direct projections from the dorsal premotor cortex to the superior … · 2015-11-18 · direct...

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

Claudia Distler1* and Klaus-Peter Hoffmann1,2,3

1Department of Zoology and Neurobiology, Ruhr-University Bochum, 44780 Bochum, Germany2Department of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany3Department of Neuroscience, Ruhr-University Bochum, 44780 Bochum, Germany

ABSTRACTThe dorsal premotor cortex (PMd) is part of the cortical

network for arm movements during reach-related

behavior. Here we investigate the neuronal projections

from the PMd to the midbrain superior colliculus (SC),

which also contains reach-related neurons, to investi-

gate how the SC integrates into a cortico-subcortical

network responsible for initiation and modulation of

goal-directed arm movements. By using anterograde

transport of neuronal tracers, we found that the PMd

projects most strongly to the deep layers of the lateral

part of the SC and the underlying reticular formation

corresponding to locations where reach-related neurons

have been recorded, and from where descending tecto-

fugal projections arise. A somewhat weaker projection

targets the intermediate layers of the SC. By contrast,

terminals originating from prearcuate area 8 mainly pro-

ject to the intermediate layers of the SC. Thus, this pro-

jection pattern strengthens the view that different

compartments in the SC are involved in the control of

gaze and in the control or modulation of reaching

movements. The PMD–SC projection assists in the par-

ticipation of the SC in the skeletomotor system and

provides the PMd with a parallel path to elicit forelimb

movements. J. Comp. Neurol. 000:000–000, 2015.

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

dexterous mammals including humans. Research during

the last decades in primates has revealed a widespread

network of brain areas involved in various aspects of

these actions. In the cerebral cortex, the main players

are the primary motor cortex (M1), premotor cortex

(PM), and posterior parietal cortex (area 5, AIP and

MIP), with their cortical input from visual, somatosen-

sory, and prefrontal cortex (Johnson et al., 1996; Hoshi

and Tanji, 2007; Padberg et al., 2007; Kaas et al.,

2012, 2013 and references therein). Based on electro-

physiological recordings, microstimulation, and anatomi-

cal investigations, all these areas display topographic

organization that, however, is somewhat crude in the

premotor and posterior parietal cortex. This led to the

concept of functional zones interconnected within and

between relevant cortical areas, which would then

together control the various sectors, joint angles, orien-

tation, etc. of the forelimb during certain movements

(Seelke et al., 2012; Kaas et al., 2012, 2013).

On functional and anatomical grounds, the premotor

cortex (Brodman area 6) can be divided in dorsal (PMd,

F2, F7) and ventral (PMv, F4, F5) compartments (Matelli

et al., 1985). Area PMv (F5) is mainly connected with

the ventral portion of the dorsolateral prefrontal cortex

(DLPC) and with the inferior parietal lobule, especially

area AIP and PF (Luppino et al., 1999; Hoshi and Tanji,

2007; Borra et al., 2008; Gharbawie et al., 2011). Func-

tionally, the PMv is involved in the preparation and exe-

cution of arm and hand movements related to grasping

and contains not only neurons related to the subject’s

own actions but to actions of others (mirror neurons)

Grant sponsor: the Deutsche Forschungsgemeinschaft; Grant number:Ho 450/25; Grant sponsor: ZEN grant from the Hertie Stiftung (toK.P.H.).

*CORRESPONDENCE TO: Claudia Distler, Allgemeine Zoologie und Neu-robiologie, Ruhr-University Bochum, Universitaetsstr. 150, ND 7/26,44780 Bochum, Germany. E-mail: [email protected]

Received January 21, 2015; Revised March 31, 2015;Accepted April 15, 2015.DOI 10.1002/cne.23794Published online Month 00, 2015 in Wiley Online Library(wileyonlinelibrary.com)VC 2015 Wiley Periodicals, Inc.

The Journal of Comparative Neurology | Research in Systems Neuroscience 00:00–00 (2015) 1

RESEARCH ARTICLE

(Rizzolatti et al., 1988; Kakei et al., 2001; Ochiai et al.,

2005; Raos et al., 2006; Hoshi and Tanji, 2007; Theys

et al., 2012; Lehmann and Scherberger, 2013; Bonini

et al., 2014).

By contrast, PMd is connected with the dorsal DLPC

and the dorsal parietal lobule including area 5 and the

MIP. Namely, the caudal part of the PMd (F2 dimple

region and F2 ventrorostral of Matelli et al., 1998;

cPMd of Ghosh and Gattera, 1995) receives its main

input from parietal areas PEc and PEip (F2 dimple), and

the MIP and V6A (F2 ventrorostral), respectively, as

well as from frontal areas SMA, M1, and the cingulate

motor areas (Ghosh and Gattera, 1995; Matelli et al.,

1998). It is also involved in the preparation and execu-

tion of arm movements but shows preparatory activity

and codes for direction, speed, and amplitude of the

arm movement during reaching and eye–hand coordina-

tion (Barbas and Pandya, 1987; Colby et al., 1988; Fu

et al., 1995; Tann�e et al., 1995; Johnson et al., 1996;

Matelli et al., 1998; Messier and Kalaska, 2000; Lup-

pino et al., 2003; Churchland et al., 2006; Pesaran

et al., 2006, 2010; Hoshi and Tanji, 2007; Yamagata

et al., 2012).

Electrical microstimulation in the PMd leads to move-

ments of the upper limb but at significantly higher

thresholds than in the M1 (Weinreich and Wise, 1982;

Preuss et al., 1996; Fujii et al., 2000; Raos et al.,

2003). A systematic survey of the dorsal premotor cor-

tex revealed a topographic order of evoked movements

with simple movements of the contralateral shoulder

mostly elicited from areas close to the precentral dim-

ple, and simple movements of the contralateral distal

forelimb mostly elicited more laterally close to the spur

of the arcuate. In addition, neurons close to the dimple

were mostly active during movements and somatosen-

sory stimulation of the arm, whereas neurons close to

the spur were active during movement and somatosen-

sory stimulation of the distal forelimb (Raos et al.,

2003). About half of the neurons were active during

grasping, and about 37% were active during reaching.

This forelimb-related region contains visual, somatosen-

sory, purely motor, visually modulated, and visuomotor

neurons (Fogassi et al., 1999; Raos et al., 2004). Elec-

trical stimulation of the PMd resulted more often in

suppression (50% of events) in upper limb muscles than

stimulation of the SMA or M1 (20% of events) (Mont-

gomery et al., 2013). With longer stimulation periods

(500 ms), complex and more naturalistic movements of

the arm could be evoked from the PMd (Graziano et al.,

2002).

In recent years, reach-related activity has also been

identified in neurons of the intermediate and deep

layers of the midbrain superior colliculus (SC). These

reach neurons are active before and during arm move-

ments, and their activity is correlated with the direction

of arm movements (Kutz et al., 1997) and/or with the

electromyogram of proximal shoulder and arm muscles

(Werner, 1993; Werner et al., 1997a, b; Stuphorn et al.,

1999, 2000). Furthermore, microstimulation at record-

ing sites of these reach neurons elicits arm movements

(Philipp and Hoffmann, 2014).

The SC receives input from multiple cortical areas.

The superficial layers are targeted mainly by early visual

areas, whereas intermediate and deep layers receive

input from the posterior parietal cortex including the

lateral intraparietal area (LIP), forelimb representation

Abbreviations

A aqueductA8 area 8Amt anterior mediotemporal sulcusAr arcuate sulcusBSC brachium of the superior colliculusCa calcarine sulcusCe central sulcusCi cingulate sulcusDMZ densely myelinated zone of the medial superior temporal areaDpc decussatio pedunculi cerebellarisec ectocalcarine sulcusFEF frontal eye fieldflm fasciculus longitudinalis medialisIC inferior colliculusio infero-occipital sulcusip intraparietal sulcusla lateral sulcusLIP lateral intraparietal areall lemniscus lateralislu lunate sulcusM2 motor area 2MIP medial intraparietal areaMT middle temporal areaNPo n. pontisNRm n. reticularis mesencephaliNRp n. reticularis parvocellularisNRpo n. reticularis pontis oralis

Nru n. ruberNTr n. trapeziusot occipito-temporal sulcusp principal sulcusPAG periaqueductal greypc pedunculus cerebripca pedunculus cerebellaris anteriorpcd precentral dimplepo parieto-occipital sulcusPt pretectumPul pulvinarRd raphe dorsalisSC superior colliculusSN substantia nigraSGI stratum griseum intermedium of the SCSGP stratum griseum profundum of the SCSGS stratum griseum superficiale of the SCSt superior temporal sulcusVIP ventral intraparietal areaV1 primary visual cortexV4t visual area 4 transitional zoneV6 visual area 6V6A visual area 6AIII n. oculomotoriusIV n. trochlearis3a 4, 5, 6, 7a, 8, 23, 24, Brodman areas 3a, 4, 5, 6, 7a, 8, 23, 245v ventral area 5

C. Distler and K.-P. Hoffmann

2 The Journal of Comparative Neurology |Research in Systems Neuroscience

of areas 2, 4, and 6, FEF, PMv, and prefrontal cortex

(Finlay et al., 1976; Kuenzle et al., 1976; Leichnetz

et al., 1981; Fries, 1984, 1985; Komatsu and Suzuki,

1985; Lynch et al., 1985; Lock et al., 2003; Borra

et al., 2014; Cerkevich et al., 2014).

Only in some instances have these anatomical con-

nections been characterized physiologically. The cortico-

tectal projection originating from the primary visual

cortex seems to be involved in the control of intracollic-

ular visual processing (Finlay et al., 1976). The FEF pro-

jection to the SC mainly carries saccade-related and

visual information about the central visual field (Seg-

raves and Goldberg, 1987). By contrast, tectal projec-

tions from the LIP carry mostly visual saccade-related

information from the peripheral field (Par�e and Wurtz,

1997; Gaymard et al., 2003). In contrast, projections

from the dorsolateral prefrontal cortex transmit task-

selective signals to the SC, i.e., neuronal signals selec-

tive for antisaccades that inhibit reflexive prosaccades

(Johnston and Everling, 2006). To date, only little data

for the premotor-tectal projections are available. Electri-

cal microstimulation revealed excitatory as well as

inhibitory influences of the PMd on forelimb muscles

(Montgomery et al., 2013). We presume that at least

part of the PMd output is mediated indirectly, e.g., via

subcortical nuclei including the SC. In a preliminary

study, antidromically identified premotor-tectal neurons

were active during reach movements. In some of these

cells the reach activity varied with the direction of

gaze, which corresponds to the firing properties of a

subset of SC reach neurons (Stuphorn et al., 1996).

In the present study we investigate the direct projec-

tions of the PMd to the SC to reveal the spatial location

of anterogradely labeled terminals relative to recording

sites of reach-related activity in the SC. This study is

part of a project to further characterize the information

transmitted from the PMd to the SC in the cortico-

subcortical network for reaching

MATERIALS AND METHODS

All experiments were approved by the local author-

ities (Regierungspr€asidium Arnsberg, now LANUV) and

the ethics committee, and were performed in accord-

ance with the Deutsche Tierschutzgesetz of 7.26.2002,

the European Communities Council Directive RL 2010/

63/EC, and NIH guidelines for care and use of animals

for experimental procedures.

AnimalsFour adult male rhesus monkeys (Macaca mulatta)

were used in the present investigation. All animals had

participated in electrophysiological experiments prior to

the tracer injections (Stuphorn et al., 2000; Kruse and

Hoffmann, 2002; Kruse et al., 2002; Philipp and Hoff-

mann, 2014).

SurgeryAfter premedication with atropine sulfate (0.04 mg/

kg) the animals were initially anesthetized with keta-

mine hydrochloride (10 mg/kg i.m., Braun, Melsungen,

Germany). After local anesthesia with 10% xylocain

(Astra Zeneka, Wedel, Germany), they were intubated

through the mouth, an intravenous catheter was intro-

duced into the saphenous vein, and, after additional

local anesthesia with bupivacaine hydrochloride 0.5%,

the animals were placed into a stereotactic apparatus.

Throughout the experiment the animals were artificially

ventilated with nitrous oxide: oxygen as 3:1 containing

0.3%–1% halothane as needed. Deep analgesia was

ensured by intravenous bolus and continuous applica-

tion of fentanyl (3 mg/kg/h, Janssen, Neuss, Germany).

Heart rate, SPO2, blood pressure, body temperature,

and end-tidal CO2 were monitored constantly and kept

at physiological levels. The corneae were protected

with contact lenses.

Injections and histological proceduresIn two of the animals, the injections were made

through recording chambers that had previously been

implanted for the electrophysiological experiments to

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

cortical area. We used biotin dextran amine (BDA) as

an anterograde tracer. In addition, in case A8 (prearcu-

ate oculomotor area 8), during the final electrophysio-

logical experiment, we injected horseradish peroxidase

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 weeksPMd2 15% BDA MW3000 in 0.1 M citrate/NaOH pH 3.3 2 2 weeksPMd3 20% BDA MW3000 in 0.9% NaCl 3 2 weeksA8 2.5% WGA-HRP in KCl/Tris/DMSO 0.3 48 hoursA8-2 10% BDA MW10000 in 0.9% NaCl 1 3 months

Direct projections of PMd to superior colliculus

The Journal of Comparative Neurology | Research in Systems Neuroscience 3

conjugated to wheat germ agglutinin (WGA-HRP) at the

same location as the BDA injection (case A8-2). Table 1

summarizes the tracers, volumes, and survival times

used in the present study.

After appropriate survival times, the animals received

a lethal overdose of pentobarbital and were perfused

through the heart with 0.9% NaCl containing 0.1% pro-

caine hydrochloride followed by paraformaldehyde–

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.



lysine–periodate with 4% paraformaldehyde. After

appropriate cryoprotection with 10% and 20% glycerol,

the brains were shock frozen and stored at 2708C until

processing.

The midbrains were cut at 40–50 mm on a vibratome

or a cryostat in a plane angled 458 from posterior and

thus approximately normal to the SC surface and paral-

lel to the electrode penetrations. Frontal or sagittal

sections of the injected cortical hemispheres were cut

on a freezing microtome at 50 mm. Neuronal transport

of BDA was visualized with the avidin-biotin method

(ABC Elite, Vector, Burlingame, CA; 1:250, RRID:

AB_2336827) with diaminobenzidine (DAB) as chromo-

gen enhanced with ammonium nickel sulfate (cases

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 mm in D; 50 mm in B,C,E,F.



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.



PMd1, PMd2, and PMd3), or in alternate sections with

tetramethylbenzidine (TMB) as chromogen (case PMd3;

after Ding and Ellberger, 1995, van der Want, 1997). In

case A8-2, WGA-HRP was visualized with TMB (after

van der Want, 1997). A subset of midbrain sections

was stained for acetylcholinesterase (AChE) histochem-

istry (Illing, 1988). Subsets of cortical sections were

stained for Nissl, and myeloarchitecture (Gallyas, 1979,

as modified by Hess and Marker, 1983).

In a further subset of cortical sections, the

neurofilament-based chemoarchitecture of cortical

areas was analyzed. Briefly, free-floating sections were

washed in 0.1 M Tris-buffered saline (TBS), and treated

for 30 minutes with 3% H2O2 and 0.2% Triton–X-100,

respectively. Sections were incubated in an antibody

against nonphosphorylated neurofilament protein for 48

hours at 48C under gentle agitation (SMI-32, 1:1,000,

Covance, Munster, Germany; cat# smi-32r; RRID:

AB_2315331; Hof and Morrison, 1995). Then sections

were washed thoroughly in TBS, and incubated over-

night in the biotinylated secondary antibody at 48C

(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.

AnalysisLabeled 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

(RRID: SciRes_000161, version 5.5).

RESULTS

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

an additional animal. The location of the injection sites

is presented on the reconstructions of the lateral view

of the left cortical hemispheres in Figure 1. All data are

presented as left hemispheres to facilitate comparison.

Case PMd1In case PMd1, the tracer injections into the PMd fol-

lowed the electrophysiological recordings from cortical

neurons that projected to the SC as identified by anti-

dromic stimulation. Three tracer injections (green areas)

were placed into the anterior part of the PMd (F2) ros-

tral to the precentral dimple (pcd) (Fig. 1A) but clearly

not encroaching on area 8 in the prearcuate gyrus or

FEF in the anterior bank of the arcuate sulcus. Exam-

ples of the anterogradely labeled fibers and terminals

are depicted in Figure 2B and C, and the location of

the labeled structures in the SC and underlying mesen-

cephalic reticular formation is given in Figure 2A.

Anterogradely labeled terminals (Fig. 2, red dots in Fig.

3) and fibers (Fig. 2, blue marks in Fig. 3) were located

in the intermediate and predominantly in the deep

Figure 4. Neurofilament protein-based chemoarchitecture used to

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

bars. For abbreviations see list. Scale bar 5 1 mm in A,B.



layers of the ipsilateral SC throughout its entire antero-

posterior and mediolateral extent (Fig. 3). As a label for

the intermediate layers, we used AChE histochemistry

(green structures in the left drawings of Fig. 3); the

other collicular layers were determined in neighboring

sections stained for cytoarchitecture. The PMd termi-

nals were located predominantly below the AChE-rich

patches. In addition, labeled terminals were found in

the mesencephalic reticular formation close to the peri-

aqueductal gray and in the pontine nuclei. To further

characterize and compare the injected area between

cases, we also analyzed the cortical connections

revealed by the injections. Here we largely follow the

criteria and nomenclature of Lewis and van Essen

(2000). Figure 4 demonstrates examples of the

neurofilament-based cytoarchitecture of various areas

of interest. The border between area 4 and the PMd

was recognized by the larger abundance of large layer

V pyramidal cells and a decrease of immunoreactivity in

supragranular layers (Fig. 4A; Preuss et al., 1997; Gab-

ernet et al., 1999). In the parietal cortex (Fig. 4B),

areas LIP, VIP, MIP, and 5V could be identified (Hof and

Morrison, 1995; Hof et al., 1995; Lewis and van Essen,

2000). Intracortical projections were limited to a few

areas, largely confirming earlier studies (Johnson et al.,

1996; Matelli et al., 1998; Leichnetz, 2001; Luppino

et al., 2003; Burman et al., 2014). In the parietal cor-

tex, retrogradely labeled cells were mainly located in

the medial bank of the intraparietal sulcus including

areas MIP, VIP, and ventral area 5, as well as in area

V6A on the medial aspect of the parietal lobe. Frontally,

numerous retrogradely labeled neurons were present in

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.



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 precentral motor cortex (area 4), within dorsal area

6 anterior to the injection site and posterior in the spur

of the arcuate sulcus, and in area M2. Medially, fewer

neurons were located in areas 23 and 24 in the cingu-

late sulcus (Fig. 5).

Case PMd2The tracer injection in case PMd2 was located more

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-

sively located in the deep layers of the lateral SC far

away from the AChE patches. There was not a continu-

ous band of labeled terminals from lateral to medial as

in case PMd1. Additionally, labeled terminals were

found in the nucleus ruber and were widespread in the

mesencephalic reticular formation (Fig. 6). Cortical pro-

jections were restricted to the medial bank of the intra-

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

23 and 24 on the medial aspect of the brain were

largely devoid of label (Fig. 7).

Case PMd3Case PMd3 represents the caudalmost injection site

in this study lying between the posterior tip of the pre-

central dimple and the posterior tip of the spur of the

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.


10 The Journal of Comparative Neurology | Research in Systems Neuroscience

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.



arcuate (Fig. 1C). Examples of the resulting anterograde

labeling are shown in Figure 2D–F. Labeled terminals

were again concentrated in the deep layers predomi-

nantly in the lateral SC and in the underlying mesence-

phalic reticular formation (Fig. 8). In the parietal cortex,

retrogradely labeled neurons were mostly found in the

anterior part of the medial bank of the intraparietal sul-

cus (area 5V) with additional label on the supraparietal

gyrus (area 5), the infraparietal gyrus (area 7a), and in

the medial bank of the lateral fissure. Fewer neurons

were labeled in the posterior bank of the intraparietal

sulcus, including area LIP. In the frontal cortex, labeled

cells were concentrated in area 4 on the precentral

gyrus, area 6V, and M2. Labeled cells in M2 were much

denser on the medial aspect of the brain than on the

crown of the cortex (Fig. 9).

Case A8As a control and for comparison, further injections

were placed into the oculomotor area on the prearcuate

gyrus (area 8) in the representation of the peripheral vis-

ual field (Komatsu and Suzuki, 1985) (Fig. 1D). In this

case, in addition to the BDA injection, WGA-HRP was

injected at the same location, resulting in a complete

overlap of the two injection sites and the resulting label-

ing. In contrast to the PMd projections, terminal labeling

from both tracer injections into area 8 was predominantly

found in the intermediate layers of the medial SC; the lat-

eral SC was notably devoid of label (Fig. 10). Intracortical

transport in this case was rather limited. In the frontal

cortex, a few patches of labeled neurons were located in

area M2 and area 6D (Fig. 11). Unfortunately, the poste-

rior cortex was not available for analysis in this case.

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.



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.



Thus, the injection in PMd1 located in the anterior

PMd and possibly encroaching on area 6Dr (F7; Luppino

et al., 2003) resulted in terminal labeling in the interme-

diate and deep layers of the entire ipsilateral SC. After

injections into more posterior parts of the PMd only the

deep lateral part of the SC was labeled. By contrast,

output from our area 8 injection mainly terminated

more superficially compared with the PMd in the inter-

mediate layers, sparing the most lateral SC.

DISCUSSION

In our experiments we were able to show that area

PMd (F2) directly projects moderately to the intermedi-

ate and more strongly to the deep layers of the ipsilat-

eral SC. These projections were particularly heavy in

the lateral part of the SC representing the ventral visual

field, and coincided with the location of reach-related

neurons in the SC (Werner et al., 1997b) as well as tec-

tofugal neurons described in other studies (Castiglioni

et al., 1978; Nudo et al., 1993; Rathelot and Strick,

personal communication).

Corticotectal projection from PMdThe existence of a direct connection between the

PMd and SC was suggested by earlier retrograde trac-

ing studies (Leichnetz et al., 1981; Fries, 1984, 1985;

but see Lock et al., 2003); however, the density of this

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

achieved by the anteriormost injection (PMd1), which

coincided with the area where neurons could be anti-

dromically activated from the SC in related electrophys-

iological experiments. Based on the location and the

cortical connections, i.e., input from the V6A and MIP

in the parietal cortex and from cingulate motor areas,

case PMd1 includes the ventrorostral part of area F2

(Matelli et al., 1998; Luppino et al., 2003). It also corre-

sponds to the region from where simple and complex

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.



movements of the distal forelimb can be elicited by

intracortical microstimulation (Raos et al., 2003) and

where grasp-related neurons are located (Raos et al.,

2004). More posterior injections mainly labeled the lat-

eral part of the SC. Both PMd2 and PMd3 were located

in the region between the precentral dimple and the

spur of the arcuate, with little or no input from the cin-

gulate cortex (Matelli et al., 1998; Luppino et al.,

2003). The core of the PMd2 injection was closer to

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.



and coworkers may again be due to the larger injection

site (Leichnetz et al., 1981).

Unfortunately we could not analyze the cortical con-

nections with the posterior cortex in our area 8 case,

but labeling in the posterior bank of the intraparietal

sulcus including the LIP as well as in visual and polymo-

dal extrastriate areas has been demonstrated in other

studies (Leichnetz et al., 1981; Schall et al., 1985),

which confirms that even our largest and most anterior

PMd injection shows an intracortical projection pattern

distinct from that of the prearcuate oculomotor cortex.

Figure 12 summarizes the spatial relationship of cort-

ical projections from the PMd (red dots) and area 8

(black dots) to the SC (this study) relative to the loca-

tion of tectofugal neurons retrogradely labeled from the

cervical spinal cord (Castiglioni et al., 1978, green

areas) or transsynaptically from the spinodeltoid muscle

(Rathelot and Strick, personal communication, blue

areas). For this chart the labeled SC regions from all

our PMd cases were combined. There is a striking over-

lap of input from PMd and the SC output to the cervical

spinal cord and the shoulder muscles, demonstrating

the putative neuronal substrate for modulating head

and arm movements via the SC.

Functional considerationsThe optic tectum of nonmammalian vertebrates and

the SC of mammals is traditionally viewed as a key struc-

ture for orienting behaviour, especially of the body,

head, eyes, and pinnae (Akert, 1949; Alstermark and Isa,

2012). With the discovery of arm-movement–related

activity in the SC, this scheme was extended to limb

movements also in monkeys in agreement with earlier

studies in the cat (Courjon et al., 2004). Reach neurons

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

1993; Werner et al., 1997a, b; Stuphorn et al., 1999,

2000) and are active before and during reach move-

ments mainly but not exclusively of the contralateral

arm. They reside in a region where descending tectofugal

projections arise (Castiglioni et al., 1978; Grantyn and

Grantyn, 1982; Olivier et al., 1991; Nudo et al., 1993;

Rathelot and Strick, personal communication).

Recent microstimulation experiments revealed that

arm movements can indeed be elicited by microstimula-

tion at recording sites of collicular reach neurons (Philipp

and Hoffmann, 2014), and that ongoing reach move-

ments can be perturbed by simultaneous SC stimulation

in the cat (Courjon et al., 2004). Another subpopulation

of SC neurons has a clear somatosensory component, as

these neurons are active when the hand touches and

pushes a target but are inactive during the reach phase

(Nagy et al., 2006). They were also located in the inter-

mediate and deep layers of the SC, between 1.2 and

4 mm below the collicular surface (median 5 3.1 mm),

i.e., in the same depths as the reach neurons

(median 5 2.8 mm, range 5 1.4–4 mm). The coincidence

of the anatomical location of SC reach and

somatosensory-motor neurons with the cortical afferents

originating from the dorsal premotor (this study) and ven-

tral premotor cortex and related cortical areas (Borra

et al., 2014) suggests that the SC is strongly involved in

arm and hand movements in addition to the well-known

gaze movements. The convergence of the reach-to-grasp

system (i.e., the PMv) and the reach-to-destination sys-

tem (the PMd) onto the same regions close to the gaze

system in the SC puts this structure in a unique position

to modulate reach and grasp movements in various

behavioral contexts involving eye–hand coordination.

ACKNOWLEDGMENTSWe thank E. Brockmann, S. Dobers, H. Korbmacher,

and G. Reuter for expert technical assistance. We are also

grateful to H. L€ubbert for lab space.

CONFLICT OF INTEREST STATEMENT

The authors state they have no conflicts of interest.

ROLE OF AUTHORS

All authors had full access to all the data in the

study and take responsibility for the integrity of the

data and the accuracy of the data analysis. Study con-

cept and design: KPH and CD, acquisition of data: KPH

and CD, analysis and interpretation of data: CD and

KPH, drafting of the manuscript: CD and KPH.

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