Progress in Brain Research, Vol. 151

ISSN 0079-6123

Copyright r 2006 Elsevier B.V. All rights reserved

CHAPTER 4

The extraocular motor nuclei: organization andfunctional neuroanatomy

J.A. Buttner-Ennever�

Institute of Anatomy, Ludwig-Maximilian University of Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany

Abstract: The organization of the motoneuron subgroups in the brainstem controlling each extraocular eyemuscle is highly stable through the vertebrate species. The subgroups are topographically organized in theoculomotor nucleus (III) and are usually considered to form the final common pathway for eye musclecontrol. Eye muscles contain a unique type of slow non-twitch, fatigue-resistant muscle fiber, the multiplyinnervated muscle fibers (MIFs). The recent identification the MIF motoneurons shows that they too havetopographic organization, but very different from the classical singly innervated muscle fiber (SIF) moto-neurons. The MIF motoneurons lie around the periphery of the oculomotor nucleus (III), trochlear nucleus(IV), and abducens nucleus (VI), slightly separated from the SIF subgroups. The location of four differenttypes of neurons in VI are described and illustrated: (1) SIF motoneurons, (2) MIF motoneurons, (3)internuclear neurons, and (4) the paramedian tract neurons which project to the flocculus. Afferents to themotoneurons arise from the vestibular nuclei, the oculomotor and abducens internuclear neurons, themesencephalic and pontine burst neurons, the interstitial nucleus of Cajal, nucleus prepositus hypoglossi,the supraoculomotor area and the central mesencephalic reticular formation and the pretectum. The MIFand SIF motoneurons have different histochemical properties and different afferent inputs. The hypothesisthat SIFs participate in moving the eye and MIFs determine the alignment seems possible but is notcompatible with the concept of a final common pathway.

Introduction

The most exciting scientific developments over thelast 10 years in the field of the extraocular motornuclei have encompassed both molecular and sys-temic approaches. First, there is the identificationof a multitude of neurotrophins, transcriptionfactors, genetic factors, membrane receptors, andtransmitters which have a specific relationship tothe extraocular motoneurons. In addition, the com-bination of histochemical and immune techniqueswith tracer tracing has permitted transmitters, orhistochemical characteristics, to be associated with

�Corresponding author. Tel.: +49 89 5160 4851;

Fax: +49 89 5160 4857;

E-mail: jean.buettner-ennever@med.uni-muenchen.de

DOI: 10.1016/S0079-6123(05)51004-5 95

identified motoneurons, or specific premotor con-nections (Horn et al., 1995; Horn and Buttner-Ennever, 1998; Eberhorn et al., 2005): and thecharacteristics can in turn be used as markers inthe human brain to locate homologous neuronalgroups. Alongside these advances has been thedevelopment of transsynaptic tracer techniques,starting with lectins, then tetanus toxin, and cul-minating in the injection of particular strainsof rabies virus, whose uptake is restricted to mo-tor terminals, but can travel over an unlimitednumber of synapses and at the same time amplifythe marker-signal (Buttner-Ennever et al., 1981;Evinger and Erichsen, 1986; Itaya, 1987; Horn andButtner-Ennever, 1990; Kuypers and Ugolini,1990; Herzog and Kummel, 2000; Erichsen andMay, 2002; Graf et al., 2002; Morcuende et al.,

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2002; Ugolini et al., 2005). This powerful virustracer technique promises to reveal major principlesupon which the oculomotor system is organized.

General features of motoneurons

Extraocular motoneurons develop within thesegmented neuroepithelium in a caudal rostralsequence, like the eye muscles they innervate;abducens nucleus (VI) is first, followed by trochl-ear (IV) and finally the oculomotor neurons (III)(Shaw and Alley, 1981; Szyszka-Mroz, 1999). Thethree extraocular motor nuclei develop from dif-ferent brain segments: abducens neurons originatefrom rhombomeres 5 and 6: trochlear neuronsdevelop in rhombomere 1, and the oculomotornucleus (III) is derived from the most caudal mid-brain segment, or mesomere, just in front of themidbrain–hindbrain boundary (Matesz, 1990;Baker, 1992; Straka et al., 1998, 2001). Theseand other reviews have dealt with the furtherdevelopment of oculomotor circuitry (Glover,2003). Although the IV may later merge intocaudal III in some species, alone from ontogeny,the two nuclei must be considered as separate en-tities. The location of the three extraocular nucleiwithin the brainstem is shown in Chapter 1, Fig. 2.

Morphometry of motoneurons

In homeotherms the soma-dendritic morphology ofthe motoneurons is constant across species; an in-creasing soma diameter leads to more, rather thanthicker dendrites. It is difficult to decide from whichspecies of mammal or bird a motoneuron recon-struction is taken (Evinger, 1988). Neverthelessthere are species differences in absolute soma size; ahuman has motoneurons with an average diameterof approximately 50mm, and 12–20 primary dend-rites (Szabo et al., 1987); whereas a guinea pig hasoculomotor neurons of about 30mm diameter, and5–6 primary dendrites. In contrast, a major changeappears in poikilotherms, where the oculomotorneurons look very different. They have much largerdiameter primary dendrites than homeotherms, andwith increasing soma diameter the dendritic diam-eter increases (Graf and Baker, 1985; Graf and

McGurk, 1985; Szabo et al., 1987). For a compre-hensive review on this topic at both the light andelectron microscopic level see Evinger (1988).

With respect to the abducens motoneuron size, astudy comparing squirrel monkey with cat foundthe diameter for monkey motoneurons was20–44 mm (mean 31.773.8 mm), and four or moreprimary dendrites per cell, compared with catabducens where the size ranged from 26 to 66 mm,and averaged 37.276.2 mm, also with four or moredendrites per cell (Russell-Mergenthal et al., 1986;McClung et al., 2001). Although there is a widevariation in the reports of abducens motoneuronsizes, reviewed by McClung and colleagues, thereis a general consensus that those of cat are largerthan those in monkey (Langer et al., 1986; McCreaet al., 1986; McClung et al., 2001). A comparisonof the sizes of medial rectus motoneurons withthose of the lateral rectus in monkey showed thatof the three MR subgroups (see below) those of theA group were indistinguishable from abducensmotoneurons while those of the B-group werelarger and the C-group smaller (Buttner-Enneverand Akert, 1981; Buttner-Ennever et al., 2001;McClung et al., 2001).

Oculomotor nucleus

Organization of motoneuron subgroups

Neurons in III innervate the ipsilateral medial andinferior rectus (MR, IR), the inferior oblique (IO)and contralateral superior rectus (SR); IV controlsthe contralateral superior oblique (SO); and VImotoneurons drive the lateral rectus (LR) muscle.The mammalian III also includes motoneuronswhich innervate the levator palpebrae superioris(LP); they lie in a slightly separate subgroup incaudal III, called the central caudal nucleus (seebelow). The precise location of the motoneuronpopulations is dependent on the sequence ofmuscle and neuronal development (Baker, 1992;Straka et al., 1998). The motoneuron subgroups inIII are organized in a topographic map, and areillustrated for a few species schematically in Fig. 1.The individual maps of many different vertebrateclasses have been reviewed and discussed by

Fig. 1. Organization of motoneuron subgroups within the oculomotor nucleus III in different species (not scaled). Note that the basic

pattern is relatively constant; however, LP moves laterally in lateral-eye mammals and the MR innervation in elasmobranchs is

crossed. The avian EW (pigeon) is large and well organized. The example of the teleost is taken from the flounder, and of the

elasmobranch from the skate (modified from Evinger, 1988).

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Evinger (1988). Here, the studies will be onlycited, since despite minor differences the generalorganization is similar in mammals: monkey(Buttner-Ennever et al., 2001), cat (Miyazaki,

1985), rabbit (Murphy et al., 1986), rat (Glicksman,1980).They follow, from rostral to caudal, the se-quence of IR, MR, IO, SR (and LP) (Shaw andAlley, 1981). The subgroups of LP and MR show

Fig. 2. Organization of the motoneuron subgroups within III

and IV, showing that an excitatory input to all the subnuclei on

the left side (e.g., RIMLF) will lead to an ipsitorsional eye

movement (right eye intorts, and left eye extorts).

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most variation. In frontal-eyed animals, like theprimate or cat, LP motoneurons lie in a bilobedcell group on the midline (nucleus centralis cau-dalis, CCN), whereby many of the motoneuronslie contralaterally within CCN (Sun and May,1993). In lateral-eyed animals, like rabbit and rat,the LP motoneurons are situated laterally, andcontralateral (Fig. 1), but in the guinea pig theyare scattered ventrolaterally within the medial lon-gitudinal fasciculus (MLF) of the contralateralside (Evinger et al., 1987). The organization of theoculomotor nucleus in lower species has been thesubject of many studies: lampreys (Fritzsch andSonntag, 1988), chameleon (El-Hassni et al.,2000), and the weakly electric fish (Szabo et al.,1987). The basic internal organization of theoculomotor nucleus (III) is remarkably constantacross almost the entire spectrum of vertebratespecies. An exception to the basic plan of organ-ization in III is seen in elasmobranchs where theMR motoneurons lie in contralateral III (Fig. 1).It is instructive to consider the consequences of thestandard pattern of extraocular innervation. Itmeans that an excitatory premotor input to the IIIand IV of one side, results in the ipsilateral torsionof both eyes (Fig. 2), conversely a lesion of thepremotor pathway would cause torsion to the otherside. A good example of this seen with stimulationand lesions of is the rostral interstitial nucleus ofthe MLF (RIMLF) see Chapter 1, Fig. 3, alsoChapter 5, and the RIMLF section of this chapter.

There is a prominent change in the arrangementof MR motoneuron subgroups in primates (Fig 1):here there are three distinct clusters of MRmotoneurons, ventral the A-group extending intothe MLF, dorsolateral the large motoneurons ofthe B-group and dorsomedially at the peripheralborder of the oculomotor nucleus the C-group,consisting of smaller motoneurons, see Fig. 3(Buttner-Ennever and Akert, 1981). RudimentaryMR cell clusters, similar to some if not all of thewell-defined A, B, and C subgroups in primates areseen in lower species such as cat (Miyazaki, 1985)and rat (Eberhorn, personal communication). TheA-group reaches its largest proportions in thehuman III. It is surprising that the different func-tions of the A-, B-, and C-groups remain to a largeextent unclear, and as yet only the C group can be

correlated with the innervation of a specific musclefiber type. Recent experiments show that themotoneurons of the C-group innervate the multi-ply innervated muscle fiber (MIF) motoneurons ofboth MR and IR (see section on motoneurontypes) (Buttner-Ennever et al., 2001). A schematicdiagram of an MIF motoneuron is shown inFig. 4, and compared to a motoneuron innervatinga singly-innervated muscle fiber (SIF).

The MIF motoneurons of the IO and SR lietogether close to the midline, sandwiched betweenthe oculomotor nuclei, and hence called the‘‘S-group’’ (Buttner-Ennever et al., 2001; Wasickyet al., 2004). Excitatory inputs to the S-groupwould lead to upward deviation of the eyes; and tothe C-group, containing MR and IR motoneurons,a similar input would result in vergence with adownward component.

Fig. 3. The MIF motoneurons, mainly supplying the global

layer of muscle (black dots), lie around the periphery of III, IV,

and VI in a different pattern from the SIF motoneurons. The

C-group contains MR and IR MIF motoneurons; the S-group

contains IO and SR MIF motoneurons. The MR SIF

motoneurons in the dorsal B-group, and ventral A-group, are

indicated by open circles.

Fig. 4. Schematic diagram of an eye muscle, showing an SIF

with a central endplate zone; and MIF with ‘‘en grappe’’

terminals along the whole length (in some cases one MIF is

innervated by several motoneurons. Note that a tracer injection

at the muscle tip, avoiding the central endplate zone, will

retorgradely label only MIFs.

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The MIF motoneurons, shown as black dots inFig. 3, were located by retrograde tracer injectionsinto the distal muscle–tendon junction of theextraocular muscles, avoiding the ‘‘en plaque’’endplate zone (Fig. 4). Therefore the tracer

was mainly taken up by the widely scattered‘‘en grappe’’ terminals of the MIF muscle fibers,and labeled the MIF motoneurons (Buttner-Ennever et al., 2001). In addition, it was arguedthat the MIFs of the global layer rather than theorbital layer, were primarily labeled, since the or-bital layer of muscle is now known to terminatemore proximally than the global layer, on Tenon’scapsule (Chapter 1, Fig. 10; and Chapter 2,Fig. 2). This argument depends heavily on thenew insights into the termination of the global andorbital layers of the eye muscles (Demer et al.,2000; Oh et al., 2001; Ruskell et al., 2005). At thepresent time the location of the motoneurons of theorbital MIFs is unknown (Eberhorn et al., 2005).

The S-group motoneurons in monkey (Fig. 3) canbe correlated with a similar cell cluster in man(Horn et al., unpublished observations). This generalregion is often referred to as the nucleus of Perlia inhumans (Olszewski and Baxter, 1982). The nucleusof Perlia appears to be a variable feature in adulthumans (Warwick, 1954), and the only evidence tosuggest that it plays a role in the control of vergenceis ‘‘the time of appearance in both the species andthe embryo which coincides with the positioning ofthe eyes in the frontal plane were convergence

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becomes possible’’ (Adler, 1950). This may not befar from the current hypotheses on the function ofthe S-group MIFs (see below), but great care mustbe taken since there are several cell groups on themidline between the oculomotor nuclei in human, soto define them as the nucleus of Perlia, the S-group,Edinger–Westphal nucleus or an interneuron sub-group needs careful analysis (Fig. 5A) (Ishikawaet al., 1990).

Motoneurons of singly and multiply innervatedmuscle fibers

It has been described above how the motoneuronsof SIFs and MIFs tend to lie separate from eachother in III, IV, and VI and have a completelydifferent organization of their subgroups (Fig. 3).This permits a differential analysis of their afferentinputs (Wasicky et al., 2004), and it shows that SIFand MIF motoneurons do not receive identicalinputs: some afferents target both, and othersinnervate one or the other (Figs. 7D, E). A majorinput to the MIF motoneurons of the C- andS-groups is the pretectum (Fig. 7E see section‘‘Pretectum’’). The elegant transsynaptic retrogradestudies of the premotor inputs to LR MIF moto-neurons, using rabies virus, show that the centralmesencephalic reticular formation (cMRF) andthe supraoculomotor area (SOA) supply afferents,as well as areas associated with the neural inte-grator, like nucleus prepositus hypoglossi (PPH)and the parvocellular parts of the medial vestib-ular nucleus (MVNp); however, the MIFs do notreceive direct afferents from premotor saccadicregions such as the paramedian pontine reticularformation (PPRF), the inhibitory burst neuronsarea and the oculomotor internuclear neurons(OMN-INTs) (see Fig. 8, Chapter 1 and Chapter5) (Buttner-Ennever et al., 2002; Ugolini et al.,2005).

The results suggest that the functional role ofMIF is different from that of the SIF, and thuschallenges the idea of a ‘‘final common pathway’’in which it is postulated that all motoneurons par-ticipate in all types of eye movements (Miller,2003). Individual recordings from MIF motoneu-rons in behaving primates have not been reported.

However, there is general agreement that twitchmotoneuron units innervate the SIFs, and the non-twitch units innervate global MIFs (Lennerstrand,1975; Nelson et al., 1986). MIF (nontwitch) firingcharacteristics may be deduced from studies infrog and cat, where nontwitch units were described(Goldberg et al., 1981; Dieringer and Precht, 1986;Nelson et al., 1986; Shall and Goldberg, 1992). Infrog, nontwitch units were shown to fire tonicallyat around 50Hz (Dieringer and Precht, 1986;Straka and Dieringer, 2004).

Both motoneuron types, SIFs and MIFs, arecholinergic (Figs. 5A–E), but they have beenshown in monkey to have different histochemicalstaining properties (Eberhorn et al., 2005). Thesedouble-labeling experiments revealed that the MIFmotoneurons in the periphery of the motor nucleido not contain nonphosphorylated neurofilaments(as detected with SMI32-immunostaining), orparvalbumin, and they lack perineuronal nets(Fig. 5E). In contrast, SIF motoneurons expressall markers at high intensity (Figs. 5D, E).

Putative role of MIF and SIF motoneurons

It is widely accepted that the unit activity of themotoneurons specifies the movements of the eye inthe head under all circumstances. Furthermore,the discharge of all motoneurons are thought tocontribute to all types of eye movements, whethersaccades, VOR or vergence (Keller and Robinson,1972; Gamlin and Mays, 1992). However, severalrecent reports have demonstrated, under certaincircumstances, a dissociation or uncouplingbetween motoneuron activity and the eye move-ments, for example, during head restrained andnonrestrained conditions (Ling et al., 1999). About66% of abducens motoneurons, in some condi-tions, fire as a result of monocular movements ofnot only the ipsilateral, but also the contralateraleye (Zhou and King, 1998). Another set of exper-iments, whose results should cause a great deal ofdeliberation, showed that during convergencethere was a slight decrease rather than increase inmuscle forces of MR and LR measured in mon-keys (Miller et al., 2002). Given that we now haverecognized the identity and location of MIF moto-neurons, and found them to possess very different

Fig. 5. Photomicrographs of transverse sections of: (A) oculomotor nucleus, (B) trochlear nucleus, and (C) abducens nucleus, double-

labeled for choline acetyltransferease (ChAT) (red) and perineuronal nets (green). All motoneurons and many EW neurons are ChAT

positive (red). Only SIF motoneurons within the motor nuclei are also ensheathed by perineuronal nets (green). MIF motoneurons

(arrows) lack perineuronals nets and lie close to EW. Histochemical differences between ABD-INT, SIF and MIF motoneurons are

shown in the high-powered photographs of the abducens nucleus neurons in (D) double-stained for perineuronal nets (brown) and

ChAT (black) motoneurons, SIF motoneurons are black (ChAT-positive) surrounded by brown nets (white arrows), a putative ABD-

INT (black arrow) is unstained (ChAT-negative) with brown nets: in E) shows three black (ChAT-positive) SIF motoneurons with

brown nets, and one black MIF motoneuron without brown nets. (Eberhorn et al., 2005). Calibration in (A)–(C) is 500mm and in (D)

and (E) it is 50 mm.

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properties than the SIF motoneurons, we mustnow ask what role they play in oculomotor control(Buttner-Ennever et al., 2001, 2002). The MIFmuscle fibres of the global layer extend throughout

the length of the eye muscle (Mayr et al., 1975),contract more slowly than SIFs, are fatigue resist-ant (Morgan and Proske, 1984), and are driven bytonically firing units (Lennerstrand, 1975; Dieringer

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and Precht, 1986). It is not clear how much theycontribute to the tension of eye muscles in naturalconditions, but experimentally exposing eyemuscle to succinylcholine causes them to contractand the effect is caused by the depolarization ofMIFs and not SIFs (Bach-y-Rita et al., 1977). Asdiscussed in Chapter 3, MIFs are associated withpalisade endings at their tips at the myotendinousjunction, and this combination has been comparedto ‘‘an inverted muscle spindle,’’ in the words ofDavid A. Robinson (Steinbach, 2000). It is possiblethat this combined structure could provide a sen-sory or proprioceptive feedback signal to the cen-tral nervous system (CNS), which regulates themuscle activity (see Chapter 3, Fig. 9). It is still tooearly to decide what role MIF motoneurons playin the control of eye movements, but currentlyevidence supports the idea that the SIF or twitchmotoneurons primarily drive the eye movements,whereas the MIF or nontwitch motoneuronsparticipate in determining the tonic muscle activity,as in gaze-holding, vergence and eye alignment(Buttner-Ennever et al., 2001, 2002).

Oculomotor interneurons

Several populations of internuclear neurons withdiverse projection targets, such as the spinal cord,the cerebellum, the abducens nucleus have beenidentified within and around the oculomotor nu-cleus (Phipps et al., 1983; Maciewicz et al., 1984;Chung et al., 1987; Clendaniel and Mays, 1994). Inlampreys, there is evidence for GABA-immunore-active neurons within the extraocular motor nuclei(Melendez-Ferro et al., 2000). The best investigat-ed of these interneurons are the oculomotor inter-nuclear neurons (OMN-INT) lying within withinthe III and in the supraoculomotor area, whichproject bilaterally to the abducens nucleus. Thesehave been demonstrated in the cat (Maciewiczet al., 1975b; Maciewicz and Phipps, 1983; Mayet al., 1987) and monkey in retrograde labelingexperiments and with antidromic activation fromthe abducens nucleus. In primates, most OMN-INTs are confined to the contralateral MR subdi-visions (Buttner-Ennever and Akert, 1981; Langeret al., 1986; Ugolini et al., 2005), contrary to the

situation in cats, where the topography of OMN-INTs is not restricted to particular divisions of theIII nucleus. The crossed pathway from OMN-INTs directly onto LR motoneurons is monosy-naptic, and was shown to target SIF (twitch) LRmotoneurons exclusively, and not MIF (non-twitch) LR motoneurons (Buttner-Ennever et al.,2003; Ugolini et al., 2005).

In primates it has been shown that OMN-INTsbehave in a remarkably similar way to MR moto-neurons during vergence and versional eye move-ments, but OMN-INTs show vertical eye positionsensitivity (Clendaniel and Mays, 1994). The iden-tified OMN-INTs display a burst-tonic pattern ofactivity during adducting saccades (Clendaniel andMays, 1994). The OMN-INT pathway is predom-inantly, if not entirely, excitatory, since microstim-ulation of the oculomotor nucleus, where bothMR motoneurons an OMN-INTs are located,induces, in addition to large adduction of theipsilateral eye (MR motoneuron activation), asmaller abduction of the contralateral eye (LRmotoneuron): moreover, reversible inactivation withlidocaine at the same III site results in hypometricand slowed abducting saccades in the contralateraleye (Clendaniel and Mays, 1994). Therefore,OMN-INTs send an excitatory signal to the cont-ralateral LR motoneurons, appropriate for hori-zontal conjugate eye movements during saccades.Although the reciprocal connectivity between LRand MR motoneurons by OMN-INTs and the re-ciprocal pathway from VI to III, by the abducensinternuclear neurons (ABD-INTs, see below) bothmight serve to coordinate LR and contralateralMR their action may not be exactly equivalent.The OMN-INTs behave exactly like MR moto-neurons, presumably because they receive axoncollaterals of MR motoneurons, at least in cats(Spencer et al., 1982). By contrast, ABD-INTs donot behave entirely like LR motoneurons and donot receive collateral input from LR motoneurons(cat: Highstein et al., 1982; squirrel monkey:McCrea et al., 1986).

In addition to their burst-tonic pattern of activityduring conjugate eye movements, most OMN-INTsshow an increase of tonic discharge for vergence

(Nakao et al., 1986; Zhang et al., 1991, 1992;Clendaniel andMays, 1994). Most LRmotoneurons

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and ABD-INTs decrease their activity during con-vergence (Gamlin et al., 1989b). Since the OMN-INTs within the MR subgroups are excitatory,they cannot be the source of the appropriate in-hibitory vergence signal to LR motoneurons: theirinput is inappropriate. However, their tonic activ-ity during vergence might explain why LR moto-neurons do not decrease their activity as much forvergence as for conjugate eye movements of sim-ilar amplitude (Gamlin et al., 1989b), implyingthat some co-contraction of LR and MR musclesoccurs during convergence.

In the cat, OMN-INTs constitute a nonuniformpopulation, showing low percentages of immuno-staining for various calcium-binding proteins,especially calbindin (De la Cruz et al., 1998). Ofthe OMN-INTs labeled retrogradely from the ab-ducens nucleus, none are serotoninergic (Mayet al., 1987) or glycinergic (Spencer et al., 1989)and only a small percentage (20%) is GABAergic(De la Cruz et al., 1992). The functional role ofthese GABAergic OMN-INTs is not clear.

Central caudal nucleus

In primates, the levator palpebrae (LP) motoneu-rons lie in the central caudal nucleus (CCN) acompact unpaired subgroup situated dorsal to thecaudal pole of the oculomotor nucleus in human,and usually considered as part of III (Schmidtkeand Buttner-Ennever, 1992). Within the CCN, themotoneurons of both eyelids appear intermixed,and recent experiments show that even in primatesthe LP motoneurons lie mainly contralateral (Sunand May, 1993; Buttner-Ennever et al., 2001).There are conflicting reports as to whether someLP motoneurons innervate the muscles of bothsides (Sekiya et al., 1992; Van der Werf et al.,1997), or whether each motoneuron innervatesonly the levator palpebrae of one side (Porteret al., 1989). The CCN motoneurons are smallercompared to those of the extraocular eye musclesand are more easily visualized with parvalbuminimmunostaining than the other motoneurons ofIII. They receive a strong supply of GABA-immunoreactive terminals and they are very spe-cifically associated with glycine transporter

immunoreactivity, indicating glycinergic afferents(Horn, personal observations).

The LP raises the upper eye lid and of necessitymust be closely coordinated with the vertical eyemovements. It develops embryologically from theSR muscle and in some ways the neural activity ofits motoneurons is very similar to SR, increasingwith upward eye movement; but during blinks theLP activity ceases, while SR motoneurons give aburst of activity (Evinger et al., 1984; Buttner-Ennever and Horn, 2004). In the primate the CCNwas shown to receive afferents from the interstitialnucleus of Cajal, the nucleus of the posterior com-missure (May et al., 2002) and from a small,recently identified cell group, medial to the rostralinterstitial nucleus of the MLF (RIMLF), whichwas called ‘‘M-group’’ and considered to helpcoordinate the activity of LP with eye movements(see Chapter 5; Horn et al., 2000; Chen and May,2002). Studies in rabbit and monkeys revealedprojections from neurons at the rostral borderof the principal and spinal trigeminal nucleus(pars oralis) to CCN, which presumably providethe inhibition during blinks (May et al., 2002;Morcuende et al., 2002; Buttner-Ennever andHorn, 2004).

Edinger–Westphal nucleus

In addition to controlling the extraocular musclesthe oculomotor complex also sends efferents in theoculomotor nerve (III) to the ipsilateral ciliaryganglion in the orbit, whose neurons control thesmooth muscle of the iris and of the lens. Thename Edinger–Westphal nucleus (EW) is oftenloosely given to this group of neurons. Currently itis generally accepted in medical circles that thecholinergic parasympathetic preganglionic neu-rons of EW carry signals to the ciliary ganglion,and mediate accommodation of the lens throughthe ciliary muscles, as well as constriction of thepupil through the contraction of the constrictor, orsphincter muscles of the iris. A more specificnomenclature of these neurons arising from studiesof the monkey, groups the neurons together as thevisceral nuclei. These are composed of two cellgroups the EW and the anteromedian nucleus

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(AM). The cholinergic cells of EW are shown inFig. 5A; it forms two slender columns of smallcells, one each side of the midline, and dorsal tothe rostral three-fifths of the somatic III; in trans-verse section of mid III each column divides intotwo smaller columns, but rostrally they merge to asingle cell group. The AM extends further rostralthan the motoneurons of III, and is continuouswith the rostral pole of EW, but this junction is notdistinctive. The location of the preganglionic neu-rons is a subject of some confusion, because insome species they lie scattered beyond the cytoar-chitectural boundaries of the visceral nuclei. Thelocation of the preganglionic neurons has beenstudied in primates (Akert et al., 1980; Burde andLoewy, 1980; Clarke et al., 1985) in nonprimates(Sugimoto et al., 1977; Loewy et al., 1978; Strassmanet al., 1987; Sun and May, 1993). In monkey thepreganglionic neurons are largely confined to EWand AM (Akert et al., 1980; Burde and Loewy,1980; Ishikawa et al., 1990; May et al., 1992; Sunand May, 1993), but some reports found cells lat-eral to EW in the lateral visceral cell columns ofthe ventrolateral PAG (Burde and Williams,1989). Unfortunately the results of the primateexperiments are confused by the use of differentsets of terminology where EW is sometimes re-ferred to as the dorsal visceral cell column (Piersonand Carpenter, 1974) and other times as the medialvisceral cell column (Carpenter et al., 1970). Mostneurons of the dorsomedial EW are larger than thesurrounding cells, Gamlin and colleagues showedthat preganglionic neurons subserving accommo-dation of the lens, and projecting to the ciliaryganglion, were confined to this cell group, andwere not found further laterally in lateral visceralcell columns (Gamlin et al., 1994). It is importantto remember that the location of EW in human asput forward by Olszewski and Baxter (1982) isbased on cytoarchitectural features alone.

In cat and rabbit the preganglionic neurons arein a completely different location from primates:neither EW nor AM contain significant numbersof preganglionic neurons; instead they lie dorsal toIII in the periaqueductal gray substance and in thetegmental area ventral to III (Sugimoto et al.,1977; Loewy et al., 1978; Strassman et al., 1987;Erichsen and May, 2002). In contrast to mammals,

in birds the characterization of the preganglionicneurons of EW is superb. The caudal-lateral sub-division of EW projects to the ciliary ganglion cellscontrolling the iris; those in the medial EW inner-vate the ganglion cells controlling the choroidcapillaries, and the rostral–lateral EW neuronscontrol the accommodation ganglion cells inner-vating the ciliary muscles (Reiner et al., 1983,1991; Gamlin et al., 1984). A less well organized,but similar topography can be demonstrated in cat(Erichsen and May, 2002).

A further complication in the assessment of EWis that some reports suggest that some neurons ofEW bypass the ciliary ganglion and innervate theiris or ciliary body directly (Jaeger and Benevento,1980; Burde, 1988; Klooster et al., 1993). In ad-dition, several studies show with tracer injectionsthat neurons in the EW area project not only tothe ciliary ganglion but also to the lower brain-stem, the cerebellum, and the spinal cord (Loewyand Saper, 1978; Loewy et al., 1978; Sugimotoet al., 1978; Roste, 1990; Klooster et al., 1993). Thedifficulty of distinguishing between the severalgroups of neurons lying close together on the mid-line of III, has been already mentioned. The samedifficulty applies to an assessment of the efferentsand afferents of the ‘‘EW region,’’ for example,from the vestibular nuclei (Balaban, 2003), fromthe pretectum (Buttner-Ennever et al., 1996b;Clarke et al., 2003) and the accessory optic nuclei(see Chapter 13; Clarke et al., 2003). Likewise, thereports of EW degeneration in Alzheimer diseasemust also be critically assessed since the exactlocation of the preganglionic cells in humans areunknown (Scinto et al., 1999, 2001).

Functional considerations of the EW mustinclude an analysis of the ‘‘near response’’or ‘‘near triad’’ (Leigh and Zee, 1999). Lensaccommodation is one part, pupillary constrictionis a second and vergence is the third component.The first two functions are controlled by EW neu-rons around the midline of the III, whose location ishardly distinguishable from the C- and S-groupMIF motoneurons (Fig. 5A). If the MIF motoneu-rons are involved in control of eye muscles before,during or after vergence, then the neuroanatomy ofthe midline III region is well suited for the synkineseof these three functions.

Fig. 6. Diagram illustrating four different types of neuron

within the abducens nucleus and their targets.

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Trochlear nucleus

The trochlear nucleus (IV) lies in the midbrainventral to the aquaeduct. In humans, it has beenobserved to consist of one large group ‘sunken’into the MLF; and several smaller groups ofmotoneurons further caudally (Olszewski andBaxter, 1982). It contains only motoneurons ofthe contralateral superior oblique muscle; howeverthe contribution of SO motor unit activity duringsome types of eye movements such as convergence(Mays et al., 1991), counterrolling during static tilt(Sasaki et al., 1991) is still not well understood.The motoneurons innervating the MIF, or slownontwitch muscle fibers, lie in a tight cluster in thethe dorsal cap of the nucleus, see Fig. 5B (Buttner-Ennever et al., 2001). In all mammals where thetrochlear nucleus has been studied (rabbit, rat,hamster, guinea pig, cat, and ferret) the percentageof ipsilaterally projecting neurons, usually of smallsize, was approximately 2–4% (Murphy et al.,1986); and in lamprey was estimated as 16%(Fritzsch and Sonntag, 1988).

Tensor tympani motoneurons

A small number of neurons around the dorsal capof the trochlear nucleus were retrogradely filledfrom the ipsilateral tensor tympani muscle (Shawand Baker, 1983). The motoneurons were smalland appeared very similar in both type and loca-tion to the SO MIF motoneurons. The tensortympani muscle and the EOM are both innervatedby the trigeminal nerve (by motor and sensorynerves, respectively), and are the only muscles inmammals known to contain MIFs (Morgan andProske, 1984), so we consider the fact that theirmotoneurons are intermingled to be highly signif-icant. No labeled cells in the trochlear nucleuswere found by Murphy et al. (1986) in the rabbitfollowing tensor tympani muscle injections.

Abducens nucleus

The abducens nucleus (VI) lies in the pontomed-ullary brainstem beneath the floor of the fourthventricle as a round nucleus adjacent to the: for a

comparison across species, see Evinger (1988). Inprimate, it contains at least four functional cellgroups (Fig. 6): (1) motoneurons innervatingthe SIF (or twitch) muscle fibers of the lateralrectus muscle; (2) motoneurons innervatingnontwitch muscle fibers of the lateral rectus mus-cle; (3) abducens internuclear neurons (ABD-INT); and (4) floccular-projecting neurons in therostral cap, which belong to the paramedian tractneurons (see Chapter 5). The motoneuronscontrolling the SIF and MIF muscle fibres arescattered throughout the motor nucleus (Fig. 7A),but those controlling the MIF fibers are arrangedaround the periphery of the nucleus in monkey, seeFig. 7B (Buttner-Ennever et al., 2001). The organ-ization of the MIF motoneurons in VI is not soclear as in III and IV (Figs. 3 and 5), but thehistochemical differences to SIFs remain identicalas described above: the abducens MIF motoneu-rons lack perineuronal nets (Fig. 5E), and do nothave nonphosphorylated neurofilaments (Eberhornet al., 2005). In teleosts the abducens is clearlydivided into a rostral and caudal division (Sterling,1977), but inspite of a clear size-difference betweenthe motoneuron of the two divisions, no differencesin the physiological properties could be found(Sterling, 1977; Pastor et al., 1991; Cabrera et al.,1992).

Fig. 7. (A)–(C) show the differential distribution of cell groups in abducens nucleus (VI) of monkey: (A) retrograde tracer filling of SIF

and MIF abducens motoneurons with a large injection of cholera-toxin subunit B into the belly of LR; (B) retrograde tracer filling of

abducens MIF motoneurons with a small injection of rabies virus into the distal tip of LR; (C) retrograde tracer filling of abducens

internuclear neurons with an injection of WGA.HRP into III of the contralateral side. (D) and (E) demonstrate different inputs to SIF

and MIF motoneurons of III: (D) fine silver grain anterograde labeling of the A- and C-groups of MR motoneurons after a [3H]

leucine injection into the right VI; (E) fine silver grain anterograde labeling of the C- and S-groups after an injection into the pretectum,

right side. Note that the SIF motoneurons of III remain mostly unlabeled, although fibers of passage are present. Calibration in

(A)–(C) is 500mm and in (D) and (E) it is 500mm.

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Abducens internuclear neurons

The internuclear neurons of the abducens nucleus(ABD-INT) project to the motoneurons of themedial rectus muscle in the contralateral oculo-motor nucleus, thereby forming the anatomicalbasis for conjugate eye movements (Buttner-

Ennever and Akert, 1981). The ABD-INTs tend tolie lateral the rootlets of the VI in primates (Fig. 7C),and in cat they are present throughout the VI, moreprevalent rostrally, but intermixed with motoneu-rons in the ratio of about 1:2, respectively (Steigerand Buttner-Ennever, 1978). This correlates withthe report of Spencer and Sterling (1977) in cat,

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and also in rabbit (Labandeira-Garcia et al., 1989)where ABD-INTs comprised 25% of abducenscells in the most successful experiments, and ABD-INTs were slightly smaller than motoneurons.Single cell reconstructions of motor and internu-clear neurons revealed minor differences in thesoma-dendritic morphology, but their axons dif-fered in that motoneurons had no collaterals, andthe crossed axon of the ABD-INT gave off collat-erals as it entered the MLF (Highstein et al., 1982).ABD-INTs have been examined in both frog(Straka and Dieringer, 1991) and goldfish (Cabreraet al., 1992).

Motoneurons and internuclear neurons exhibitthe same burst-tonic firing pattern during eyemovements (Fuchs et al., 1988), and while themotoneurons activate the LR, the ascending axonsof the ABD-INT cross the midline, enter the MLF,terminate in MR motoneuron subgroups of the IIIand drive the contralateral eye in a conjugatemovement. Hence, damage to the MLF (internu-clear ophthalmoplegia, INO) causes paresis of theMR. Only MR motoneurons, and not the inter-nuclear neurons, carry vergence-related signals,and therefore in INO vergence remains intact butconjugate eye movements are disrupted (Delgado-Garcia et al., 1986a and b; Zhou and King, 1998).

A cell group of the paramedian tracts

The paramedian tract (PMT) cell groups havebeen brought to the attention of oculomotorneuroanatomists on account of their projectionto the flocculus and ventral paraflocculus region,demonstrated in experimental tract tracing exper-iments (Blanks et al., 1983; Sato et al., 1983;Langer et al., 1985; Buttner-Ennever and Buttner,1988; Blanks, 1990). It is well known that thevestibular nuclei project to the floccular region,but it is less well known that probably even morefloccular-projecting neurons lie scattered amongthe fascicles of the MLF in the pons and medulla.These neuronal groups have been called variousnames, but are collectively referred to here as PMTcell groups. There are at least six relatively sepa-rate ‘‘PMT groups’’ scattered in the MLF, rostral,caudal, and even within, the abducens nucleus.

The PMT cell groups receive afferents from eithervertical premotor cell groups, such as INC and theY-group, or from horizontal premotor structureslike PPRF or oculomotor internuclear neurons.We have recently found both vertical and hori-zontal PMT cell groups close to or within VI. Thelocation of two PMT groups are seen in Fig. 7C(arrows) where the light gray (WGA.HRP)anterograde labeling from OMN-INT afferentsmarks (1) the dorsomedial abducens, and (2) thesupragenual region (Langer et al., 1985). The PMTgroups could provide the flocculus and ventralpara-flocculus of the cerebellum with a copy of theoculomotor input signal. Damage could lead to adisturbance in gaze-holding, see also Chapters 1and 5 (Buttner et al., 1995).

Accessory abducens nucleus

In addition to the extraocular eye muscles rotatingthe eye, most land-dwelling animals have a set ofmuscles controlling the nictitating membrane orthird eyelid (Chapter 2). The accessory abducensnucleus (AC-VI) innervates these muscles via theabducens nerve (NVI). The AC-VI lies in the ven-tral pons just above the superior olive and near thespinal trigeminal nucleus from which it receivesplentiful afferents (see below). The motoneurons inamphibian and mammalian AC-VI innervate theipsilateral retractor bulbi muscles (RBMs) (Grantet al., 1979; Spencer et al., 1980; Spencer andPorter, 1981; Murphy et al., 1986; Evinger et al.,1987; Barbas-Henry and Lohman, 1988). Retrac-tor bulbi contraction pulls the eye back into theorbit, which in turn squeezes the nictitatingmembrane out of the orbit, up over the front ofthe eye. In birds, the AC-VI supplies the quadrateand pyramidalis muscles, which replace the RBM(Isomura, 1981; Labandeira-Garcia et al., 1987).Since the nictitating membrane is a tendon ofthe pyramidalis muscle, contraction causes thenictitating membrane to sweep across the front ofthe eye, without retracting or rotating the globe. Inspecies without a movable nicitating membranethe retractor bulbi and its innervation is poorlydeveloped, as for example in the guinea pig where

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less than 20 AC-VI motoneurons supply the thinsheet of retractor bulbi (Evinger et al., 1987).

The AC-VI lies about 0.6mm ventral to theabducens nucleus in rabbit. It contains about 250motoneurons and almost all are labeled by tracerinjections into the four slips of RBM (Murphyet al., 1986). The RBM in rabbit, cat, and rat ismade up of four slips of muscle which insert prox-imal to the equator of the globe. Gross dissectionshowed that branches of both the oculomotor andabducens nerves entered the RBM, but never fromthe trochlear nerve (Murphy et al., 1986). Therewas usually leakage from the RBM injections, so itis difficult to estimate how many neurons in ab-ducens and the OMN also supplied the RBM.However, both anatomical and physiological ex-periments confirm that abducens and oculomotorneurons also innervate the RBM (Crandall et al.,1981; Meredith et al., 1981). In primates, neuronsjust ventral to, and in, the VI innervate the acces-sory lateral rectus muscle which is a vestigial formof the retractor bulbi (Chapter 2; Spencer andPorter, 1981; Schnyder, 1984). In squirrel monkeyit was estimated that there are 1418 abducens neu-rons, and roughly 75% motoneurons were labelledfrom R and 50% from retractor bulbi in rabbit(Murphy et al., 1986). But different numbers werepublished for the rabbit: 400 abducens neurons,36% motoneurons were labelled from LR, and72% from retractor bulbi (Gray et al., 1981).

Afferent pathways

Many neural networks converge on the extraocu-lar motoneurons to drive the various differenttypes of eye movement and to maintain the correctalignment of the eyes (Fig. 9A). The relative inde-pendence of saccadic circuits from vestibular net-works, or of vertical saccade premotor regions,from horizontal saccade premotor areas, is usuallyemphasized to simplify the neuroanatomical pic-ture (Buttner-Ennever and Horn, 2004). However,it is well to remember that all six eye muscles par-ticipate in all types of eye movements. The highlysensitive transsynaptic tracing with rabies indicatesthat there is a cross-activation between verticaland horizontal systems, whereby the RIMLF,

INC, SVN, and the Y-group send a small numberof projections to LR motoneurons (Graf et al.,2002; Ugolini et al., 2005). This has been inter-preted as a necessity for spatial coordination of eyemovement coordinates, and adaptive plasticity(Graf et al., 1993). Some afferents to the oculo-motor nuclei are found only in certain species; forexample, the accessory optic nuclei in the pigeonare reported to project to III (Brecha and Karten,1979; Brecha et al., 1980).

Vestibular afferents

The projections from the vestibular nuclei to theoculomotor nuclei are formed by several parallelpathways, subserving compensatory and pursuiteye movements. The best studied pathway is thethree neuron arc involving the primary canalafferents projecting to the secondary vestibularneurons, which in turn send axons to the moto-neurons in VI, IV, and III (Tarlov, 1970; Graybieland Hartwieg, 1974; Gacek, 1977; Carpenter andCowie, 1985; Epema et al., 1990).

Secondary vestibulo-ocular neurons

Careful intra-axonal staining reconstructions ofsecondary vestibular neurons receiving canalafferents demonstrated ascending axons that donot just excite or inhibit the motoneurons of oneeye muscle, but project to the extraocular moto-neuron pools of yoked muscle pairs, e.g., SO-IR;SR-IO, and generate a particular conjugate eye

movement, such as upward, downward, torsional,or horizontal movements. Many studies were usedto compile the scheme of connections shown inFig. 8, and also in Chapter 1, Fig. 7 (Highstein,1973; Cohen, 1974; King et al., 1978; Andersonet al., 1979; Precht, 1979; McCrea et al., 1980,1987a, b; Graf et al., 1983; Isu and Yokota, 1983;Mitsacos et al., 1983; Hirai and Uchino, 1984b;Graf and Ezure, 1986; Isu et al., 1988; Ohgakiet al., 1988a, b; Buttner-Ennever, 2000). These sec-ond-order vestibular cells tend to lie in the centralmagnocellular regions of the vestibular complex(MVNm and SVNm). The magnocellular regionsare considered to provide the main output path-ways of the vestibular complex, and in some

Fig. 8. Basic circuitry of the direct vestibulo-ocular reflex pathways by which horizontal and vertical canals activate functionally

organized eye muscles pairs, and inhibit their antagonist pair. Note that inhibitory pathways ascend ipsilaterally in MLF, and

excitatory pathways in crossed MLF. The secondary anterior canal neurons in SVN form an additional ascending pathway (gray), the

crossed ventral tegmental tract (CVT); (int), abducens internuclear neuron.

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reviews is referred to as zone 1 (Buttner-Ennever,1992, 2000). The secondary vestibular neuronshave a dominant canal input, and project to themotoneurons via the MLF. Ipsilateral pathwaysare inhibitory and contralateral pathways excita-tory; whereby the inhibitory transmitter for hor-izontal VOR is glycine, that for the vertical VOR isGABA, and both use glutamate and/or aspartateas their excitatory transmitter (Spencer et al., 1989,2003; McElligott and Spencer, 2000). Some oculo-motor afferents from the SVN in rabbit may as-cend via the brachium conjuctivum and cross withit in the caudal mesencephalon (Yamamoto et al.,1978). A second, parallel pathway running furtherventrally and crossing at roughly the same level(just rostral to nucleus reticularis tegmenti pontis)has been described, and called the ‘‘crossing ven-tral tegmental tract’’ (CVT) (Fig. 8). It carries sec-ondary anterior canal afferents from SVN to themotoneurons in III of the upward moving eyemuscles, SR and IO (Stanton, 1980; Sato et al.,1984; Hirai and Uchino, 1984b; Uchino and Hirai,1984; Uchino et al., 1994), and also carries affer-ents from the floccular target neurons in the dorsalY-group (Sato et al., 1984; Carpenter and Cowie,1985). Further experiments are needed to excludethe possibility that the CVT has not been mistakenfor the brachium conjunctivum in some cases(Sato et al., 1984).

Non-second-order vestibulo-ocular neurons

Many non-second-order vestibular neurons,including the NO-producing neurons describedbelow, also project to the oculomotor nuclei, butthere is less information on these pathways. Theylie in the rostral MVNp, marginal zone adjacent toPPH, SVN and the dorsal Y-group, for review seeChapter 6 (Buttner-Ennever, 1992, 2000). Those inthe rostral MVNp become very numerous inprimate, compared to cat (Langer et al., 1986;Highstein and McCrea, 1988). The marginal zonecells lie slightly further caudal; many are inhibitoryneurons using glycine as their transmitter, andwith axons that cross the midline and terminate inthe abducens nucleus (Langer et al., 1986; Spenceret al., 1989; McFarland and Fuchs, 1992). Theyare also particularly prominent in primates andmay play a role in pursuit eye movements. Neuronsin the dorsal division of the Y-group, also called theinfracerebellar nucleus, are floccular target neuronswhich are active during upward optokinetic andsmooth pursuit eye movements, also in vestibulo-ocular suppression but not in pure vestibular com-pensatory eye movements (e.g., in dark) (Chubband Fuchs, 1982; Plazquez et al., 2000). They havea strong excitatory monosynaptic connection toupward motoneurons in III which utilizes the CVT(Fig. 8) or the brachium conjuctivum (Sato et al.,1984; Yamamoto et al., 1986; Sato and Kawasaki,

Fig. 9. (A) Summary diagram of the inputs to all extraocular

motoneurons. The accessory optic nuclei are only proved in

avian species. (B) The main inputs to the MIF motoneurons of

LR are limited to areas involved in gaze-holding, or tonic

functions. The faint gray arrows indicate the other regions

shown in (A) which possibly contribute a weak input (see

Ugolini et al., 2005).

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1987), and also an inhibitory pathway to thetrochlear and inferior rectus motoneurons, whichmay serve to inhibit the neurons during pursuit eyemovements (Partsalis and Highstein, 1996).

Vestibulo-oculo-collic neurons are widelyspread over MVN and DVN, and possess bifur-cating axons which project both to the oculomotornuclei and to the spinal cord (Minor et al., 1990).Their axons travel rostrally in the MLF, and cau-dally mainly in the contralateral MVST. This typeof neuron is not modulated by floccular influences,and therefore plays no role in the floccular adap-tation the vestibulo-ocular reflex (Hirai andUchino, 1984a; Stanton, 2001).

The otolith projections to the oculomotor nucleifollow a completely different pattern from those ofthe canals; for a review, see Buttner-Ennever(1999). Primary afferents from the sacculus andutricle terminate mainly in the LVN, DVN, caudalSVN, and nodulus (Ishizuka et al., 1980; Imagawaet al., 1995). In the vestibular nuclei there is someconvergence of canal and otolith signals onto thesecondary neurons (Uchino et al., 2005). Utricularinformation can reach the abducens motoneuronsand ABD-INTs via monosynaptic (Imagawa et al.,1995), disynaptic (Uchino et al., 1997), and mul-tisynaptic routes (Uchino and Isu, 1996). Saccularafferents probably only use multisynaptic path-ways to extraocular motoneurons. It is interestingin this respect that there is no strong eye move-ment response to a loud click on the mastoid bone,which activates the underlying sacculus relativelyspecifically. In contrast, there is overwhelmingevidence for powerful projections of the utricle andsacculus to neck muscle motoneurons (Uchinoet al., 2005).

Ascending tract of Deiters

The medial rectus subgroup in the oculomotornucleus receives vestibular activation via ABD-INTs, and in addition a noteworthy set of directafferents from secondary vestibular neurons inMVN. Their axons travel in the lateral wing of theMLF and are called the ‘‘ascending tract ofDeiters’’ (ATD), see Fig. 8 (for a review, seeButtner-Ennever and Gerrits, 2004). It is oftenhard to see these ascending fibers in tract tracingexperiments presumably because they are scat-tered. Single cell reconstructions of three ATDcells in MVN revealed terminals over the A- andB-groups of MR motoneurons but none over theMIF motoneurons of the C-group (McCrea et al.,1987b). This finding should be substantiated. TheATD neurons transmit a PVP signal (position-vestibular-pause activity, see Chapter 1) to the MRmotoneurons along with head velocity (Reisineand Highstein, 1979). More recently, an excitingstudy has shown that ATD neurons carry autricular signal combined with a horizontal canalactivity, which generated vergence during linear

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acceleration. The size of the utricular signaldepended on the viewing distance, implying theexistence of a neural multiplier in the vestibularnuclei, and not just a simple disynaptic utricle-oculomotor relay (Chen-Huang and McCrea,1998).

Paramedian pontine reticular formation

The excitatory burst neurons (EBNs) for horizon-tal saccades lie in the nucleus reticularis pontiscaudalis, and form a cluster of neurons under theMLF just rostal to the abducens nucleus in thepontine reticular formation (PRF). The neuronsare essential for the generation of a horizontalsaccade (Fuchs et al., 1985; Moschovakis et al.,1996). They project monosynaptically onto theabducens motoneurons, and internuclear neurons,see Chapter 5 (Igusa et al., 1980; Langer et al.,1986; McCrea et al., 1986; Strassman et al., 1986a;Horn et al., 1995). These burst neurons have beenwell characterized anatomically as medium-sizedand parvalbumin-positive both in monkey andhumans (Horn et al., 1995). The cluster of premo-tor neurons projecting monosynaptically ontomotoneurons extend as far rostrally as nucleusreticularis tegmenti pontis (NRTP), where a smallgroup of premotor neurons form a nest in theNRTP itself (Chapter 5, Fig. 3E, arrow). Theevidence from single cell recordings in PPRF areless easy to interpret, they were found to carry amonocular signal to the motoneurons, and oftenthe activity was correlated with the activity in thecontralateral LR (Zhou and King, 1998). Anexciting finding using transsynaptic tract tracingshowed that the EBNs overwhelmingly targetedSIF motoneurons, implying that the MIF moto-neurons, with slow-tonic characteristics, do notdirectly participate in saccadic eye movements(Buttner-Ennever et al., 2002; Ugolini et al., 2005).The same was true for the inhibitory burst neurons(IBNs), which lie caudal to the EBNs in the dorsalparagigantocellular nucleus, and innervate mainlythe contralateral VI SIF motoneurons (Langeret al., 1986; Strassman et al., 1986b; Scudder et al.,1988; Robinson et al., 1994; Horn et al., 1995).

Rostral interstitial nucleus of the MLF

The burst neurons for vertical and torsional sac-cades, which make up all of the medium-sizedneurons within the rostral interstitial nucleus ofthe MLF (RIMLF), project monosynaptically tothe motoneurons of the vertical pulling extraocu-lar eye muscle pairs in the oculomotor and trochl-ear nuclei, see also Chapter 5 (Moschovakis et al.,1991a, b; Horn and Buttner-Ennever, 1998). Invery exacting studies three types of burst neuronshave been found in RIMLF and their terminalsreconstructed: (1) upward EBNs which fire withupward eye movements, and terminate on the IOand SR motoneurons of III, (2) upward IBNs

which fire with upward eye movements, andterminate on IR and SO; these may produceinhibition of these motoneurons in upward gaze,and (3) downward EBNs which fire with down-ward saccades, and terminate on IR and SO(Moschovakis et al., 1991a, b). The projectionsfrom RIMLF to III are mainly ipsilateral, there-fore for conjugate upward saccades, the concom-itant activation of the contralateral upwardmuscles, probably takes place via axons crossingthe midline in III (Moschovakis et al., 1996), andthereby providing an anatomical substrate forHerings law of equal innervation (Moschovakis,1995).

Interstitial nucleus of Cajal

The interstitial nucleus of Cajal (INC) lies imme-diately adjacent and caudal to RIMLF, further-more this cytoarchitectural boundary is indistinct(Chapter 5). For this reason the studies of Hornand colleagues, in which histological stainsare used to differentiate between the two regions,are useful (Horn and Buttner-Ennever, 1998). Thetwo areas are interrelated in function, both con-trolling the vertical eye position: RIMLF for ver-tical saccades and INC for vertical gaze-holding,(Fukushima, 1987; Fukushima et al., 1992). TheINC receives axon collaterals from all secondaryvestibular neurons that supply III (McCrea et al.,1987a). Descending projections from INC throughMLF innervate the ipsilateral oculomotor and

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trochlear nucleus (Kokkoroyannis et al., 1996);however, the inhomogeneous character of INCleaves doubt as to exactly what type of informa-tion is relayed to III or IV (see Chapter 5).

Nucleus prepositus hypoglossi

All areas that project to the abducens nucleus alsoproject to the nucleus prepositus hypoglossi (PPH)(Belknap and McCrea, 1988; McCrea, 1988). ThePPH and the adjacent marginal zone of the medialvestibular nucleus are widely belived to be anessential part of the neural integrator for horizontaleye movements (see Chapters 1 and 7) (McFarlandand Fuchs, 1992; Fukushima and Kaneko, 1995).The larger (principal) cells in PPH give rise towidespread projections to the oculomotor cellgroups, including bilateral afferents to the abduc-ens nuclei and the MR subgroups of III (Belknapand McCrea, 1988; McCrea, 1988). The monosy-naptic nature of the PPH input to extraocularmotoneurons has been verified with transsynaptictract tracing, and demonstrates that they contactMIF, and perhaps SIF, motoneurons (Buttner-Ennever et al., 2002; Ugolini et al., 2005). Themarginal zone is thought to provide the majoroutput of the horizontal integrator, and sends amassive pathway to the contralateral VI nucleus(Langer et al., 1986; McCrea et al., 1987b). Theseefferents are glycinergic (Spencer et al., 1989).

Nitric oxide (NO) is a freely diffusible gaseousmolecule that has recently been found to be pro-duced in the central nervous system. The localiza-tion of NO-positive neurons and neuropile mainlyto MVN and PPH suggests pivotal role of thisregion, since NO has a very short half-life it prob-ably has very local effects. Interestingly, the mar-ginal zone between MVN and PPH in cat, isdevoid of NO-releasing neurons but containsnumerous NO-sensitive neurons (Moreno-Lopezet al., 2001). In a series of double-labeling exper-iments to determine which functional group ofvestibular neurons are the NO-producing cellsKevetter and colleagues showed that virtually allcells in the NO-producing cells in caudal MVNand DVN could be retrogradely filled from theoculomotor nucleus, but not from the cerebellum,

spinal cord vestibular ganglion or thalamus: thisrather dramatic result was interpreted to meanthat there is a specific population of oculomotor-projecting NO producing cells in the vestibularnuclei (Kevetter et al., 2000).

Supraoculomotor area

The term supraoculomotor area (SOA) describesthe part of the periaqueductal gray substanceslocated immediately above the caudal two-thirdsof the oculomotor nucleus: laterally it is continu-ous with the mesencephalic reticular formation.The EW nucleus lies within, or adjacent, to theSOA and the region is closely associated with thecontrol of the near-response (May et al., 1992).

The afferent inputs to the SOA come from thesuperior colliculus (Edwards and Henkel, 1978),the deep cerebellar nuclei (May et al., 1992),the pretectum (Buttner-Ennever et al., 1996b), andthe accessory optic nuclei (Blanks et al., 1995).Direct projections from the frontal and supple-mentary eye fields to the SOA have also beentraced (Stanton et al., 1988; Shook et al., 1990), aswell as two regions of the cerebral cortex wherevergence responses have been recorded (Gamlinand Yoon, 2000; Fukushima et al., 2005).

Premotor neurons encoding vergence have beenrecorded in the SOA, and laterally in the adjacentMRF, from behaving monkeys (Mays and Porter,1984; Judge and Cumming, 1986; Zhang et al.,1992). The premotor vergence neurons were shownto be a source of the monosynaptic excitatorydrive to MR motoneurons in III during conver-gence (Zhang et al., 1991), and the connection wasverified anatomically (Graf et al., 2002). In addi-tion, the SOA projects bilaterally to VI, andhas been discussed above as OMN-INTs (cat:Maciewicz et al., 1975a; Maciewicz and Phipps,1983; May et al., 1987; monkey: Langer et al.,1986). Recent transsynaptic tracing studies usingrabies virus have verified the SOA input as mo-nosynaptic onto abducens motoneurons as well,and shown that they have a direct monosynapticinput onto the MIF (nontwitch) motoneurons.

In primates, both abducens motoneurons andinternuclear neurons decrease their firing rate

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during convergence (Mays and Porter, 1984;Gamlin et al., 1989a). Some SOA neurons areGABAergic and could participate in the inhibition(De la Cruz et al., 1992). A decrease in firing rateof the excitatory ABD-INTs is ‘‘inappropriate,’’because alone it would lead to decreased dischargeof MR motoneurons. Therefore, it must be com-pensated by a powerful (excitatory) vergence inputto MR motoneurons. It is possible that the SOAmay provide this excitatory signal (Mays andPorter, 1984). It has been long recognized thatinternuclear ophthalmoplegia, characterized bydamage of the MLF which interrupts the ABD-INT excitatory pathway, is characterized by loss ofconjugate adduction on the side of the lesion, butadduction for vergence is spared. By contrast,certain midbrain lesions lead to vergence deficits,but spare conjugate eye movements (reviewed byLeigh and Zee, 1999). The connectivity of SOAand its neural activity are indicative of animportant, and often underestimated, premotorrole in vergence.

Central mesencephalic reticular formation

This region of the reticular formation is part ofnucleus cuneiformis (see Chapter 5), and lieslateral to III and IV, and medially adjoining theSOA, has assumed new functional significancerecently. Rabies virus transsynaptic tracer exper-iments have shown somewhat unexpectedly thatcMRF has monosynaptic connections to abducensMIF motoneurons (Buttner-Ennever et al., 2002;Ugolini et al., 2005). As a result a new and excitingpremotor functional role for cMRF is opened up,a possible contribution to proprioceptive feedbackcircuits is fully discussed in Chapter 3 (see also Fig.10 in Chapter 3). Projections of the cMRF toMIFs in III have not yet been investigated, butMRF and the adjacent SOA (see above) areknown to contain premotor neurons encodingvergence, which have monosynaptic contacts tomedial rectus motoneurons (Zhang et al., 1991;Graf et al., 2002). The cMRF was orginiallydefined by Cohen et al. (1986) as an area fromwhich horizontal saccades could be evoked byelectrical stimulation. Since then the region has

been investigated with several techniques: two re-gions have been recognized, one lying rostrally andassociated with vertical saccades, and a caudalMRF area participating in horizontal saccades(Waitzman et al., 2000a, b; 2002). The result ofsingle unit recordings, electrical stimulation andinactivation experiments indicate an involvementin combined eye and head movements in the stab-ilization of gaze, the determination of primaryposition and saccadic metrics. Anatomically theMRF is very closely associated with the superiorcolliculus (Cohen and Buttner-Ennever, 1984; Chenand May, 2000; Buttner-Ennever et al., 2002) andalso to PPRF, NRTP, and the omnipause neurons(Edwards, 1975; personal observation).

Pretectum

The nuclei of the pretectum that are associatedwith oculomotor function are: (1) the nucleus ofthe optic tract (NOT) and (2) the pretectal olive(PON) (see Chapter 12). Unlike lower vertebrates,PON is embedded within NOT in primates. Thisregion has the connectivity to influence many dif-ferent premotor networks of the oculomotor sys-tem (Chapter 12, Fig. 6) (Buttner-Ennever et al.,1996a). With respect to direct connections toocular motoneurons, tracer injections into thepretectum labelled efferent axons crossing in theposterior commissure, and terminating over EWand the MIF motoneurons of the oculomotor andtrochlear nuclei (Fig. 7E), but not over the SIFmotoneurons (Buttner-Ennever et al., 1996b). Theprojections were verified with transsynaptic tracers(tetanus toxin BIIb) injected into medial rectus.The efferents to the oculomotor complex werefound to arise from the dorsomedial NOT andPON. In addition these neuroanatomic experi-ments confirmed the monosynaptic character ofthe pretectal projection to MIF motoneurons. Upto now the pretectal afferents to the MIF moto-neurons appears to be their strongest single input.The function of the pretectal premotor pathway isunknown; but since vergence premotor neuronshave been located in the pretectum and MIFmotoneurons tend to be associated with tonicoculomotor functions, the results fit with the

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suggestion that PON and NOT may play a role insome aspects of the near-response, i.e., vergence oreye alignment.

Histochemistry of motoneurons

Transmitters in oculomotor and trochlear nuclei

The motoneurons in the oculomotor, trochlearand abducens nuclei are cholinergic, as are someneurons in EW nucleus (see Fig. 4 and Chapter 5)(Spencer and Wang, 1996; Kus et al., 2003). Themotoneurons of vertical-pulling eye muscles in theoculomotor and trochlear nuclei receive a strongGABAergic, but a rather weak glycinergic input,in contrast to the abducens nucleus which receive astrong glycinergic input from the vestibular nuclei(De la Cruz et al., 1992). These results have led tothe concept that inhibition in horizontal eye move-ment pathways is provided by glycine, while thosefor vertical eye movement pathways utilize GABA.GABAergic afferents to the oculomotor andtrochlear nucleus originate from inhibitory sec-ondary vestibulo-ocular neurons in the ipsilateralsuperior vestibular nucleus (rabbit: Wentzel et al.,1995; cat: De la Cruz et al., 1992) and, at least inthe cat, from the RIMLF, however, this was notthe case in monkey (Horn et al., 2003).

In contrast to RIMLF, the medium-sized andlarge neurons in INC provided crossed GABA-ergic projections to the downward moving eyemuscles SO and IR (Horn et al., 2003). There areconflicting reports about a strong GABAergicinput to medial rectus motoneurons mediatinghorizontal eye movements: some authors did notsee an obvious difference in GABA terminal den-sity between different motoneuron subgroups inrabbit and cat (De la Cruz et al., 1992; Wentzelet al., 1996), whereas a much weaker innervationby GABAergic terminals over MR was observedin cat and monkey (Spencer and Baker, 1992;Horn, personal observation). A possible source forGABAergic afferents to MR-motoneurons aresmall GABAergic interneurons scattered in andabove the oculomotor nucleus in the supraoculo-motor area (SOA) (De la Cruz et al., 1992).

The contralateral excitatory afferents fromsecondary vestibulo-ocular neurons in MVN andSVN probably use glutamate and aspartate astransmitter (Dememes and Raymond, 1982),whereas the afferents from the ATD use onlyglutamate as a transmitter (Nguyen and Spencer,1999).

Transmitters in abducens nucleus

In the abducens nucleus identified, abducensinternuclear neurons have been shown not to becholinergic (Fig. 5D) (Spencer and Baker, 1986;Carpenter et al., 1992), but appear to use gluta-mate and aspartate as transmitters (Nguyen andSpencer, 1999). The PMT cell groups (see Chapter5) can be identified by the intense choline acetyl-transferase and cytochrome oxidase staining oftheir neuropile. We have found the PMT neuronsin primate to be noncholinergic, but there is someconflicting reports from studies in rats (Rodellaet al., 1996). In cat, serotonin-immunoreactivesynaptic contacts were disclosed on the dendritesof abducens neurons, but the serotoninergic dorsalraphe nucleus lying above the caudal oculomotornucleus was shown not to be the source of theseafferents (May et al., 1987). The abducens nucleusreceives a strong supply of glycinergic inhibitoryafferents, which originate from IBNs in the cont-ralateral PGD, the PPH and the ipsilateral medialvestibular nucleus (Spencer et al., 1989). Anatom-ical studies revealed a rather weak GABAergicinput to the abducens nucleus with a slight tenden-cy of motoneurons being more heavily contactedthan internuclear neurons (De la Cruz et al., 1992).

Nitric oxide (NO) has been discussed abovein relation to PPH. Through a known set ofinteractions it can affect ion channels, also inthe vestibular complex (Kevetter et al., 2000). Apharmacological study in the alert cat revealedthat the balanced production of NO by PPHis necessary for the correct performance of eyemovements (Moreno-Lopez et al., 1996). NO-pro-ducing neurons are prevalent in MVN/DVN, andsurprisingly are found to be particularly importantin vestibulo-ocular pathways (Kevetter et al., 2000;Saxon and Beitz, 2000). The interplay between NO

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mechanisms in MVN and PPH, including themarginal zone, was worked out by Moreno-Lopezet al. (2001).

Calcium-binding proteins

The analysis of different brain regions suggeststhat calcium-binding proteins, such as calbindinD-28k, calretinin, or parvalbumin are involved inregulating calcium pools critical for synapticplasticity (Schwaller et al., 2002). Systems usingcalretinin have been rather well preserved duringvertebrate evolution, and are found in oculomotorneurons in bony fish (Diaz-Regueira and Anadon,2000). Motoneurons in III, IV, and VI expressparvalbumin immunoreactivity (De la Cruz et al.,1998). In internuclear neurons at least 80% con-tain a different calcium-binding protein, calretinin,which could serve as a histological marker forinternuclear neurons in cat, but this may bedifferent in other species (De la Cruz et al., 1998).

Parvalbumin first appears in rats at embryonicday 13 in the oculomotor (III, IV, VI), vestibularand the trigeminal system and the sensory systemof the spinal cord, and develops rapidly during thefollowing days. In these locations the expression ofparvalbumin was found to coincide with thebeginning of physiological activity in nerve cells(Solbach and Celio, 1991). In the cerebral cortexand hippocampus, as well as in the Purkinje cellsof the cerebellum, parvalbumin only appearedpostnatally. Although it has been suggested thatcalcium-binding proteins could act as majorendogenous neuroprotectants, the hypothesis hasnot been generally supported (Schwaller et al., 2002).However, a disruption of the calcium-signalingcascade in mutant mice leads to severe deficits insynaptic transmission and in cerebellar motorcontrol (Barski et al., 2003).

Other factors (neurotrophins, membrane receptors,etc.)

The screening of the brainstem for specific growthor transcription factors has lead to a wealth ofdetailed properties of the extraocular motoneurons.Their significance with regard to the oculomotor

system is exciting but at present is very difficultto evaluate. For example, some neurotrophinswere found to specifically target extraocular moto-neurons: in the adult cat there is extensive neu-ronal co-expression of neurotrophin receptors, TrkA, B, and C, in the neurons of the III, IV, and VInuclei. In all three nuclei, TrkB expression pre-dominated but the degree of expression varied be-tween the three nuclei (Benitez-Temino, 2004). Aninteresting finding was that abducens internuclearneurons have the same Trk expression pattern asabducens motoneurons, though the two popula-tions have different targets (Benitez-Temino,2004). Since both neuron types have similar affer-ent inputs, the authors pointed out, that theafferents could be a factor that determined theexpression of Trk receptors and not the target cells— the theory favored by most at present. Theresults are in line with other findings, wherespecific GDNF factors were selective for specificmuscle motoneuron circuits, for example, gfralpha1and gfralpha2 were only expressed in III and IV butnot in the abducens nucleus (Mikaels et al., 2000).However, there is contrasting evidence indicatingthat the target cells can regulate the Trk expression:the trophic support from brain-derived neurotrophin

factor (BDNF) for the oculomotor and trochlearneurons was shown to be derived from their targets(Steljes et al., 1999).

In contrast to developing neurons (Chen et al.,2003), mature motoneurons do not depend onneurotrophins as survival factors, but rather asregulators of multiple functional properties, suchas membrane excitability (Gonzalez and Collins,1997; Yamuy et al., 1999), synaptic input(Novikov et al., 2000), and plasticity (McAllisteret al., 1999). Since the co-expression of multipleneurotrophin receptors in the same neuronal typeis not limited to oculomotor neurons but presentin various brain regions (e.g., in the trigeminalsystem; see Jacobs and Miller, 1999), this indicatesa role, broader than oculomotor function. Onepossibility raised by these findings is that eachneurotrophin receptor regulates independently, orin concert with each other, multiple aspects ofneuronal physiology.

Other studies report a particular associationbetween extraocular motoneurons and specific

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membrane properties: for example, the Slack

potassium channel (Bhattacharjee et al., 2002), orthe membrane proteins cadherins, important foradhesive mechanisms (Heyers et al., 2004). Adifferential distribution was reported for theexpression of synaptosomal-associated protein

SNAP 25 involved in the molecular regulation ofneurotransmitter release, where two isoforms,SNAP 25a and SNAP 25b, were demonstrated inEW and III, respectively (Jacobsson et al., 1999).Finally, the use of transgenic mice as models forthe effects of diseases, such as progressive motorneuropathy or ALS, on extraocular motoneuronsare highly promising (Haenggeli and Kato, 2002).The above section highlights only a few of thecurrent studies, but from these it is clear that thebehavior of motoneurons in the oculomotor nucleiis influenced by many more factors than premotorinnervation alone.

In conclusion, the rapid advances in our knowl-edge of extraocular motoneurons has enableddifferent types of motoneurons to be identified,MIFs and SIFs. Their premotor inputs clearlydiffer, but the function of MIF motoneurons isnot yet clear. A role of MIF motoneurons in gaze-holding or eye alignment, their dysfunction incases of strabismus or, together with palisadeendings, a role in proprioception are all possibil-ities that can be tested in the future.

Abbreviations

III oculomotor nucleusIV trochlear nucleusVI abducens nucleusABD-INT abducens internuclear neuronsAC anterior canalAC-VI accessory abducens nucleusAM anteromedian nucleusATD ascending tract of DeitersCCN central caudal nucleus of IIICVT crossing ventral tegmental tractcMRF central mesencephalic reticular

formationDPG dorsal paragigantocellular

reticular formation (IBNs)EBN excitatory burst neuronEW Edinger–Westphal nucleus

EOM extraocular musclesHC horizontal canalIBN inhibitory burst neuronsINC interstitial nucleus of CajalINO internuclear ophthalmoplegiaIO inferior oblique muscleLP levator palpebrae superiorisLR lateral rectus musdeMed RF medullary reticular formationMIF multiply innervated muscle fiber

(nontwitch)MLF medial longitudinal fasciculusMR medial rectus muscleMVNm medial vestibular nucleus pars

magnocellularMVNp medial vestibular nucleus pars

parvocellularNOT nucleus of the optic tractNRTP nucleus reticularis tegmenti

pontisNIII oculomotor nerveNVI abducens nerveOMN-INT oculomotor internuclear neuronPC posterior canalPMT paramedian tract (cell groups)PON pretectal olivary nucleusPPH nucleus prepositus hypoglossiPPRF paramedian pontine reticular

formationPRF pontine reticular formationRBM retractor bulbi musclesRIMLF rostral interstitial nucleus of the

MLFSIF singly innervated muscle fiber

(twitch)SO superior oblique muscleSOA supraoculomotor areaSR superior rectus muscleSVNm superior vestibular nucleus, pars

parvocellularis

Acknowledgments

This study is supported by a grant from theDeutsche Forschungsgemeinschaft (Ho 1639/4-1).

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