The extraocular motor nuclei: organization and

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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 and functional neuroanatomy J.A. Bu¨ttner-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 eye muscle is highly stable through the vertebrate species. The subgroups are topographically organized in the oculomotor nucleus (III) and are usually considered to form the final common pathway for eye muscle control. Eye muscles contain a unique type of slow non-twitch, fatigue-resistant muscle fiber, the multiply innervated muscle fibers (MIFs). The recent identification the MIF motoneurons shows that they too have topographic organization, but very different from the classical singly innervated muscle fiber (SIF) motoneurons. 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 different types 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 the motoneurons arise from the vestibular nuclei, the oculomotor and abducens internuclear neurons, the mesencephalic 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 MIF and SIF motoneurons have different histochemical properties and different afferent inputs. The hypothesis that SIFs participate in moving the eye and MIFs determine the alignment seems possible but is not compatible with the concept of a final common pathway. identified motoneurons, or specific premotor connections (Horn et al., 1995; Horn and Bu¨ttnerEnnever, 1998; Eberhorn et al., 2005): and the characteristics can in turn be used as markers in the human brain to locate homologous neuronal groups. Alongside these advances has been the development of transsynaptic tracer techniques, starting with lectins, then tetanus toxin, and culminating in the injection of particular strains of rabies virus, whose uptake is restricted to motor terminals, but can travel over an unlimited number of synapses and at the same time amplify the marker-signal (Bu¨ttner-Ennever et al., 1981; Evinger and Erichsen, 1986; Itaya, 1987; Horn and Bu¨ttner-Ennever, 1990; Kuypers and Ugolini, 1990; Herzog and Ku¨mmel, 2000; Erichsen and May, 2002; Graf et al., 2002; Morcuende et al.,

Introduction The most exciting scientific developments over the last 10 years in the field of the extraocular motor nuclei have encompassed both molecular and systemic approaches. First, there is the identification of a multitude of neurotrophins, transcription factors, genetic factors, membrane receptors, and transmitters which have a specific relationship to the extraocular motoneurons. In addition, the combination of histochemical and immune techniques with tracer tracing has permitted transmitters, or histochemical characteristics, to be associated with Corresponding author. Tel.: +49 89 5160 4851; Fax: +49 89 5160 4857; E-mail: [email protected] DOI: 10.1016/S0079-6123(05)51004-5

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2002; Ugolini et al., 2005). This powerful virus tracer technique promises to reveal major principles upon which the oculomotor system is organized. General features of motoneurons Extraocular motoneurons develop within the segmented neuroepithelium in a caudal rostral sequence, like the eye muscles they innervate; abducens nucleus (VI) is first, followed by trochlear (IV) and finally the oculomotor neurons (III) (Shaw and Alley, 1981; Szyszka-Mroz, 1999). The three extraocular motor nuclei develop from different brain segments: abducens neurons originate from rhombomeres 5 and 6: trochlear neurons develop in rhombomere 1, and the oculomotor nucleus (III) is derived from the most caudal midbrain segment, or mesomere, just in front of the midbrain–hindbrain boundary (Matesz, 1990; Baker, 1992; Straka et al., 1998, 2001). These and other reviews have dealt with the further development of oculomotor circuitry (Glover, 2003). Although the IV may later merge into caudal III in some species, alone from ontogeny, the two nuclei must be considered as separate entities. The location of the three extraocular nuclei within the brainstem is shown in Chapter 1, Fig. 2.

McGurk, 1985; Szabo et al., 1987). For a comprehensive review on this topic at both the light and electron microscopic level see Evinger (1988). With respect to the abducens motoneuron size, a study comparing squirrel monkey with cat found the diameter for monkey motoneurons was 20–44 mm (mean 31.773.8 mm), and four or more primary dendrites per cell, compared with cat abducens where the size ranged from 26 to 66 mm, and averaged 37.276.2 mm, also with four or more dendrites per cell (Russell-Mergenthal et al., 1986; McClung et al., 2001). Although there is a wide variation in the reports of abducens motoneuron sizes, reviewed by McClung and colleagues, there is a general consensus that those of cat are larger than those in monkey (Langer et al., 1986; McCrea et al., 1986; McClung et al., 2001). A comparison of the sizes of medial rectus motoneurons with those of the lateral rectus in monkey showed that of the three MR subgroups (see below) those of the A group were indistinguishable from abducens motoneurons while those of the B-group were larger and the C-group smaller (Bu¨ttner-Ennever and Akert, 1981; Bu¨ttner-Ennever et al., 2001; McClung et al., 2001).

Oculomotor nucleus

Morphometry of motoneurons

Organization of motoneuron subgroups

In homeotherms the soma-dendritic morphology of the motoneurons is constant across species; an increasing soma diameter leads to more, rather than thicker dendrites. It is difficult to decide from which species of mammal or bird a motoneuron reconstruction is taken (Evinger, 1988). Nevertheless there are species differences in absolute soma size; a human has motoneurons with an average diameter of approximately 50 mm, and 12–20 primary dendrites (Szabo et al., 1987); whereas a guinea pig has oculomotor neurons of about 30 mm diameter, and 5–6 primary dendrites. In contrast, a major change appears in poikilotherms, where the oculomotor neurons look very different. They have much larger diameter primary dendrites than homeotherms, and with increasing soma diameter the dendritic diameter increases (Graf and Baker, 1985; Graf and

Neurons in III innervate the ipsilateral medial and inferior rectus (MR, IR), the inferior oblique (IO) and contralateral superior rectus (SR); IV controls the contralateral superior oblique (SO); and VI motoneurons drive the lateral rectus (LR) muscle. The mammalian III also includes motoneurons which innervate the levator palpebrae superioris (LP); they lie in a slightly separate subgroup in caudal III, called the central caudal nucleus (see below). The precise location of the motoneuron populations is dependent on the sequence of muscle and neuronal development (Baker, 1992; Straka et al., 1998). The motoneuron subgroups in III are organized in a topographic map, and are illustrated for a few species schematically in Fig. 1. The individual maps of many different vertebrate classes have been reviewed and discussed by

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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).

Evinger (1988). Here, the studies will be only cited, since despite minor differences the general organization is similar in mammals: monkey (Bu¨ttner-Ennever et al., 2001), cat (Miyazaki,

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

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most variation. In frontal-eyed animals, like the primate or cat, LP motoneurons lie in a bilobed cell group on the midline (nucleus centralis caudalis, CCN), whereby many of the motoneurons lie contralaterally within CCN (Sun and May, 1993). In lateral-eyed animals, like rabbit and rat, the LP motoneurons are situated laterally, and contralateral (Fig. 1), but in the guinea pig they are scattered ventrolaterally within the medial longitudinal fasciculus (MLF) of the contralateral side (Evinger et al., 1987). The organization of the oculomotor nucleus in lower species has been the subject of many studies: lampreys (Fritzsch and Sonntag, 1988), chameleon (El-Hassni et al., 2000), and the weakly electric fish (Szabo et al., 1987). The basic internal organization of the oculomotor nucleus (III) is remarkably constant across almost the entire spectrum of vertebrate species. An exception to the basic plan of organization in III is seen in elasmobranchs where the MR motoneurons lie in contralateral III (Fig. 1). It is instructive to consider the consequences of the standard pattern of extraocular innervation. It means that an excitatory premotor input to the III and IV of one side, results in the ipsilateral torsion of both eyes (Fig. 2), conversely a lesion of the premotor pathway would cause torsion to the other side. A good example of this seen with stimulation and lesions of is the rostral interstitial nucleus of the MLF (RIMLF) see Chapter 1, Fig. 3, also Chapter 5, and the RIMLF section of this chapter. There is a prominent change in the arrangement of MR motoneuron subgroups in primates (Fig 1): here there are three distinct clusters of MR motoneurons, ventral the A-group extending into the MLF, dorsolateral the large motoneurons of the B-group and dorsomedially at the peripheral border of the oculomotor nucleus the C-group, consisting of smaller motoneurons, see Fig. 3 (Bu¨ttner-Ennever and Akert, 1981). Rudimentary MR cell clusters, similar to some if not all of the well-defined A, B, and C subgroups in primates are seen in lower species such as cat (Miyazaki, 1985) and rat (Eberhorn, personal communication). The A-group reaches its largest proportions in the human III. It is surprising that the different functions of the A-, B-, and C-groups remain to a large extent unclear, and as yet only the C group can be

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).

correlated with the innervation of a specific muscle fiber type. Recent experiments show that the motoneurons of the C-group innervate the multiply innervated muscle fiber (MIF) motoneurons of both MR and IR (see section on motoneuron types) (Bu¨ttner-Ennever et al., 2001). A schematic diagram of an MIF motoneuron is shown in Fig. 4, and compared to a motoneuron innervating a singly-innervated muscle fiber (SIF). The MIF motoneurons of the IO and SR lie together close to the midline, sandwiched between the oculomotor nuclei, and hence called the ‘‘S-group’’ (Bu¨ttner-Ennever et al., 2001; Wasicky et al., 2004). Excitatory inputs to the S-group would lead to upward deviation of the eyes; and to the C-group, containing MR and IR motoneurons, a similar input would result in vergence with a downward component.

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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.

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.

The MIF motoneurons, shown as black dots in Fig. 3, were located by retrograde tracer injections into the distal muscle–tendon junction of the extraocular 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 (Bu¨ttnerEnnever et al., 2001). In addition, it was argued that the MIFs of the global layer rather than the orbital layer, were primarily labeled, since the orbital layer of muscle is now known to terminate more proximally than the global layer, on Tenon’s capsule (Chapter 1, Fig. 10; and Chapter 2, Fig. 2). This argument depends heavily on the new insights into the termination of the global and orbital layers of the eye muscles (Demer et al., 2000; Oh et al., 2001; Ruskell et al., 2005). At the present time the location of the motoneurons of the orbital MIFs is unknown (Eberhorn et al., 2005). The S-group motoneurons in monkey (Fig. 3) can be correlated with a similar cell cluster in man (Horn et al., unpublished observations). This general region is often referred to as the nucleus of Perlia in humans (Olszewski and Baxter, 1982). The nucleus of Perlia appears to be a variable feature in adult humans (Warwick, 1954), and the only evidence to suggest that it plays a role in the control of vergence is ‘‘the time of appearance in both the species and the embryo which coincides with the positioning of the eyes in the frontal plane were convergence

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becomes possible’’ (Adler, 1950). This may not be far from the current hypotheses on the function of the S-group MIFs (see below), but great care must be taken since there are several cell groups on the midline between the oculomotor nuclei in human, so to define them as the nucleus of Perlia, the S-group, Edinger–Westphal nucleus or an interneuron subgroup needs careful analysis (Fig. 5A) (Ishikawa et al., 1990).

Motoneurons of singly and multiply innervated muscle fibers It has been described above how the motoneurons of SIFs and MIFs tend to lie separate from each other in III, IV, and VI and have a completely different organization of their subgroups (Fig. 3). This permits a differential analysis of their afferent inputs (Wasicky et al., 2004), and it shows that SIF and MIF motoneurons do not receive identical inputs: some afferents target both, and others innervate one or the other (Figs. 7D, E). A major input to the MIF motoneurons of the C- and S-groups is the pretectum (Fig. 7E see section ‘‘Pretectum’’). The elegant transsynaptic retrograde studies of the premotor inputs to LR MIF motoneurons, using rabies virus, show that the central mesencephalic reticular formation (cMRF) and the supraoculomotor area (SOA) supply afferents, as well as areas associated with the neural integrator, like nucleus prepositus hypoglossi (PPH) and the parvocellular parts of the medial vestibular nucleus (MVNp); however, the MIFs do not receive direct afferents from premotor saccadic regions such as the paramedian pontine reticular formation (PPRF), the inhibitory burst neurons area and the oculomotor internuclear neurons (OMN-INTs) (see Fig. 8, Chapter 1 and Chapter 5) (Bu¨ttner-Ennever et al., 2002; Ugolini et al., 2005). The results suggest that the functional role of MIF is different from that of the SIF, and thus challenges the idea of a ‘‘final common pathway’’ in which it is postulated that all motoneurons participate in all types of eye movements (Miller, 2003). Individual recordings from MIF motoneurons in behaving primates have not been reported.

However, there is general agreement that twitch motoneuron units innervate the SIFs, and the nontwitch units innervate global MIFs (Lennerstrand, 1975; Nelson et al., 1986). MIF (nontwitch) firing characteristics may be deduced from studies in frog and cat, where nontwitch units were described (Goldberg et al., 1981; Dieringer and Precht, 1986; Nelson et al., 1986; Shall and Goldberg, 1992). In frog, nontwitch units were shown to fire tonically at around 50 Hz (Dieringer and Precht, 1986; Straka and Dieringer, 2004). Both motoneuron types, SIFs and MIFs, are cholinergic (Figs. 5A–E), but they have been shown in monkey to have different histochemical staining properties (Eberhorn et al., 2005). These double-labeling experiments revealed that the MIF motoneurons in the periphery of the motor nuclei do not contain nonphosphorylated neurofilaments (as detected with SMI32-immunostaining), or parvalbumin, and they lack perineuronal nets (Fig. 5E). In contrast, SIF motoneurons express all markers at high intensity (Figs. 5D, E).

Putative role of MIF and SIF motoneurons It is widely accepted that the unit activity of the motoneurons specifies the movements of the eye in the head under all circumstances. Furthermore, the discharge of all motoneurons are thought to contribute to all types of eye movements, whether saccades, VOR or vergence (Keller and Robinson, 1972; Gamlin and Mays, 1992). However, several recent reports have demonstrated, under certain circumstances, a dissociation or uncoupling between motoneuron activity and the eye movements, for example, during head restrained and nonrestrained conditions (Ling et al., 1999). About 66% of abducens motoneurons, in some conditions, fire as a result of monocular movements of not only the ipsilateral, but also the contralateral eye (Zhou and King, 1998). Another set of experiments, whose results should cause a great deal of deliberation, showed that during convergence there was a slight decrease rather than increase in muscle forces of MR and LR measured in monkeys (Miller et al., 2002). Given that we now have recognized the identity and location of MIF motoneurons, and found them to possess very different

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Fig. 5. Photomicrographs of transverse sections of: (A) oculomotor nucleus, (B) trochlear nucleus, and (C) abducens nucleus, doublelabeled 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 ABDINT (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 500 mm and in (D) and (E) it is 50 mm.

properties than the SIF motoneurons, we must now ask what role they play in oculomotor control (Bu¨ttner-Ennever et al., 2001, 2002). The MIF muscle fibres of the global layer extend throughout

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

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and Precht, 1986). It is not clear how much they contribute to the tension of eye muscles in natural conditions, but experimentally exposing eye muscle to succinylcholine causes them to contract and the effect is caused by the depolarization of MIFs and not SIFs (Bach-y-Rita et al., 1977). As discussed in Chapter 3, MIFs are associated with palisade endings at their tips at the myotendinous junction, and this combination has been compared to ‘‘an inverted muscle spindle,’’ in the words of David A. Robinson (Steinbach, 2000). It is possible that this combined structure could provide a sensory or proprioceptive feedback signal to the central nervous system (CNS), which regulates the muscle activity (see Chapter 3, Fig. 9). It is still too early to decide what role MIF motoneurons play in the control of eye movements, but currently evidence supports the idea that the SIF or twitch motoneurons primarily drive the eye movements, whereas the MIF or nontwitch motoneurons participate in determining the tonic muscle activity, as in gaze-holding, vergence and eye alignment (Bu¨ttner-Ennever et al., 2001, 2002).

Oculomotor interneurons Several populations of internuclear neurons with diverse projection targets, such as the spinal cord, the cerebellum, the abducens nucleus have been identified within and around the oculomotor nucleus (Phipps et al., 1983; Maciewicz et al., 1984; Chung et al., 1987; Clendaniel and Mays, 1994). In lampreys, there is evidence for GABA-immunoreactive neurons within the extraocular motor nuclei (Melendez-Ferro et al., 2000). The best investigated of these interneurons are the oculomotor internuclear neurons (OMN-INT) lying within within the III and in the supraoculomotor area, which project bilaterally to the abducens nucleus. These have been demonstrated in the cat (Maciewicz et al., 1975b; Maciewicz and Phipps, 1983; May et al., 1987) and monkey in retrograde labeling experiments and with antidromic activation from the abducens nucleus. In primates, most OMNINTs are confined to the contralateral MR subdivisions (Bu¨ttner-Ennever and Akert, 1981; Langer et al., 1986; Ugolini et al., 2005), contrary to the

situation in cats, where the topography of OMNINTs is not restricted to particular divisions of the III nucleus. The crossed pathway from OMNINTs directly onto LR motoneurons is monosynaptic, and was shown to target SIF (twitch) LR motoneurons exclusively, and not MIF (nontwitch) LR motoneurons (Bu¨ttner-Ennever et al., 2003; Ugolini et al., 2005). In primates it has been shown that OMN-INTs behave in a remarkably similar way to MR motoneurons during vergence and versional eye movements, but OMN-INTs show vertical eye position sensitivity (Clendaniel and Mays, 1994). The identified OMN-INTs display a burst-tonic pattern of activity during adducting saccades (Clendaniel and Mays, 1994). The OMN-INT pathway is predominantly, if not entirely, excitatory, since microstimulation of the oculomotor nucleus, where both MR motoneurons an OMN-INTs are located, induces, in addition to large adduction of the ipsilateral eye (MR motoneuron activation), a smaller abduction of the contralateral eye (LR motoneuron): moreover, reversible inactivation with lidocaine at the same III site results in hypometric and slowed abducting saccades in the contralateral eye (Clendaniel and Mays, 1994). Therefore, OMN-INTs send an excitatory signal to the contralateral LR motoneurons, appropriate for horizontal conjugate eye movements during saccades. Although the reciprocal connectivity between LR and MR motoneurons by OMN-INTs and the reciprocal pathway from VI to III, by the abducens internuclear neurons (ABD-INTs, see below) both might serve to coordinate LR and contralateral MR their action may not be exactly equivalent. The OMN-INTs behave exactly like MR motoneurons, presumably because they receive axon collaterals of MR motoneurons, at least in cats (Spencer et al., 1982). By contrast, ABD-INTs do not behave entirely like LR motoneurons and do not 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 activity during conjugate eye movements, most OMN-INTs show an increase of tonic discharge for vergence (Nakao et al., 1986; Zhang et al., 1991, 1992; Clendaniel and Mays, 1994). Most LR motoneurons

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and ABD-INTs decrease their activity during convergence (Gamlin et al., 1989b). Since the OMNINTs within the MR subgroups are excitatory, they cannot be the source of the appropriate inhibitory vergence signal to LR motoneurons: their input is inappropriate. However, their tonic activity during vergence might explain why LR motoneurons do not decrease their activity as much for vergence as for conjugate eye movements of similar amplitude (Gamlin et al., 1989b), implying that some co-contraction of LR and MR muscles occurs during convergence. In the cat, OMN-INTs constitute a nonuniform population, showing low percentages of immunostaining for various calcium-binding proteins, especially calbindin (De la Cruz et al., 1998). Of the OMN-INTs labeled retrogradely from the abducens nucleus, none are serotoninergic (May et 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 of these GABAergic OMN-INTs is not clear.

Central caudal nucleus In primates, the levator palpebrae (LP) motoneurons lie in the central caudal nucleus (CCN) a compact unpaired subgroup situated dorsal to the caudal pole of the oculomotor nucleus in human, and usually considered as part of III (Schmidtke and Bu¨ttner-Ennever, 1992). Within the CCN, the motoneurons of both eyelids appear intermixed, and recent experiments show that even in primates the LP motoneurons lie mainly contralateral (Sun and May, 1993; Bu¨ttner-Ennever et al., 2001). There are conflicting reports as to whether some LP motoneurons innervate the muscles of both sides (Sekiya et al., 1992; Van der Werf et al., 1997), or whether each motoneuron innervates only the levator palpebrae of one side (Porter et al., 1989). The CCN motoneurons are smaller compared to those of the extraocular eye muscles and are more easily visualized with parvalbumin immunostaining than the other motoneurons of III. They receive a strong supply of GABAimmunoreactive terminals and they are very specifically associated with glycine transporter

immunoreactivity, indicating glycinergic afferents (Horn, personal observations). The LP raises the upper eye lid and of necessity must be closely coordinated with the vertical eye movements. It develops embryologically from the SR muscle and in some ways the neural activity of its motoneurons is very similar to SR, increasing with upward eye movement; but during blinks the LP activity ceases, while SR motoneurons give a burst of activity (Evinger et al., 1984; Bu¨ttnerEnnever and Horn, 2004). In the primate the CCN was shown to receive afferents from the interstitial nucleus of Cajal, the nucleus of the posterior commissure (May et al., 2002) and from a small, recently identified cell group, medial to the rostral interstitial nucleus of the MLF (RIMLF), which was called ‘‘M-group’’ and considered to help coordinate the activity of LP with eye movements (see Chapter 5; Horn et al., 2000; Chen and May, 2002). Studies in rabbit and monkeys revealed projections from neurons at the rostral border of the principal and spinal trigeminal nucleus (pars oralis) to CCN, which presumably provide the inhibition during blinks (May et al., 2002; Morcuende et al., 2002; Bu¨ttner-Ennever and Horn, 2004).

Edinger– Westphal nucleus In addition to controlling the extraocular muscles the oculomotor complex also sends efferents in the oculomotor nerve (III) to the ipsilateral ciliary ganglion in the orbit, whose neurons control the smooth muscle of the iris and of the lens. The name Edinger–Westphal nucleus (EW) is often loosely given to this group of neurons. Currently it is generally accepted in medical circles that the cholinergic parasympathetic preganglionic neurons of EW carry signals to the ciliary ganglion, and mediate accommodation of the lens through the ciliary muscles, as well as constriction of the pupil through the contraction of the constrictor, or sphincter muscles of the iris. A more specific nomenclature of these neurons arising from studies of the monkey, groups the neurons together as the visceral nuclei. These are composed of two cell groups the EW and the anteromedian nucleus

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(AM). The cholinergic cells of EW are shown in Fig. 5A; it forms two slender columns of small cells, one each side of the midline, and dorsal to the rostral three-fifths of the somatic III; in transverse section of mid III each column divides into two smaller columns, but rostrally they merge to a single cell group. The AM extends further rostral than the motoneurons of III, and is continuous with the rostral pole of EW, but this junction is not distinctive. The location of the preganglionic neurons is a subject of some confusion, because in some species they lie scattered beyond the cytoarchitectural boundaries of the visceral nuclei. The location of the preganglionic neurons has been studied in primates (Akert et al., 1980; Burde and Loewy, 1980; Clarke et al., 1985) in nonprimates (Sugimoto et al., 1977; Loewy et al., 1978; Strassman et al., 1987; Sun and May, 1993). In monkey the preganglionic neurons are largely confined to EW and AM (Akert et al., 1980; Burde and Loewy, 1980; Ishikawa et al., 1990; May et al., 1992; Sun and May, 1993), but some reports found cells lateral to EW in the lateral visceral cell columns of the ventrolateral PAG (Burde and Williams, 1989). Unfortunately the results of the primate experiments are confused by the use of different sets of terminology where EW is sometimes referred to as the dorsal visceral cell column (Pierson and Carpenter, 1974) and other times as the medial visceral cell column (Carpenter et al., 1970). Most neurons of the dorsomedial EW are larger than the surrounding cells, Gamlin and colleagues showed that preganglionic neurons subserving accommodation of the lens, and projecting to the ciliary ganglion, were confined to this cell group, and were not found further laterally in lateral visceral cell columns (Gamlin et al., 1994). It is important to remember that the location of EW in human as put forward by Olszewski and Baxter (1982) is based on cytoarchitectural features alone. In cat and rabbit the preganglionic neurons are in a completely different location from primates: neither EW nor AM contain significant numbers of preganglionic neurons; instead they lie dorsal to III in the periaqueductal gray substance and in the tegmental 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 preganglionic neurons of EW is superb. The caudal-lateral subdivision of EW projects to the ciliary ganglion cells controlling the iris; those in the medial EW innervate the ganglion cells controlling the choroid capillaries, and the rostral–lateral EW neurons control the accommodation ganglion cells innervating 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 EW is that some reports suggest that some neurons of EW bypass the ciliary ganglion and innervate the iris or ciliary body directly (Jaeger and Benevento, 1980; Burde, 1988; Klooster et al., 1993). In addition, several studies show with tracer injections that neurons in the EW area project not only to the ciliary ganglion but also to the lower brainstem, the cerebellum, and the spinal cord (Loewy and Saper, 1978; Loewy et al., 1978; Sugimoto et al., 1978; Roste, 1990; Klooster et al., 1993). The difficulty of distinguishing between the several groups of neurons lying close together on the midline of III, has been already mentioned. The same difficulty applies to an assessment of the efferents and afferents of the ‘‘EW region,’’ for example, from the vestibular nuclei (Balaban, 2003), from the pretectum (Bu¨ttner-Ennever et al., 1996b; Clarke et al., 2003) and the accessory optic nuclei (see Chapter 13; Clarke et al., 2003). Likewise, the reports of EW degeneration in Alzheimer disease must also be critically assessed since the exact location of the preganglionic cells in humans are unknown (Scinto et al., 1999, 2001). Functional considerations of the EW must include an analysis of the ‘‘near response’’ or ‘‘near triad’’ (Leigh and Zee, 1999). Lens accommodation is one part, pupillary constriction is a second and vergence is the third component. The first two functions are controlled by EW neurons around the midline of the III, whose location is hardly distinguishable from the C- and S-group MIF motoneurons (Fig. 5A). If the MIF motoneurons are involved in control of eye muscles before, during or after vergence, then the neuroanatomy of the midline III region is well suited for the synkinese of these three functions.

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Trochlear nucleus The trochlear nucleus (IV) lies in the midbrain ventral to the aquaeduct. In humans, it has been observed to consist of one large group ‘sunken’ into the MLF; and several smaller groups of motoneurons further caudally (Olszewski and Baxter, 1982). It contains only motoneurons of the contralateral superior oblique muscle; however the contribution of SO motor unit activity during some 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 slow nontwitch muscle fibers, lie in a tight cluster in the the dorsal cap of the nucleus, see Fig. 5B (Bu¨ttnerEnnever et al., 2001). In all mammals where the trochlear nucleus has been studied (rabbit, rat, hamster, guinea pig, cat, and ferret) the percentage of ipsilaterally projecting neurons, usually of small size, 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 cap of the trochlear nucleus were retrogradely filled from the ipsilateral tensor tympani muscle (Shaw and Baker, 1983). The motoneurons were small and appeared very similar in both type and location to the SO MIF motoneurons. The tensor tympani muscle and the EOM are both innervated by the trigeminal nerve (by motor and sensory nerves, respectively), and are the only muscles in mammals known to contain MIFs (Morgan and Proske, 1984), so we consider the fact that their motoneurons are intermingled to be highly significant. No labeled cells in the trochlear nucleus were found by Murphy et al. (1986) in the rabbit following tensor tympani muscle injections. Abducens nucleus The abducens nucleus (VI) lies in the pontomedullary brainstem beneath the floor of the fourth ventricle as a round nucleus adjacent to the: for a

Fig. 6. Diagram illustrating four different types of neuron within the abducens nucleus and their targets.

comparison across species, see Evinger (1988). In primate, it contains at least four functional cell groups (Fig. 6): (1) motoneurons innervating the SIF (or twitch) muscle fibers of the lateral rectus muscle; (2) motoneurons innervating nontwitch muscle fibers of the lateral rectus muscle; (3) abducens internuclear neurons (ABDINT); and (4) floccular-projecting neurons in the rostral cap, which belong to the paramedian tract neurons (see Chapter 5). The motoneurons controlling the SIF and MIF muscle fibres are scattered throughout the motor nucleus (Fig. 7A), but those controlling the MIF fibers are arranged around the periphery of the nucleus in monkey, see Fig. 7B (Bu¨ttner-Ennever et al., 2001). The organization of the MIF motoneurons in VI is not so clear as in III and IV (Figs. 3 and 5), but the histochemical differences to SIFs remain identical as described above: the abducens MIF motoneurons lack perineuronal nets (Fig. 5E), and do not have nonphosphorylated neurofilaments (Eberhorn et al., 2005). In teleosts the abducens is clearly divided into a rostral and caudal division (Sterling, 1977), but inspite of a clear size-difference between the motoneuron of the two divisions, no differences in the physiological properties could be found (Sterling, 1977; Pastor et al., 1991; Cabrera et al., 1992).

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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 500 mm and in (D) and (E) it is 500 mm.

Abducens internuclear neurons The internuclear neurons of the abducens nucleus (ABD-INT) project to the motoneurons of the medial rectus muscle in the contralateral oculomotor nucleus, thereby forming the anatomical basis for conjugate eye movements (Bu¨ttner-

Ennever and Akert, 1981). The ABD-INTs tend to lie lateral the rootlets of the VI in primates (Fig. 7C), and in cat they are present throughout the VI, more prevalent rostrally, but intermixed with motoneurons in the ratio of about 1:2, respectively (Steiger and Bu¨ttner-Ennever, 1978). This correlates with the 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 abducens cells in the most successful experiments, and ABDINTs were slightly smaller than motoneurons. Single cell reconstructions of motor and internuclear neurons revealed minor differences in the soma-dendritic morphology, but their axons differed in that motoneurons had no collaterals, and the crossed axon of the ABD-INT gave off collaterals as it entered the MLF (Highstein et al., 1982). ABD-INTs have been examined in both frog (Straka and Dieringer, 1991) and goldfish (Cabrera et al., 1992). Motoneurons and internuclear neurons exhibit the same burst-tonic firing pattern during eye movements (Fuchs et al., 1988), and while the motoneurons activate the LR, the ascending axons of the ABD-INT cross the midline, enter the MLF, terminate in MR motoneuron subgroups of the III and drive the contralateral eye in a conjugate movement. Hence, damage to the MLF (internuclear ophthalmoplegia, INO) causes paresis of the MR. Only MR motoneurons, and not the internuclear neurons, carry vergence-related signals, and therefore in INO vergence remains intact but conjugate eye movements are disrupted (DelgadoGarcia et al., 1986a and b; Zhou and King, 1998).

A cell group of the paramedian tracts The paramedian tract (PMT) cell groups have been brought to the attention of oculomotor neuroanatomists on account of their projection to the flocculus and ventral paraflocculus region, demonstrated in experimental tract tracing experiments (Blanks et al., 1983; Sato et al., 1983; Langer et al., 1985; Bu¨ttner-Ennever and Bu¨ttner, 1988; Blanks, 1990). It is well known that the vestibular nuclei project to the floccular region, but it is less well known that probably even more floccular-projecting neurons lie scattered among the fascicles of the MLF in the pons and medulla. These neuronal groups have been called various names, but are collectively referred to here as PMT cell groups. There are at least six relatively separate ‘‘PMT groups’’ scattered in the MLF, rostral, caudal, and even within, the abducens nucleus.

The PMT cell groups receive afferents from either vertical premotor cell groups, such as INC and the Y-group, or from horizontal premotor structures like PPRF or oculomotor internuclear neurons. We have recently found both vertical and horizontal PMT cell groups close to or within VI. The location of two PMT groups are seen in Fig. 7C (arrows) where the light gray (WGA.HRP) anterograde labeling from OMN-INT afferents marks (1) the dorsomedial abducens, and (2) the supragenual region (Langer et al., 1985). The PMT groups could provide the flocculus and ventral para-flocculus of the cerebellum with a copy of the oculomotor input signal. Damage could lead to a disturbance in gaze-holding, see also Chapters 1 and 5 (Bu¨ttner et al., 1995).

Accessory abducens nucleus In addition to the extraocular eye muscles rotating the eye, most land-dwelling animals have a set of muscles controlling the nictitating membrane or third eyelid (Chapter 2). The accessory abducens nucleus (AC-VI) innervates these muscles via the abducens nerve (NVI). The AC-VI lies in the ventral pons just above the superior olive and near the spinal trigeminal nucleus from which it receives plentiful afferents (see below). The motoneurons in amphibian and mammalian AC-VI innervate the ipsilateral retractor bulbi muscles (RBMs) (Grant et al., 1979; Spencer et al., 1980; Spencer and Porter, 1981; Murphy et al., 1986; Evinger et al., 1987; Barbas-Henry and Lohman, 1988). Retractor bulbi contraction pulls the eye back into the orbit, which in turn squeezes the nictitating membrane out of the orbit, up over the front of the eye. In birds, the AC-VI supplies the quadrate and pyramidalis muscles, which replace the RBM (Isomura, 1981; Labandeira-Garcia et al., 1987). Since the nictitating membrane is a tendon of the pyramidalis muscle, contraction causes the nictitating membrane to sweep across the front of the eye, without retracting or rotating the globe. In species without a movable nicitating membrane the retractor bulbi and its innervation is poorly developed, as for example in the guinea pig where

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less than 20 AC-VI motoneurons supply the thin sheet of retractor bulbi (Evinger et al., 1987). The AC-VI lies about 0.6 mm ventral to the abducens nucleus in rabbit. It contains about 250 motoneurons and almost all are labeled by tracer injections into the four slips of RBM (Murphy et al., 1986). The RBM in rabbit, cat, and rat is made up of four slips of muscle which insert proximal to the equator of the globe. Gross dissection showed that branches of both the oculomotor and abducens nerves entered the RBM, but never from the trochlear nerve (Murphy et al., 1986). There was usually leakage from the RBM injections, so it is difficult to estimate how many neurons in abducens and the OMN also supplied the RBM. However, both anatomical and physiological experiments confirm that abducens and oculomotor neurons also innervate the RBM (Crandall et al., 1981; Meredith et al., 1981). In primates, neurons just ventral to, and in, the VI innervate the accessory lateral rectus muscle which is a vestigial form of the retractor bulbi (Chapter 2; Spencer and Porter, 1981; Schnyder, 1984). In squirrel monkey it was estimated that there are 1418 abducens neurons, and roughly 75% motoneurons were labelled from R and 50% from retractor bulbi in rabbit (Murphy et al., 1986). But different numbers were published for the rabbit: 400 abducens neurons, 36% motoneurons were labelled from LR, and 72% from retractor bulbi (Gray et al., 1981).

Afferent pathways Many neural networks converge on the extraocular motoneurons to drive the various different types of eye movement and to maintain the correct alignment of the eyes (Fig. 9A). The relative independence of saccadic circuits from vestibular networks, or of vertical saccade premotor regions, from horizontal saccade premotor areas, is usually emphasized to simplify the neuroanatomical picture (Bu¨ttner-Ennever and Horn, 2004). However, it is well to remember that all six eye muscles participate in all types of eye movements. The highly sensitive transsynaptic tracing with rabies indicates that there is a cross-activation between vertical and horizontal systems, whereby the RIMLF,

INC, SVN, and the Y-group send a small number of projections to LR motoneurons (Graf et al., 2002; Ugolini et al., 2005). This has been interpreted as a necessity for spatial coordination of eye movement coordinates, and adaptive plasticity (Graf et al., 1993). Some afferents to the oculomotor nuclei are found only in certain species; for example, the accessory optic nuclei in the pigeon are reported to project to III (Brecha and Karten, 1979; Brecha et al., 1980). Vestibular afferents The projections from the vestibular nuclei to the oculomotor nuclei are formed by several parallel pathways, subserving compensatory and pursuit eye movements. The best studied pathway is the three neuron arc involving the primary canal afferents projecting to the secondary vestibular neurons, which in turn send axons to the motoneurons in VI, IV, and III (Tarlov, 1970; Graybiel and Hartwieg, 1974; Gacek, 1977; Carpenter and Cowie, 1985; Epema et al., 1990). Secondary vestibulo-ocular neurons Careful intra-axonal staining reconstructions of secondary vestibular neurons receiving canal afferents demonstrated ascending axons that do not just excite or inhibit the motoneurons of one eye muscle, but project to the extraocular motoneuron 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 used to compile the scheme of connections shown in Fig. 8, and also in Chapter 1, Fig. 7 (Highstein, 1973; Cohen, 1974; King et al., 1978; Anderson et 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; Ohgaki et al., 1988a, b; Bu¨ttner-Ennever, 2000). These second-order vestibular cells tend to lie in the central magnocellular regions of the vestibular complex (MVNm and SVNm). The magnocellular regions are considered to provide the main output pathways of the vestibular complex, and in some

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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.

reviews is referred to as zone 1 (Bu¨ttner-Ennever, 1992, 2000). The secondary vestibular neurons have a dominant canal input, and project to the motoneurons via the MLF. Ipsilateral pathways are inhibitory and contralateral pathways excitatory; whereby the inhibitory transmitter for horizontal VOR is glycine, that for the vertical VOR is GABA, and both use glutamate and/or aspartate as their excitatory transmitter (Spencer et al., 1989, 2003; McElligott and Spencer, 2000). Some oculomotor afferents from the SVN in rabbit may ascend via the brachium conjuctivum and cross with it in the caudal mesencephalon (Yamamoto et al., 1978). A second, parallel pathway running further ventrally and crossing at roughly the same level (just rostral to nucleus reticularis tegmenti pontis) has been described, and called the ‘‘crossing ventral tegmental tract’’ (CVT) (Fig. 8). It carries secondary anterior canal afferents from SVN to the motoneurons in III of the upward moving eye muscles, SR and IO (Stanton, 1980; Sato et al., 1984; Hirai and Uchino, 1984b; Uchino and Hirai, 1984; Uchino et al., 1994), and also carries afferents from the floccular target neurons in the dorsal Y-group (Sato et al., 1984; Carpenter and Cowie, 1985). Further experiments are needed to exclude the possibility that the CVT has not been mistaken for 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 described below, also project to the oculomotor nuclei, but there is less information on these pathways. They lie in the rostral MVNp, marginal zone adjacent to PPH, SVN and the dorsal Y-group, for review see Chapter 6 (Bu¨ttner-Ennever, 1992, 2000). Those in the rostral MVNp become very numerous in primate, compared to cat (Langer et al., 1986; Highstein and McCrea, 1988). The marginal zone cells lie slightly further caudal; many are inhibitory neurons using glycine as their transmitter, and with axons that cross the midline and terminate in the abducens nucleus (Langer et al., 1986; Spencer et al., 1989; McFarland and Fuchs, 1992). They are also particularly prominent in primates and may play a role in pursuit eye movements. Neurons in the dorsal division of the Y-group, also called the infracerebellar nucleus, are floccular target neurons which are active during upward optokinetic and smooth pursuit eye movements, also in vestibuloocular suppression but not in pure vestibular compensatory eye movements (e.g., in dark) (Chubb and Fuchs, 1982; Plazquez et al., 2000). They have a strong excitatory monosynaptic connection to upward motoneurons in III which utilizes the CVT (Fig. 8) or the brachium conjuctivum (Sato et al., 1984; Yamamoto et al., 1986; Sato and Kawasaki,

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The otolith projections to the oculomotor nuclei follow a completely different pattern from those of the canals; for a review, see Bu¨ttner-Ennever (1999). Primary afferents from the sacculus and utricle terminate mainly in the LVN, DVN, caudal SVN, and nodulus (Ishizuka et al., 1980; Imagawa et al., 1995). In the vestibular nuclei there is some convergence of canal and otolith signals onto the secondary neurons (Uchino et al., 2005). Utricular information can reach the abducens motoneurons and ABD-INTs via monosynaptic (Imagawa et al., 1995), disynaptic (Uchino et al., 1997), and multisynaptic routes (Uchino and Isu, 1996). Saccular afferents probably only use multisynaptic pathways to extraocular motoneurons. It is interesting in this respect that there is no strong eye movement response to a loud click on the mastoid bone, which activates the underlying sacculus relatively specifically. In contrast, there is overwhelming evidence for powerful projections of the utricle and sacculus to neck muscle motoneurons (Uchino et al., 2005).

Ascending tract of Deiters 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).

1987), and also an inhibitory pathway to the trochlear and inferior rectus motoneurons, which may serve to inhibit the neurons during pursuit eye movements (Partsalis and Highstein, 1996). Vestibulo-oculo-collic neurons are widely spread over MVN and DVN, and possess bifurcating axons which project both to the oculomotor nuclei and to the spinal cord (Minor et al., 1990). Their axons travel rostrally in the MLF, and caudally mainly in the contralateral MVST. This type of neuron is not modulated by floccular influences, and therefore plays no role in the floccular adaptation the vestibulo-ocular reflex (Hirai and Uchino, 1984a; Stanton, 2001).

The medial rectus subgroup in the oculomotor nucleus receives vestibular activation via ABDINTs, and in addition a noteworthy set of direct afferents from secondary vestibular neurons in MVN. Their axons travel in the lateral wing of the MLF and are called the ‘‘ascending tract of Deiters’’ (ATD), see Fig. 8 (for a review, see Bu¨ttner-Ennever and Gerrits, 2004). It is often hard to see these ascending fibers in tract tracing experiments presumably because they are scattered. Single cell reconstructions of three ATD cells in MVN revealed terminals over the A- and B-groups of MR motoneurons but none over the MIF motoneurons of the C-group (McCrea et al., 1987b). This finding should be substantiated. The ATD neurons transmit a PVP signal (positionvestibular-pause activity, see Chapter 1) to the MR motoneurons along with head velocity (Reisine and Highstein, 1979). More recently, an exciting study has shown that ATD neurons carry a utricular signal combined with a horizontal canal activity, which generated vergence during linear

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acceleration. The size of the utricular signal depended on the viewing distance, implying the existence of a neural multiplier in the vestibular nuclei, and not just a simple disynaptic utricleoculomotor relay (Chen-Huang and McCrea, 1998).

Paramedian pontine reticular formation The excitatory burst neurons (EBNs) for horizontal saccades lie in the nucleus reticularis pontis caudalis, and form a cluster of neurons under the MLF just rostal to the abducens nucleus in the pontine reticular formation (PRF). The neurons are essential for the generation of a horizontal saccade (Fuchs et al., 1985; Moschovakis et al., 1996). They project monosynaptically onto the abducens 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 been well characterized anatomically as medium-sized and parvalbumin-positive both in monkey and humans (Horn et al., 1995). The cluster of premotor neurons projecting monosynaptically onto motoneurons extend as far rostrally as nucleus reticularis tegmenti pontis (NRTP), where a small group of premotor neurons form a nest in the NRTP itself (Chapter 5, Fig. 3E, arrow). The evidence from single cell recordings in PPRF are less easy to interpret, they were found to carry a monocular signal to the motoneurons, and often the activity was correlated with the activity in the contralateral LR (Zhou and King, 1998). An exciting finding using transsynaptic tract tracing showed that the EBNs overwhelmingly targeted SIF motoneurons, implying that the MIF motoneurons, with slow-tonic characteristics, do not directly participate in saccadic eye movements (Bu¨ttner-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 dorsal paragigantocellular nucleus, and innervate mainly the contralateral VI SIF motoneurons (Langer et 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 saccades, which make up all of the medium-sized neurons within the rostral interstitial nucleus of the MLF (RIMLF), project monosynaptically to the motoneurons of the vertical pulling extraocular eye muscle pairs in the oculomotor and trochlear nuclei, see also Chapter 5 (Moschovakis et al., 1991a, b; Horn and Bu¨ttner-Ennever, 1998). In very exacting studies three types of burst neurons have been found in RIMLF and their terminals reconstructed: (1) upward EBNs which fire with upward eye movements, and terminate on the IO and SR motoneurons of III, (2) upward IBNs which fire with upward eye movements, and terminate on IR and SO; these may produce inhibition of these motoneurons in upward gaze, and (3) downward EBNs which fire with downward saccades, and terminate on IR and SO (Moschovakis et al., 1991a, b). The projections from RIMLF to III are mainly ipsilateral, therefore for conjugate upward saccades, the concomitant activation of the contralateral upward muscles, probably takes place via axons crossing the midline in III (Moschovakis et al., 1996), and thereby providing an anatomical substrate for Herings law of equal innervation (Moschovakis, 1995).

Interstitial nucleus of Cajal The interstitial nucleus of Cajal (INC) lies immediately adjacent and caudal to RIMLF, furthermore this cytoarchitectural boundary is indistinct (Chapter 5). For this reason the studies of Horn and colleagues, in which histological stains are used to differentiate between the two regions, are useful (Horn and Bu¨ttner-Ennever, 1998). The two areas are interrelated in function, both controlling the vertical eye position: RIMLF for vertical saccades and INC for vertical gaze-holding, (Fukushima, 1987; Fukushima et al., 1992). The INC receives axon collaterals from all secondary vestibular neurons that supply III (McCrea et al., 1987a). Descending projections from INC through MLF innervate the ipsilateral oculomotor and

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

spinal cord vestibular ganglion or thalamus: this rather dramatic result was interpreted to mean that there is a specific population of oculomotorprojecting NO producing cells in the vestibular nuclei (Kevetter et al., 2000).

Nucleus prepositus hypoglossi Supraoculomotor area All areas that project to the abducens nucleus also project to the nucleus prepositus hypoglossi (PPH) (Belknap and McCrea, 1988; McCrea, 1988). The PPH and the adjacent marginal zone of the medial vestibular nucleus are widely belived to be an essential part of the neural integrator for horizontal eye movements (see Chapters 1 and 7) (McFarland and Fuchs, 1992; Fukushima and Kaneko, 1995). The larger (principal) cells in PPH give rise to widespread projections to the oculomotor cell groups, including bilateral afferents to the abducens nuclei and the MR subgroups of III (Belknap and McCrea, 1988; McCrea, 1988). The monosynaptic nature of the PPH input to extraocular motoneurons has been verified with transsynaptic tract tracing, and demonstrates that they contact MIF, and perhaps SIF, motoneurons (Bu¨ttnerEnnever et al., 2002; Ugolini et al., 2005). The marginal zone is thought to provide the major output of the horizontal integrator, and sends a massive pathway to the contralateral VI nucleus (Langer et al., 1986; McCrea et al., 1987b). These efferents are glycinergic (Spencer et al., 1989). Nitric oxide (NO) is a freely diffusible gaseous molecule that has recently been found to be produced in the central nervous system. The localization of NO-positive neurons and neuropile mainly to MVN and PPH suggests pivotal role of this region, since NO has a very short half-life it probably has very local effects. Interestingly, the marginal zone between MVN and PPH in cat, is devoid of NO-releasing neurons but contains numerous NO-sensitive neurons (Moreno-Lopez et al., 2001). In a series of double-labeling experiments to determine which functional group of vestibular neurons are the NO-producing cells Kevetter and colleagues showed that virtually all cells in the NO-producing cells in caudal MVN and DVN could be retrogradely filled from the oculomotor nucleus, but not from the cerebellum,

The term supraoculomotor area (SOA) describes the part of the periaqueductal gray substances located immediately above the caudal two-thirds of the oculomotor nucleus: laterally it is continuous with the mesencephalic reticular formation. The EW nucleus lies within, or adjacent, to the SOA and the region is closely associated with the control of the near-response (May et al., 1992). The afferent inputs to the SOA come from the superior colliculus (Edwards and Henkel, 1978), the deep cerebellar nuclei (May et al., 1992), the pretectum (Bu¨ttner-Ennever et al., 1996b), and the accessory optic nuclei (Blanks et al., 1995). Direct projections from the frontal and supplementary eye fields to the SOA have also been traced (Stanton et al., 1988; Shook et al., 1990), as well as two regions of the cerebral cortex where vergence responses have been recorded (Gamlin and Yoon, 2000; Fukushima et al., 2005). Premotor neurons encoding vergence have been recorded in the SOA, and laterally in the adjacent MRF, from behaving monkeys (Mays and Porter, 1984; Judge and Cumming, 1986; Zhang et al., 1992). The premotor vergence neurons were shown to be a source of the monosynaptic excitatory drive to MR motoneurons in III during convergence (Zhang et al., 1991), and the connection was verified anatomically (Graf et al., 2002). In addition, the SOA projects bilaterally to VI, and has 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 using rabies virus have verified the SOA input as monosynaptic onto abducens motoneurons as well, and shown that they have a direct monosynaptic input onto the MIF (nontwitch) motoneurons. In primates, both abducens motoneurons and internuclear neurons decrease their firing rate

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during convergence (Mays and Porter, 1984; Gamlin et al., 1989a). Some SOA neurons are GABAergic and could participate in the inhibition (De la Cruz et al., 1992). A decrease in firing rate of the excitatory ABD-INTs is ‘‘inappropriate,’’ because alone it would lead to decreased discharge of MR motoneurons. Therefore, it must be compensated by a powerful (excitatory) vergence input to MR motoneurons. It is possible that the SOA may provide this excitatory signal (Mays and Porter, 1984). It has been long recognized that internuclear ophthalmoplegia, characterized by damage of the MLF which interrupts the ABDINT excitatory pathway, is characterized by loss of conjugate adduction on the side of the lesion, but adduction for vergence is spared. By contrast, certain midbrain lesions lead to vergence deficits, but spare conjugate eye movements (reviewed by Leigh and Zee, 1999). The connectivity of SOA and its neural activity are indicative of an important, and often underestimated, premotor role in vergence.

Central mesencephalic reticular formation This region of the reticular formation is part of nucleus cuneiformis (see Chapter 5), and lies lateral to III and IV, and medially adjoining the SOA, has assumed new functional significance recently. Rabies virus transsynaptic tracer experiments have shown somewhat unexpectedly that cMRF has monosynaptic connections to abducens MIF motoneurons (Bu¨ttner-Ennever et al., 2002; Ugolini et al., 2005). As a result a new and exciting premotor functional role for cMRF is opened up, a possible contribution to proprioceptive feedback circuits is fully discussed in Chapter 3 (see also Fig. 10 in Chapter 3). Projections of the cMRF to MIFs in III have not yet been investigated, but MRF and the adjacent SOA (see above) are known to contain premotor neurons encoding vergence, which have monosynaptic contacts to medial rectus motoneurons (Zhang et al., 1991; Graf et al., 2002). The cMRF was orginially defined by Cohen et al. (1986) as an area from which horizontal saccades could be evoked by electrical stimulation. Since then the region has

been investigated with several techniques: two regions have been recognized, one lying rostrally and associated with vertical saccades, and a caudal MRF area participating in horizontal saccades (Waitzman et al., 2000a, b; 2002). The result of single unit recordings, electrical stimulation and inactivation experiments indicate an involvement in combined eye and head movements in the stabilization of gaze, the determination of primary position and saccadic metrics. Anatomically the MRF is very closely associated with the superior colliculus (Cohen and Bu¨ttner-Ennever, 1984; Chen and May, 2000; Bu¨ttner-Ennever et al., 2002) and also to PPRF, NRTP, and the omnipause neurons (Edwards, 1975; personal observation).

Pretectum The nuclei of the pretectum that are associated with oculomotor function are: (1) the nucleus of the optic tract (NOT) and (2) the pretectal olive (PON) (see Chapter 12). Unlike lower vertebrates, PON is embedded within NOT in primates. This region has the connectivity to influence many different premotor networks of the oculomotor system (Chapter 12, Fig. 6) (Bu¨ttner-Ennever et al., 1996a). With respect to direct connections to ocular motoneurons, tracer injections into the pretectum labelled efferent axons crossing in the posterior commissure, and terminating over EW and the MIF motoneurons of the oculomotor and trochlear nuclei (Fig. 7E), but not over the SIF motoneurons (Bu¨ttner-Ennever et al., 1996b). The projections were verified with transsynaptic tracers (tetanus toxin BIIb) injected into medial rectus. The efferents to the oculomotor complex were found to arise from the dorsomedial NOT and PON. In addition these neuroanatomic experiments confirmed the monosynaptic character of the pretectal projection to MIF motoneurons. Up to now the pretectal afferents to the MIF motoneurons appears to be their strongest single input. The function of the pretectal premotor pathway is unknown; but since vergence premotor neurons have been located in the pretectum and MIF motoneurons tend to be associated with tonic oculomotor functions, the results fit with the

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suggestion that PON and NOT may play a role in some aspects of the near-response, i.e., vergence or eye alignment.

Histochemistry of motoneurons

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

Transmitters in oculomotor and trochlear nuclei Transmitters in abducens nucleus The motoneurons in the oculomotor, trochlear and abducens nuclei are cholinergic, as are some neurons in EW nucleus (see Fig. 4 and Chapter 5) (Spencer and Wang, 1996; Kus et al., 2003). The motoneurons of vertical-pulling eye muscles in the oculomotor and trochlear nuclei receive a strong GABAergic, but a rather weak glycinergic input, in contrast to the abducens nucleus which receive a strong glycinergic input from the vestibular nuclei (De la Cruz et al., 1992). These results have led to the concept that inhibition in horizontal eye movement pathways is provided by glycine, while those for vertical eye movement pathways utilize GABA. GABAergic afferents to the oculomotor and trochlear nucleus originate from inhibitory secondary vestibulo-ocular neurons in the ipsilateral superior vestibular nucleus (rabbit: Wentzel et al., 1995; cat: De la Cruz et al., 1992) and, at least in the cat, from the RIMLF, however, this was not the case in monkey (Horn et al., 2003). In contrast to RIMLF, the medium-sized and large neurons in INC provided crossed GABAergic projections to the downward moving eye muscles SO and IR (Horn et al., 2003). There are conflicting reports about a strong GABAergic input to medial rectus motoneurons mediating horizontal eye movements: some authors did not see an obvious difference in GABA terminal density between different motoneuron subgroups in rabbit and cat (De la Cruz et al., 1992; Wentzel et al., 1996), whereas a much weaker innervation by GABAergic terminals over MR was observed in cat and monkey (Spencer and Baker, 1992; Horn, personal observation). A possible source for GABAergic afferents to MR-motoneurons are small GABAergic interneurons scattered in and above the oculomotor nucleus in the supraoculomotor area (SOA) (De la Cruz et al., 1992).

In the abducens nucleus identified, abducens internuclear neurons have been shown not to be cholinergic (Fig. 5D) (Spencer and Baker, 1986; Carpenter et al., 1992), but appear to use glutamate and aspartate as transmitters (Nguyen and Spencer, 1999). The PMT cell groups (see Chapter 5) can be identified by the intense choline acetyltransferase and cytochrome oxidase staining of their neuropile. We have found the PMT neurons in primate to be noncholinergic, but there is some conflicting reports from studies in rats (Rodella et al., 1996). In cat, serotonin-immunoreactive synaptic contacts were disclosed on the dendrites of abducens neurons, but the serotoninergic dorsal raphe nucleus lying above the caudal oculomotor nucleus was shown not to be the source of these afferents (May et al., 1987). The abducens nucleus receives a strong supply of glycinergic inhibitory afferents, which originate from IBNs in the contralateral PGD, the PPH and the ipsilateral medial vestibular nucleus (Spencer et al., 1989). Anatomical studies revealed a rather weak GABAergic input to the abducens nucleus with a slight tendency of motoneurons being more heavily contacted than internuclear neurons (De la Cruz et al., 1992). Nitric oxide (NO) has been discussed above in relation to PPH. Through a known set of interactions it can affect ion channels, also in the vestibular complex (Kevetter et al., 2000). A pharmacological study in the alert cat revealed that the balanced production of NO by PPH is necessary for the correct performance of eye movements (Moreno-Lopez et al., 1996). NO-producing neurons are prevalent in MVN/DVN, and surprisingly are found to be particularly important in 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 the marginal zone, was worked out by Moreno-Lopez et al. (2001). Calcium-binding proteins The analysis of different brain regions suggests that calcium-binding proteins, such as calbindin D-28k, calretinin, or parvalbumin are involved in regulating calcium pools critical for synaptic plasticity (Schwaller et al., 2002). Systems using calretinin have been rather well preserved during vertebrate evolution, and are found in oculomotor neurons in bony fish (Diaz-Regueira and Anadon, 2000). Motoneurons in III, IV, and VI express parvalbumin immunoreactivity (De la Cruz et al., 1998). In internuclear neurons at least 80% contain a different calcium-binding protein, calretinin, which could serve as a histological marker for internuclear neurons in cat, but this may be different in other species (De la Cruz et al., 1998). Parvalbumin first appears in rats at embryonic day 13 in the oculomotor (III, IV, VI), vestibular and the trigeminal system and the sensory system of the spinal cord, and develops rapidly during the following days. In these locations the expression of parvalbumin was found to coincide with the beginning of physiological activity in nerve cells (Solbach and Celio, 1991). In the cerebral cortex and hippocampus, as well as in the Purkinje cells of the cerebellum, parvalbumin only appeared postnatally. Although it has been suggested that calcium-binding proteins could act as major endogenous neuroprotectants, the hypothesis has not been generally supported (Schwaller et al., 2002). However, a disruption of the calcium-signaling cascade in mutant mice leads to severe deficits in synaptic transmission and in cerebellar motor control (Barski et al., 2003). Other factors (neurotrophins, membrane receptors, etc.) The screening of the brainstem for specific growth or transcription factors has lead to a wealth of detailed properties of the extraocular motoneurons. Their significance with regard to the oculomotor

system is exciting but at present is very difficult to evaluate. For example, some neurotrophins were found to specifically target extraocular motoneurons: in the adult cat there is extensive neuronal co-expression of neurotrophin receptors, Trk A, B, and C, in the neurons of the III, IV, and VI nuclei. In all three nuclei, TrkB expression predominated but the degree of expression varied between the three nuclei (Benitez-Temin˜o, 2004). An interesting finding was that abducens internuclear neurons have the same Trk expression pattern as abducens motoneurons, though the two populations have different targets (Benitez-Temin˜o, 2004). Since both neuron types have similar afferent inputs, the authors pointed out, that the afferents could be a factor that determined the expression of Trk receptors and not the target cells — the theory favored by most at present. The results are in line with other findings, where specific GDNF factors were selective for specific muscle motoneuron circuits, for example, gfralpha1 and gfralpha2 were only expressed in III and IV but not in the abducens nucleus (Mikaels et al., 2000). However, there is contrasting evidence indicating that the target cells can regulate the Trk expression: the trophic support from brain-derived neurotrophin factor (BDNF) for the oculomotor and trochlear neurons 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 on neurotrophins as survival factors, but rather as regulators of multiple functional properties, such as membrane excitability (Gonzalez and Collins, 1997; Yamuy et al., 1999), synaptic input (Novikov et al., 2000), and plasticity (McAllister et al., 1999). Since the co-expression of multiple neurotrophin receptors in the same neuronal type is not limited to oculomotor neurons but present in various brain regions (e.g., in the trigeminal system; see Jacobs and Miller, 1999), this indicates a role, broader than oculomotor function. One possibility raised by these findings is that each neurotrophin receptor regulates independently, or in concert with each other, multiple aspects of neuronal physiology. Other studies report a particular association between extraocular motoneurons and specific

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membrane properties: for example, the Slack potassium channel (Bhattacharjee et al., 2002), or the membrane proteins cadherins, important for adhesive mechanisms (Heyers et al., 2004). A differential distribution was reported for the expression of synaptosomal-associated protein SNAP 25 involved in the molecular regulation of neurotransmitter release, where two isoforms, SNAP 25a and SNAP 25b, were demonstrated in EW and III, respectively (Jacobsson et al., 1999). Finally, the use of transgenic mice as models for the effects of diseases, such as progressive motor neuropathy or ALS, on extraocular motoneurons are highly promising (Haenggeli and Kato, 2002). The above section highlights only a few of the current studies, but from these it is clear that the behavior of motoneurons in the oculomotor nuclei is influenced by many more factors than premotor innervation alone. In conclusion, the rapid advances in our knowledge of extraocular motoneurons has enabled different types of motoneurons to be identified, MIFs and SIFs. Their premotor inputs clearly differ, but the function of MIF motoneurons is not yet clear. A role of MIF motoneurons in gazeholding or eye alignment, their dysfunction in cases of strabismus or, together with palisade endings, a role in proprioception are all possibilities that can be tested in the future.

DPG EBN EW

MLF MR MVNm MVNp NOT NRTP NIII NVI OMN-INT PC PMT PON PPH PPRF PRF RBM RIMLF

Abbreviations III IV VI ABD-INT AC AC-VI AM ATD CCN CVT cMRF

EOM HC IBN INC INO IO LP LR Med RF MIF

oculomotor nucleus trochlear nucleus abducens nucleus abducens internuclear neurons anterior canal accessory abducens nucleus anteromedian nucleus ascending tract of Deiters central caudal nucleus of III crossing ventral tegmental tract central mesencephalic reticular formation dorsal paragigantocellular reticular formation (IBNs) excitatory burst neuron Edinger–Westphal nucleus

SIF SO SOA SR SVNm

extraocular muscles horizontal canal inhibitory burst neurons interstitial nucleus of Cajal internuclear ophthalmoplegia inferior oblique muscle levator palpebrae superioris lateral rectus musde medullary reticular formation multiply innervated muscle fiber (nontwitch) medial longitudinal fasciculus medial rectus muscle medial vestibular nucleus pars magnocellular medial vestibular nucleus pars parvocellular nucleus of the optic tract nucleus reticularis tegmenti pontis oculomotor nerve abducens nerve oculomotor internuclear neuron posterior canal paramedian tract (cell groups) pretectal olivary nucleus nucleus prepositus hypoglossi paramedian pontine reticular formation pontine reticular formation retractor bulbi muscles rostral interstitial nucleus of the MLF singly innervated muscle fiber (twitch) superior oblique muscle supraoculomotor area superior rectus muscle superior vestibular nucleus, pars parvocellularis

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

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