemonstrate that glutamic acid (Noga et al., 1988),acetylcholine (ACh) and substance P (Garcia-Rilland Skinner, 1987a) can evoke locomotion whenapplied to the MRF in the mesencephalic cat.Application of picrotoxin reduces the threshold forevoking locomotion by electrical stimulation of the

490 }’.J. Whelan

MRF but, in isolation, it is not capable of evokinglocomotion. The chemical activation of the MRFdemonstrates that activation of cell bodies, and notfibers of passage, can evoke locomotion. One wouldexpect from these studies that neurones containingsubstance P, ACh or glutamate would exist within theMLR; however, the experimental evidence is mixed.There is little evidence for the existence of AC!] orsubstance P neurons in the MLR (Leger er al., 1983;Lee PI al., 1986), although Garcia-Rill and Skinner1987a), 1987b) have obtained some evidence fol theexistence of cholinergic neurons contained withil thePPN.

Similar to the MLR region, MRF locomotor areashave been found in other species such as the lamprey(McClellan and Grinner, 1984; McClellan, 1(88),stingray (Livingston and Leonard, 1990; Belnauet al., 1991), bird (Steeves et al., 1987; Sholomt nkoet al., 1991)and rat preparations (Kinyo et al., 1(~90).

2.4.1. Regulation qf”Ongoing Locomotion

The MRF can regulate as well as initiale alocomotor pattern. Orlovsky (1970) found th:t inpostmammillary and premammillary cats, cells o’ thereticular formation (located in the medial longit udi-nal fasciculus) responded mainly during the fl:xorportion of the step cycle, and that stimulation oi thisregion increased the amplitude of the flexor bl lrstsduring swing (Orlovsky, 1972a). More recent studiesin premammillary and intact cats have shown thatrecording from cells in the MRF show considel:~blymore complex response characteristics (Drew andRossignol, 1984; Drew et al., 1986; Drew, 1991bI. Inpremammiilary decerebrate cats (Drew and Rossig-n 1 c w f t iphysically with high firing rates during the stance andswing phase of the step cycle.

Since MRF neurons can affect different muscl .x inall limbs in a phase-dependent manner, it has teenproposed that the descending signal is sculpted b:. theactions of the central pattern generator (CPG) (1h-ewet a/., 1986). It is not known at present how tl is isaccomplished; however, gating of the descendinginput could occur by presynaptic inhibition o(’ themonosynaptic projecting MRF fibers, or by post syn-aptic modulation of the motoneuron and/or m]du-Iation of interneuronal connections. Output fronl theCPG could provide the phasic signal that allow: thisto occur (cf Fleeter et al., 1993).

It was discovered recently that the phasic !Iringpatterns of MRF cells are qualitatively simikr infictively locomoting cats that lack phasic affcrentinput (Perreault et al., 1993). These data demonstratethat the phasic modulation of neurons withir theMRF is, to some extent, produced centrally. Thephasic modulation of reticulospinal neurons isdependent on the integrity of the ventral spino:ere-bellar tract (VSCT). The VSCT carries informatitm tothe cerebellum regarding the activity of rhythmicallyactive interneurons within the spinal cord and relectsthe activity of the locomotor CPG (Arshavsky cr al.,1972a, 1972b, 1972c). Even though MRF neurons arerhythmically active during fictive locomotion. evi-dence suggests that afferent (especially cutam:ous)input has access to these neurons (Shimamura e~al.,

1982, 1985, 1990; Shimamura and Kogure, 1979,1983; Eccles et a/,, 1975; Drew et al., 1986).Shimamura and colleagues have shown (Shimamuraand Livingston, 1963) that there is a spino-bulbo-spinal reflex pathway which is activated mainly byascending cutaneous input from the limbs (Shima-mura and Kogure, 1979, 1983) and which primarilyaugments the flexor burst in premammillary cats(Shimamura et a/., 1982; Shimamura et al., 1990).Supporting evidence for afferent regulation of MRFcells was obtained by Drew et al. (1986) from intactwalking cats. In these animals, MRF cells that firedin response to light touch from many areas of thehindlimb and trunk were recorded at rest.

One of the functional roles that has been suggestedfor the MRF is that it may be involved in interlimbcoordination during normal walking (Drew et al.,1986; Shimamura and Kogure, 1983). This is basedon evidence which shows that microstimulation of theMRF region using short stimulus trains can producephase-dependent activity in muscles in all four limbsthat is incorporated into the ongoing step cycle inpremammillary cats (Drew and Rossignol, 1984),postmammillary (Perreault et al., 1994b) and intactcats (Drew, 1991b; Drew and Rossignol, 1990a,1990b). Using longer stimulus trains can increase theduration of the ipsilateral swing phase, with acorresponding increase in the contralateral stancephase (Drew and Rossignol, 1984; Drew, 1991b; cfRussel and Zajac, 1979), resulting in a change in thetiming of the step cycle. In support of these findings,Shimamura and Kogure (1983) illustrated thatmaximum firing of reticulospinal cells was dependenton the correct position of all limbs in relation to eachother in premammillary cats.

2.5. The Ventrolateral Funiculus (VLF)

In the cat and other species (Steeves et a/., 1987;Webster and Steeves, 1991; Magnuson et al., 1995;Garcia-Rill et al., 1990; Eidelberg et al., 1981b), theprojections from the MRF region to the spinal corddescend in the VLF of the spinal cord [Fig. 2(A) andFig. 5]. Orlovsky (1969) found that there was anincrease in impulse traffic in the VLF afterstimulation of the MRF in decerebrate cats.Furthermore, in the decerebrate cat, the integrity ofthe VLF tract is essential for the production oflocomotion (Afelt, 1974; Steeves and Jordan, 1980;Eidelberg et a/., 1981b), while Iesioning of thedorsolateral tract containing the descending tractfrom the PLS does not affect the ability to evokelocomotion (Noga et al., 1991). In intact cats,Eidelberg (1981) found that the recovery oflocomotion was dependent on the ventrolateralquadrant of the spinal cord being intact. However,recent experiments which have Iesioned areas of theVLF and/or DLF have found that lesions of the DLFcan have large effects on interlimb coordination inintact animals (Bern er al., 1995; Gorska et al., 1993).Similar tindings have been made by Brustein et al.(1995), in which intact animals with extensive lesionsof the VLF regained the ability to walk. Thesefindings suggest that there may be parallel pathwaysthat can trigger or enable the pattern generator forlocomotion. However, it must be kept in mind in any


A p r e

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F precool

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I

,P17

Fig. 5. Effectsof reversiblecoolingof the dorsal columns,DLF, or VLF of the spinal cord on hindlimblocomotionelicitedby stimulationof the ipsilateralPLSat the P17level[solidlesionsite indicatedin (I)].(A)-(C) Illustrate the responsesproducedby stimulationof the PLSprior to, duringand followingcoolingof the dorsal columns to a probe-tip temperature of – 3“C.The effectsof cooling the DLF (1‘C) andVLF (6”C)are illustratedin (D) and (G), respectively.The extentof fiber(hatched)and synaptic(stippled)is estimated in (1)for each of the trials. Letters beneath spinal cord sections indicate the correspondingcooling trials in (B), (D) and (G). The PLR stimulation parameters were 30 Hz, 0.5 msec duration (alltrials). Modified from Noga et al. (1991), with permission. Abbreviations: PLS, pontomedullary

locomotor strip; DLF, dorsolateral funiculus;VLF, ventrolateral funiculus.

lesion study that reorganization of the CNS islikely to be taking place (Devor and Wall, 1978;Goldberger and Murray, 1988; Mendell, 1984;Kandel, 1981), so any results gained must beinterpreted cautiously.

2.6. Interneurons Activated within the Spinal Cord

It is currently unknown which neurotransmittersare released at the terminals of the VLF axons,

although recent evidence from the neonatal ratstrongly suggests that it may be glutamate (Elliot andWallis, 1993; Magnuson et al., 1995; Wallis and Wu,1993). Furthermore, it is not known which inter-neurons in the spinal cord receive the VLF afferentsand whether they form part of the CPG. In the last10years, some progress has been made on two fronts:(1) the location of the interneurons that arerhythmically active during MLR stepping, and (2)which neurotransmitters may be involved in transmit-

W

ting the descending command for evoking loco-motion.

2.6.1. Location qfRhythmically Active Interneurons

Gaining knowledge of where rhythmically activeinterneurons exist that could form part of the spinalCPG is one of the first steps towards understandingthe circuitry involved in the production of alocomotor pattern. As mentioned by Noga e[ ,11,,1995a), there have been many studies which h:~vedocumented the occurrence of rhythmically ac[lveinterneurons in the spinal cord during evokedlocomotion (Arshavsky et a/., 1972a, 1972b;Orlovsky and Feldman, 1972; Fleeter et al., 1993;Feldman and Orlovsky, 1975; Edgerton et a/., 1976;Baev et al., 1979; McCrea et al., 1980;Noga et d,,1987; Pratt and Jordan, 1987; Hishinuma : ndYamaguchi, 1990; Ichikawa et al., 1991; Viala e[ id.,199I; Yamaguchi, 1991, 1992), but only a few typesof spinal neurons have been examined in correla[ ionwith activation of the MLR or the cuneiform nuclars(Kazennikov et al., 1979, 1983; Edgley et al., 1988;Jankowska and Noga, 1990; Shefchyk et ![/.,1990;Noga er al., 1995a). Over the last 10 years, 1.woinnovative applications of established techniqueshave been used in the decerebrate cat to localizerhythmically active interneurons.

The first technique (Noga er al., 1995a) combiredthe use of cord dorsum and focal recordings ofextracellu]ar field potentials (Skinner and Wi Ilis,1970; Fu ef al., 1974; Skinner and Remmel, 1(78)using isopotential maps (see Willis, 1980, fo- areview) to localize areas of rhythmic neuronal acti itywithin the cat spinal cord upon stimulation of theMLR region. Since this technique is relatively Eew,the methods used will be outlined in some de.aii.When fictive locomotion was evoked using M LRstimulation, the intraspinal field potentials recoldedin the spinal cord were sampled at evenly spicedpoints (every 250 urn) in both the horizontal .indvertical planes using sharp microelectrodes. f_heaverage amplitude of these intraspinal field poten idswas then recorded at fixed Iatencies triggered ol~ ofthe onset of the MLR stimulus using a win~iowdiscriminator. A matrix of intraspinal amplitudes wasthen assembled that correlated to fixed points in thewhite and gray matter of the spinal cord. After $inga spline function to generate a matrix of higherresolution, lines of equal amplitude were joine~i toone another creating an isopotential contour ef~ect.Finally, the isopotential maps were transposed (intodigitized sections of the spinal cord (points in thematrix were identified by electrode tracks in thespinal cord) to generate the pictures in Fig. 6. Lsingthis method of isopotential mappings in the fictivelylocomoting cat, monosynaptic activation of illter-neurons by MLR stimulation has mainly “:~eenconfined to Iamina VII (Noga et al., 19Q5a).Disynaptic innervation has mainly been localized tolaminae VIII, IX and X (Noga et al., 1995a).

The second method that has been used in thedecerebrate cat with some success has been the u>eofc-~os, an activity-dependent marker, to identifyvisually neurons that are active during locomotion(Carr et al., 1995; Carr et al., 1994; Dai et al., 1990)

or scratching (Barajon et al., 1992). Most c+irsimmunoreactive neurons were found to be distributedin medial laminae VI and VII and in laminae VIIIand X during MLR-evoked walking. This result issimilar to that reported for the distribution of c-~o.rimmunoreactive neurons during fictive scratching(Barajon et al., 1992) and qualitatively matches thatobserved using isopotential mapping techniques(Noga et al., 1995a).

In summary, localization of rhythmically activeinterneurons in fictively locomoting animals is usuallyconfined to the intermediate and ventral quadrants ofthe spinal cord [ Noga et al,, 1995a; Carr et a[., 1995;Kjaerulff et al., 1994 (rat); Ho and O’Donovan, 1993(embryonic chick)] and is distributed along theIumbosacral spinal cord (Deliagina etal., 1984;Grinner and Zangger, 1984). In all of the studiesmentioned thus far, it must be realized that theexistence of these rhythmically active interneuronsdoes not imply that they form part of the spinal CPG.More research on the identification of these neuronsand their synaptic inputs must be completed beforeany firm conclusions can be made on this issue.

2.6.2. Neurotran~mitiers Inuohwl in Activatingthe CPG

For many years, it was thought that monoaminer-gic pathways were responsible for the activation ofthe spinal CPG because L-DOPA (a precursor fordopamine and noradrenaline) could initiate loco-motion in acute cats that had a transected spinal cord(Grinner, 1973). Furthermore, noradrenaline wasthought to be especially important because: (1)clonidine (a noradrenergic agonist) mimicked thee of L-DOPA in spinal animals (Forssberg andGrinner, 1973); and (2) when the enzymatic stepsbetween L-DOPA, dopamine and noradrenaline wereblocked, the actions of L-DOPA could be prevented(Anden et al., 1966). However, Steeves etcd.(1980)found that depletion of noradrenaline and serotoninin cats did not abolish locomotion, indicating thatother neurotransmitters were at least partly respon-sible for triggering the locomotor rhythm. It has sincebeen suggested that the noradrenaline and serotoninmay act as enablers of the locomotor pattern and notinitiators (Harris-Warrick, 1988).

One class of neurotransmitters capable of elicitinga locomotor rhythm in a variety of preparations is theexcitatory amino acids (EAA). The EAA agonists,such as N-methyl-D-aspartate (NMDA), have beenfound to elicit a locomotor rhythm in a variety ofin uitro preparations including the lamprey (Grinnerer al., 1981; see Grinner et al., 1995, for a review), thetadpole (Dale and Roberts, 1984), neonatal rat(Kudo and Yamada, 1987; Cazalets et al., 1992) andmudpuppy (Wheatley et al., 1992). A major obstaclethat existed in extrapolating this work to the intactanimal was that drugs that antagonize or agonize theEAAs cannot cross the blood–brain barrier. Thisproblem was addressed recently by Douglas et al.(1993), who developed a method for the intrathecalinjection of drugs directly into the sub-arachnoidspace of the lumbar spinal cord in cats. By addingthese drugs during MLR-evoked walking, it waspossible to see what effects they had on the stepping

L5 map

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VII

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a

b

c

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Fig. 6. Localizationofinterneurons usingisopotentialmappingofextracellular potentials.The followingfigures[(A)and (B)]illustrate fieldpotentials (left hand traces) and isopotentialsmaps on the right fromtwo separate experiments. (A) Amplitude measurement latencies following the MLR stimulus areindicatedas numberedarrowheadsand correspondto the numberedisopotentialmaps on the right. Largenegativecurrent sinks (solid isopotential lines)are evident in IaminaeVII–X.The earliest fieldpotentialsweregeneratedin the intermediateareas (IaminaeVIand/or VII) withlater fieldpotentialsbeinggeneratedin Iaminae VIII, IX or X as cells in the ventral horn and around the central canal displayedincreasedactivity. In (A), the foci of positivitywere localizedto the medial aspect of Iaminae II, III, IV and VIand to the dorsal columns. In (B), foci of positivitywere apparent to the medial part of Iamina VI and

to the middle aspect of Iamina VII. Modifiedfrom Noga et al., 1995a),with permission.

494

A

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APV 47 mmutes

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pattern. When 2-amino-5 -phosphonovaleric ~cid(APV), a specific NMDA antagonist, was injected intothe spinal cord, the ensuing rhythm in the hindl; mbsevoked by MLR stimulation was blocked [Fig. 7:C)].Upon washout of APV, the rhythm resumed[Fig. 7(D)]. Application of 6-cyano-7-nitroquinoxa-line-2,3-dione (CNQX) (a non-NMDA glutamateantagonist) had similar effects to APV, indicating thatat least two glutaminergic receptor pathways werecontributing to the initiation of locomotion. WhenNMDA was added to the spinal cord, bouts oflocomotor activity were generated; however, theydiffered from that produced by MLR stimulation asthe flexor and extensor electroneurogram (E?JG)bursts occurred synchronously. On the other hand,when NMDA was added with dihydrokainic acid(DHK), which is an EAA uptake blocker, thelocomotor pattern was improved greatly andproduced an alternating pattern that was comparableto that produced by MLR stimulation. These findingsstrongly suggest that glutamate contributes tc theproduction of the locomotor pattern in cats.

There are two ways in which locomotion can beevoked by glutaminergic agonists. Firstly, theghttaminergic agonists that are released intrathecally

activate the glutaminergic receptors that receiveaxons from the descending retictdospinal fibers.Although the neurotransmitters that are releasedfrom the terminals of the reticulospinal axons thatdescend from the MRF have not been identified, it isthought that they are probably glutaminergic. Thisassumption is based mainly on studies from in vi[romodels such as the lamprey (Ohta and Grinner, 1989;Grinner etal., 1995) and neonatal rat (Hockmanet al., 1994; Magnuson ef al., 1995; Kjaerulff et al.,1994). Secondly, the addition of gltttaminergicagonists (or antagonists) causes a generalizedexcitation of the interneurons in the spinal cord thatare normally rhythmically active during MLR-evoked locomotion. It is known that large areas ofthe spinal cord contain neurons that are rhythmicallyactive during MLR-evoked walking (Noga et al.,1995a) and that there is a wide distribution of EAAreceptors in the spinal cord (Mayer and Westerbrook,1987). In support of this, Douglas et al. (1993)observed both locomotor and paw-shaking motorpatterns when DHK and NMDA were addedintrathecally, which suggested that the EAA agonistswere exciting two sets of interneuronal networks eachresponsible for producing a different behavior.


2.7. Interaction of Posture and Locomotion

Normal stepping does not occur without posturalcorrections that allow the animal to maintain itsbalance and stability. Even in the decerebrate cat,postural changes occur before an animal begins tolocomote (Takakusaki et al., 1993; Oka et al.,1993). Before locomotion occurs in a cat, there istypically an increase in extensor tone that can, attimes, be large enough to support an animal’sweight. Using walking decerebrate and intact cats,Mori and colleagues have discovered two regionswithin the brainstem that influence the level ofpostural tone (Mori, 1987; Mori et al., 1992).Stimulation of an area within the dorsal tegmentalfield (DTF) of the brainstem caused a reduction inextensor tone, while stimulation of the ventraltegmental field (VTF) increased the level of extensortone (Fig. 1, Fig. 2). Moreover, stimulation of theMLR region could interact with stimuli of the DTFor VTF by reducing or increasing the vigor oflocomotion respectively. With paired stimulation ofthe MLR and DTF area, four-legged locomotion inthe decerebrate cat was changed to locomotion ofthe hindlimbs only, and from hindlimb locomotionto total suppression of the ongoing steppingpattern with graded increases in the intensity ofstimulation to the DTF (Mori et al., 1978). Incontrast, simultaneous stimulation of the MLR andVTF region could change the pattern of locomotionfrom a walking to a galloping gait, depending on

A. DTF; Locomotor and Postural Suppression

the activation level of the paired stimuli. Neu-roanatomical and electrophysiological evidence haveled to the identification of the DTF and VTFpathways.

Electrical stimulation of the DTF mainly activatesfibers of passage originating from cholinergic neurons(Takakusaki et al., 1993) contained within thenucleus reticularis pontis oralis. These fibers projectto the nucleus reticularis gigantocellularis that iscontained within the MRF (Matsuyama et al., 1993,1988; Iwakiri et al., 1994; Oka et al., 1993; Moriet al., 1992). Similar to previous studies on theinitiation of locomotion (Noga et al., 1991),descending axons of neurons contained within theMRF descended within the VLF of the spinal cordbefore terminating in laminae VIII and VII(Matsuyama et al., 1988). The location of the VTFarea corresponds to the rostral portion of the raphenucleus (Mori et al., 1985) which is known to projectdescending axons through the VLF. Preliminaryevidence suggests that the VTF receives inputs fromthe lateral hypothalamic area and the cuneiformnucleus (Mori and Ohta, 1986).

Mori and colleagues compared the responsesobtained from decerebrate cats with similar acti-vation of the DLF and VTF as well as the MLR andSLR in intact cats (Mori et al., 1989). Stimulation ofthe DLF in a cat that was freely moving would leadprogressively to the cessation of walking followed bysitting and lying of the animal [Fig. 8(A)].Conversely, stimulation of the VTF would cause a

B. VTF; Postural a ( a l

c

D. SLR; s l b “ r

Fig. 8. Effectof stimulatingdifferentlocomotor regionsin the intact freelymovingcat (see text for moredetails). Abbreviations:DTF, dorsal tegmental field;VTF, ventral tegmental field;MLR, mesencephalic

locomotor region; SLR, subthalamic locomotor region.

496 l). J. Whelan

postural augmentation in a sitting cat followed bystanding and spastic locomotion [Fig. 8(B)]. Afterstimulation of the MLR region, a cat would begi:l towalk or run without stopping, but it retained itsability to avoid obstacles [Fig. 8(C)]. If DLFstimulation was paired with the MLR stimulation inchronic cats, the postural support of the hindlimbswas suppressed and the cat stopped walk ing.Stimulation of the SLR region in the chronic cat .dsomade a sitting cat locomote, but this time themovements, in contrast to VTF and MLR stinu-Iation, were indistinguishable from normal mt,ve-ments [Fig. 8(D)]. It appeared that the aninlaisadopted a searching type of behavior typical ofnormal cats. From these observations, Mori e/ al.(1992) suggested that the postural and Iocom,,torsynergies are structured in a hierarchy within therostro-caudal axis of the brainstem, and that thecommand routing depends on interactions with theSLR, the MLR/PPN complex, the DTF and the \’TFareas which are partly integrated at the MRF bel’orecontinuing to the spinal cord.

2.8. Summary

The pathways that lead to the production oflocomotion in the decerebrate cat have been p:rtlytraced. The MLR region of the brainstem recc ivesinputs from the lateral tegmental area of thehypothalamus, the basal ganglia and the Iilrbicsystem. It is believed that these inputs lead to theproduction of different locomotor behaviors in theintact cat. A major pathway from the MLR continuesto the MRF in the medulla. The MRF reccivesinformation from the forebrain, brainstem, certbel-lttm and from cutaneous afferents and is believeii tobe involved in the integration of posture andlocomotion. The MRF can initiate and regulate theongoing step cycle. Evidence from recent experimentssuggests that one functional role for the M RF is thecontrol of interlimb coordination. Although t isknown that neurons from nuclei in the MRF projectvia the VLF of the spinal cord and that they can havepolysynaptic and monosynaptic connections withmotoneurons in the spinal cord, it is not known howthese projections can lead to the initiation oflocomotion. However, a first step in realizing thisgoal has been the correlation of MLR stimulationwith rhythmically active interneurons in the spinalcord. It has been shown recently that rhythmicallyactive neurons that respond to stimuli delivered to thelocomotor producing regions of the brainstem arelocated in Iaminae VII, VIII and around the centralcanal. Recent experiments using decerebrate catshave demonstrated that MLR-evoked walking can beblocked reversibly using NMDA antagonists,suggesting that glutaminergic and not monoamlner-gic drugs are essential for the development of arhythmic motor pattern in the decerebrate cat. Areasthat evoke postural changes accompanying loco-motion have been identified in areas of the brain>temknown as the DTF and VTF. It is thought thatlocomotor and postural control signals are integratedin the MRF and the spinal cord.

3. AFFERENT CONTROL OF LOCOMOTION

I f o Gi a a s c s

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(Sherrington, 1924, as cited by Gossardand Hultborn, 1991).

3.1. Introduction

Animals rarely move about in an unchangingenvironment. Fish, for example, must be able tomaneuver and change course in responsecurrents, vegetation and rocks. Terrestrial animalsface far more variability as they move acrossuneven terrain rife with its own dangers. Tosurvive, animals must possess motor patterns that arerobust yet flexible enough to handle unusualsituations.

It is generally accepted that the basic rhythm-generating network is contained within the spinalcord and afferent input can access this circuitryand modify the ongoing pattern. An example ofthe power of afferent feedback can be observedwhen chronic cats with a transected spinal cordrecover the ability to walk when trained daily on atreadmill (Barbeau and Rossignol, 1987). After 3weeks, the cats can easily adjust their gait to thespeed of the treadmill. Since these animals have atransected spinal cord, only afferent feedbackfrom the moving limbs can provide the inform-ation necessary to adjust the output of the CPG.Another example which demonstrates the adap-tability of the motor pattern by afferent feedbacko when a split treadmill is used to driveeach hindlimb of intact cats at different speeds. Ifone side is sped up in relation to the other, perfectcoordination is maintained. The stance phase ofthe “fast” side is decreased relative to the “slow”side. These adjustments can be made not only inintact cats (Halbertsma, 1983)but also in decerebrate(Kulagin and Shik, 1970; Yanagihara et al., 1993)and low-spinal locomoting cats (Forssberg et al.,1980b).

During changes in gait it is the stance phase of thestep cycle that is adjusted to the greatest degree.Consequently, when a cat speeds up, the length of thestance phase is reduced while the swing phase remainsmore or less the same (Grinner, 1981; Rossignol,1996). From these observations, it was proposed thatafferent feedback from a moving limb may controlaspects of extensor muscle activity during the stancephase. Another possible role of afferent feedback is togauge the amount of propulsive force that needs tobe generated under different environmental con-ditions. For example, when a cat is walking uphill,the EMG amplitude of the extensors is increasedcompared to walking on a flat surface, while theflexor bursts remain unaltered (Pierotti et al., 1989).Recently, substantial progress has been made inidentifying the types of afferents that contribute tothe control of the duration and the amplitude of the


extensor burst. The next section is devoted to adiscussion of these findings.

3.2. Reinforcement of the Ongoing Step Cycle

When an animal is walking, there must be asufficient amount of tone in the extensor muscles tocarry the weight of the animal. As mentionedpreviously (Section 2.7), before locomotion com-mences there is an increase in the level of posturaltone in the extensor muscles which occurs byactivation of descending pathways (Mori et al., 1992).Afferent feedback from extensor muscles adds to themaintenance of this postural tone and ensures that itis adjusted depending on the load carried by the limb.The concept that afferent feedback acts to reinforceactivity in muscles has endured for over 30 years. Forexample, Yang et al. (1991) have estimated that3&60Y0 of the EMG amplitude in the soleus musclemay be accounted for by monosynaptic excitation ofthe motoneuron alone. Moreover, in the decerebratelocomoting cat, Severin (1970) estimated by revers-ible inactivation of the gamma motoneuron axons(thus eliminating the fusimotor drive to the extensormuscle spindles) that 50°A of the extensor EMGactivity was produced by group Ia activity. Inaddition to the monosynaptic pathway, a newoligosynaptic excitatory pathway has been discoveredin the cat that is only open during locomotion andlikely receives convergent afferent input from bothgroups Ia and Ib afferents (Figs 9 and 10) (Gossardet al., 1994;Pearson and Collins, 1993;Guertin et al.,1995a). The output from this pathway producesexcitatory postsynaptic potentials (EPSP) in extensormotoneurons that are modulated in a phase-depen-dent manner. Studies from reduced preparations havedemonstrated that input from extensor group Iafferents that project onto this oligosynaptic pathwaycan reinforce the extensor burst. The followingsection will discuss the contribution from extensorgroup I afferents to the reinforcement of the extensorburst.

In the cat (Pearson and Collins, 1993), as in otherspecies (DiCaprio and Clarac, 1981; Bassler, 1983,1986; Lacquaniti et al., 1991; Skorupski, 1996;Skorupski and Sillar, 1986), there is a reflex reversalof the central effects of input from the force or stretchdetecting afferents [Fig. 9(A)]. In the walking systemof the cat, input from Golgi tendon organs (GTO) inextensor muscles onto extensor motoneurons isreversed from inhibitory to excitatory at the onset oflocomotion (Pearson and Collins, 1993; Gossardet al., 1994). The pathway that has been usedpreferentially to show this effect is the one fromplantaris (Pi) to medial gastrocnemius (MG). This isbecause P1 does not project any group Ia afferentsdirectly to the MG motoneurons (Eccles et al.,1957b), thus all effects onto MG from PI are mediatedby polysynaptic pathways. In the resting spinal cat,stimulation of the P1nerve at group I strengths resultsin the classic inhibition of the extensor burst[Fig. 9(A)] (originally described by Eccles et al.,1957a). However, when the locomotor CPG isactivated (by adding clonidine) similar stimulation ofthe P1 nerve during mid-stance results in an increasein the amplitude of the MG EMG [Fig. 9(A)]. It has

been suggested that a locomotor-dependent oligosy-naptic pathway that accesses the extensor half-centerof the CPG is responsible for mediating this effect(Gossard et al., 1994); this is supported by studieswhich show that activation of group Ib afferents bystretching the triceps surae muscles can entrain andre-set the locomotor rhythm (Conway et al., 1987;Pearson et al., 1992). Recent evidence suggests thatgroup Ia feedback from extensor muscles also canincrease the amplitude of the extensor burst using thesame oligosynaptic pathways as group Ib afferents(Guertin et al., 1995a).

Intracellular studies have complemented the abovefindings and have found that more than oneexcitatory group I pathway is opened duringlocomotion. The first oligosynaptic pathway has onlybeen observed in fictively locomoting decerebrate cats(McCrea et al., 1995b). When extensor group Iafferents are stimulated, a disynaptic EPSP can beobserved in extensor motoneurons which is physicallymodulated during the locomotor cycle. The func-tional role of this pathway is unknown, although itmay provide more flexibility in the reinforcement ofthe extensor burst (McCrea et al., 1995a, 1995b),since it is hypothesized that this pathway lies outsidethe CPG. The second oligosynaptic pathway isopened after the administration of L-DOPA in spinalcats [Fig. 1O(A)]or during MLR-evoked locomotionin decerebrate cats [Fig. 1O(B)](Gossard et al., 1994).Before L-DOPA is injected into an acute spinal cat,stimulation of group I extensor afferents [stimulustrains: 300 Hz (3–10 pulses)] causes summating IPSPSin the lateral gastrocnemius and soleus (LGS)motoneuron. When L-DOPA was added, the IPSPSwere reduced gradually in size and replaced by slowrising EPSPS that, after 30 rein, were large enough tocause a cell to fire an action potential. The MLRstimulation was equally effective in opening up thislong-latency excitatory pathway. It is likely that theoligosynaptic pathway accesses the extensor half-cen-ter (CPG) since: (1) similar feedback that elicits thisslow potential can entrain and reset the locomotorrhythm (Conway et al., 1987; Pearson et al., 1992);(2) the group I feedback can interact with the FRAsystem that is hypothesized to share circuitry with thehalf-centers (see Lundberg, 1981for a review); and (3)extracelhdar recordings from rhythmically activecandidate interneurons illustrate that contralateralFRA stimulation can increase the firing rate and canaugment the excitation produced by ipsilateral groupI excitation (Gossard et al., 1994). Furthermore,these interneurons are located in Iamina VII, an areathat contains interneurons that are rhythmicallyactive in response to MLR stimulation (Noga et al.,1995a).

An important question is whether these findingsare functionally relevant in the intact animal.Unfortunately, there are no studies in intact cats thathave specifically tested whether stimulation of groupI afferents can affect the amplitude of the extensorEMG burst. However, a study by Whelan et al.,1995a) found that in decerebrate walking cats,stimulation of the extensor group I afferents duringstance tended to increase the amplitude of theextensor burst especially during late stance[Fig. 11(A)]. This suggests that extensor group I

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reproduced from Proclazka et (/1,(1989),with permission,

feedback is functionally relevant when the animal is phase) when the extensor muscles are stretched as thereceiving full afferent feedback from the step~~ing weight of the animal is partly borne by the limb.limbs. Afferent reinforcement of stance would be Presumably, the positive feedback from the increasedexpected to be especially useful during mid-stance (Ej firing of GTO afferents combined with negative

Control of L,ocomotion 499

feedback from spindle afferents would act to resistthis Ej stretch. Recent modeling studies havesupported the idea that positive feedback can act inthis manner (Prochazka, 1996). Another proposal isthat the reduction in positive feedback from extensorgroup Ib afferents at the end of stance allows swingto commence (Pearson, 1995a; Section 3.3.1).

Consistent with both of these proposals, ensemblerecordings from both group Ib and Ia afferents inintact freely moving cats show that both have a highrate of firing during the stance phase [Fig. 9(B)](Prochazka et al., 1989; Prochazka and Wand, 1980;Appenteng and Prochazka, 1984). For example, theensemble firing rate of group Ib afferents from the

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F 10. (A) Excitatory actions of group I volleysrecorded intracelhdarly in a LGS motoneuron afterstimulatingthe PL nerve at 1.4 x T. Before the injectionof L-DOPAand nialamide, stimulation of thePL nerve produceda small EPSPwhichwas predominatedby summatingIPSPSwhichcontribute to theclassic non-reciprocalinhibitionproduced by the group Ib afferents.After treatment with L-DOPAandnialamide, the IPSPSwere inhibited and is replaced by a slow rising EPSP that increases progressivelyin size as the locomotor pathway opens. (B) This trace shows the emergenceof the group I excitatoryresponse before and after stimulation of the MLR region in a paralyzed cat. (A) From top to bottom:tilted verticallyare the high-gainintracellular responses(100msec sweeps)to group I stimulation of thePL nerve (2 x T). Note that the first trace in this sequenceshowsthe classic Ib inhibition,but the thirdtrace in the sequencewith MLR stimulation shows an excitatory response.The Em trace indicates theslow low gain intracellular record which indicates the locomotordrive potential. The last two traces areENG t from the tricepssurae (GS)and the tibialisanterior (TA)respectively.Modifiedfrom Gossard

et al. (1994),with permission.Abbreviation:PL, plantaris.

W

triceps surae muscles follows the activity of thegastrocnemius EMG with the highest firing rateoccurring when the leg is loaded maximally duringmid-stance [Fig. 9(B)]. Group Ia afferents from thetriceps surae also fire at an appreciable rate duringthe stance phase (Prochazka et al., 1989; for re~iewof spindle function see Hulliger (1984); Gladden(1992)). These results demonstrate that extensorgroup I afferents are active during stance in the intactcat and could participate in the reinforcement! ofstance.

3.3. The Control of the Stance to Swing Transition

Sensory feedback from the hindlimb can influenceaspects of a cat’s locomotor pattern during walking.When a cat speeds up or slows down, adjustment: aremade to the length of the extensor burst, while theflexor burst remains unaltered. This adaptation iscaused by afferent signals that regulate the transitionfrom the stance to the swing phase. At the presenttime there are two proposals regarding the afferentcontrol of the timing of the stance to swing transitionduring stepping. The first proposal is that a reductionin force feedback, due to the unloading of theextensor muscles at the end of stance, is the signa ! forinitiating the transition from the stance to swingphase. This idea was advanced by Duysens andPearson (1980) to explain the observation thatstretches of the extensor muscles in decerebrate catswalking on a treadmill could inhibit the generation ofthe flexor bursts. The generation of the flexor burstwas conditional on the force level being redl Icedbelow a level of 40 N. This led to the proposal thatsignals generated by the GTO and carried b). lbafferents could prolong the stance phase. The se( ondproposal is that afferents from the hip signal the endof the stance phase when the hip angle extends past95°. Grinner and Rossignol (1978) found that if acat’s hindlimb was extended past 95 , flexion wasinduced, but if the limb was kept in a flexed posi~ion,tonic extension occurred. This section addresses therecent advancements that have supported theseproposals. Although the two proposals are addressedseparately in this review, it is quite likely th.it acombination of afferents signaling both load an(i legposition forms the basis for the transition from st mceto swing.

3.3.1. Extensor Muscle Ajjerents

Input from proprioceptors can reset or entraili themotor rhythm in many vertebrate and invertebratespecies (Andersson and Grinner, 1983; Bassler,1983,1986, 1987; Clarac and Chrachri, 1986; Zill,1985; McClellan and Jang, 1993;Pearson et al., 1992;Conway et al., 1987; Kiehn et al., 1992; for a re] iew,see Pearson, 1993). Similarly, in the cat, input I’romgroup I extensor afferents can reset and en:rain(Conway et al., 1987; Pearson et al., 1992; Gu:rtinet al., 1995a) the ongoing locomotor rhythm inclonidine and L-DOPA treated spinal cats as well asdecerebrate cats. There is substantial evidence thatsuggests that group Ib afferents that signal the loadcarried by the limb contribute substantially tc thetiming of the step cycle: (1) in clonidine and L-DOPA

treated spinal cats vibration of extensor muscles didnot entrain the rhythm while stimulation of the groupI afferents or stretch of the actively contractingmuscle did (Conway et al., 1987; Pearson et al.,1992); (2) in the decerebrate walking cat it wasnecessary to stimulate the group I afferents at levelswhich recruited a majority of both group Ia andgroup Ib afferents for stance to be prolonged (Whelanet al., 1995a). While Ib afferents can powerfully affectthe timing of the locomotor rhythm, the evidencedoes not exclude the idea that group Ia afferentscould contribute as well. Recent evidence demon-strates that vibration of the triceps surae, whichpreferentially recruits group Ia afferents, can reset thestep cycle and increase the duration of the extensorENG burst in fictively locomoting decerebrate cats(Guertin et al., 1995a). This has led to the suggestionthat group Ia and Ib afferents likely converge ontothe oligosynaptic pathway that is open duringlocomotion (Guertin et al., 1995a).

One important issue is whether or not the group Ifeedback contributes to the timing of the step cyclewhen an animal is receiving full afferent feedback.Recently, Whelan et al., 1995a) observed inpremammillary decerebrate cats that were walking ona treadmill, that stimulation of the extensor group Iafferents during stance can prolong the extensorphase of the step cycle as shown in Fig. 11. Moreover,similar stimulation applied during swing resets thestep cycle to extension. While these results are useful,it will be interesting to look at the effects of group Iinput in intact cats. The only study that has lookedat this issue was done by Duysens and Stein (1978),who stimulated the LGS nerve at group I strengthsduring the step cycle and noticed virtually no effecton the rhythm. However, it is likely that theyunderestimated the effects of group I stimulationbecause: (1) the stimulus train frequency was too low(Whelan et al., 1995a); and (2) they tested their catstypically 3–7 days after the surgery and the efficacyof the LGS declines during this period of time(Whelan et al., 1995b).

3.3.2. F[e.ror Muscle Ajjerents

If a limb of a chronically walking spinal cat is heldin a flexed position, the rhythm in that limb stops,while the contralateral limb continues to step. If thehip is extended past an angle of 95<”’,stepping resumeswith the initiation of swing (Grinner and Rossignol,1978). Similar effects of hip position were found inthe generation of the scratch reflex in decerebrate cats(Berkinblit et al., 1978; Deliagina er al., 1984). Incontrast to stepping, however, fle.~ion of the hip wasnecessary for scratching to occur. Studies byAndersson and Grinner (1981, 1983)) showed thatsinusoidal movements of the hips in fictivelylocomoting spinal cats were capable of entraining thelocomotor rhythm. In these studies, most of thehindlimb was deafferented, leaving only hip jointafferents and the muscles around the hip intact. Thespecific afferents that could be modulating this effectwere not identified, although the flexor musclespindle afferents activated due to stretch of the hip(Prochazka et al., 1976, 1977) were suspected (cfKriellaars et al., 1994). Qualitatively similar results


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Fig. 11. (A) Rectifiedand filtered EMG traces during spontaneoussteppingof a premammillarycat ona treadmill. During mid-stance, a stimulus train applied to the LGS nerve (trains: 1.8x T; 1000msecduration; 150Hz) extendedthe duration of the ipsilateral MG nerve and delayedthe onset of the flexorburst. The contralateral legindicatedby the contralateral St continuedto step normallyReproducedfromWhelanet al., 1 with permission.(B)Stickfigureswhichshowthe movementof the limb (indicatedby horizontal arrow) during the stance phase of normal walking(left trace) and a stimulated step (righttrace). The heavylines indicatewhenthe stimulusto the LGS was appliedand the arrow points to whereflexion would have occurred normally without stimulation. (C) Kinematic information showing theexcursionof the hip, knee and ankle joints during a normal step (thin line) and a stimulated step (thickline). Note that the hip, knee, and especiallythe ankle, joints remainedin extensionduring the stimulus(black bar) and that flexion resumed after the stimulus offset (previouslyunpublished information).Abbreviations:LGS,lateral gastrocnemius-soleus;St, semitendinosis;Co, contralateral; I, ipsilateral;MG,

medial gastrocnemius.

have been obtained in the forelimb. Retraction of theshoulder (which extends the flexors of the shoulder)increases the amplitude of the flexors and inhibits theactivity in extensors (Rossignol et al., 1993).

Recently, Hiebert et al. (1996) have identifiedproprioceptive inputs from flexor muscles that canalter the timing of the step cycle in the hindlimb. Toidentify the afferents involved, Hiebert et al. (1996)stretched the iliopsoas, and/or tibialis anterior,and/or extensor digitorum longus muscles during thestance phase in spontaneously walking decerebratecats [Fig. 12(A)]. Stretch of these flexor musclesinhibited the ongoing stance phase and promoted anearlier onset of flexion [Fig. 12(B)]. One conclusionfrom these data is that activation of muscle receptorsin both the hip and the ankle have similar effects onshortening the stance phase and initiating swing.Another conclusion is that the length sensitive spindleafferents from flexor muscles in the hip and ankleaffect the transition from stance to swing sincevibration (EDL and/or 1P) or electrical stimulation atgroup Ia strengths (EDL) or electrical stimulation atgroup H strengths (TA) each inhibit stance. However,

contrary results have been obtained by Perreauhet al. (1995). In this study, in which fictivelylocomoting decerebrate cats were used, stimulation ofgroup 11 afferents reset the locomotor rhythm toextension. It is conceivable that the use of differentpreparations [spontaneously walking (Hiebert et al.,1996) vs fictively locomoting decerebrate cats(Perrear,dt et al., 1995)] may explain why the resultsdiffered.

3.3.3. Cutaneous Afferents

Nearly a century ago, it was recognized thatcutaneous stimulation of the distal foot couldproduce various excitatory extensor reflexes inanimals at rest (extensor thrust: Sherrington, 1906;positive supporting reaction: Magnus, 1926; toeextensor reflex: Engberg, 1964), and hence it washypothesized that cutaneous reflexes might serve toreinforce the stance phase during locomotion. Sincethat time, it has been shown that the extent to whichcutaneous input affects the step cycle depends firstlyon the phase of the step cycle that the perturbation

502

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is delivered and secondly, on the strength and ty[c ofstimulation (Duysens and Stein, 1978;Duysens, 1 )77;Duysens and Pearson, 1976; Grinner and Rossignol,1978; Forssberg, 1979). Activation of cutantousafferents can elicit complex patterns of behavior thatare functionally relevant to the animal. For example,stimulation of cutaneous afferents from the dorsumof the foot can evoke the well known stumblingcorrective response (Forssberg, 1979). This resp{~nseensures that an exaggerated flexion response occurs ifa perturbation is encountered during the swing phase,while in contrast if the perturbation is encounteredduring stance the extensor burst is enhanced.However, it is less known to what extent cutaneousafferents control the stance to swing transition duringunperturbed locomotion.

When discussing this issue, it must be kept in rlindthat cutaneous afferents can, in theory, signal lergth,pressure (force), and velocity information duringwalking as well as nociception depending on the lypeof receptor and its placement (Loeb, 198I).Experiments in premammillary cats which haveelectrically stimulated cutaneous afferents thatinnervate areas of the skin which sense yield 01’theankle (sural) and innervate the foot-pad (posteriortibial) have shown that stance can be prolonged andenhanced (Duysens, 1977; Duysens and Pearson,

1976; Duysens and Stein, 1978). For example, weakelectrical stimulation of the sural nerve during lateflexion terminates flexion prematurely and resets therhythm to extension, [n contrast, if the same stimulusis applied during early flexion, the flexor bursts arefrequently augmented and the subsequent extensorburst is shortened (Duysens, 1977). In many cases,stimulation of the sural nerve during late stanceincreases the duration and the amplitude of theextensor burst by over 100% and completelyabolishes the ongoing ipsilateral flexor burst (Duy-sens and Pearson, 1976). It is not known whether thespinal circuitry mediating this effect shares commoninterneurons with proprioceptive afferents from theextensor and flexor muscles (Sections 3.3. I and 3.3.2).

3.4. A Model Circuit

A scheme summarizing the inputs from theproprioceptive and exteroceptive afferents is shown inFig. 13, It is assumed that the locomotor rhythm isgenerated by mutually inhibiting half-centers (Lund-berg, 1981; Jankowska et al., 1967a, 1967b). One ofthe problems with the half-center model initiallyproposed by Lundberg (1969) was that it predicted asimple alternation between flexors and extensorsduring walking. The complex activity of flexors and


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Fig. 13. Pathways indicating how afferents from proprioceptor and cutaneous receptors can affect theextensor burst activity. The shaded box represents the CPG that generates locomotionvia the mutuallyinhibiting extensor and flexor half-centers (as proposed by Lundberg, 1981).During locomotion, thenormallyinhibitorypathwayfromthe group Ib and groupIa afferents(2)is inhibitedand an oligosynapticpathwayopens(4)whichexcitesthe extensorhalf-centerwhengroup Ib and Ia afferentsare activeduringstance. In addition to the excitatory input from the extensors, the extensor half-center also receivesinhibitoryfeedback(5) from the flexormuscleafferentswhichare activeduring late stance. A disynapticexcitatoryinput from group Ia and group Ib afferentsis open also during locomotion(3),whichhas beendocumentedonlyduringMLR-evokedlocomotion.Cutaneousinput (as indicatedby the dotted line)maycontribute also to the excitationof the extensorhalf-center,but this has not beenestablishedconclusively.Parts of this circuit diagram were published by Pearson (1996), from which it was modified, with

permission.

extensors that is observed during walking (Engbergand Lundberg, 1969) was hypothesized initially to bedue to afferent feedback which sculpted the simplerhythm produced by the half-center (Lundberg,1969). This proposal was contradicted by experimen-tal data obtained from postmammiilary decerebratecats that were walking on the treadmill which clearlyshowed that a complex pattern of muscle activitycould be produced without afferent input (Grilhterand Zangger, 1984). In light of this, the half-centermodel has been expanded by Perret (1983) to allowfor a central oscillatory network (half-center model)that produces the general timing of the network anda system of premotoneuronal interneurons whichsculpts the final output and produces the complexactivation of extensor and flexor muscles that isobserved during stepping [similar proposals havebeen made for the operation of the scratch reflex(Koshland and Smith, 1989), and for the respiratorysystem (Feldman, 1983)]. As a resuk, the half-centerhypothesis remains a convenient model for discussingthe actions of afferent feedback on the timing of thelocomotor pattern. For the sake of simplicity thepremotoneuronal network proposed by Perret (1983)is not indicated in Fig. 13. In this model, it is assumedthat both extensor and flexor afferents project ontothe extensor half-center and affect the timing and theamplitude of the extensor burst (pathways 4 and 5 in

Fig. 13). Afferent input from group I extensorafferents also affects the amplitude of the extensorburst by acting on the premotoneuronal network thatlies outside the CPG (McCrea et al., 1995b; pathway3 in Fig. 13).

During locomotion, group I afferent feedback fromthe extensors causes both an excitation of theextensor burst and an alteration in the timing of thestep cycle. Due to the long latency of the EPSP inextensor motoneurons when group I extensorafferents are stimulated, the pathway is likely to bepolysynaptic. This pathway receives convergentafferent information from many different extensormuscles (Whelan et al., 1995a; however, see Gossardet al., 1994)and globally excites the extensor musclesin the ipsilateral limb by an excitatory action on theextensor half-center (Guertin et al., 1995a). Group Iafeedback from muscle spindle afferents also excitesthe extensor half-center (Guertin et a/., 1995a) as wellas directly exciting extensor motoneurons (pathway 1in Fig. 13). Thus, combined activity from group Iaand Ib afferents located in extensor muscles tends toprolong the extensor burst and prevent prematureflexion of the limb while the limb is loaded.

The flexor muscle spindle afferents inhibit theextensor half-center (pathway 5 in Fig. 13) and thusact to curtail the extensor burst and cause the onsetof the swing phase (Hiebert et al,, 1996). In theory,

504 I’. W

t two possibilities by which the flexor muscleafferents could affect the timing of the step cycle: (1)the flexor muscle afferents could directly activate theflexor half-center and inhibit extensor activity by theresultant inhibition of the extensor half-center; oi (2)the flexor afferents could activate the fl(xorhalf-center by inhibiting the activity of the activeextensor half-center. Although both are plausible,evidence favors the latter possibility. This assertic n isbased on two pieces of evidence: (1) the latency forinhibition to occur in the extensor muscle isextremely rapid (3o msec) and is similar to hatreported for extensor afferents while in contrast: (2)the minimum latency for the initiation of fl(xoractivity was 90 msec, indicating that the extel Isorhalf-center is inhibited before the flexor half-cc lter(Hiebert ef al., 1996). The stance to swing transi ionis likely to be signaled by a combination c f areduction in extensor dferent feedback due to theunloading of the limb combined with an inhibitio 1ofthe extensor half-center by flexor muscle afferenls asthe leg is extended and the flexor muscles arestretched. However, it is clear that during stimula: ionof the LGS grow I afferents the leg is power! ullyextended [Fig. I l(C); Whelan et al., 1995a]. In thiscase, it is clear that signals from the flexor m~scleafferents that are stretched cannot overcome thispowerful extension. This may be functionally rele antas the maintenance of ground support is critical v henextensor muscles are loaded and under t ~eseconditions feedback from flexor muscle afferents naybe less effective.

A contribution from certain low-threshold cu-taneous afferents such as those within the sural n :rve(Duysens and Pearson, 1976;Duysens, 1977;Du> ens

S 1 is likely to contribute to theexcitation of’the extensor half-center, as indicate I bythe dotted line in Fig. 13. While it is assumed in [hismodel, for the sake of simplicity, that many o! theeffects on the step cycle from groups of affel.mtsexcite or inhibit interneurons that comprise theextensor half-center, it is entirely possible that t leseafferents may also project onto the flexor haif-ce)lter.For example, in fictively locomoting decerebrate ats,resetting of the locomotor rhythm by stimulatio)l ofthe group I extensor afferents during the flexor p meof the locomotor cycle is accompanied b ~~•asimultaneous excitation of the extensor motoneu :onsand by an inhibition of the flexor motoneuons(Guertin etd.,1995b). These results suggest a rloreglobal regulation of the central pattern gener:tor,rather than a selective input to the extersorhalf-center.

3.5. Summary

In the intact and the reduced animal, chang!s incadence are mainly due to an alteration of the st.mceand not the swing phase. This finding led to theassumption that the afferent control of the step ( ycleis directed at modulating the duration and amp]]~udeof the extensor burst. The transition from stare e toswing is a point in the step cycle that appears IJ beespecially susceptible to afferent control. Thus theCPG can be accessed by signals from extensor andflexor muscle afferents that can powerfully alte the

duration of stance and reset the step cycle (Whelanet al., 1995a; Hiebert et al., 1996; Conway e[ al.,1987;Pearson et al., 1992). It is hypothesized that thesignal for the end of stance is conveyed by afferentfeedback in two ways to the CPG: (1) unloading ofthe limb causes a reduction in the positive feedbackfrom the group lb extensor muscle afferents onto theextensor half-center; and (2) increased inhibition ofthe extensor half-center by inputs from the flexormuscle afferents which are lengthened throughout thestance phase of the step cycle. It must be kept in mindthat the motor control system is multisensorial and islikely to be highly redundant. Information concern-ing the appropriate rhythm to adopt comes from theactivity of afferents in all the stepping limbs includingthe forelimbs and by the descending drive onto thespinal CPG, as well as any modulation from otherdescending inputs. In light of this, the inputs from theproprioceptors should be considered in global terms(Pearson and Ramirez, 1996). Indeed, it would bevery surprising to find that the nervous system relieson only one single modality to calibrate motorprograms considering the amount of convergence ofdifferent afferent w-ouus onto interneurons in thespinal cord (Baldi~sera”et al., 1981: Harrison et al.,1983;1983;

Janko’wska, 1992; Jankowska and McCrea,Jankowska et al,, 1981).

4. PLASTICITY OF LOCOMOTORPATHWAYS INVOLVED IN THE

PRODUCTION OF LOCOMOTION

C m p s p aB p s f t

a b e c fa R i e c r

f p a process t i me d t t s ic e s rm p t i m pa t p c m l

(Lisberger, 1988)

The ability of animals to learn a new behavior isan essential cotnponent of the developmental processand is critical f~r their survival. Many exam-pies ofadaptation in general are known in neurophysiology,including the re-mapping of the auditory system inthe barn owl (Knudsen and Knudsen, 1990), theadaptation of the vestibulo-occular reflex (Lisberger,1988), chronic spinal cats can regain their ability towalk following regular training (Barbeau andRossignol, 1994, 1987; Barbeau et al., 1993; Barbeauand Blunt, 1991; Edgerton et al., 1992; Lovely et al.,1986) and the re-mapping of the spinal cord sensorymap after injury (Devor and Wall, 1978). However,relatively little is known about how locomotorsystems adapt in response to new environmentalconditions or injury. Recently, plasticity has beenfound to occur in an afferent pathway that isfunctionally important in the control of the stance toswing transition (Whelan et al., 1995b) after partialaxotomy of the extensor afferents. The recalibration


of the afferent pathway occurs in a manner that isbeneficial to the animal and may be related to therecovery of function after the injury. Another recentdevelopment is the demonstration that decerebratecats (Yanagihara et al., 1993) and ferrets (Lou andBloedel, 1988; Bloedel et al., 1987; Bloedel et al.,1991) can quickly learn new locomotor behaviors.These studies open the door for an investigation intothe areas of the brainstem and spinal cord that couldbe involved in the adaptive modification of motortasks. These studies are among the first to concentrateon functional plasticity in decerebrate animals.

The Ability of the Decerebrate Animal toLearn New Behaviors

Ithas been known for quite some time that thedecerebrate animal can learn new patterns ofbehavior. For example, the eye-blink response can beclassically conditioned in the decerebrate cat by usingauditory discriminating stimuli (Norman et al.,1977). The flexor withdrawal reflex can be classicallyconditioned in both the decerebrate dog (Bromiley,1948) and the spinal cat (Patterson et al., 1973).However, until recently it was not known whether adecerebrate animal could alter a behavior in afunctionally relevant manner while walking.

Yanagihara et al. (1993) found that chronicdecerebrate cats can adapt their interlimb coordi-nation appropriately when their limbs are driven atdifferent velocities relative to each other. Animalswere mounted over a treadmill, which allowed the leftforelimb of the animals to be driven at differentvelocities. When the left forelimb was driven at twicethe velocity of the other three limbs, there was animmediate disruption of the stance phase of the leftforelimb. However, within 50 steps the step cycle ofthe left (and right) forelimb stabilized. Subsequentperturbations showed an immediate adaptationindicating that the decerebrate animal had some“memory” of the perturbation. Recently, Lou andBloedel (1988) have shown that the trajectory of aforelimb in decerebrate locomoting ferrets can beconditioned to avoid an obstacle. What is quitesurprising [Fig. 14(A)] is that the new behavior islearned within 5–15 trials, and moreover the behaviorcan be eliminated after a number of trials if the baris removed. The authors later combined recordingsfrom Purkinje cells [Fig. 14(B)] and monitored bothsimple and complex spikes during perturbed andunperturbed walking (Lou and Bloedel, 1992).During unperturbed walking, the complex spikeactivity was not correlated with the step cycle. Whenthe bar was introduced, the production of thecomplex spikes became highly correlated to theperturbation. Studies by Yanagihara and Udo (1994)confirmed that in the decerebrate locomoting catsimilar perturbations of the forelimb lead tosynchronization of the complex spikes (cf Matsukawaand Udo, 1985)and to an altered firing of the left andright Deiter’s nucleus (Udo et al., 1982). Bloedel(1992) has hypothesized that synchronization ofclimbing fiber input activates sagitally alignedPurkinje cells and causes an on-line change in theefficacy of mossy fiber inputs. This would lead to analteration in the output of cerebella nuclear neurons

every time the perturbation is encountered by theanimal. Thus, instead of the cerebellum beinginvolved in the teaching of the new behavior, it is apart of the circuit that controls the new behavior(Bloedel, 1992; Bloedel and Ebner, 1985). Consistentwith this idea, preliminary evidence suggests thatablation of areas of the cerebellum does not abolishthe acquisition of the bar avoidance task indecerebrate ferrets (Bloedel et al., 1987;Bloedel et al.,1991), although it does alter the performance of themovement.

It is not known whether the site of plasticity for allthe behaviors discussed above is located in thebrainstem or cervical spinal cord. It is possible thatthe site of plasticity may not be located within adefined area and may be distributed in the spinal cordand brainstem (Bloedel and Bracha, 1995; Dr JamesBloedel, personal communication).

4.2. Plasticity of the Extensor Group I Pathway

Plasticity of reflex pathways can occur in responseto muscle inactivity, axotomy of peripheral nerves,conduction block of afferent activity, and operantconditioning (for a review, see Mendell, 1984;Mendell, 1988; Wolpaw and Carp, 1993). Moststudies on reflex pathways have concentrated on theadaptation of the monosynaptic group Ia pathwaydue to its relative simplicity. In contrast, research onplasticity within polysynaptic pathways is not as wellestablished. Recently, it has been found that apolysynaptic pathway that functionally regulates thetiming and reinforcement of the stance phase can berecalibrated in a functionally relevant manner(Whelan et al., 1995b). It was found that the strengthof this oligosynaptic reflex can be altered if the loadon an extensor muscle is increased by cutting thenerve supplying a synergistic extensor muscle(Whelan et al., 1995b). In this study, the left LGSnerve was cut in intact cats, resulting in increasedloading of the intact MG muscle. After recoveringfrom this minor surgical procedure, the cats typicallyshowed a yield in the ankle during the stance phasewhich returned to normal in a period of one week (cfWetzel et al., 1973). To test whether adaptation hadoccurred in the group I excitatory pathways, the catsin the study were decerebrated at various times afterthe initial cut of the LGS nerve (3–28 days) andimplanted with small neural stimulating cuffs aroundthe LGS and MG nerves in both the operated andcontrol hindlimbs. During stepping, each extensornerve was stimulated separately during stance usinglong stimulus trains (1000 msec train; 200 Hzstimulation at 1.8 x Tand 0.2 msec pulse width). Asexpected in the control limb, stimulation of the LGSnerve extended the duration of the stance phase forthe duration of the stimulus [Fig. 15(C)] (Whelanet al., 1995a), while stimulation of the synergistic MGnerve extended the duration of stance relativelyweakly [Fig. 15(A)]. The situation in the experimentallimb was quite different. Starting as soon as threedays after the axotomy of the LGS nerve, stimulationof the MG nerve could powerfully prolong stance[Fig. 15(B)],while in contrast, the previously cut LGSnerve typically only weakly prolonged the stancephase [Fig. 15(D)]. The time course of this effect was

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not addressed in this study, although it was noted thatdeclines in LGS and increases in MG efficacy can occurasearlyas 3days after the initial cut [Fig. 15(E)anc~(F)].

There are two main differences between thechanges that presumably occur in the oligosynapticpathway and those that occur at the monosynapticjunction. Firstly, the time course for the changes inreflex efficacy is much faster than those observed forthe monosynaptic reflex (for a review, see Mendell,1984), in which the Ia EPSP evoked from the cutextensor nerve does not decrease until at least 7 daysafter the axotomy (Eccles et al., 1959; Eccle: andMcIntyre, 1953). Secondly, although some re-searchers have reported that the monosynaptic reflexfrom synergismscan increase after axotomy (Iccleset al., 1962; cf Decima and Morales, 1983), otherresearchers have failed to replicate this result (Walsh

et al., 1978; Gallego et al., 1979). In contrast, theoligosynaptic response from the synergismsincreasedpredictably and quickly (within 5 days) (Whelaner a/., 1995b). Accordingly, whatever the systemresponsible for the plasticity in the locomotordependent group I pathway, it is likely different thanthe mechanisms that alter the strength at themonosynaptic connection between the Ia afferentsand motoneurons upon axotomy of extensor nerves.

At present, there are a number of unresolved issuesregarding the development of the plasticity within thegroup I oligosynaptic pathway: (1) the site ofplasticity has not been determined; (2) if the site ofplasticity is contained within the spinal cord it wouldbe interesting to know whether the neural circuitrywithin the spinal cord can reconfigure in isolation orwhether supraspinal descending commands from the

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s x 1 m d H S c MG nerve(A) weaklyextended the VL extensor burst whereas, in the experimental limb (B), a similar stimulus powerfullyprolonged stance for the duration of the stimulus train. In contrast to MG, stimulation of the LGS inthe control leg powerfullyprolongedstance (D) whereas, in the experimentalleg (E), a similar stimulusapplied to the previouslycut LGS nerve resulted in a small effecton the duration of the extensor burst.(C) and (F) These bar graphs show the average effectsof the experimentaland control LGS and MGnerves for each experimentand are compiledfrom 13experimentsthat were performed2–28days afteraxotomyof the LGSnerve. Each bar representsthe averagepercentageeffectivenessof the stimulusburstin enhancingthe extensorburst during a singleexperiment,whichis calculatedby the followingequation:0 effectiveness= [(b —a)/(c —a)] x 100.The error bars represent the S.D. Modifiedfrom Whelanef al,,1995b),with permission.Abbreviations:LGS, lateral gastrocnemius-soleus;MG, medial gastrocnemius.

cerebellum, for example are necessary; (3) intracelhr-Iar recordings similar to those of Gossard et al. (1994)will have to be performed to confirm the hypothesisformed by Whelan et al., 1995b)that the oligosynapticpathway outlined by Gossard et al, (1994) is indeedchanging in strength independently of the group Iamonosynaptic pathway; and (4) the possibility that therecovery of function of the animal after the cutting ofLGS is correlated to the plasticity that has been ob-

al., needs to be expiored.

Summary

P s b

understood. Mammals can still show compIexadaptive behavior after decerebration illustratingthat, even in these reduced preparations, functionallyrelevant adaptation can take place. Decerebrateferrets, for example, can learn a new trajectory oflocomotion if a bar is pIaced in the path of themoving leg (Lou and Bloedel, 1988, 1992). These newbehaviors can be produced after as little as from fiveto ten presentations of the bar. It is unknown whichstructures in the brainstem could be controlling thechange in trajectory. Plasticity of the group Ioligosynaptic pathway that occurs after chronicaxotomy can be retained after decerebration (Whelanet al., i

508 J’, W

contained within an area caudal to the premaminil-Iary transection.

5. CONCLUDING REMARKS

t w t k mt c o s w h e

h g a oq w k tm c w a h S

s t t s a h dy c For indeed it is one of the lessons [~fthe history of science that each age steps on tlieshoulders a w h g b

(Foster, 1901, p. 299).

Watching a decerebrate cat walk is a remark tbleexperience*. At times the walking pattern is sinlilarto that of an intact animal with perfect inter-limbcoordination and weight support. The abilit! togenerate locomotion is a result of interactionsbetween the descending command signals from thebrainstem, the CPG in the spinal cord and affcrentfeedback. This mutual dependence among structuresis one of the common principles in the generation oflocomotion. For example, stimulation of the MRFcan cause changes in the amplitude of all four IImbsin the cat in a phase-dependent fashion duringlocomotion, suggesting that the descending signalsare optimized by the CPG (Drew and Rossi~.nol,1984). Other brainstem areas reinforce activity duringlocomotion, such as Deiter’s nucleus that affect:. theanti-gravity muscles (Orlovsky, 1972a), and the rednucleus which affects the flexor portion of the stepcycle (Orlovsky, 1972a). The phasic pattern of’ thebrainstem nuclei is in turn dependent on feedbackfrom the CPG arriving via the VSCT (Arshavskyet al., 1972a, 1972b, 1972c; Arshavsky et al., 1986;Orlovsky, 1970; Or-lovsky, 1972b, 1972c). Thecerebellum filters the ascending information fron] theVSCT and outputs a phasic signal to Deiter’s nucleus,the MRF, and the red nucleus (Arshavsky ef a/.,1986; Arshavsky and Orlovsky, 1986). In additit,n tofeedback from the CPG, the MRF region alsoreceives direct input from afferents in the limbs andin turn outputs signals that reinforce activity in flexormotoneurons (Shimamura et al., 1990). Besidesreinforcing the activity of neurons in the brainstem,afferent input from the hindlimb potently affects thestance to swing transition in the cat. Thus the rh:.thmgenerated by the CPG can be altered and molded byafferent feedback to reflect variations in the tei-rain.

Another common principle in the control oflocomotion is that the connections between andwithin structures involved in controlling locomt~tion

*A c a f t m G1 t d a d cl a t a f BM A ( 1 Copies forpurchase can be obtained by writing to: BMA/BLATFilmLibrary, BLAT Centre, BMA House, Tavistock Square,London, WCIH 9JP, U.K.

are extremely flexible. It is this flexibility that ensuresthat appropriate responses can be made to an everchanging environment. For example, when loco-motion is initiated in the decerebrate cat, there is astate change that causes many systems in thebrainstem and spinal cord to be optimized for thetask at hand. To cite an instance, many neuronswithin the brainstem MRF alter their responsecharacteristics during locomotion so that cutaneousinput is gated out during phases of the step cyclewhen the cells are inactive. Gating of afferent inputsoccurs at the segmental level within the spinal cordduring locomotion. Phasic presynaptic inhibition ofcutaneous (Gossard et al., 1990) and proprioceptiveafferents (Baev and Kostyuk, 1982) ensure thatafferent input can only affect the locomotor rhythmwhen appropriate. More radically, the actions ofsome reflex pathways are fully reversed whenlocomotion commences. A case in point is the reflexreversal that occurs in the reflex pathway from Golgitendon organs. At rest, afferent input from extensorGTOS inhibit the extensor burst, but duringlocomotion similar stimuli reinforce the extensorburst. Thus, throughout the neuraxis, locomotorpathways are not hard-wired and can be flexiblyrewired depending on the “state” of the animal (seeProchazka, 1989, for a review of this issue).

In conclusion, the decerebrate cat can produce alocomotor pattern that is dependent on its “state”and the mutual interdependence of all the structurespresent. But how does the locomotor performance ofthe decerebrate cat compare with the intact animal?The intact cat is capable of a large amount of motorbehaviors. For example, as I am writing this review,my pet cat is waiting for his ball to be thrown, anactivity that gives him a great deal of pleasure. WhenI throw the ball around the corner, he leaps out of mylap and gallops after the ball and often catches it inmid-air. He then turns around, slowly walks back tome, and drops the ball into my lap so that 1can throwit again. If we look at this behavior from theperspective of this review this activity is breathtak-ingly complex. In response to a visual stimulus (theball), a command signal is initiated in the cortex thatis presumably sent to the MLR and MRF to initiatea galloping pattern. When the animal turns thecorner, the interlimb coordination has to be adjustedso that the outer limb cycles at a slower rate than theinner limb. Finally, the animal has to superimpose ajumping behavior on top of the preexisting gallopingpattern. To make the jump, the animal has to takeinto account the velocity of the ball relative to its ownand judge the necessary acceleration necessary tocatch it. Research into understanding how complexlocomotor behaviors, like the one described, areinitiated and controlled, is at an early stage, but someprinciples are emerging. For example, when a cat islocomoting in a predictable environment it appearsthat much of the locomotor pattern is produced by“lower” structures such as the brainstem and spinalcord (Beloozerova and Sirota, 1993; Drew, 1988,1991a Armstrong, 1988). This is equivalent to mycat’s slow walk after catching the ball. However, if ananimal unexpectedly encounters an obstacle, neuronsin the motor cortex are activated that may beinvolved in adjusting the pattern in both the fore and

C Locomotion 509

h oW al., M

al., 1993; Prentice and Drew, 1995). Recordingsthus far have only

c ru r t ci tc p e ca u

l i

Acknowledgements—Iwould like to thank Dr K. Pearsonfor manyworthwhilediscussionsconcerningpreviousdraftsof this manuscript. I wouldalso liketo thank Dr R. B. Steinand G. Hiebert for reading the manuscript and offeringsuggestions for its improvement. This work has beensupported in part by the Alberta Heritage Foundation forMedical Research, tbe Natural sciences and EngineeringCouncil of Canada and the Medical Research Council ofCanada.

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