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. 2019 Mar 6;121(5):1692–1703. doi: 10.1152/jn.00846.2018

Central mesencephalic reticular formation control of the near response: lens accommodation circuits

Paul J May 1,✉, Isabelle Billig 2, Paul D Gamlin 3, Julie Quinet 3
PMCID: PMC6589714  PMID: 30840529

Abstract

To view a nearby target, the three components of the near response are brought into play: 1) the eyes are converged through contraction of the medial rectus muscles to direct both foveae at the target, 2) the ciliary muscle contracts to allow the lens to thicken, increasing its refractive power to focus the near target on the retina, and 3) the pupil constricts to increase depth of field. In this study, we utilized retrograde transsynaptic transport of the N2c strain of rabies virus injected into the ciliary body of one eye of macaque monkeys to identify premotor neurons that control lens accommodation. We previously used this approach to label a premotor population located in the supraoculomotor area. In the present report, we describe a set of neurons located bilaterally in the central mesencephalic reticular formation that are labeled in the same time frame as the supraoculomotor area population, indicating their premotor character. The labeled premotor neurons are mostly multipolar cells, with long, very sparsely branched dendrites. They form a band that stretches across the core of the midbrain reticular formation. This population appears to be continuous with the premotor near-response neurons located in the supraoculomotor area at the level of the caudal central subdivision of the oculomotor nucleus. The central mesencephalic reticular formation has previously been associated with horizontal saccadic eye movements, so these premotor cells might be involved in controlling lens accommodation during disjunctive saccades. Alternatively, they may represent a population that controls vergence velocity.

NEW & NOTEWORTHY This report uses transsynaptic transport of rabies virus to provide new evidence that the central mesencephalic reticular formation (cMRF) contains premotor neurons controlling lens accommodation. When combined with other recent reports that the cMRF also contains premotor neurons supplying medial rectus motoneurons, these results indicate that this portion of the reticular formation plays an important role in directing the near response and disjunctive saccades when viewers look between targets located at different distances.

Keywords: eye movement, midbrain, oculomotor, saccade, vergence, viral tracer

INTRODUCTION

In 1868, Hering proposed that eye movements in the horizontal plane are controlled by two different systems: one that regulates conjugate eye movements that redirect the eyes to different target positions, and a second that controls disjunctive movements needed to compensate for target distance (Hering 1977). Compensation for target distance also requires that the target be focused properly on the retina. This is accomplished by changing the tension in the ciliary muscle. Contraction of the ciliary muscle reduces tension in the zonule of Zinn, which allows the anterior surface of the lens to obtain a more spherical shape and focus nearer targets. The pupil is also constricted for near targets, increasing depth of field. These three actions that serve observation of a near target (convergence, lens accommodation, and pupillary constriction) are commonly termed the near response or near triad (Leigh and Zee 2015).

Initial evidence in support of Hering’s proposal came from recording studies that revealed the presence of a conjugate horizontal gaze center located in the paramedian pontine reticular formation (PPRF) (Cohen and Komatsuzaki 1972; Keller 1974; Luschei and Fuchs 1972; Strassman et al. 1986a; 1986b). This was followed by studies showing that neurons whose activity correlated with changes in vergence angle are located in the midbrain in the vicinity of the oculomotor nucleus (III) (Judge and Cumming 1986; Mays 1984). These cells often encode lens accommodation, as well (Zhang et al. 1992). Indeed, vergence signals are even found on preganglionic motoneurons in the Edinger-Westphal nucleus (Gamlin et al. 1994), indicating how closely vergence and accommodation are tied. Because the majority of the premotor neurons displayed activity that was correlated with moving from a far to a near target, they were termed “midbrain near-response neurons.” These near-response cells were described as lying dorsal and lateral to III. The subdivision lying immediately dorsal to III is called the supraoculomotor area (SOA; Edwards and Henkel 1978). Das (2011, 2012) has recorded from this same population in strabismic monkeys and has shown that they displayed activity changes that are correlated with the increased vergence angle displayed by these monkeys due to their exotropic strabismus. Microlesions placed at the site of these recordings lay within the SOA.

Further investigation revealed that more than one type of near-response neuron is present in the midbrain. Mays and colleagues (1986) characterized a set of cells whose activity correlated with vergence velocity. These neurons displayed a burst of activity at the beginning of the vergence movement. They were described as being located just lateral to III. The region of the midbrain lateral to III, lying between the fibers of the medial longitudinal fasciculus and medial lemniscus, has been termed the central mesencephalic reticular formation (cMRF) by Cohen and colleagues (Cohen and Büttner-Ennever 1984; Cohen et al. 1985, 1986). Stimulation of the cMRF produces contraversive horizontal saccades, and the activity of neurons in this region shows bursts before the initiation of contraversive horizontal saccades with a time course similar to that seen in the superior colliculus (Cohen et al. 1986; Cromer and Waitzman 2006, 2007; Moschovakis et al. 1988b; Waitzman et al. 1996). Taken together, these studies leave open the question of whether the cMRF is solely involved in conjugate eye movements or whether it also plays a role in vergence.

Recent anatomical work has suggested that the cMRF supplies medial rectus motoneurons with input (Bohlen et al. 2017). Such a projection might serve either versional or vergence eye movements. We reasoned that if cMRF pathways supported the near response, they would also supply input to the preganglionic Edinger-Westphal nucleus (EWpg) for lens and pupil control. We recently utilized retrograde transsynaptic transport of the N2c strain of rabies virus to identify lens-related premotor neurons in the SOA that supply the EWpg (May et al. 2018). This was done by injecting the virus into the ciliary body, where it was taken up by the axons that supply the ciliary muscle and transported to the postganglionic motoneurons in the ciliary ganglion. After replication, the viral particles were transferred to preganglionic motoneuron axons synapsing in the ganglion and transported to EWpg. After replication in the preganglionic motoneurons, the virus was transferred across the synapses on these cells to the axons of the premotor neurons controlling lens accommodation and subsequently transported to their cell bodies for replication. In this report, we examined the same material used to describe the SOA neuronal population, to determine whether premotor lens control cells are also present in the cMRF. A brief report of this work has appeared in abstract form (May et al. 2017).

METHODS

The surgical procedures were performed at the Systems Neuroscience Center with the support of the Center for Neuroanatomy with Neurotropic Viruses, both located at the University of Pittsburgh Medical Center and both under the direction of Dr. Peter L. Strick. A total of seven adult and young adult animals (Macaca fascicularis) of both sexes were injected with the N2c strain of rabies virus. The injections were directed at the ciliary body of the left eye. The procedures for making these injections were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh. Before surgery, animals were sedated with ketamine HCl (15 mg/kg im). They were then provided with a surgical level of anesthesia by the use of isoflurane (3.0% in oxygen) delivered through an endotracheal tube. In addition, the surface of the eye was treated with proparacaine drops. Dexamethasone (0.5 mg/kg im) was given to preclude conjunctival inflammation. Following the procedure, animals received 0.01 mg/kg buprenorphine (Buprenex) intramuscularly as a postoperative analgesic. More detailed procedures can be found in May et al. (2018).

With the head stabilized by a stereotaxic device, the fixed N2c strain of rabies virus was injected into the ciliary body by use of a 100-µl Hamilton syringe equipped with a 25-gauge needle. The needle was inserted at 12–16 sites along the perimeter of the cornea so that between 130 and 170 µl of viral solution were injected. The survival times and concentration in plaque forming units (pfu) of the virus varied as follows: 58 h, 5 × 109 pfu/ml (n = 1); 66 h, 1 × 109 pfu/ml (n = 2); 72 h, 1 × 109 pfu/ml (n = 2), or 76 h, 5 × 109 pfu/ml (n = 2). At the end of the survival period, animals were again sedated with ketamine HCl (15 mg/kg im) and deeply anesthetized with pentobarbital sodium (40 mg/kg ip) before cardiac perfusion. An initial wash with phosphate-buffered saline was followed by 4% paraformaldehyde fixative in 0.1 M, pH 7.2 phosphate buffer (PB). During the final stage of the perfusion, fixative containing 10% glycerol as a cryoprotectant was used, and after being blocked in the frontal plane, the brain was postfixed in this same solution at 4°C.

The brain was frozen and sectioned in the frontal plane on an American Optical sliding microtome at 50 µm. Sections were collected in 0.1 M, pH 7.4 phosphate-Trizma buffer with 0.05% sodium azide (PTA) as 10 series, spaced 500 µm apart. From two to five such series were reacted using immunohistochemistry to reveal the location of the cells containing virus. At least one of these series or an adjacent series was counterstained with cresyl violet. The immunohistochemical procedures began with a 0.3% H2O2 step to decrease background peroxidase levels. This was followed by a blocking step of 1.5% normal horse serum with 0.3% Triton X-100 in PTA. Incubation in a primary antibody, a mouse monoclonal against rabies diluted 1:1,000 in PTA, lasted for 2 days at 4°C. (The antibody, designated 31G10, was a gracious gift of Matthias Schnell of Thomas Jefferson University, Philadelphia, PA.) This antibody and other antibodies to rabies virus have been previously characterized and shown to be highly specific and effective (Raux et al. 1997; Ruigrok et al. 2016). In addition, we performed tests in which either the primary or secondary antibody steps were eliminated and found no labeling. Sections were then rinsed, and the antibody was tagged with biotin and then avidin-horseradish peroxidase complex using the appropriate ABC kit (Vector Laboratories). To visualize the labeled cells, sections were reacted in a 0.05% diaminobenzidene solution in 0.1 M, pH 7.2 PB through the addition of 0.016% H2O2. Sections were then mounted onto glass slides, counterstained in some cases, and then dehydrated, cleared, and coverslipped. The ciliary, pterygopalatine, superior cervical, and trigeminal ganglia were also harvested bilaterally, to be cut and reacted to ensure that rabies uptake was confined to the ciliary ganglia pathway, as previously described (May et al. 2018).

Sections were drawn using a Wild M-8 stereoscope equipped with a drawing tube, and labeled cells were charted or drawn using an Olympus BH-2 microscope equipped with a drawing tube. The somata of labeled neurons in the cMRF and SOA from two 76-h cases were outlined using a ×40 objective for measurement of the long axis of the cell and compared for significance using a t-test. Initial drawings were converted to ink and then scanned and assembled into the figures using Photoshop (Adobe). Photomicrographs of the labeled cells were taken with a Nikon E-60 microscope equipped with a Nikon DS-Ri1 digital camera. The contrast, brightness, and color of the images was adjusted in Photoshop to best resemble their appearance when viewed through the eyepieces.

RESULTS

At the shortest survival time, 58 h, the only labeled neurons in the brain were found in the EWpg ipsilateral to the injection. Because we have described these previously (May et al. 2018), we do not illustrate them in this report. At the 66-h survival time point, labeled cells were first observed beyond the bounds of the EWpg. The region of SOA that includes EWpg is shown in Fig. 1, A–C. The boundaries of EWpg were defined in the adjacent Nissl-stained section, and the identity of these cells as cholinergic motoneurons was confirmed immunohistochemically in our previous study (May et al. 2018). In Fig. 1C, motoneurons in the left (ipsilateral to the injection) EWpg were intensely labeled, with chromagen evident throughout their dendritic tree. Their dendrites extend into the surrounding SOA. Much more lightly labeled cells, in which the chromagen just extended into the proximal dendrites, were evident both within EWpg and outside its limits in the SOA. Additional lightly labeled neurons were present on both sides in the cMRF, lateral to the medial longitudinal fasciculus (MLF; Fig. 1, A and B). Examples of these cells from the cMRF ipsilateral to the injected ciliary body (Fig. 1D) and contralateral to it (Fig. 1, E and F) show that the label does not extend beyond their primary dendrites.

Fig. 1.

Fig. 1.

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Appearance of rabies-labeled cells at the 66-h survival time point. Low-magnification views of the anti-rabies staining (A) and cresyl violet staining (B) of the midbrain show the preganglionic Edinger-Westphal nucleus (EWpg) and supraoculomotor area (SOA) located dorsal to the oculomotor nucleus (III). The central mesencephalic reticular formation (cMRF) is located lateral to the medial longitudinal fasciculus (MLF). Boxes indicate the samples enlarged in C and F. Examples of brown, intensely labeled cells (red arrowheads) in which the labeling extended into the distal dendrites were present in the left EWpg ipsilateral to the injected eye (C). In addition, a small number of lightly labeled neurons (blue arrows) in which the labeling was confined to the soma and proximal dendrites were present in the SOA and EWpg (C). They are also found in both the ipsilateral (ipsi; D) and contralateral (contra; E and F) cMRF. Scale in A is same as in B; scale in D and E is same as in F. Dorsal direction is upward in A–F; medial is to the right in E and to the left in D and F.

A better feeling for the distribution of labeled cells at this time point can be obtained from the chartings in Fig. 2. In this illustration, intensely labeled cells and lightly labeled cells, similar to those in Fig. 1, are indicated with separate symbols. The intensely labeled cells were largely confined to the left EWpg (Fig. 2, C–G) and its rostral extension, the left anteromedian nucleus (AM; Fig. 2, A and B). They represent the preganglionic motoneurons located ipsilateral to the injected left ciliary body. A few lightly labeled cells were found in the left EWpg (Fig. 2, C and D), but they were also found outside its borders within the SOA on both sides of the midline (Fig. 2, E–I). In addition, a small number of lightly labeled neurons, with little dendritic labeling, were also present on both sides of the brain stem in the cMRF (Fig. 2, F and G).

Fig. 2.

Fig. 2.

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Distribution of rabies-labeled cells at the 66-h survival time point. Intensely labeled neurons (red dots), like those shown in Fig. 1, were confined to the preganglionic Edinger-Westphal nucleus (EWpg), ipsilateral to the injected eye (B–G), and its rostral extension, known as the anteromedian nucleus (AM; A). These represent preganglionic parasympathetic motoneurons projecting to the ciliary ganglion. Premotor neurons (blue diamonds) were only lightly labeled (see Fig. 1) at this time point. They were distributed bilaterally in the supraoculomotor area (SOA; E–I) and in the central mesencephalic reticular formation (cMRF; F and G). A few lightly labeled cells were also present in EWpg. The region illustrated in the high-magnification view is indicated by a box in the low-magnification drawing of each section. Illustration shows a rostral-to-caudal series in which the sections are 500 µm apart. 3n, third nerve; CC, caudal central subdivision; III, oculomotor nucleus; InC, interstitial nucleus of Cajal; MLF, medial longitudinal fasciculus; RN, red nucleus.

The pattern of retrograde transsynaptic labeling present at 66 h was considerably intensified at the 72- and 76-h survival time points. As shown in Fig. 3, neurons outside of EWpg were now intensely labeled by the chromagen at 76 h, with far more staining of the dendritic tree. In addition, far more neurons were labeled. Labeled neurons were still present in the left EWpg and bilaterally in SOA (Fig. 3A). In addition, the labeled population extended bilaterally across the MLF into the cMRF on both sides of the brain stem (Fig. 3A). Within the left (ipsilateral) cMRF (Fig. 3B) and right (contralateral) cMRF (Fig. 3C), multipolar and scattered fusiform cells with long, sparsely branched dendrites were fully labeled by the rabies virus. A charting of the labeled cells in a case with a 76-h survival provides a better view of the overall distribution of these neurons (Fig. 4). Labeled preganglionic neurons were present ipsilateral to the injection site within the left EWpg (Fig. 4, A–E). Labeled premotor neurons were present bilaterally dorsal to III in the SOA (Fig. 4, A–H). In addition, numerous labeled premotor neurons were present bilaterally within the cMRF (Fig. 4, D–H). These formed a band that occupied the middle portion of the dorsoventral extent of the cMRF and extended more than halfway to its lateral border. A small number of labeled neurons were found within the bordering peri-interstitial nucleus of Cajal portion of the mesencephalic reticular formation (piMRF), but this distribution faded rostrally (Fig. 4, A–C).

Fig. 3.

Fig. 3.

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Appearance of rabies-labeled cells at the 76-h survival time point. Brown, intensely labeled cells displaying fully stained dendrites are no longer confined to the preganglionic Edinger-Westphal nucleus (EWpg) ipsilateral to the injected eye, as shown in this counterstained section (A). They are also distributed bilaterally in the supraoculomotor area (SOA) and in the central mesencephalic reticular formation (cMRF). Boxes in the left and right cMRF indicate the locations of the cells shown at higher magnification in B and C, respectively. The premotor neurons in the ipsilateral (ipsi; B) and contralateral (contra; C) cMRF were multipolar neurons with long, sparsely branched dendrites. Scale in B is same as in C. III, oculomotor nucleus; MLF, medial longitudinal fasciculus.

Fig. 4.

Fig. 4.

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Distribution of rabies-labeled cells at the 76-h survival time point. Labeled neurons (red dots) were found in the left preganglionic Edinger-Westphal nucleus (EWpg) ipsilateral to the injected eye (A–F). Presumed premotor neurons were distributed bilaterally in the supraoculomotor area (SOA; A–H) and in the central mesencephalic reticular formation (cMRF; D–H). A few labeled cells were also present in the peri-interstitial nucleus of Cajal portion of the mesencephalic reticular formation (piMRF; A–C). The region illustrated in the high-magnification view is indicated by a box in the low-magnification drawing of each section. Illustration shows a rostral-to-caudal series in which the sections are 500 µm apart. CC, caudal central subdivision; III, oculomotor nucleus; InC, interstitial nucleus of Cajal; MLF, medial longitudinal fasciculus.

In Fig. 4F, the distributions of the populations of labeled cells in the SOA and cMRF appear to be in continuity. To better examine this, we illustrated the morphology of cells in this region in Fig. 5B. The labeled neurons within the cMRF are multipolar, and occasionally fusiform, cells with long, very sparsely branched dendrites. Within the 50-µm section, dendrites could be followed up to 330 µm from the soma. The dendritic fields of individual neurons displayed random orientations. However, they tended to extend mediolaterally, and they largely arborized within the region of the cMRF that contains the labeled cells. This represents slightly more than the medial half of the cMRF and the central third of its dorsoventral extent (Fig. 5C). The labeled cells in the cMRF and SOA appear to distribute as a continuous band at this level, although they sit in separate populations more rostrally. A striking characteristic at this level is the fact that the dendritic fields of the SOA cells extend out toward and overlap with the dendrites of the labeled cells in the cMRF.

Fig. 5.

Fig. 5.

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Dendritic organization of lens-related neurons in the midbrain tegmentum. The illustration in B shows the arrangement of the dendrites of the motoneurons in the preganglionic Edinger-Westphal nucleus (EWpg) and the premotor neurons in the supraoculomotor area (SOA) and the central mesencephalic reticular formation (cMRF) on the left (ipsilateral) side of the midbrain. The labeled premotor neurons and dendrites form a continuous band that extends from the SOA into the cMRF. (Arrows indicate the border between SOA and the cMRF.) The general distribution of labeled cells (dots) in this section is shown in C, and the low-magnification view (A) provides insight into the brain stem level from which the sample was taken. BC, brachium conjunctivum; III, oculomotor nucleus; SGI, intermediate gray layer.

In most respects, the illustrated labeled neurons in the cMRF (Fig. 5B) are quite similar to those found within the SOA. This morphological similarity is further supported by examination of the photomicrographs in Fig. 6. The somata of labeled multipolar premotor neurons within the cMRF (Fig. 6A) and within SOA (Fig. 6B) were both generally multipolar or fusiform in shape. Both populations were heterogeneous with respect to soma size (cMRF long-axis range = 13–35 µm; SOA long-axis range = 13–42 µm). Overall, they were similar in soma size. We found no difference (P = 0.4483) when we compared measurements of the long axis of their somata (cMRF: 24.30 ± 6.54 µm, n = 180; SOA: 24.80 ± 5.39 µm, n = 145; means ± SD). They both displayed very sparsely branched dendritic fields that could be followed for over 300 µm within a 50-µm section. The two regions did differ in that the labeled cell density is greater within the SOA than in the cMRF. Thus, with respect to the morphology and distribution of the lens-related cMRF and SOA premotor neurons, it appears that they may represent a continuous population. There was some variation in the density of staining present in individual cells, with a few lightly stained examples present in both regions (Fig. 6). We believe this represents differences related to a spread in the timing of the initial uptake of viral particles within the ciliary body, not movement to fourth-order neurons, because no fourth-order populations were apparent at other sites in the brain at this time point.

Fig. 6.

Fig. 6.

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Comparison of the morphology of lens-related premotor neurons in the central mesencephalic reticular formation (cMRF; A) and supraoculomotor area (SOA; B) ipsilateral to the ciliary muscle injection. Brown, rabies-labeled multipolar and fusiform neurons with long, sparsely branched dendrites are present in both structures. Boxes in insets show the region from which the sample was taken in an adjacent cresyl violet-stained section. Scale in A is same as in B; scale in B, inset, is same as in A, inset. CC, caudal central subdivision; EWpg, preganglionic Edinger-Westphal nucleus; III, oculomotor nucleus; MLF, medial longitudinal fasciculus

DISCUSSION

The findings described in the present report provide clear evidence that the cMRF is an important contributor to the near response. More specifically, they indicate that the cMRF contains premotor neurons supplying lens-related preganglionic motoneurons in the EWpg. When combined with other studies, which show premotor neurons in the cMRF that supply medial rectus motoneurons (Bohlen et al. 2017), there is compelling anatomical evidence that the cMRF plays a role in the responses used to foveate and focus on near targets with the accuracy needed for stereopsis. The morphological similarities between the cells labeled in the cMRF and those labeled in the SOA suggest these two regions have similar input/output functions. Thus the physiological differences between neurons in the SOA that encode vergence angle and lens accommodation and those in the cMRF that encode vergence velocity may be primarily related to the fact that they receive different inputs. Indeed, the overlap in the distribution of the dendritic fields suggests that these two physiological populations may shade into one another, as opposed to being clearly demarcated. In the following sections, we 1) cover the evidence that the data are valid (see Technical considerations), 2) review the evidence from previous work that the role of the cMRF is to produce conjugate horizontal saccades, and 3) lay out a new argument that the cMRF plays a central role in directing the eyes between targets that lie at different distances from the viewer.

Technical considerations.

The first technical point to be considered in evaluating the strength of these results is the question of whether the zone of virus uptake was confined to the ciliary muscle and solely involved the postganglionic parasympathetic motoneurons supplying this muscle. To test this, we excised, cut, and reacted the superior cervical ganglion and pterygopalatine ganglion. No labeled cells were present in these ganglia, indicating that virus did not enter the central nervous system via these autonomic pathways (May et al. 2018). It should also be noted that no retrogradely labeled neurons were present in the olivary pretectal nucleus at the illustrated time points. This indicates that uptake from the pupillary constrictor muscle did not occur, so the populations labeled were purely related to lens accommodation. The other possible retrograde route would be uptake by axons supplying the extraocular muscles. However, at the shortest time points (58 h), labeling was only present in EWpg, and even at 66 h, when the first light premotor labeling appeared, no labeled cells were present in the extraocular motor nuclei. Thus we conclude that no uptake outside the target zone occurred. The second technical point to consider is the specificity of the antibody techniques used. We feel that the low background shown in the photomicrographs, which are representative of the material as a whole, provides ample evidence that the antibody and procedures used did not produce spurious labeling. The third point of consideration relates to whether these cells all represent premotor neurons, given that the labeling developed in the cMRF over a 10-h time period between 66 and 76 h. We feel that the fact that the locations of the labeled neurons did not change over this time period, i.e., that they were consistently found in the cMRF and SOA, strongly suggests that the virus was labeling a unitary premotor neuron population in these nuclei. The only changes that were observed consisted of increased labeling intensity and increased numbers of labeled cells, further supporting this interpretation. A final point to be made is that we saw no evidence of microglial activation until 76 h, and the EWpg motoneurons still appeared intact. Consequently, we believe that all the viral labeling was due to movement of the viral particles across synapses.

Role in conjugate saccades.

The first intimations that the midbrain reticular formation might be involved in oculomotor function came from an electrical stimulation and lesion study by Bender and Shanzer (1964). However, the first detailed examination of the role of the cMRF in eye movements came through the pioneering studies of Bernard Cohen and colleagues in which they coined the term “central mesencephalic reticular formation” (Cohen and Büttner-Ennever 1984; Cohen et al. 1985). They showed that electrical stimulation of the core region of the midbrain reticular formation produced contraversive horizontal saccades and that the amplitude of these saccades was dependent on the location of the electrode. In a follow-up paper, Cohen et al. (1986) demonstrated that these saccades were not due to activation of passing tectoreticular fibers by removing these fibers with a lesion of the superior colliculus. Finally, they provided evidence that the cMRF received a topographically organized input from the superior colliculus (Cohen and Büttner-Ennever 1984; Cohen et al. 1986).

A subsequent detailed examination of cMRF neurons in trained monkeys revealed that not only did these cells fire for horizontal saccades, but also that some cells appeared to encode motor error during the saccade (Waitzman et al. 1996). The idea that the cMRF is strictly related to the horizontal component of saccades was questioned by Handel and Glimcher (1997), who observed activity related to vertical saccades, as well. However, Waitzman et al. (2000b) suggested that there is a topographic difference in the encoding of saccades such that horizontal components are handled by the caudally located cMRF and vertical components are handled by the rostrally located piMRF. In agreement with this, it was demonstrated that cells projecting bilaterally to the superior colliculus, an organization that might be expected for vertical gaze neurons, were primarily located rostrally in the cat midbrain reticular formation (Perkins et al. 2014).

Further investigations of cMRF horizontal saccade-related activity pointed to the existence of a number of saccade-related neuron subtypes within the cMRF, cells whose firing was best related to saccade amplitude, duration, or velocity (Cromer and Waitzman 2006). In these studies, it was suggested that one role of the cMRF was to provide a feedback pathway from the pontine gaze centers to the superior colliculus. However, in squirrel monkeys, it was shown that cMRF reticulotectal neurons display saccade-related activity nearly identical to that seen in the colliculus (Moschovakis et al. 1988a, 1988b). When intracellularly stained, these cMRF neurons displayed bilateral projections to the collicular intermediate gray layer (SGI). It is this layer that contains tectoreticular neurons projecting to the horizontal gaze centers located in the PPRF by way of the predorsal bundle. Evidence from cats suggested this cMRF projection is inhibitory (Appell and Behan 1990), and further examination in macaques indicated that the cMRF provides a purely GABAergic projection to the predorsal bundle neurons located in SGI of the ipsilateral colliculus, but a mixed projection to the contralateral colliculus (Fig. 7) (Wang et al. 2010). The reticulotectal neurons in the cMRF are themselves targeted by tectoreticular projections from the ipsilateral superior colliculus (Chen and May 2000) through collaterals contributed by predorsal bundle axons before decussation (Grantyn and Grantyn 1982; Moschovakis et al. 1988a). Thus, it appears that one role of the cMRF is to provide monosynaptic inhibitory feedback to the superior colliculus during the generation of saccades. It has been suggested that this feedback might contribute to winner-take-all activity patterns within the tectum (Wang et al. 2010).

Fig. 7.

Fig. 7.

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Schematic of central mesencephalic reticular formation (cMRF) conjugate gaze pathways (see text for references). Pathways connecting the cMRF to the intermediate gray layer (SGI) of the superior colliculus and the horizontal burst neurons in the paramedian pontine reticular formation (PPRF) and the omnipause neurons in the nucleus raphe interpositus (RIP) underlie the production of conjugate saccades. Pathways connecting the cMRF and SGI to the medullary reticular formation (MdRF) and cervical spinal cord support gaze-related head turns. Green solid lines indicate excitatory pathways. Red dashed lines indicate inhibitory pathways. Purple lines indicate pathways having both excitatory and inhibitory elements. Black lines indicate pathways whose valence is unknown. Thickness of the lines indicates strength of the projection. Dotted line in SGI indicates border between upper and lower subdivisions.

A second role in saccade production, suggested by Cromer and Waitzman (2006), was to aid in the transformation of the spatial map of saccade amplitude present in the superior colliculus into the temporal code present in the PPRF. In a later study, they compared saccade-related activity in the cMRF and PPRF and found very similar firing characteristics (Cromer and Waitzman 2007). Projections of the cMRF to the contralateral PPRF were proposed for this role. Examination of the descending projections of the cMRF does reveal a projection to the PPRF (Fig. 7) (Wang et al. 2017). However, the projection was found to be predominantly ipsilateral, not contralateral, and the ipsilateral projection was a mixed one, with only about a third of the terminals having GABAergic characteristics. Consequently, the role of this descending projection is currently unclear, for it seems that the saccade-related activity present in both the cMRF and PPRF is conferred on their neurons by collicular inputs.

Yet another suggestion made by Cromer and Waitzman (2006) was that a population of cMRF neurons helped control the duration of saccades through projections to omnipause neurons in the nucleus raphe interpositus. Such a projection was revealed anatomically (Fig. 7) (Wang et al. 2013). Approximately half of the anterogradely labeled reticuloraphe terminals were found to be GABAergic. This anatomy suggests that the GABAergic component of the tectoreticuloraphe projection might serve to suppress omnipause activity when the tectoreticular projection attempts to elicit a saccade-related burst of activity in the brain stem gaze centers. In agreement with this, inactivation of the cMRF releases spontaneous saccades (Waitzman et al. 2000a). However, there is evidence that the pause in the activity of omnipause neurons requires glycinergic, not GABAergic, activity (Kanda et al. 2007; Soetedjo et al. 2002). Thus, although the cMRF likely plays a role in controlling the interplay between fixation and saccades, it is liable to be just one of the players controlling this dynamic.

Finally, it should be noted that there is evidence from cMRF inactivation (Waitzman et al. 2000a, 2000b) and recording studies (Pathmanathan et al. 2006a, 2006b), as well as connectional studies (Perkins et al. 2009; Warren et al. 2008; Zhou et al. 2008), that the cMRF plays a role in the head component of gaze changes, as well (Fig. 7).

Role in vergence and lens accommodation.

In view of the present findings, it is reasonable to consider the possibility that the cMRF has functions other than directing horizontal conjugate saccades. Mays et al. (1986) described a second set of neurons that fired for vergence movements. Because they differed from the previously described midbrain near-response neurons encoding vergence angle in that they displayed a burst of action potentials that encoded the vergence velocity, they were termed vergence burst neurons. Based on microlesions and their relationship to oculomotor neurons, they were mapped to the region just lateral to III. This would place them in the medial part of the cMRF where we observed labeled cells related to the lens, but the relationship of their firing to lens accommodation was not tested. Other support for the presence of this population came from injections of rabies virus into the medial rectus muscle of guinea pigs, which bilaterally labeled neurons in the reticular formation just lateral to III at a time point consistent with these cells being premotor neurons (Graf et al. 2002). These might be assumed to be convergent vergence velocity cells. In monkeys that received rabies injections in the lateral rectus muscle, neurons were again labeled bilaterally in the reticular formation just lateral to III at a survival time indicating these were premotor neurons (Ugolini et al. 2006). These might be assumed to be divergent vergence velocity cells. The location of these two rectus muscle premotor populations overlaps with the lens accommodation premotor neurons described in the present report, although the lens-related population extends further laterally within the cMRF (Fig. 3).

Rabies virus also labeled neurons within the cMRF following injections confined to the distal portion of the lateral rectus muscle, which only labeled motoneurons in the periphery of the abducens nucleus (Ugolini et al. 2006). This is the location of motoneurons supplying multiply innervated muscle fibers (MIFs) in this muscle (Büttner-Ennever et al. 2001). MIFs are believed to have graded responses, as opposed to the all-or-none contraction of singly innervated fibers (SIFs), are slow to fatigue, and represent a distinct minority (10%) of the fibers in the global layer (Spencer and Porter 2006). The MIFs in the medial rectus muscle are supplied by MIF motoneurons lying in the C-group, which is found at the dorsomedial aspect of III in SOA (Büttner-Ennever and Akert 1981; Büttner-Ennever et al. 2001). In fact, these motoneurons extend their dendrites throughout SOA and largely avoid entry into III (Erichsen et al. 2014; Tang et al. 2015). In view of this location, when we found that the cMRF terminated extensively within the SOA in macaques (Bohlen et al. 2016; also in cats, see Edwards 1975), we explored the possibility of a direct cMRF projection onto these MIF motoneurons. We found that there was indeed a monosynaptic input by cMRF terminals onto medial rectus MIF motoneurons located in the C-group on both sides of the brain (Fig. 8) (Bohlen et al. 2017). We also observed a less dense, ipsilateral projection to the medial rectus SIF motoneurons (Fig. 8) (Bohlen et al. 2017).

Fig. 8.

Fig. 8.

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Schematic for central mesencephalic reticular formation (cMRF) vergence pathways (see text for references). Possible vergence velocity pathways are shown on the left and possible disjunctive saccade pathways are shown on the right for convenience. Left: cMRF vergence velocity cells (purple trapezoids) project bilaterally to lens-related motoneurons in the preganglionic Edinger-Westphal nucleus (EWpg) and to motoneurons that supply medial rectus multiply innervated fibers (MIFs). It is likely that they also project to vergence angle cells (yellow trapezoid) in the supraoculomotor area (SOA). These near-response SOA cells project to medial rectus motoneurons and preganglionic motoneurons in EWpg. Right: cMRF disjunctive saccade cells (blue square) project to medial rectus motoneurons that supply singly innervated fibers (SIFs) on the ipsilateral side. These pathways may also influence preganglionic motoneurons in the ipsilateral EWpg. They may also target vergence angle neurons in the SOA. Whether vergence projections to the two sides are actually via collaterals, as shown, will require further study. On the other hand, individual vergence neurons might project to both MIF and EWpg neurons.

The EWpg is embedded within the SOA in primates (Kozicz et al. 2011), and it appeared to contain terminals following cMRF injections (Bohlen et al. 2016). We directly investigated this and found evidence that anterogradely labeled cMRF terminals contact cholinergic, preganglionic parasympathetic motoneurons within EWpg (Fig. 8) (May et al. 2016). The present experiment confirmed this finding with respect to the lens-related population, clearly indicating that the cMRF contains lens-related premotor neurons. The present results further show that this population projects bilaterally to the EWpg and is distributed over a considerable part of the cMRF immediately lateral to III. Similarly, neurons were labeled retrogradely in the midbrain reticular formation immediately lateral to III of pigeons following injection of EW (Gamlin and Reiner 1991). This suggests that the presence of a midbrain reticular formation area for controlling lens accommodation may in fact be a common vertebrate trait. A possible interpretation of the above findings is that the cMRF contains a mixed population of vergence neurons, similar to the near-response neurons found in the SOA. There, the majority of the cells displayed firing that correlated with both vergence angle and lens accommodation, along with others encoding only one of these properties (Zhang et al. 1992).

The distribution of lens-related neurons in the cMRF is more constrained than the distribution of saccade-related reticulotectal neurons in the cMRF (Chen and May 2000), with the former not extending quite as far laterally as the latter, but there is considerable overlap. Up until 2008, studies describing saccade-related activity in the cMRF used targets projected on a screen and only recorded from one eye. Waitzman and colleagues (2008) then reported the results of an investigation of the cMRF in which the Muller paradigm (where the targets are aligned with one eye and move closer to or farther from the viewer) was employed to investigate the response of cells during disjunctive saccades. They found that a portion of cMRF neurons is active during saccades that are not conjugate and that some neurons show activity that is eye specific; i.e., their firing is mainly predicted by the movement of one of the eyes. They further demonstrated that electrical stimulation of the cMRF can produce disjunctive saccades.

On the basis of the findings described above, it seems likely that the cMRF contains at least two types of cells that play a role in controlling vergence angle. The first is vergence velocity burst neurons (Fig. 8, left). It is likely that this population projects bilaterally to both medial rectus MIF motoneurons and to the lens-related preganglionic parasympathetic motoneurons in EWpg. It is noteworthy that the contraction characteristic of the ciliary muscle and MIFs are similar. It is also likely that this population also targets tonically active vergence angle neurons in the SOA (Bohlen et al. 2016), and it has been suggested that these SOA neurons integrate the velocity signal (Mays et al. 1986). SOA neurons supply vergence angle signals to medial rectus SIF neurons, as well as to EWpg (Gamlin and Mays 1992; Gamlin et al. 1994). The second cMRF population would be neurons coding for disjunctive saccades (Fig. 8, right). These cells may modulate the effects of the abducens internuclear pathway, which brings conjugate saccade signals from the PPRF, by targeting ipsilateral medial rectus SIF motoneurons. They may also modulate lens focus in an individual eye by projecting to EWpg, allowing eye-specific lens compensation for target distance. These findings pose the question of how target distance information accesses the cMRF. Vergence and/or lens accommodation signals have been reported in the rostral superior colliculus (Chaturvedi and Van Gisbergen 1999; 2000; Sawa and Ohtsuka 1994; Suzuki et al. 2004; Van Horn et al. 2013; but see Walton and Mays 2003), deep cerebellar nuclei (Bando et al. 1979; Hosoba et al. 1978; Zhang and Gamlin 1998), and frontal eye fields (Gamlin and Yoon 2000). It is possible that these signals access the cMRF, raising the interesting question of whether they supply near-response input to the cMRF.

GRANTS

This work was supported by National Institutes of Health Grant EY014263 (to P. J. May and P. D. Gamlin).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

P.J.M. and P.G. conceived and designed research; P.J.M. and I.B. performed experiments; P.J.M. and J.Q. analyzed data; P.J.M., I.B., and P.G. interpreted results of experiments; P.J.M. and J.Q. prepared figures; P.J.M. drafted manuscript; P.J.M., I.B., P.G., and J.Q. edited and revised manuscript; P.J.M., I.B., P.G., and J.Q. approved final version of manuscript.

ACKNOWLEDGMENTS

We thank Jinrong Wei for excellent work in cutting and processing the tissue. We also thank the staff of the Systems Neuroscience Center and its director, Peter L. Strick, PhD, who provided the support needed for the surgeries and who patiently trained P. J. May in the details of the rabies technique.

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