RESEARCH ARTICLE

Direct Projections From the Dorsal to the Superior Colliculus in the Macaque (Macaca mulatta)

Claudia Distler1* and Klaus-Peter Hoffmann1,2,3 1Department of Zoology and Neurobiology, Ruhr-University Bochum, 44780 Bochum, Germany 2Department of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany 3Department of Neuroscience, Ruhr-University Bochum, 44780 Bochum, Germany

ABSTRACT have been recorded, and from where descending tecto- The dorsal premotor cortex (PMd) is part of the cortical fugal projections arise. A somewhat weaker projection network for arm movements during reach-related targets the intermediate layers of the SC. By contrast, behavior. Here we investigate the neuronal projections terminals originating from prearcuate area 8 mainly pro- from the PMd to the midbrain superior colliculus (SC), ject to the intermediate layers of the SC. Thus, this pro- which also contains reach-related neurons, to investi- jection pattern strengthens the view that different gate how the SC integrates into a cortico-subcortical compartments in the SC are involved in the control of network responsible for initiation and modulation of gaze and in the control or modulation of reaching goal-directed arm movements. By using anterograde movements. The PMD–SC projection assists in the par- transport of neuronal tracers, we found that the PMd ticipation of the SC in the skeletomotor system and projects most strongly to the deep layers of the lateral provides the PMd with a parallel path to elicit forelimb part of the SC and the underlying reticular formation movements. J. Comp. Neurol. 000:000–000, 2015. corresponding to locations where reach-related neurons VC 2015 Wiley Periodicals, Inc.

INDEXING TERMS: dorsal premotor; corticotectal; eye–hand coordination; sensorimotor; reaching; AB_2336827; AB_2315331

Reaching and grasping are everyday activities for all On functional and anatomical grounds, the premotor dexterous mammals including humans. Research during cortex (Brodman area 6) can be divided in dorsal (PMd, the last decades in primates has revealed a widespread F2, F7) and ventral (PMv, F4, F5) compartments (Matelli network of brain areas involved in various aspects of et al., 1985). Area PMv (F5) is mainly connected with these actions. In the , the main players the ventral portion of the dorsolateral prefrontal cortex are the primary motor cortex (M1), premotor cortex (DLPC) and with the inferior parietal lobule, especially (PM), and posterior parietal cortex (area 5, AIP and area AIP and PF (Luppino et al., 1999; Hoshi and Tanji, MIP), with their cortical input from visual, somatosen- 2007; Borra et al., 2008; Gharbawie et al., 2011). Func- sory, and prefrontal cortex (Johnson et al., 1996; Hoshi tionally, the PMv is involved in the preparation and exe- and Tanji, 2007; Padberg et al., 2007; Kaas et al., cution of arm and hand movements related to grasping 2012, 2013 and references therein). Based on electro- and contains not only neurons related to the subject’s physiological recordings, microstimulation, and anatomi- own actions but to actions of others (mirror neurons) cal investigations, all these areas display topographic organization that, however, is somewhat crude in the premotor and posterior parietal cortex. This led to the Grant sponsor: the Deutsche Forschungsgemeinschaft; Grant number: Ho 450/25; Grant sponsor: ZEN grant from the Hertie Stiftung (to concept of functional zones interconnected within and K.P.H.). between relevant cortical areas, which would then *CORRESPONDENCE TO: Claudia Distler, Allgemeine Zoologie und Neu- robiologie, Ruhr-University Bochum, Universitaetsstr. 150, ND 7/26, together control the various sectors, joint angles, orien- 44780 Bochum, Germany. E-mail: [email protected] tation, etc. of the forelimb during certain movements Received January 21, 2015; Revised March 31, 2015; (Seelke et al., 2012; Kaas et al., 2012, 2013). Accepted April 15, 2015. DOI 10.1002/cne.23794 Published online Month 00, 2015 in Wiley Online Library VC 2015 Wiley Periodicals, Inc. (wileyonlinelibrary.com)

The Journal of Comparative Neurology | Research in Systems Neuroscience 00:00–00 (2015) 1 C. Distler and K.-P. Hoffmann

(Rizzolatti et al., 1988; Kakei et al., 2001; Ochiai et al., of the arcuate. In addition, neurons close to the dimple 2005; Raos et al., 2006; Hoshi and Tanji, 2007; Theys were mostly active during movements and somatosen- et al., 2012; Lehmann and Scherberger, 2013; Bonini sory stimulation of the arm, whereas neurons close to et al., 2014). the spur were active during movement and somatosen- By contrast, PMd is connected with the dorsal DLPC sory stimulation of the distal forelimb (Raos et al., and the dorsal parietal lobule including area 5 and the 2003). About half of the neurons were active during MIP. Namely, the caudal part of the PMd (F2 dimple grasping, and about 37% were active during reaching. region and F2 ventrorostral of Matelli et al., 1998; This forelimb-related region contains visual, somatosen- cPMd of Ghosh and Gattera, 1995) receives its main sory, purely motor, visually modulated, and visuomotor input from parietal areas PEc and PEip (F2 dimple), and neurons (Fogassi et al., 1999; Raos et al., 2004). Elec- the MIP and V6A (F2 ventrorostral), respectively, as trical stimulation of the PMd resulted more often in well as from frontal areas SMA, M1, and the cingulate suppression (50% of events) in upper limb muscles than motor areas (Ghosh and Gattera, 1995; Matelli et al., stimulation of the SMA or M1 (20% of events) (Mont- 1998). It is also involved in the preparation and execu- gomery et al., 2013). With longer stimulation periods tion of arm movements but shows preparatory activity (500 ms), complex and more naturalistic movements of and codes for direction, speed, and amplitude of the the arm could be evoked from the PMd (Graziano et al., arm movement during reaching and eye–hand coordina- 2002). tion (Barbas and Pandya, 1987; Colby et al., 1988; Fu In recent years, reach-related activity has also been et al., 1995; Tanne et al., 1995; Johnson et al., 1996; identified in neurons of the intermediate and deep Matelli et al., 1998; Messier and Kalaska, 2000; Lup- layers of the midbrain superior colliculus (SC). These pino et al., 2003; Churchland et al., 2006; Pesaran reach neurons are active before and during arm move- et al., 2006, 2010; Hoshi and Tanji, 2007; Yamagata ments, and their activity is correlated with the direction et al., 2012). of arm movements (Kutz et al., 1997) and/or with the Electrical microstimulation in the PMd leads to move- electromyogram of proximal shoulder and arm muscles ments of the upper limb but at significantly higher (Werner, 1993; Werner et al., 1997a, b; Stuphorn et al., thresholds than in the M1 (Weinreich and Wise, 1982; 1999, 2000). Furthermore, microstimulation at record- Preuss et al., 1996; Fujii et al., 2000; Raos et al., ing sites of these reach neurons elicits arm movements 2003). A systematic survey of the dorsal premotor cor- (Philipp and Hoffmann, 2014). tex revealed a topographic order of evoked movements The SC receives input from multiple cortical areas. with simple movements of the contralateral shoulder The superficial layers are targeted mainly by early visual mostly elicited from areas close to the precentral dim- areas, whereas intermediate and deep layers receive ple, and simple movements of the contralateral distal input from the posterior parietal cortex including the forelimb mostly elicited more laterally close to the spur lateral intraparietal area (LIP), forelimb representation

Abbreviations

A aqueduct Nru n. ruber A8 area 8 NTr n. trapezius Amt anterior mediotemporal sulcus ot occipito-temporal sulcus Ar arcuate sulcus p principal sulcus BSC brachium of the superior colliculus PAG periaqueductal grey Ca calcarine sulcus pc pedunculus cerebri Ce central sulcus pca pedunculus cerebellaris anterior Ci cingulate sulcus pcd precentral dimple DMZ densely myelinated zone of the medial superior temporal area po parieto-occipital sulcus Dpc decussatio pedunculi cerebellaris Pt pretectum ec ectocalcarine sulcus Pul pulvinar FEF frontal eye field Rd raphe dorsalis flm fasciculus longitudinalis medialis SC superior colliculus IC inferior colliculus SN substantia nigra io infero-occipital sulcus SGI stratum griseum intermedium of the SC ip intraparietal sulcus SGP stratum griseum profundum of the SC la lateral sulcus SGS stratum griseum superficiale of the SC LIP lateral intraparietal area St superior temporal sulcus ll lemniscus lateralis VIP ventral intraparietal area lu lunate sulcus V1 primary M2 motor area 2 V4t visual area 4 transitional zone MIP medial intraparietal area V6 visual area 6 MT middle temporal area V6A visual area 6A NPo n. pontis III n. oculomotorius NRm n. reticularis mesencephali IV n. trochlearis NRp n. reticularis parvocellularis 3a 4, 5, 6, 7a, 8, 23, 24, Brodman areas 3a, 4, 5, 6, 7a, 8, 23, 24 NRpo n. reticularis pontis oralis 5v ventral area 5

2 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

TABLE 1. Summary of the Database, Tracers Used, Volume Injected, and Survival Time in the Different Cases

Case Tracer Volume (ml) Survival time PMd1 15% BDA MW3000 in 0.1 M citrate/NaOH pH 3.3 4 2 weeks PMd2 15% BDA MW3000 in 0.1 M citrate/NaOH pH 3.3 2 2 weeks PMd3 20% BDA MW3000 in 0.9% NaCl 3 2 weeks A8 2.5% WGA-HRP in KCl/Tris/DMSO 0.3 48 hours A8-2 10% BDA MW10000 in 0.9% NaCl 1 3 months of areas 2, 4, and 6, FEF, PMv, and prefrontal cortex ance with the Deutsche Tierschutzgesetz of 7.26.2002, (Finlay et al., 1976; Kuenzle et al., 1976; Leichnetz the European Communities Council Directive RL 2010/ et al., 1981; Fries, 1984, 1985; Komatsu and Suzuki, 63/EC, and NIH guidelines for care and use of animals 1985; Lynch et al., 1985; Lock et al., 2003; Borra for experimental procedures. et al., 2014; Cerkevich et al., 2014). Only in some instances have these anatomical con- Animals nections been characterized physiologically. The cortico- Four adult male rhesus monkeys (Macaca mulatta) tectal projection originating from the primary visual were used in the present investigation. All animals had cortex seems to be involved in the control of intracollic- participated in electrophysiological experiments prior to ular visual processing (Finlay et al., 1976). The FEF pro- the tracer injections (Stuphorn et al., 2000; Kruse and jection to the SC mainly carries saccade-related and Hoffmann, 2002; Kruse et al., 2002; Philipp and Hoff- visual information about the central visual field (Seg- mann, 2014). raves and Goldberg, 1987). By contrast, tectal projec- tions from the LIP carry mostly visual saccade-related Surgery information from the peripheral field (Pare and Wurtz, After premedication with atropine sulfate (0.04 mg/ 1997; Gaymard et al., 2003). In contrast, projections kg) the animals were initially anesthetized with keta- from the dorsolateral prefrontal cortex transmit task- mine hydrochloride (10 mg/kg i.m., Braun, Melsungen, selective signals to the SC, i.e., neuronal signals selec- Germany). After local anesthesia with 10% xylocain tive for antisaccades that inhibit reflexive prosaccades (Astra Zeneka, Wedel, Germany), they were intubated (Johnston and Everling, 2006). To date, only little data through the mouth, an intravenous catheter was intro- for the premotor-tectal projections are available. Electri- duced into the saphenous vein, and, after additional cal microstimulation revealed excitatory as well as local anesthesia with bupivacaine hydrochloride 0.5%, inhibitory influences of the PMd on forelimb muscles the animals were placed into a stereotactic apparatus. (Montgomery et al., 2013). We presume that at least Throughout the experiment the animals were artificially part of the PMd output is mediated indirectly, e.g., via ventilated with nitrous oxide: oxygen as 3:1 containing subcortical nuclei including the SC. In a preliminary 0.3%–1% halothane as needed. Deep analgesia was study, antidromically identified premotor-tectal neurons ensured by intravenous bolus and continuous applica- were active during reach movements. In some of these tion of fentanyl (3 mg/kg/h, Janssen, Neuss, Germany). cells the reach activity varied with the direction of Heart rate, SPO2, blood pressure, body temperature, gaze, which corresponds to the firing properties of a and end-tidal CO2 were monitored constantly and kept subset of SC reach neurons (Stuphorn et al., 1996). at physiological levels. The corneae were protected In the present study we investigate the direct projec- with contact lenses. tions of the PMd to the SC to reveal the spatial location of anterogradely labeled terminals relative to recording Injections and histological procedures sites of reach-related activity in the SC. This study is In two of the animals, the injections were made part of a project to further characterize the information through recording chambers that had previously been transmitted from the PMd to the SC in the cortico- implanted for the electrophysiological experiments to subcortical network for reaching probe the PMd for neurons antidromically activated from the SC. In the remaining two animals, the record- ing chamber was removed to provide access to a larger MATERIALS AND METHODS cortical area. We used biotin dextran amine (BDA) as All experiments were approved by the local author- an anterograde tracer. In addition, in case A8 (prearcu- ities (Regierungspr€asidium Arnsberg, now LANUV) and ate oculomotor area 8), during the final electrophysio- the ethics committee, and were performed in accord- logical experiment, we injected horseradish peroxidase

The Journal of Comparative Neurology | Research in Systems Neuroscience 3 C. Distler and K.-P. Hoffmann

Figure 1. Reconstructions of the left hemispheres of cases PMd1 (A), PMd2 (B), PMd3 (C), and A8 (D). The core of the tracer injections is shown in solid green, and the diffusion area in stippled green. For abbreviations see list. Scale bar 5 5 mm.

conjugated to wheat germ agglutinin (WGA-HRP) at the After appropriate survival times, the animals received same location as the BDA injection (case A8-2). Table 1 a lethal overdose of pentobarbital and were perfused summarizes the tracers, volumes, and survival times through the heart with 0.9% NaCl containing 0.1% pro- used in the present study. caine hydrochloride followed by paraformaldehyde–

4 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

Figure 2. Examples of anterogradely labeled fibers and terminals after BDA injections into the PMd in case PMd1 (A–C) and case PMd3 (D–F). Gray dots in A mark labeled terminals, and black lines in A mark labeled fibers The regions where the microphotographs shown in B and C were taken are marked in the reconstruction of the midbrain section (A). D: Darkfield photomicrograph of labeled fibers and ter- minals in the lateral SC of PMd3 visualized with TMB as a chromogen. The single asterisk marks the approximate location of the label shown in E, and the double asterisk marks the approximate location of F. E,F: Fibers and terminals in the deep lateral SC of PMd3. In B– D and E–F, labeled structures were visualized with enhanced DAB as a chromogen. Scale bar 5 500 mminD;50mm in B,C,E,F.

lysine–periodate with 4% paraformaldehyde. After lel to the electrode penetrations. Frontal or sagittal appropriate cryoprotection with 10% and 20% glycerol, sections of the injected cortical hemispheres were cut the brains were shock frozen and stored at 2708C until on a freezing microtome at 50 mm. Neuronal transport processing. of BDA was visualized with the avidin-biotin method The midbrains were cut at 40–50 mm on a vibratome (ABC Elite, Vector, Burlingame, CA; 1:250, RRID: or a cryostat in a plane angled 458 from posterior and AB_2336827) with diaminobenzidine (DAB) as chromo- thus approximately normal to the SC surface and paral- gen enhanced with ammonium nickel sulfate (cases

The Journal of Comparative Neurology | Research in Systems Neuroscience 5 C. Distler and K.-P. Hoffmann

Figure 3. Camera lucida drawings of serial sections through the midbrain of case PMd1. Sections are arranged from posterior (upper left) to anterior (lower right). Intersection distance is 480 mm from the third section onward. Sections in the left row present the anatomical areas as seen in Nissl-stained sections, and green dashed lines indicate AChE-rich areas in the intermediate layers of the SC and the underlying midbrain. Anterogradely labeled fibers are shown in blue, and labeled terminals in red. In this case almost the entire anteropos- terior and the entire mediolateral extent of the SC contains labeled terminals. Additional label is found in the pontine nuclei and in multi- ple locations within the mesencephalic reticular formation. For abbreviations see list. Scale bar 5 2 mm.

6 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

(sheep anti-mouse, 1:200, Amersham, GE Healthcare Life Sciences, Braunschweig, Germany; cat# RPN1001). After thorough washing, sections were incubated in ABC Elite (Vector, 1:250, RRID: AB_2336827) for 2 hours at room temperature, and antigenic sites were visualized with DAB. Controls omitting the primary anti- body resulted in no labeling.

Analysis Labeled fibers and terminals in midbrain sections were drawn with a camera lucida under a microscope (Zeiss Axioplan) coupled to a reconstruction system (AccuStage MDPlot v5), and cortical connections were plotted with the reconstruction system. Cortical areas were identified based on cyto-, myelo-, and neurofilament-based chemoarchitecture (Barbas and Pandya, 1987; Blatt et al., 1990; Colby et al., 1993; Hof and Morrsion, 1995; Hof et al., 1995; Preuss et al., 1997; Gabernet et al., 1999; Rozzi et al., 2006; Belma- lih et al., 2007; Takahara et al., 2012) largely following the criteria summarized and demonstrated by Lewis and van Essen (2000). The histological sections were photographed under a photomicroscope (Zeiss Axioplan) equipped with a Canon EOS 600D camera, and bright- ness and contrast were adjusted with Adobe Photoshop Figure 4. Neurofilament protein-based chemoarchitecture used to (RRID: SciRes_000161, version 5.5). distinguish motor (area 4) and premotor (area 6) cortex (A), and intraparietal cortical areas LIP, VIP, and MIP (B) in case PMd1. Transition zones between neighboring areas are marked by black RESULTS bars. For abbreviations see list. Scale bar 5 1 mm in A,B. The present study is based on three tracer injections into the dorsal premotor cortex. For comparison, the prearcuate oculomotor cortex (area 8) was injected in PMd1, PMd2, and PMd3), or in alternate sections with an additional animal. The location of the injection sites tetramethylbenzidine (TMB) as chromogen (case PMd3; is presented on the reconstructions of the lateral view after Ding and Ellberger, 1995, van der Want, 1997). In of the left cortical hemispheres in Figure 1. All data are case A8-2, WGA-HRP was visualized with TMB (after presented as left hemispheres to facilitate comparison. van der Want, 1997). A subset of midbrain sections was stained for acetylcholinesterase (AChE) histochem- Case PMd1 istry (Illing, 1988). Subsets of cortical sections were In case PMd1, the tracer injections into the PMd fol- stained for Nissl, and myeloarchitecture (Gallyas, 1979, lowed the electrophysiological recordings from cortical as modified by Hess and Marker, 1983). neurons that projected to the SC as identified by anti- In a further subset of cortical sections, the dromic stimulation. Three tracer injections (green areas) neurofilament-based chemoarchitecture of cortical were placed into the anterior part of the PMd (F2) ros- areas was analyzed. Briefly, free-floating sections were tral to the precentral dimple (pcd) (Fig. 1A) but clearly washed in 0.1 M Tris-buffered saline (TBS), and treated not encroaching on area 8 in the prearcuate gyrus or for 30 minutes with 3% H2O2 and 0.2% Triton–X-100, FEF in the anterior bank of the arcuate sulcus. Exam- respectively. Sections were incubated in an antibody ples of the anterogradely labeled fibers and terminals against nonphosphorylated neurofilament protein for 48 are depicted in Figure 2B and C, and the location of hours at 48C under gentle agitation (SMI-32, 1:1,000, the labeled structures in the SC and underlying mesen- Covance, Munster, Germany; cat# smi-32r; RRID: cephalic reticular formation is given in Figure 2A. AB_2315331; Hof and Morrison, 1995). Then sections Anterogradely labeled terminals (Fig. 2, red dots in Fig. were washed thoroughly in TBS, and incubated over- 3) and fibers (Fig. 2, blue marks in Fig. 3) were located night in the biotinylated secondary antibody at 48C in the intermediate and predominantly in the deep

The Journal of Comparative Neurology | Research in Systems Neuroscience 7 C. Distler and K.-P. Hoffmann

Figure 5. A–E: Frontal sections through the left cerebral cortex of case PMd1 exemplifying the main intracortical projections resulting from the tracer injection into the PMd. The sections are arranged from anterior (upper left) to posterior (lower right), and their positions in the brain are indicated in the inset. Dash-dot lines mark the border between the gray and white matter, areal borders determined from SMI-32 immunohistochemistry; myelo- or cytoarchitecture are marked by arrows and/or by black bars underlying the transition zones. Each red dot represents a retrogradely labeled neuron. Blue lines indicate the location of anterogradely labeled fibers and terminals. The injection site is marked solid green, and the diffusion area stippled green. For abbreviations see list. Scale bar 5 5 mm. layers of the ipsilateral SC throughout its entire antero- of interest. The border between area 4 and the PMd posterior and mediolateral extent (Fig. 3). As a label for was recognized by the larger abundance of large layer the intermediate layers, we used AChE histochemistry V pyramidal cells and a decrease of immunoreactivity in (green structures in the left drawings of Fig. 3); the supragranular layers (Fig. 4A; Preuss et al., 1997; Gab- other collicular layers were determined in neighboring ernet et al., 1999). In the parietal cortex (Fig. 4B), sections stained for cytoarchitecture. The PMd termi- areas LIP, VIP, MIP, and 5V could be identified (Hof and nals were located predominantly below the AChE-rich Morrison, 1995; Hof et al., 1995; Lewis and van Essen, patches. In addition, labeled terminals were found in 2000). Intracortical projections were limited to a few the mesencephalic reticular formation close to the peri- areas, largely confirming earlier studies (Johnson et al., aqueductal gray and in the pontine nuclei. To further 1996; Matelli et al., 1998; Leichnetz, 2001; Luppino characterize and compare the injected area between et al., 2003; Burman et al., 2014). In the parietal cor- cases, we also analyzed the cortical connections tex, retrogradely labeled cells were mainly located in revealed by the injections. Here we largely follow the the medial bank of the intraparietal sulcus including criteria and nomenclature of Lewis and van Essen areas MIP, VIP, and ventral area 5, as well as in area (2000). Figure 4 demonstrates examples of the V6A on the medial aspect of the . Frontally, neurofilament-based cytoarchitecture of various areas numerous retrogradely labeled neurons were present in

8 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

Figure 6. Camera lucida drawings of serial sections through the midbrain of case PMd2. Intersection distance is 800 mm. For other con- ventions see Figure 3. The injection in PMd2 resulted in anterograde labeling restricted to the deep layers of the lateral part of the SC, to the nucleus ruber, and to multiple sites within the mesencephalic reticular formation. For abbreviations see list. Scale bar 5 2 mm.

The Journal of Comparative Neurology | Research in Systems Neuroscience 9 C. Distler and K.-P. Hoffmann

Figure 7. A–E: Coronal sections through the frontal cortex and sagittal sections through the parietal cortex of the left cerebral cortex of case PMd2 demonstrating the intracortical projections resulting from the tracer injection into the PMd. The sections are arranged from anterior (left, A) to posterior (right, C), and from lateral (D) to medial (E), respectively. Their positions in the brain are indicated on the insets; shaded areas show the extent of the anterior and posterior block of tissue. For other conventions see Figure 5. For abbreviations see list. Scale bar 5 5 mm. the precentral motor cortex (area 4), within dorsal area in case PMd1. Additionally, labeled terminals were 6 anterior to the injection site and posterior in the spur found in the nucleus ruber and were widespread in the of the arcuate sulcus, and in area M2. Medially, fewer mesencephalic reticular formation (Fig. 6). Cortical pro- neurons were located in areas 23 and 24 in the cingu- jections were restricted to the medial bank of the intra- late sulcus (Fig. 5). parietal sulcus including area MIP/ventral area 5, to the precentral area 4, and to area 6V. In contrast to case PMd1, area M2 was far less heavily labelled; areas Case PMd2 23 and 24 on the medial aspect of the brain were The tracer injection in case PMd2 was located more largely devoid of label (Fig. 7). posterior than PMd1, between the anterior half of the pcd and the spur of the arcuate sulcus (Fig. 1B). Anterogradely labeled terminals in the SC were exclu- Case PMd3 sively located in the deep layers of the lateral SC far Case PMd3 represents the caudalmost injection site away from the AChE patches. There was not a continu- in this study lying between the posterior tip of the pre- ous band of labeled terminals from lateral to medial as central dimple and the posterior tip of the spur of the

10 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

Figure 8. Camera lucida drawings of serial sections through the midbrain of case PMd3. Intersection distance is 320 mm. For other con- ventions see Figure 3. Anterogradely labeled terminals are present mainly in the deep layers of the lateral SC and in the underlying mes- encephalic reticular formation. For abbreviations see list. Scale bar 5 2 mm.

The Journal of Comparative Neurology | Research in Systems Neuroscience 11 C. Distler and K.-P. Hoffmann

Figure 9. A–E: Frontal sections through the left cerebral cortex of case PMd3 showing the intracortical projections resulting from the tracer injection into the PMd. For other conventions see Figure 5. For abbreviations see list. Scale bar 5 5 mm. arcuate (Fig. 1C). Examples of the resulting anterograde Case A8 labeling are shown in Figure 2D–F. Labeled terminals As a control and for comparison, further injections were again concentrated in the deep layers predomi- were placed into the oculomotor area on the prearcuate nantly in the lateral SC and in the underlying mesence- gyrus (area 8) in the representation of the peripheral vis- phalic reticular formation (Fig. 8). In the parietal cortex, ual field (Komatsu and Suzuki, 1985) (Fig. 1D). In this retrogradely labeled neurons were mostly found in the case, in addition to the BDA injection, WGA-HRP was anterior part of the medial bank of the intraparietal sul- injected at the same location, resulting in a complete cus (area 5V) with additional label on the supraparietal overlap of the two injection sites and the resulting label- gyrus (area 5), the infraparietal gyrus (area 7a), and in ing. In contrast to the PMd projections, terminal labeling the medial bank of the lateral fissure. Fewer neurons from both tracer injections into area 8 was predominantly were labeled in the posterior bank of the intraparietal found in the intermediate layers of the medial SC; the lat- sulcus, including area LIP. In the frontal cortex, labeled eral SC was notably devoid of label (Fig. 10). Intracortical cells were concentrated in area 4 on the precentral transport in this case was rather limited. In the frontal gyrus, area 6V, and M2. Labeled cells in M2 were much cortex, a few patches of labeled neurons were located in denser on the medial aspect of the brain than on the area M2 and area 6D (Fig. 11). Unfortunately, the poste- crown of the cortex (Fig. 9). rior cortex was not available for analysis in this case.

12 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

Figure 10. Camera lucida drawings of serial sections through the midbrain of case A8. The plots demonstrate the WGA-HRP labeling. Inter- section distance is 300 mm. For other conventions see Figure 3. In contrast to the PMd injections, the area 8 injection resulted in terminal labeling predominantly but not exclusively in the intermediate layers of the medial SC. For abbreviations see list. Scale bar 5 2 mm.

The Journal of Comparative Neurology | Research in Systems Neuroscience 13 C. Distler and K.-P. Hoffmann

Figure 11. A–C: Frontal sections through the left cerebral cortex of case A8 showing the intracortical projections resulting from the tracer injection into area 8. For other conventions see Figure 5. For abbreviations see list. Scale bar 5 5 mm.

Thus, the injection in PMd1 located in the anterior et al., 1978; Nudo et al., 1993; Rathelot and Strick, PMd and possibly encroaching on area 6Dr (F7; Luppino personal communication). et al., 2003) resulted in terminal labeling in the interme- diate and deep layers of the entire ipsilateral SC. After Corticotectal projection from PMd injections into more posterior parts of the PMd only the The existence of a direct connection between the deep lateral part of the SC was labeled. By contrast, PMd and SC was suggested by earlier retrograde trac- output from our area 8 injection mainly terminated ing studies (Leichnetz et al., 1981; Fries, 1984, 1985; more superficially compared with the PMd in the inter- but see Lock et al., 2003); however, the density of this mediate layers, sparing the most lateral SC. projection seemed rather low. Our anterograde data indicate that the PMd projects primarily to the deep layers of the SC, below the AChE-rich patches in the intermediate layers. The most complete labeling was DISCUSSION achieved by the anteriormost injection (PMd1), which In our experiments we were able to show that area coincided with the area where neurons could be anti- PMd (F2) directly projects moderately to the intermedi- dromically activated from the SC in related electrophys- ate and more strongly to the deep layers of the ipsilat- iological experiments. Based on the location and the eral SC. These projections were particularly heavy in cortical connections, i.e., input from the V6A and MIP the lateral part of the SC representing the ventral visual in the parietal cortex and from cingulate motor areas, field, and coincided with the location of reach-related case PMd1 includes the ventrorostral part of area F2 neurons in the SC (Werner et al., 1997b) as well as tec- (Matelli et al., 1998; Luppino et al., 2003). It also corre- tofugal neurons described in other studies (Castiglioni sponds to the region from where simple and complex

14 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

movements of the distal forelimb can be elicited by in the region between the precentral dimple and the intracortical microstimulation (Raos et al., 2003) and spur of the arcuate, with little or no input from the cin- where grasp-related neurons are located (Raos et al., gulate cortex (Matelli et al., 1998; Luppino et al., 2004). More posterior injections mainly labeled the lat- 2003). The core of the PMd2 injection was closer to eral part of the SC. Both PMd2 and PMd3 were located the dimple in the region where microstimulation leads to movements of the proximal forelimb (Raos et al., 2003). PMd3 included the entire distance between the dimple and spur, thus including both proximal and distal forelimb regions (Raos et al., 2003). Therefore, all our PMd injections were in the part of area F2 that controls arm reaching movements. The differences in our SC labeling could well be due to topographical differences between the injected regions, but could also be the result of different sizes of injections. The tracer volume injected and the resulting injection site was slightly larger in PMd1 than in PMd2 and PMd3 (Table 1, Fig. 1). Similarly, topographic differences have also been reported for the projections from the basal ganglia to rostral and caudal regions of F2 (Saga et al., 2011). Interestingly, corticotectal projections from the PMv (F5) and other areas of the cortical network for grasp- ing, e.g., ventral prefrontal areas 46 and 12, parietal area AIP, but also from saccade-related area LIP, also terminate in the deep and intermediate layers mainly of the lateral SC (Lynch et al., 1985; Selemon and Goldman-Rakic, 1988; Borra et al., 2010, 2014). The same SC region also receives direct input from the oro- facial primary motor cortex (Tokuno et al., 1995). Injec- tions into area 6DC (supplementary eye field) at the crown of the cerebral cortex also revealed projections to the intermediate layers of the lateral SC (Shook et al., 1990), thus placing this part of the SC in an even wider context. Our control injection into prearcuate area 8 confirms findings of previous studies. It resulted in labeling of the intermediate layers of the SC that was stronger in the medial than in the lateral part of the SC, which may be due to the topography in the corticotectal projection from the prearcuate oculomotor cortex. Similar results were achieved by comparable injections in other stud- ies (Komatsu and Suzuki, 1985; Lynch et al., 1985; Stanton et al., 1988; Shook et al., 1990; Tokuno et al., 1995); the labeling of the entire SC shown by Leichnetz

Figure 12. Schematic summary of the relationship of the cortical input to the SC from the PMd (red) and prearcuate oculomotor cortex (area 8, black) with the location of tectofugal neurons pro- jecting to the cervical spinal cord (green, data taken from Casti- glioni et al., 1979) and indirectly to the shoulder muscles, e.g., the spinodeltoid muscle (blue, Rathelot and Strick, personal com- munication). Cortical input from the PMd largely overlaps with the tectospinal output in the deep layers of the SC.

The Journal of Comparative Neurology | Research in Systems Neuroscience 15 C. Distler and K.-P. Hoffmann

and coworkers may again be due to the larger injection (Nagy et al., 2006). They were also located in the inter- site (Leichnetz et al., 1981). mediate and deep layers of the SC, between 1.2 and Unfortunately we could not analyze the cortical con- 4 mm below the collicular surface (median 5 3.1 mm), nections with the posterior cortex in our area 8 case, i.e., in the same depths as the reach neurons but labeling in the posterior bank of the intraparietal (median 5 2.8 mm, range 5 1.4–4 mm). The coincidence sulcus including the LIP as well as in visual and polymo- of the anatomical location of SC reach and dal extrastriate areas has been demonstrated in other somatosensory-motor neurons with the cortical afferents studies (Leichnetz et al., 1981; Schall et al., 1985), originating from the dorsal premotor (this study) and ven- which confirms that even our largest and most anterior tral premotor cortex and related cortical areas (Borra PMd injection shows an intracortical projection pattern et al., 2014) suggests that the SC is strongly involved in distinct from that of the prearcuate oculomotor cortex. arm and hand movements in addition to the well-known Figure 12 summarizes the spatial relationship of cort- gaze movements. The convergence of the reach-to-grasp ical projections from the PMd (red dots) and area 8 system (i.e., the PMv) and the reach-to-destination sys- (black dots) to the SC (this study) relative to the loca- tem (the PMd) onto the same regions close to the gaze tion of tectofugal neurons retrogradely labeled from the system in the SC puts this structure in a unique position cervical spinal cord (Castiglioni et al., 1978, green to modulate reach and grasp movements in various areas) or transsynaptically from the spinodeltoid muscle behavioral contexts involving eye–hand coordination. (Rathelot and Strick, personal communication, blue areas). For this chart the labeled SC regions from all ACKNOWLEDGMENTS our PMd cases were combined. There is a striking over- We thank E. Brockmann, S. Dobers, H. Korbmacher, lap of input from PMd and the SC output to the cervical and G. Reuter for expert technical assistance. We are also spinal cord and the shoulder muscles, demonstrating grateful to H. Lubbert€ for lab space. the putative neuronal substrate for modulating head and arm movements via the SC. CONFLICT OF INTEREST STATEMENT Functional considerations The authors state they have no conflicts of interest. The optic tectum of nonmammalian vertebrates and the SC of mammals is traditionally viewed as a key struc- ROLE OF AUTHORS ture for orienting behaviour, especially of the body, head, eyes, and pinnae (Akert, 1949; Alstermark and Isa, All authors had full access to all the data in the 2012). With the discovery of arm-movement–related study and take responsibility for the integrity of the activity in the SC, this scheme was extended to limb data and the accuracy of the data analysis. Study con- movements also in monkeys in agreement with earlier cept and design: KPH and CD, acquisition of data: KPH studies in the cat (Courjon et al., 2004). Reach neurons and CD, analysis and interpretation of data: CD and KPH, drafting of the manuscript: CD and KPH. are located in the intermediate and deep layers predomi- nantly in the lateral part of the monkey SC and in the underlying mesencephalic reticular formation (Werner LITERATURE CITED 1993; Werner et al., 1997a, b; Stuphorn et al., 1999, Akert K. 1949. The visual grasp reflex. Helv Physiol Acta 7: 112–134. 2000) and are active before and during reach move- Alstermark B, Isa T. 2012. Circuits for skilled reaching and ments mainly but not exclusively of the contralateral grasping. Annu Rev Neurosci 35:559–578. arm. They reside in a region where descending tectofugal Barbas H, Pandya DN. 1987. Architecture and frontal cortical connections of the premotor cortex (area 6) in the rhe- projections arise (Castiglioni et al., 1978; Grantyn and sus monkey. J Comp Neurol 256:211–228. Grantyn, 1982; Olivier et al., 1991; Nudo et al., 1993; Belmalih A, Borra E, Contini M, Gerbella M, Rozzi S, Luppino Rathelot and Strick, personal communication). G. 2007. A multiarchitectonic approach for the definition of functionally distinct areas and domains in the monkey Recent microstimulation experiments revealed that . J Anat 211:199–211. arm movements can indeed be elicited by microstimula- Blatt GJ, Andersen RA, Stoner GR. 1990. Visual receptive field tion at recording sites of collicular reach neurons (Philipp organization and cortico-cortical connections of the lat- and Hoffmann, 2014), and that ongoing reach move- eral intraparietal area (area LIP) in the macaque. J Comp Neurol 299:421–445. ments can be perturbed by simultaneous SC stimulation Bonini L, Maranesi M, Livi A, Fogassi L, Rizzolatti G. 2014. in the cat (Courjon et al., 2004). Another subpopulation Space-dependent representation of objects and other’s of SC neurons has a clear somatosensory component, as action in monkey ventral premotor grasping neurons. J Neurosci 34:4108–4119. these neurons are active when the hand touches and Borra E, Belmalih A, Calzavara R, Gerbella M, Murata A, Rozzi pushes a target but are inactive during the reach phase S, Luppino G. 2008. Cortical connections of the

16 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

macaque anterior intraparietal (AIP) area. Cereb Cortex Gharbawie OA, Stepniewska I, Qi H, Kaas JH. 2011. Multiple 18:1094–1111. parietal-frontal pathways mediate grasping in macaque Borra E, Belmalih A, Gerbella M, Rozzi S, Luppino G. 2010. monkeys. J Neurosci 31:11660–11677. Projections of the hand field of the macaque ventral pre- Ghosh S, Gattera R. 1995. A comparison of the ipsilateral motor area F5 to the brainstem and spinal cord. J Comp cortical projections to the dorsal and ventral subdivisions Neurol 518:2570–2591. of the macaque premotor cortex. Somatosens Motor Res Borra E, Gerbella M, Rozzi S, Tonelli S, Luppino G. 2014. Pro- 12:359–378. jections to the superior colliculus from inferior parietal, Graziano MSA, Taylor CSR, Moore T. 2002. Complex move- ventral premotor, and ventrolateral prefrontal areas ments evoked by microstimulation of precentral cortex. involved in controlling goal-directed hand actions in the Neuron 34:841–851. macaque. Cereb Cortex 24:1054–1065. Grantyn A, Grantyn R. 1982. Axonal patterns and sites of ter- Burman KJ, Bakola S, Richardson KE, Reser DH, Rosa MGP. mination of cat superior colliculus neurons projecting in 2014. Patterns of afferent input to the caudal and ros- the tecto-bulbo-spinal tract. Exp Brain Res 46:243–256. tral areas of the dorsal premotor cortex (6DC and 6DR) Hess DT, Merker BH. 1983. Technical modifications of Gal- in the marmoset monkey. J Comp Neurol 522:3683– lyas’ silver stain for myelin. J Neurosci Methods 8:95–97. 3716. Hof PR, Morrison JH. 1995. Neurofilament protein defines Castiglioni AJ, Gallaway MC, Coulter JD. 1978. Spinal projec- regional patterns of cortical organization in the macaque tions from the midbrain in monkey. J Comp Neurol 178: monkey : a quantitative immunohistochemi- 329–346. cal analysis. J Comp Neurol 352:161–186. Cercevich CM, Lyon DC, Balaram P, Kaas JH. 2014. Distribu- Hof PR, Nimchinsky EA, Morrison JH. 1995. Neurochemical tion of cortical neurons projecting to the superior collicu- phenotype of corticocortical connections in the macaque lus in macaque monkeys. Eye Brain 6:121–137. monkey: quantitative analysis of a subset of neurofila- Churchland MM, Santhanam G, Shenoy KV. 2006. Preparatory ment protein-immunoreactive projection neurons in fron- activity in premotor and motor cortex reflects the speed tal, parietal, temporal, and cingulated cortices. J Comp of the upcoming reach. J Neurophysiol 96:3130–3146. Neurol 362:109–133. Colby CL, Gattass R, Olson CR, Gross GG. 1988. Topographi- Hoshi E, Tanji J. 2007. Distinctions between dorsal and ventral cal organization of cortical afferents to extrastriate visual premotor areas: anatomical connectivity and functional area PO in the macaque: a dual tracer study. J Comp properties. Curr Opin Neurobiol 17:1–9. Neurol 269:392–413. Illing RB. 1988. Spatial relation of the acetylcholinesterase- Colby CL, Duhamel J-R, Goldberg ME. 1993. Ventral intraparie- rich domain to the visual topography in the feline supe- tal area of the macaque: anatomic location and visual rior colliculus. Exp Brain Res 73:589–594. response properties. J Neurophysiol 69:902–914. Johnson PB, Ferraina S, Bianchi L, Caminiti R. 1996. Cortical Courjon JH, Olivier E, Pelisson D. 2004. Direct evidence for networks for visual reaching: physiological and anatomi- the contribution of the superior colliculus in the control cal organization of frontal and parietal lobe arm regions. of visually guided reaching movements in the cat. Cereb Cortex 6:102–119. J Physiol 556:675–681. Johnston K, Everling S. 2006. Monkey dorsolateral prefrontal Ding SL, Ellberger AJ. 1995. A modification of biotinylated cortex sends task-selective signals directly to the supe- dextran amine histochemistry for labeling the developing rior colliculus. J Neurosci 26:12471–12478. mammalian brain. J Neurosci Methods 57:67–75. Kaas JH, Stepniewska I, Gharbawie OA. 2012. Cortical net- Finlay BL, Schiller PH, Volman SF. 1976. Quantitative studies works subserving upper limb movements in primates. of single-cell properties in monkey striate cortex. IV. Cor- Eur J Phys Rehabil Med 48:299–306. ticotectal cells. J Neurophysiol 39:1352–1361. Kaas JH, Gharbawie OA, Stepniewska I. 2013. Cortical net- Fogassi L, Raos V, Franchi G, Gallese V, Luppino G, Matelli M. works for ethologically relevant behaviors in primates. 1999. Visual responses in the dorsal premotor area F2 Am J Primatol 75:407–414. of the macaque monkey. Exp Brain Res 128:194–199. Kakei S, Hoffman DS, Strick PL. 2001. Direction of action is Fries W. 1984. Cortical projections to the superior colliculus represented in the ventral premotor cortex. Nat Neurosci in the macaque monkey: a retrograde study using horse- 4:1020–1025. radish peroxidase. J Comp Neurol 230:55–76. Komatsu H, Suzuki H. 1985. Projections from the functional Fries W. 1985. Inputs from motor and premotor cortex to the subdivisions of the frontal eye field to the superior colli- superior colliculus of the macaque monkey. Behav Brain culus in the monkey. Brain Res 327:324–327. Res 18:95–105. Kruse W, Hoffmann K-P. 2002. Fast gamma oscillations in Fu QG, Flament D, Coltz JD, Ebner TJ. 1995. Temporal encod- areas MT and MST occur during visual stimulation, but ing of movement kinematics in the discharge of primate not during visually guided manual tracking. Exp Brain primary motor and premotor neurons. J. Neurophysiol Res 147:360–373. 73:836–854. Kruse W, Dannenberg S, Kleiser R, Hoffmann K-P. 2002. Tem- Fujii N, Mushiake H, Tanji J. 2000. Rostrocaudal distinction of poral relation of population activity in visual areas MT/ the dorsal premotor area based on oculomotor involve- MST and in primary motor cortex during visually guided ment. J Neurophysiol 83:1764–1769. tracking movements. Cerebr Cortex 12:166–176. Gabernet L, Meskena€ıte V, Hepp-Reymond M-C. 1999. Parcel- Kuenzle H, Akert K, Wurtz RH. 1976. Projection of area 8 lation of the lateral premotor cortex of the macaque (frontal eye field) to superior colliculus in the monkey. monkey based on staining with the neurofilament anti- An autoradiographic study. Brain Res 117:487–492. body SMI-32. Exp Brain Res 128:188–193. Kutz DF, Dannenberg S, Werner W, Hoffmann K-P. 1997. Pop- Gallyas F. 1979. Silver staining of myelin by means of physi- ulation coding of arm-movement-related neurons in and cal development. Neurol Res 1:203–209. below the superior colliculus of Macaca mulatta. Biol Gaymard B, Lynch J, Ploner CJ, Condy C, Rivaud-Pechoux S. Cybern 76:331–337. 2003. The parieto-collicular pathway: anatomical location Leichnetz GR. 2001. Connections of the medial posterior pari- and contribution to saccade generation. Eur J Neurosci etal cortex (area 7m) in the monkey. Anat Rec 263:215– 17:1518–1526. 236.

The Journal of Comparative Neurology | Research in Systems Neuroscience 17 C. Distler and K.-P. Hoffmann

Leichnetz GR, Spencer F, Hardy SGP, Astruc J. 1981. The pre- Preuss TM, Stepniewska I, Jain N, Kaas JH. 1996. Movement frontal corticotectal projection in the monkey: an antero- representation in the dorsal and ventral premotor areas grade and retrograde horseradish peroxidase study. of owl monkeys: a microstimulation study. J Comp Neu- Neuroscience 6:1023–1041. rol 371:649–676. Lehmann SJ, Scherberger H. 2013. Reach and gaze represen- Preuss TM, Stepniewska I, Jain N, Kaas JH. 1997. Multiple divi- tations in macaque parietal and premotor grasp areas. sions of macaque precentral motor cortex identified with J Neurosci 33:7038–7049. neurofilament antibody SMI-32. Brain Res 767:148–153. Lewis JW, van Essen D. 2000. Mapping of architectonic subdi- Raos V, Franchi G, Gallese V, Fogassi L. 2003. Somatotopic orga- visions in the macaque monkey, with emphasis on nization of the lateral part of area F2 (dorsal premotor cor- parieto-occipital cortex. J Comp Neurol 428:79–111. tex) of the macaque monkey. J Neurophysiol 89:1503–1518. Lock TM, Baizer JS, Bender DB. 2003. Distribution of cortico- Raos V, Umilta MA, Gallese V, Fogassi L. 2004. Functional tectal cells in macaque. Exp Brain Res 151:455–470. properties of grasping-related neurons in the dorsal pre- Luppino G, Murata A, Govoni P, Matelli M. 1999. Large segre- motor area F2 of the macaque monkey. J Neurophysiol gated parietofrontal connections linking rostral intraparie- 92:1990–2002. tal cortex (areas AIP and VIP) and the ventral premotor Raos V, Umilta MA, Murata A, Fogassi L, Gallese V. 2006. cortex (area F5 and F4). Exp Brain Res 128:181–187. Functional properties of grasping-related neurons in the Luppino G, Rozzi S, Calzavara R, Matelli M. 2003. Prefrontal ventral premotor area F5 of the macaque monkey. and agranular cingulate projections to the dorsal premo- J Neurophysiol 95:709–729. tor areas F2 and F7 in the macaque monkey. Eur J Neu- Rizzolatti G, Camarda R, Fogassi L, Gentilucci M, Luppino G, rosci 17:559–578. Matelli M. 1988. Functional organization of inferior area Lynch JC, Graybiel AM, Lobeck LJ. 1985. The differential pro- 6 in the macaque monkey. II. Area F5 and the control of jection of two cytoarchitectonic subregions of the inferior distal movements. Exp Brain Res 71:491–507. parietal lobule of macaque upon the deep layers of the Rozzi S, Calzavara R, Belmalih A, Borra E, Gregoriou GG, superior colliculus. J Comp Neurol 235:241–254. Matelli M, Luppino G. 2006. Cortical connections of the Matelli M, Luppino G, Rizzolatti G. 1985. Patterns of cyto- inferior parietal cortical convexity of the macaque mon- chrome oxidase activity in the frontal agranular cortex of key. Cereb Cortex 16:1389–1417. the macaque monkey. Behav Brain Res 18:125–136. Saga Y, Hirata Y, Takahara D, Inoue K, Miyachi S, Nambu A, Matelli M, Govoni P, Galletti C, Kutz DF, Luppino G. 1998. Supe- Tanji J, Takada M, Hoshi E. 2011. Origins of multisynap- rior area 6 afferents from the superior parietal lobule in tic projections from the basal ganglia to rostrocaudally the macaque monkey. J Comp Neurol 402:327–352. distinct sectors of the dorsal premotor area in maca- Messier J, Kalaska JF. 2000. Covariation of primate dorsal premo- ques. Eur J Neurosci 33:285–297. tor cell activity with direction and amplitude during a Schall JD, Morel A, King DJ, Bullier J. 1995. Topography of vis- memorized-delay reaching task. J Neurophysiol 84:152–165. ual cortex connections with frontal eye field in macaque: Montgomery LR, Herbert WJ, Buford JA. 2013. Recruitment of convergence and segregation of processing streams. ipsilateral and contralateral upper limb muscles following J Neurosci 15:4464–4487. stimulation of the cortical motor areas in the monkey. Seelke AMH, Padberg JJ, Disbrow E, Purnell SM, Recanzone G, Exp Brain Res 230:153–164. Krubitzer L. Topographic maps within Brodman area 5 of Nagy A, Kruse W, Rottmann S, Dannenberg S, Hoffmann K-P. macaque monkeys. Cereb Cortex 22:1834–1850. 2006. Somatosensory-motor neuronal activity in the Segraves MA, Goldberg ME. 1987. Functional properties of superior colliculus of the primate. Neuron 52:525–534. corticotectal neurons in the monkey’s frontal eye field. Nudo RJ, Sutherland DP, Masterton RB. 1993. Inter- and intra- J Neurophysiol 58:1387–1419. laminar distribution of tectospinal neurons in 23 mam- Selemon LD, Goldman-Rakic PS. 1988. Common cortical and mals. Brain Behav Evol 42:1–23. subcortical targets of the dorsolateral prefrontal and pos- Ochiai T, Mushiake H, Tanji J. 2005. Involvement of the ven- terior parietal cortices in the rhesus monkey: evidence tral premotor cortex in controlling image motion of the for a distributed neural network subserving spatially hand during performance of a target-capturing task. guided behaviour. J Neurosci 8:4049–4068. Cereb Cortex 15:929–937. Shook BL, Schlag-Rey M, Schlag J. 1990. Primate supplemen- Olivier E, Chat M, Grantyn A. 1991. Rostrocaudal and latero- tary eye field: I. Comparative aspects of mesencephalic medial density distributions of superior colliculus neu- and pontine connections. J Comp Neurol 301:618–642. rons projecting in the predorsal bundle and to the spinal Stanton GB, Goldberg ME, Bruce CJ. 1988. Frontal eye field effer- cord: a retrograde HRP study in the cat. Exp Brain Res ents in the macaque monkey: II. Topography of terminal 87:268–282. fields in midbrain and pons. J Comp Neurol 271:493–506. Padberg J, Franca JG, Cooke DF, Soares JGM, Rosa MGP, Stuphorn V, Bauswein E, Hoffmann K-P. 1996. Cortico-collicu- Fiorani M Jr, Gattass R, Krubitzer L. 2007. Parallel evolu- lar control of arm movements. In: Lacquaniti F, Viviani P, tion of cortical areas involved in skilled hand use. editors. Neural bases of motor behaviour. Kluwer Aca- J Neurosci 27:10106–10115. demic Publishers, New York, NY. pp 185–204. Pare M, Wurtz RH. 1997. Monkey posterior parietal neurons Stuphorn V, Hoffmann K-P, Miller LE. 1999. Correlation of pri- antidromically activated from the superior colliculus. mate superior colliculus and reticular formation dis- J Neurophysiol 78:3493–3497. charge with proximal limb muscle activity. Pesaran B, Nelson MJ, Andersen RA. 2006. Dorsal premotor J Neurophysiol. 81:1978–1982. neurons encode the relative position of the hand, eye, Stuphorn V, Bauswein E, Hoffmann K-P. 2000. Neurons in the and goal during reach planning. Neuron 51:125–134. primate superior colliculus coding for arm movements in Pesaran B, Nelson MJ, Andersen RA. 2010. A relative position gaze-related coordinates. J Neurophysiol. 83:1283–1299. code for saccades in dorsal premotor cortex. J Neurosci Takahara D, Inoue K, Hirata Y, Miyaci S, Nambu A, Takada M, 30:6527–6537. Hoshi E. 2012. Multisynaptic projections from the ventro- Philipp R, Hoffmann K-P. 2014. Arm movements induced by lateral prefrontal cortex to the dorsal premotor cortex in electrical microstimulation in the superior colliculus of macaques—anatomical substrate for conditional visuomo- the macaque monkey. J Neurosci 34:3350–3363. tor behaviour. Eur J Neurosci 36:3365–3375.

18 The Journal of Comparative Neurology | Research in Systems Neuroscience Direct projections of PMd to superior colliculus

Tanne J, Boussaoud D, Boyer-Zeller N, Rouiller EM. 1995. Werner W. 1993. Neurons in the primate superior colliculus Direct visual pathways for reaching movements in the are active before and during arm movements to visual macaque monkey. NeuroReport 7:267–272. targets. Eur J Neurosci 5:335–340. Theys T, Pani P, van Loon J, Goffin J, Janssen P. 2012. Selec- Werner W, Dannenberg S, Hoffmann K-P. 1997a. Arm-move- tivity for three-dimensional shape and grasping-related ment-related neurons in the primate superior colliculus activity in the macaque ventral premotor cortex. and underlying reticular formation: comparison of neuro- J Neurosci 32:12038–12050. nal activity with EMGs of muscles of the shoulder, arm Tokuno H, Takada M, Nambu A, Inase M. 1995. Direct projec- and trunk during reaching. Exp Brain Res 115:191–205. tions from the orofacial region of the primary motor cor- Werner W, Hoffmann K-P, Dannenberg S. 1997b. Anatomical tex to the superior colliculus in the macaque monkey. distribution of arm-movement-related neurons in the pri- Brain Res 703:217–222. mate superior colliculus and underlying reticular forma- van der Want JJL, Klooster J, Nunes Cardozo B, de Weerd H, tion in comparison with visual and saccadic cells. Exp Liem RSB. 1997. Tract-tracing in the nervous system of Brain Res 115:206–216. vertebrates using horseradish peroxidase and its conju- Yamagata T, Nakayama Y, Tanji J, Hoshi E. 2012. Distinct gates: tracers, chromogens, and stabilization for light and information representation and processing for goal- electron microscopy. Brain Res Protocols 1:269–279. directed behaviour in the dorsolateral and ventrolateral Weinrich M, Wise SP. 1982. The premotor cortex of the mon- prefrontal cortex and the dorsal premotor cortex. key. J Neurosci 2:1329–1345. J Neurosci 32:12934–12949.

The Journal of Comparative Neurology | Research in Systems Neuroscience 19