Abstract

Corticostriatal projections from the primate cortical motor areas partially overlap in different zones of a large postcommissural putaminal sector designated as “motor” putamen. These zones are at the origin of parallel basal ganglia-thalamocortical subloops involved in modulating the cortical motor output. However, it is still largely unknown how parietal and prefrontal areas, connected to premotor areas, and involved in controlling higher order aspects of motor control, project to the basal ganglia. Based on tracer injections at the cortical level, we analyzed the corticostriatal projections of the macaque hand-related ventrolateral prefrontal, ventral premotor, and inferior parietal areas forming a network for controlling purposeful hand actions (lateral grasping network). The results provided evidence for partial overlap or interweaving of these projections in correspondence of 2 putaminal zones, distinct from the motor putamen, one located just rostral to the anterior commissure, the other in the caudal and ventral part. Thus, the present data provide evidence for partial overlap or interweaving in specific striatal zones (input channels) of projections from multiple, even remote, areas taking part in a large-scale functionally specialized cortical network. Furthermore, they suggest the presence of multiple hand-related input channels, possibly differentially involved in controlling goal-directed hand actions.

Introduction

A series of connectional studies (Rozzi et al. 2006; Borra et al. 2008, 2011; Gerbella et al. 2011; Gerbella, Borra, Tonelli, et al. 2015) has provided evidence for the involvement of hand-related ventral premotor (PMv), inferior parietal lobule (IPL), and ventrolateral prefrontal (VLPF) areas in a cortical network, designated as “lateral grasping network” (Fig. 1). In this network, the IPL and PMv areas are jointly involved in visuomotor transformations for grasping and the VLPF hand-related areas (Rozzi et al. 2011) possibly contribute to selecting and organizing hand actions, based on memory-related information about object properties or identity and information on behavioral goals or behavioral guiding rules. The selected hand motor acts could be then put into action thanks to the connections of PMv area F5p with the primary motor cortex and subcortical motor centers (Borra et al. 2010).

Figure 1.

Summary view of the areas of the lateral grasping network object of the present study and of their interconnections. C, central sulcus; IA, inferior arcuate sulcus; IO, inferior occipital; IP, intraparietal sulcus; i12r, intermediate part of area 12r; L, lateral fissure; P, principal sulcus; r46vc, rostral part of ventrocaudal area 46; SA, superior arcuate sulcus; ST, superior temporal sulcus.

Figure 1.

Summary view of the areas of the lateral grasping network object of the present study and of their interconnections. C, central sulcus; IA, inferior arcuate sulcus; IO, inferior occipital; IP, intraparietal sulcus; i12r, intermediate part of area 12r; L, lateral fissure; P, principal sulcus; r46vc, rostral part of ventrocaudal area 46; SA, superior arcuate sulcus; ST, superior temporal sulcus.

Cortical control of motor behavior relies on information processing occurring not only through cortico-cortical connections, but also through the basal ganglia and cerebellar loops

As far as the basal ganglia are concerned, Alexander et al. (1986) have proposed a general model of connectional architecture in which different cortical regions project to specific striatal territories at the root of largely segregated basal ganglia-thalamocortical loops. Five major loops were originally identified, designated as “motor,” “oculomotor,” “dorsolateral prefrontal,” “lateral orbitofrontal,” and “limbic,” respectively. Subsequent studies confirmed this view and, as already suggested by Alexander et al. (1986), showed up a finer modular organization in which each main loop consists of several largely segregated closed subloops. Accordingly, each subloop originates from, and projects to, individual cortical areas or limited sets of functionally related areas and involves distinct, relatively restricted striatal zones, or “input channels” (Strick et al. 1995; Middleton and Strick 2000). Based on their cortical origin and termination, individual subloops could be then functionally distinct and their definition is thus essential for understanding the mode of information processing in the basal ganglia for different motor and nonmotor functions. In recent years, the advent of transneuronal transport of viruses has greatly contributed to clarify the organization of the basal ganglia output to the cortical level (see, e.g., Middleton and Strick 2000; Kelly and Strick 2004). However, incomplete knowledge on the distribution of the corticostriatal projections from every individual area still precludes a full description of the organization of the basal ganglia circuitry.

This appears to be the case also for the organization of the “motor” basal ganglia loop. Indeed, it is well assessed (see, e.g., Nambu 2011; Takada et al. 2013) that agranular frontal and cingulate motor areas are sources of partially overlapping projections to a large putaminal sector located caudal to the level of the anterior commissure (AC). In turn, this “motor” putaminal sector is at the root of parallel, largely segregated reentrant subloops involved in modulating the cortical motor output for controlling voluntary motor behavior (see, e.g., Middleton and Strick 2000; Kelly and Strick 2004). However, it is still largely unknown how parietal and prefrontal areas, connected to premotor areas and forming functionally specialized networks for controlling higher order aspects of motor control, project to the basal ganglia. Specifically, it is still poorly understood whether projections from these areas converge in specific striatal sectors or involve distinct striatal zones according to the general topography of the corticostriatal projections.

In the present study, we used the “lateral grasping network” as a model for addressing the issue of how signals related to higher order aspects of motor control could be conveyed through the basal ganglia circuitry. Accordingly, we examined the projections to the basal ganglia labeled after injections of anterograde tracers in the VLPF, PMv, and IPL nodes of the network. Parts of this article have been published previously in an abstract form (Gerbella, Borra, Rozzi, et al. 2013).

Methods

Subjects, Surgical Procedures, and Selection of the Injection Sites

The present study is based on results from 10 macaque monkeys (6 Macaca mulatta, 2 M. nemestrina, and 2 M. fascicularis), in which anterograde tracers were injected in VLPF, PMv, and IPL hand-related areas and in the hand field of the primary motor area F1 (Table 1). All these cases, except for the tracer injections in Case 62l have already been used in previous studies focused on the cortical (Rozzi et al. 2006; Borra et al. 2008, 2011; Gerbella et al. 2011; Gerbella, Borra, Tonelli, et al. 2013) and/or corticotectal (Borra et al. 2014) connectivity of the areas under study.

Table 1

Monkey species, localization of the injection sites, and tracers employed in the experiments

Monkey Species (MacacaLeft/right Area Tracer Amount Core sizei (mm) 
Case 13 fascicularis PFGa WGA/HRP 4% 1 × 0.1 µL 1.8 × 1 
Case 30 nemestrina AIPb BDA 10% 4 × 1 µL 4 × 1.2
4 × 0.8 
 F5ag WGA/HRP 4% 1 × 0.1 µL 2.8 × 1.4 
Case 31 nemestrina F5pc FR 10% 1 × 1 µL 3.8 × 2 
Case 34 fascicularis F5ac BDA 10% 2 × 1 µL 2 × 0.5
2.3 × 0.5 
Case 35 mulatta F5pc BDA 10% 1 × 1 µL 2.3 × 0.8 
Case 44 mulatta i12rd LYD 10%h 1 × 1 µL 1.6 × 1 
Case 52 mulatta r46vcf BDA 10% 1 × 2 µL 2 × 1 
 r46vcf LYD 10% 1 × 1.3 µL 1.8 × 1 
Case 54 mulatta PFGg FR 10% 4 × 1 µL 1.5 × 0.8
1.2 × 0.8
1.3 × 0.5
1.3 × 0.8 
 AIPg BDA 10% 4 × 1 µL 3 × 0.5
2 × 0.5 
Case 55 mulatta i12rd FR 10% 2 × 1 µL 1.5 × 1.2
1.5 × 1 
Case 62 mulatta i12r/r46vc CTBg 1% 2 × 1.2 µL 1.8 × 1.2
1.8 × 1.5 
 F5a BDA 10% 2 × 1 µL 2.5 × 1 
 F1 FR 10% 2 × 1 µL 3 × 2
3 × 1.8 
 AIP/PFG LYD 10% 3 × 1 µL 1.8 × 1
1.7 × 1
4 × 1 
Monkey Species (MacacaLeft/right Area Tracer Amount Core sizei (mm) 
Case 13 fascicularis PFGa WGA/HRP 4% 1 × 0.1 µL 1.8 × 1 
Case 30 nemestrina AIPb BDA 10% 4 × 1 µL 4 × 1.2
4 × 0.8 
 F5ag WGA/HRP 4% 1 × 0.1 µL 2.8 × 1.4 
Case 31 nemestrina F5pc FR 10% 1 × 1 µL 3.8 × 2 
Case 34 fascicularis F5ac BDA 10% 2 × 1 µL 2 × 0.5
2.3 × 0.5 
Case 35 mulatta F5pc BDA 10% 1 × 1 µL 2.3 × 0.8 
Case 44 mulatta i12rd LYD 10%h 1 × 1 µL 1.6 × 1 
Case 52 mulatta r46vcf BDA 10% 1 × 2 µL 2 × 1 
 r46vcf LYD 10% 1 × 1.3 µL 1.8 × 1 
Case 54 mulatta PFGg FR 10% 4 × 1 µL 1.5 × 0.8
1.2 × 0.8
1.3 × 0.5
1.3 × 0.8 
 AIPg BDA 10% 4 × 1 µL 3 × 0.5
2 × 0.5 
Case 55 mulatta i12rd FR 10% 2 × 1 µL 1.5 × 1.2
1.5 × 1 
Case 62 mulatta i12r/r46vc CTBg 1% 2 × 1.2 µL 1.8 × 1.2
1.8 × 1.5 
 F5a BDA 10% 2 × 1 µL 2.5 × 1 
 F1 FR 10% 2 × 1 µL 3 × 2
3 × 1.8 
 AIP/PFG LYD 10% 3 × 1 µL 1.8 × 1
1.7 × 1
4 × 1 

Cortical or corticotectal labeling described in:

hMix 1/1 of the MW 3000/10 000.

iMajor per minor axis of the core of the injection site.

Animal handling, as well as surgical and experimental procedures, complied with the European guidelines (86/609/ EEC and 2003/65/EC Directives) and Italian laws in force regarding the care and use of laboratory animals, and were approved by the Veterinarian Animal Care and Use Committee of the University of Parma and authorized by the Italian Health Ministry.

Under general anesthesia (Zoletil®, initial dose: 20 mg/kg, i.m.; supplemental: 5–7 mg/kg/h, i.m., or Ketamine, 5 mg/kg i.m. and Medetomidine, 0.08–0.1 mg/kg i.m.) and aseptic conditions, each animal was placed in a stereotaxic apparatus, and an incision was made in the scalp. The skull was trephined to remove the bone overlying the target region, and the dura was opened. The criteria for the selection of the injection sites have been described in detail in previous studies (see Table 1). Briefly, the choice of the injection sites was based on identified anatomical landmarks, that is, the principal sulcus, the infraprincipal dimple, the inferior arcuate sulcus, the central sulcus, and the intraparietal sulcus. For the tracer injections in PMv and F1, the architectonic map of Belmalih et al. (2009) was also used as frame of reference. In the IPL, the injection sites in anterior intraparietal (AIP) area were placed in the lateral bank of the intraparietal sulcus at anteroposterior (AP) stereotaxic levels between −2 and 6 (Borra et al. 2008) and those in PFG were chosen by using as frame of reference the architectonic map of Gregoriou et al. (2006) referred in terms of stereotaxic coordinates and location of anatomical landmarks such as the intraparietal sulcus and the lateral fissure. After the tracer injections were placed, the dural flap was sutured, the bone was replaced, and the superficial tissues were sutured in layers. During surgery, hydration was maintained with saline, and temperature was maintained using a heating pad. Heart rate, blood pressure, respiratory depth, and body temperature were continuously monitored. Upon recovery from anesthesia, the animals were returned to their home cages and closely monitored. Prophylactic broad-spectrum antibiotics (Ceftriaxone 80 mg/kg i.m.), cortisonics (Dexamethasone 2 mg, i.m.), and analgesics (Ketoprofen, 5 mg/kg, i.m.) were administered intra- and postoperatively for up to 1 week.

Tracer Injections and Histological Procedures

Once the appropriate site was chosen, biotinylated dextran amine ([BDA] 10 000 molecular weight [MW], 10% 0.1 M phosphate buffer, pH 7.4; Life Technologies, Eugene, OR, USA), dextran conjugated with tetramethylrhodamine (Fluoro-Ruby [FR], 10 000 MW, or equal mixture of 10 000 and 3000 MW volumes, 10% 0.1 M phosphate buffer, pH 7.4; Life Technologies) or with lucifer yellow (Lucifer Yellow Dextrane [LYD], 10 000 MW, 10% in 0.1 M phosphate buffer, pH 7.4; Life Technologies), Cholera Toxin B subunit, conjugated with Alexa 488 (CTB green, CTBg 1% in 0.01 M phosphate buffered saline at pH 7.4, Life Technologies) and wheat germ agglutinin-horseradish peroxidase conjugated (WGA–HRP, 4% in distilled water, Sigma, St Louis, MO, USA) were slowly pressure-injected through a glass micropipette (tip diameter: 50–100 µm) attached to a 1- or 5-µL Hamilton microsyringe (Reno, NV, USA). Table 1 summarizes the locations of the injections, the injected tracers, and their amounts.

After appropriate periods following the injections (21–28 days for BDA, FR, LYD, and CTBg and 2 days for WGA–HRP), each animal was deeply anesthetized with an overdose of sodium thiopental and perfused consecutively with saline, 3.5–4% paraformaldehyde, and 5% glycerol, prepared in 0.1 M phosphate buffer, pH 7.4, through the left cardiac ventricle. Each brain was then blocked coronally on a stereotaxic apparatus, removed from the skull, photographed, and placed in 10% buffered glycerol for 3 days and 20% buffered glycerol for 4 days. Finally, all brains were cut frozen into coronal sections of 60-µm thickness, except for Case 62, cut into coronal sections of 50-µm thickness. As in all the subjects, except Case 62, the controlateral hemisphere was used for injecting retrograde fluorescent tracers, for technical reasons, after cutting, the 2 hemispheres were separated and only the sections through the ipsilateral hemisphere were processed for the visualization of the BDA, FR, and LYD labeling.

In all cases of BDA injections, one series of each fifth section (each sixth section in Case 62) was processed to visualize BDA (incubation 60 h), using a Vectastain ABC kit (Vector Laboratories, Burlingame, CA, USA) and 3,3′-diaminobenzidine (DAB) as a chromogen. The reaction product was intensified with cobalt chloride and nickel ammonium sulfate. In all cases of FR, LYD, CTBg injections, in which BDA was also injected in areas under study or in other cortical areas, one series of each fifth section (each sixth section in Case 62) was processed to visualize FR and BDA, or LYD and BDA, or CTBg and BDA using the double-labeling protocol described in detail in Gerbella et al. (2010). Briefly, the sections were first processed to visualize BDA, with a shorter (i.e., overnight) incubation period in the ABC solution, and BDA was then stained brown using DAB. The sections were then incubated overnight in avidin–biotin blocking reagent (Vector SP-2001), for 72 h at 4 °C in a primary antibody solution of rabbit anti-FR or rabbit anti-LY (1:3000; Life Technologies) in 0.3% Triton, or anti-Alexa 488 (1:15 000, Life Technologies), 5% normal goat serum in PBS, and for 1 h in biotinylated secondary antibody (1:200, Vector) in 0.3% Triton, 5% normal goat serum in PBS. Finally, FR or LYD or CTBg labeling was visualized using the Vectastain ABC kit (Vector Laboratories) and the Vector SG peroxidase substrate kit (SK-4700, Vector) as a chromogen. With this procedure, BDA labeling was stained brown, and the FR or the LYD or the CTBg labeling was stained blue in the same tissue sections. However, in this material, the BDA labeling, because of the shorter incubation period, was less dense than that observed using the standard 60-h incubation period. In Cases 13r and 30l, one series of each fifth section was processed for HRP histochemistry following the protocol described by Mesulam (1982). Sections were rinsed in 0.01 M acetate buffer, pH 3.3, and developed at 4°C in an acetate buffer solution, 0.09% sodium ferricyanide, using tetramethylbenzidine as chromogen. In all cases, one series of each fifth section (each sixth section in Case 62) was stained with the Nissl method (0.1% thionin in 0.1 M acetate buffer, pH 3.7).

Data Analysis

The distribution of the anterograde labeling in the ipsilateral basal ganglia was analyzed in sections every 300 µm in all the cases, except for Case 62 in which the analysis was extended to the contralateral side.

The projection fields in the basal ganglia were typically organized in patches of very dense labeled terminals, surrounded by less densely labeled zones, designated as “focal” and “diffuse” projections, respectively, by Haber et al. (2006). The extent of the observed terminal fields and the density of labeled terminals varied across cases, even after injections in the same cortical area. This variability could be accounted for by several factors, intrinsic to the tract-tracing experimental approach (e.g., differences in amount, spread, and sensitivity of injected tracers), thus precluding any reliable quantitative comparison between the projections originating from the various studied areas.

In the cases of BDA, FR, LYD, and CTBg injections, focal projections were clearly visible even at relatively low magnification under bright field illumination (Fig. 2C,D). In these cases, to obtain faithful reproductions of the labeling distribution, as in other studies (e.g., Parthasarathy et al. 1992; Calzavara et al. 2007; Borra et al. 2015), the distribution of the observed projection fields was visualized by extracting the labeling from digitalized photographs taken with a ×10 objective (Fig. 2A,B). Specifically, using Adobe Photoshop (Adobe Systems Incorporated, San Jose, CA, USA), in each image, the outlines of the basal ganglia and of adjacent structures were delineated on a separate layer. Then, striatal projection fields were selected and converted into a black-and-white images applying a threshold appropriate to extract the labeling, stained in black or blue, from the lighter background and, in the cases of FR-, LYD-, or CTBg-labeled fields, from the brown BDA labeling when present. Comparison with the original image ensured that the labeling was accurately extracted and no false positives were included in the image. In Case 62l, to compare the distribution of the FR, LYD, BDA, and CTBg projection fields visualized in adjacent sections, focal projections were delineated in each section and their outlines superimposed on a single section, using the borders of the striatal structures and blood vessels for the alignment. In the cases of WGA–HRP injections, in which the labeling was best visualized under dark field illumination, the presence of sparse artifacts and uneven brightness of the tissue precluded reliable extraction of the projections fields with image processing. Accordingly, focal and diffuse projections were plotted qualitatively, together with the outlines of the basal ganglia and of adjacent structures, using a computer-based charting system.

Figure 2.

(A) Low-power view of a digitalized photomicrograph, taken with a ×10 objective, showing the distribution of the striatal anterograde labeling at about 1.8 mm rostral to the AC in Case 34l BDA. Dashed boxes indicate the location of the higher magnification views shown in (C) and (D). (B) Same image as in (A) after the delineation of the outlines of the nuclear structures and extraction of the labeling using Adobe Photoshop as described in Materials and Methods section. (C and D) Higher magnification views of patches of dense labeled terminals (focal projections), relatively sharply demarcated from surrounding zones in which labeled terminals were sparser (diffuse projections), taken from the section shown in (A). Scale bar in (A) applies also to (B). Scale bar in (C) applies also to (D). Cd, caudate nucleus; ic, internal capsule; Put, putamen.

Figure 2.

(A) Low-power view of a digitalized photomicrograph, taken with a ×10 objective, showing the distribution of the striatal anterograde labeling at about 1.8 mm rostral to the AC in Case 34l BDA. Dashed boxes indicate the location of the higher magnification views shown in (C) and (D). (B) Same image as in (A) after the delineation of the outlines of the nuclear structures and extraction of the labeling using Adobe Photoshop as described in Materials and Methods section. (C and D) Higher magnification views of patches of dense labeled terminals (focal projections), relatively sharply demarcated from surrounding zones in which labeled terminals were sparser (diffuse projections), taken from the section shown in (A). Scale bar in (A) applies also to (B). Scale bar in (C) applies also to (D). Cd, caudate nucleus; ic, internal capsule; Put, putamen.

Data from individual sections, including outlines of the striatal structures and of the focal projections, were also imported into 3D reconstruction software (Bettio et al. 2001), providing volumetric reconstructions of the striatum. The distribution in the putamen of the focal projections was then visualized for each individual case in the lateral views of the 3D reconstructions. In these views, the caudate labeling was not visualized, as it was not possible to distinguish it from the putaminal one. Furthermore, as putaminal focal projections typically tended to be organized in an oblique band running from the dorsomedial to the ventrolateral direction, 3D reconstructions were sectioned obliquely as follows (Fig. 3). First, in Case 34l, in which at the level of the AC the labeling was particularly rich and organized into an almost continuous band, a 2-mm-thick oblique slice was sectioned from the 3D reconstruction to include its entire extent. The plan of this section intersected the midline at 13 mm above the upper border of the AC with an angle of 35°. These same parameters were then used to obtain oblique slice from the 3D reconstructions of all the other cases to visualize the distribution of the focal projections at an as far as possible comparable level of the striatum. In Case 62l, 1-mm-thick horizontal sections were also obtained from the 3D reconstruction to visualize the distribution of the various focal projections fields at different dorso-ventral levels. Finally, to obtain composite views of the overall distribution of the focal projections observed after all the tracer injections in a given region, data from coronal and oblique sections taken from every individual case were warped to template sections by using Adobe Photoshop. As the sections taken at the same level from different cases were very similar, the distortions caused by this warping procedure were generally quite small.

Figure 3.

Sectioning procedure of the 3D reconstructions of the striatum. Based on the distribution of the labeling, a 2-mm-thick plane was first sectioned from the 3D reconstruction of Case 34l (upper part of the figure). The lower part of the figure shows the position of this plane in the striatum at 3 different rostrocaudal levels indicated in the re-sliced section in the upper right part of the figure. At the level of the AC (lower left), this plane intersects the midline at 13 mm above the upper border of the AC with an angle of 35°. These same parameters were then used to obtain similar oblique slices from the 3D reconstructions of all the other cases. For the sake of comparison, all the striatum reconstructions and sections in this and subsequent figures are shown as right. AC, anterior commissure; GPe, external globus pallidus; GPi, internal globus pallidus; LV, Lateral Ventricle. Other abbreviations as in Figure 2.

Figure 3.

Sectioning procedure of the 3D reconstructions of the striatum. Based on the distribution of the labeling, a 2-mm-thick plane was first sectioned from the 3D reconstruction of Case 34l (upper part of the figure). The lower part of the figure shows the position of this plane in the striatum at 3 different rostrocaudal levels indicated in the re-sliced section in the upper right part of the figure. At the level of the AC (lower left), this plane intersects the midline at 13 mm above the upper border of the AC with an angle of 35°. These same parameters were then used to obtain similar oblique slices from the 3D reconstructions of all the other cases. For the sake of comparison, all the striatum reconstructions and sections in this and subsequent figures are shown as right. AC, anterior commissure; GPe, external globus pallidus; GPi, internal globus pallidus; LV, Lateral Ventricle. Other abbreviations as in Figure 2.

Results

The upper part of Figure 4 shows a composite view of the location of the injection sites placed in the hand-related VLPF, PMv, and IPL areas taking part in the lateral grasping network in all the cases except Case 62, shown in the lower part. Photomicrographs of representative injection sites are shown in Supplementary Figure 1. In the VLPF, 2 injection sites involved each of the 2 hand-related sectors (Rozzi et al. 2011), located in the rostral part of ventrocaudal area 46 (r46vc) and in the intermediate part of area 12r (i12r), respectively, which display consistent connections with areas F5a and AIP and, for r46vc, also area PFG (Borra et al. 2011; Gerbella, Borra, Tonelli, et al. 2013). In the PMv, 2 injections involved area F5a, a visuomotor hand-related field (Theys et al. 2012) tightly connected to F5p and displaying consistent connections with r46vc, i12r, and with the IPL areas AIP and PFG (Gerbella et al. 2011). Two other tracer injections were placed in area F5p, a visuomotor hand-related area (Raos et al. 2006) connected to F5a, AIP, PFG, and to the hand field of the primary motor area F1 (Gerbella et al. 2011) and source of corticospinal projections (He et al. 1993; Borra et al. 2010). In the IPL, 2 tracer injections involved PFG, a visuomotor hand-related area (Rozzi et al. 2008) consistently connected to F5p, F5a, and r46vc (Rozzi et al. 2006). Two other tracer injections involved AIP, a visuomotor hand-related area (Murata et al. 2000) consistently connected to F5p, F5a, r46vc, and i12r (Borra et al. 2008). In Case 62l, the CTBg and the LYD injections involved both the 2 VLPF and the 2 IPL hand-related areas, respectively, and the BDA injection was confined to area F5a. Finally, the FR injection was placed in the location of the hand field of area F1. The distribution of the cortico-cortical labeling observed in this case was fully congruent with that expected based on our previous studies (Rozzi et al. 2006; Borra et al. 2008, 2011; Gerbella et al. 2011; ,Gerbella, Borra, Tonelli, et al. 2013) and from studies of the M1 connectivity (e.g., Muakkassa and Strick 1979). Specifically, the rich retro-anterograde labeling observed in F5p, confirmed the involvement of the M1 hand field by the injection site (Borra et al. 2010).

Figure 4.

Location of injection sites. Upper part: composite view of all the injection sites mapped on a template right hemisphere, except for those in Case 62. Each injection site is numbered and reported, based on anatomical landmarks and stereotaxic coordinates, in the inferior parietal lobule (A), in the posterior bank of the arcuate sulcus (B), and in the ventrolateral prefrontal cortex (C). Arrows indicate the location of the injections sites in anterior intraparietal (AIP) in the lateral bank of the inferior parietal sulcus and in r46vc in the ventral bank of PS. Arrowheads in (A) indicate the rostrocaudal extent of area AIP, which does not extend on the lateral surface. Lower part: location of the injection sites in Cases 62l (shown as a right hemisphere) shown on dorsolateral views of the injected hemisphere and in coronal sections through the core (shown in black) and the halo (shown in lighter grey). Cg, cingulate sulcus; LO, lateral orbital sulcus; Lu, lunate sulcus; MO, medial orbital sulcus. Other abbreviations as in Figure 1. Scale bar in (A) applies also to (BC). Scale bar in (a) applies also to (bf).

Figure 4.

Location of injection sites. Upper part: composite view of all the injection sites mapped on a template right hemisphere, except for those in Case 62. Each injection site is numbered and reported, based on anatomical landmarks and stereotaxic coordinates, in the inferior parietal lobule (A), in the posterior bank of the arcuate sulcus (B), and in the ventrolateral prefrontal cortex (C). Arrows indicate the location of the injections sites in anterior intraparietal (AIP) in the lateral bank of the inferior parietal sulcus and in r46vc in the ventral bank of PS. Arrowheads in (A) indicate the rostrocaudal extent of area AIP, which does not extend on the lateral surface. Lower part: location of the injection sites in Cases 62l (shown as a right hemisphere) shown on dorsolateral views of the injected hemisphere and in coronal sections through the core (shown in black) and the halo (shown in lighter grey). Cg, cingulate sulcus; LO, lateral orbital sulcus; Lu, lunate sulcus; MO, medial orbital sulcus. Other abbreviations as in Figure 1. Scale bar in (A) applies also to (BC). Scale bar in (a) applies also to (bf).

Corticostriatal Projections from the Lateral Grasping Network

All the studied areas were sources of corticostriatal projections. In general, as described in other studies (e.g., Haber et al. 2006; Calzavara et al. 2007) terminal fields typically consisted of largely distinct patches of dense labeled terminals (focal projections), often surrounded by irregularly shaped zones in which labeled terminals were much sparser (diffuse projections). The extent of the observed terminal fields and the density of labeled terminals varied across cases, even after injections in the same cortical area.

The distribution of the striatal terminal fields observed in all the cases of tracer injections in each studied area is shown in Figures 5–7 and in Supplementary Figures 2–4. The distribution of the putaminal focal projections is also shown in lateral views of the 3D reconstructions of the striatum in Figure 8 and Supplementary Figure 5. As it will be described in detail below, the topography of the observed striatal terminal fields, in general, varied mostly according to the injected region. In contrast, in spite of some differences in the extent and density of the labeling observed across cases, it tended to be very similar for each pair of areas belonging to the same region.

Figure 5.

Drawings of coronal sections through the striatum showing the distribution of the anterograde labeling observed in Case 44r after the LYD injection in i12r (upper part) and in Case 52r after the BDA injection in r46vc (lower part). The sections are shown in a rostral to caudal order (af and a′–f′) and their AP level is indicated in terms of distance in mm from the AC. Scale bar in a applies also to (bf) and to (a′–f′). Abbreviations as in Figures 1–4.

Figure 5.

Drawings of coronal sections through the striatum showing the distribution of the anterograde labeling observed in Case 44r after the LYD injection in i12r (upper part) and in Case 52r after the BDA injection in r46vc (lower part). The sections are shown in a rostral to caudal order (af and a′–f′) and their AP level is indicated in terms of distance in mm from the AC. Scale bar in a applies also to (bf) and to (a′–f′). Abbreviations as in Figures 1–4.

Figure 6.

Drawings of coronal sections through the striatum showing the distribution of the anterograde labeling observed in Case 34l after the BDA injection in F5a (upper part) and in Case 31l after FR injection in F5p (lower part). Conventions and abbreviations as in Figures 1–5.

Figure 6.

Drawings of coronal sections through the striatum showing the distribution of the anterograde labeling observed in Case 34l after the BDA injection in F5a (upper part) and in Case 31l after FR injection in F5p (lower part). Conventions and abbreviations as in Figures 1–5.

Figure 7.

Drawings of coronal sections through the striatum showing the distribution of the anterograde labeling observed in Case 30l after the BDA injection in AIP (upper part) and in Case 54r after FR injection in PFG (lower part). Conventions and abbreviations as in Figures 1–5.

Figure 7.

Drawings of coronal sections through the striatum showing the distribution of the anterograde labeling observed in Case 30l after the BDA injection in AIP (upper part) and in Case 54r after FR injection in PFG (lower part). Conventions and abbreviations as in Figures 1–5.

Figure 8.

Distribution of the focal projections (indicated by shaded areas) observed in the putamen after tracer injections in the hand-related VLPF (upper part), PMv (middle part), and in IPL (lower part) areas shown in lateral views of the 3D reconstructions of the striatum. In each reconstruction the arrow marks the AP level of the AC and the dashed lines indicate the level of the sections showed in Figures 5 (VLPF injections), 6 (PMv injections), and 7 (IPL injections). Scale bar in upper left part applies to all the 3D reconstructions. Abbreviations as in Figures 2 and 3.

Figure 8.

Distribution of the focal projections (indicated by shaded areas) observed in the putamen after tracer injections in the hand-related VLPF (upper part), PMv (middle part), and in IPL (lower part) areas shown in lateral views of the 3D reconstructions of the striatum. In each reconstruction the arrow marks the AP level of the AC and the dashed lines indicate the level of the sections showed in Figures 5 (VLPF injections), 6 (PMv injections), and 7 (IPL injections). Scale bar in upper left part applies to all the 3D reconstructions. Abbreviations as in Figures 2 and 3.

After the injections in r46vc or i12r, terminal fields were observed in both the putamen and the caudate. In the putamen, in all the cases, most of the labeling was located in a sector extending in rostrocaudal direction from about 1 mm caudal to about 3–4 mm rostral to the level of the AC (sections ad and a′–d′ in Fig. 5 and Supplementary Fig. 2; upper part of Fig. 8 and Supplementary Fig. 5). At this level, several, relatively small patches of focal projections tended to distribute within a slab of putaminal tissue, running obliquely from the dorsomedial to the ventrolateral direction. Within this zone, focal projections varied in their location across cases, even after tracer injections in the same area, but tended to involve more constantly the ventrolateral part, at about 1.5–3 mm rostral to the AC. After the injections in r46vc, patches of focal projections were observed also at more rostral levels of the putamen. More caudally, the putamen was virtually devoid of labeling, except for a caudal and ventral relatively restricted zone in which focal projections were observed in all the cases (sections f and f′ in Fig. 5 and Supplementary Fig. 2; upper part of Fig. 8 and Supplementary Fig. 5). This zone extended in rostrocaudal direction from about 5 mm to about 8 mm caudal to the AC. In the caudate, most of the labeling was located in a sector extending in rostrocaudal direction from about 1 mm caudal to about 3–4 mm rostral to the AC (sections ad and a′–d′ in Fig. 5 and Supplementary Fig. 2). In this caudate sector, focal projections tended to be located in the lateral part, in some cases invading the bridge of striatal tissue connecting the caudate to the putamen.

After the injections in the PMv areas F5a or F5p, most of the labeling was located in the putamen, which was extensively involved from about 3 mm rostral to the AC up to its caudalmost part (middle part of Fig. 8 and Supplementary Fig. 5). However, in Case 31l FR, the striatal labeling was more extensive and richer than that observed in Case 35r BDA even though the injection sites involved approximately the same portion of area F5p. This difference, at least in part, could be accounted for by the relatively larger size of the injection site in Case 31l FR, which involved a wider portion of the postarcuate bank than in Case 35r BDA (Table 1). In all the cases, more rostrally, focal projections tended to mostly distribute along an oblique slab of putaminal tissue that appeared to largely correspond to that observed after the VLPF injections (sections ad and a′–d′ in Fig. 6 and Supplementary Fig. 3). In Cases 34l BDA and 31l FR, in which the overall striatal labeling was especially dense, this zone was extensively involved by largely confluent focal projections. Caudal to the AC, the focal projections extended almost continuously in the location of the forelimb representation of the motor putamen up to the caudal end in the case of those from F5p (sections e, e′, and f′ in Fig. 6 and Supplementary Fig. 3). Some variability was observed across cases in the mediolateral distribution of the focal projections in this putaminal zone. While in all the cases, the medial part was constantly labeled, much more variable was the involvement of the lateral part. After the injections in F5a, but not after those in F5p, focal projections were also observed in a caudal and ventral part of the putamen (sections e and f in Fig. 6 and Supplementary Fig. 3). This labeled zone appeared to occupy a location very similar to that observed after the VLPF injections, though more extended in rostrocaudal direction (middle part of Fig. 8 and Supplementary Fig. 5). After tracer injections in F5p, the labeling in the caudate was very poor whereas, after tracer injections in F5a, some small patches of focal projections were observed in a location very similar to that of the projections observed after the tracer injections in VLPF (sections ad and a′–d′ in Fig. 6 and Supplementary Fig. 3).

After the tracer injections in PFG or AIP, the distribution of the labeling was very similar across cases, though more extensive in Case 13r WGA–HRP (PFG injection), possibly because of differences in uptake and transport of the tracer used in this case. In all cases, virtually all the labeling was located in the putamen, mostly involving 2 distinct zones (lower part of Fig. 8 and Supplementary Fig. 5). One more rostral zone extended from about 1 mm caudal to 3–4 mm rostral to the AC (sections ad and a′–d′ in Fig. 7 and Supplementary Fig. 4) and appeared to largely correspond to the rostral putaminal zone labeled after the injections in VLPF or PMv areas. However, after the injections in PFG some patches of focal projections were observed also at more rostral levels. The second zone appeared to partially involve the same caudal and ventral part of the putamen labeled after the tracer injections in the VLPF or F5a (sections f and f′ in Fig. 7 and Supplementary Fig. 4). Few, small patches of focal projections were inconstantly observed in the medialmost part of the motor putamen and in the lateralmost part of the caudate body, caudal to the level of the AC.

To look for possible additional evidence for the involvement of specific striatal zones by projections from all, or almost all, the areas under study, oblique sections were re-sliced from the 3D reconstructions of the striatum in all the cases at approximately the same level. These sections (Fig. 9 and Supplementary Fig. 6) were quite useful in showing that an obliquely oriented putaminal zone, located mostly just rostral the AC and extending for about 4–5 mm in rostrocaudal direction, was a target of focal projections from all the areas under study. These projections tended, with variability across cases, to be scattered along the entire mediolateral extent of the putamen, though more constantly located in the more lateral (and ventral) part. Furthermore, these sections showed that the focal projections observed in the caudal and ventral part of the putamen in all the cases, except for those of tracer injections in F5p, appeared to share a common, relatively restricted zone located at about 5–8 mm caudal to the AC. All together, these data suggested overlap or, at least, interweaving of the striatal projections from the various nodes of the lateral grasping network into at least 2 distinct putaminal zones. These 2 zones will be here referred to as rostral and caudal lateral grasping network input channel, respectively.

Figure 9.

Distribution of the striatal focal projections observed after tracer injections in the hand-related VLPF (upper part), PMv (middle part), and in IPL (lower part) areas shown in 2-mm-thick oblique sections re-sliced from the 3D reconstruction at the level shown in Figure 3. Conventions and abbreviations as in Figures 2, 3, and 8.

Figure 9.

Distribution of the striatal focal projections observed after tracer injections in the hand-related VLPF (upper part), PMv (middle part), and in IPL (lower part) areas shown in 2-mm-thick oblique sections re-sliced from the 3D reconstruction at the level shown in Figure 3. Conventions and abbreviations as in Figures 2, 3, and 8.

To obtain more direct evidence for these observations, resulting from comparison of different cases, in Case 62 3 different anterograde tracers were injected in the VLPF and IPL hand-related regions and in the PMv area F5a, respectively. In general, the results from this case (Figs 10 and 11) were quite comparable with those described above, obtained after tracer injections in individual areas. Furthermore, the superimposition of the focal projections delineated in adjacent coronal sections (Fig. 10, upper part), or in the same horizontal or oblique (Fig. 10, lower part) sections re-sliced from the 3D reconstruction provided clear evidence for both overlapping and interweaving of the striatal VLPF, PMv, and IPL projections in both the rostral and the caudal lateral grasping network input channels (see also Fig. 12). In the caudate, as expected from the results obtained after tracer injections in individual areas, the VLPF focal projections were the most extensive. Several spots of PMv focal projections were also observed in the lateral part of the caudate body, which in part overlapped with the VLPF projections (Fig. 10, coronal sections b and c, and horizontal section a′). Finally, a small spot of IPL focal projections at about the level of the AC overlapped with those from VLPF and PMv.

Figure 10.

Distribution of the striatal focal projections observed in Case 62l after tracer injections in hand-related VLPF and IPL regions (green and blue lines, respectively), in area F5a (red lines), and in the hand field of the primary motor area F1 (yellow lines), shown in coronal sections and in 1-mm-thick horizontal sections and a 2-mm-thick oblique section re-sliced from the 3D reconstruction. The horizontal sections are shown in dorsal to ventral order (a′–c′). The level at which the coronal and horizontal sections were taken is indicated in the 3D reconstruction in the right lower part. Abbreviations as in Figures 2 and 3.

Figure 10.

Distribution of the striatal focal projections observed in Case 62l after tracer injections in hand-related VLPF and IPL regions (green and blue lines, respectively), in area F5a (red lines), and in the hand field of the primary motor area F1 (yellow lines), shown in coronal sections and in 1-mm-thick horizontal sections and a 2-mm-thick oblique section re-sliced from the 3D reconstruction. The horizontal sections are shown in dorsal to ventral order (a′–c′). The level at which the coronal and horizontal sections were taken is indicated in the 3D reconstruction in the right lower part. Abbreviations as in Figures 2 and 3.

Figure 11.

Distribution of the focal projections observed in Case 62l after tracer injections in hand-related VLPF and IPL regions, in PMv area F5a, and in primary motor area F1 shown in lateral views of the 3D reconstruction of the striatum. Other conventions and abbreviations as in Figures 2, 3, and 8.

Figure 11.

Distribution of the focal projections observed in Case 62l after tracer injections in hand-related VLPF and IPL regions, in PMv area F5a, and in primary motor area F1 shown in lateral views of the 3D reconstruction of the striatum. Other conventions and abbreviations as in Figures 2, 3, and 8.

Figure 12.

(AF) Low-power photomicrographs showing the distribution of striatal anterograde labeling observed in Case 62l after tracer injections in hand-related VLPF region (A and D), in PMv area F5a (B and E), and in hand-related IPL region (C and F). Sections AC are adjacent and correspond to an AP level 3.3 mm rostral to the AC. Sections D–F are adjacent and correspond to an AP level 6.3 mm caudal to the AC. (A–F′) Higher magnification views, taken from the sections shown in (A–F). Arrows point to the same blood vessel. In the left and right panels, the labeling was visualized with a double-labeling protocol (see Materials and Methods) in which the CTBg (in A, A, D, and D′) and the LYD (in C, C′, F, and F′) labeling was stained blue and the BDA labeling was stained brown. In the middle panels (B, B′, E, and E′), the BDA labeling was visualized with the much more sensitive standard protocol. Scale bar in (A) applies also to (B–F). Scale bar in (A′) applies also to (B′–F′). Abbreviations as in Figures 2 and 3.

Figure 12.

(AF) Low-power photomicrographs showing the distribution of striatal anterograde labeling observed in Case 62l after tracer injections in hand-related VLPF region (A and D), in PMv area F5a (B and E), and in hand-related IPL region (C and F). Sections AC are adjacent and correspond to an AP level 3.3 mm rostral to the AC. Sections D–F are adjacent and correspond to an AP level 6.3 mm caudal to the AC. (A–F′) Higher magnification views, taken from the sections shown in (A–F). Arrows point to the same blood vessel. In the left and right panels, the labeling was visualized with a double-labeling protocol (see Materials and Methods) in which the CTBg (in A, A, D, and D′) and the LYD (in C, C′, F, and F′) labeling was stained blue and the BDA labeling was stained brown. In the middle panels (B, B′, E, and E′), the BDA labeling was visualized with the much more sensitive standard protocol. Scale bar in (A) applies also to (B–F). Scale bar in (A′) applies also to (B′–F′). Abbreviations as in Figures 2 and 3.

In this same case, a fourth anterograde tracer was injected in the hand field of M1. In agreement with previous studies (Strick et al. 1995; Inase et al. 1996; Takada et al. 1998), M1 striatal projection fields were limited to the intermediate-lateral part of the putamen caudal to the AC, corresponding to the hand representation of the motor putamen (Figs 10 and 11).

Case 62 was the only case of the present study in which it was possible to look also for projections in the contralateral striatum. Striatal projections were observed after all the tracer injections, but, compared with those observed in the ipsilateral side, were considerably weaker, mostly consisting of few, relatively small patches of labeled terminals located in striatal territories substantially corresponding to those labeled in the ipsilateral side.

Cortico-subthalamic Projections from the Lateral Grasping Network

In all the cases of the present study, anterogradely labeled terminals were also observed in the subthalamic nucleus. However, these projections compared with those observed in the striatum, were considerably weaker. Specifically, relatively dense clusters of labeled terminals were observed only after the tracer injections in PMv areas F5a and F5p and after the tracer injection in F1 (Fig. 13). In agreement with previous observations (Monakow et al. 1978; Nambu et al. 1996), projections from M1, tended to involve mostly the dorsolateral part of the subthalamic nucleus. More diffuse was the labeling observed after the injections in F5a and F5p. After injections in VLPF and IPL areas, only very sparse terminals, mostly located in the midventral part of the subthalamic nucleus, were observed. The paucity of labeling observed after the VLPF injections is in line with data of Monakow et al. (1978).

Figure 13.

Drawings of coronal sections through the subthalamic nucleus showing the distribution of the anterograde labeling observed in Case 34l after the BDA injection in F5a, in Case 35r after BDA injection in F5p, and in Case 62l after the FR injections in F1. For each case, the AP level is indicated in terms of distance in mm from the AC. Small arrows point to the field shown in the photomicrographs in the lower part of the figure.

Figure 13.

Drawings of coronal sections through the subthalamic nucleus showing the distribution of the anterograde labeling observed in Case 34l after the BDA injection in F5a, in Case 35r after BDA injection in F5p, and in Case 62l after the FR injections in F1. For each case, the AP level is indicated in terms of distance in mm from the AC. Small arrows point to the field shown in the photomicrographs in the lower part of the figure.

Discussion

The present study provides evidence for partial overlap and interweaving of corticostriatal projections from the VLPF, PMv, and IPL hand-related areas of the lateral grasping network in correspondence of 2 putaminal zones, located at different rostrocaudal levels and distinct from the hand-related zones of the motor putamen. These 2 zones have been referred in the present study to as rostral and caudal lateral grasping network input channel (Fig. 14). The rostral lateral grasping network input channel occupies a slab of putaminal tissue, running obliquely from the dorsomedial to the ventrolateral direction in the midventral part of the putamen and extending from about 4 mm rostral to about 1 mm caudal to the AC. This zone was consistently involved by focal projections originating from all the areas of the lateral grasping network object of present study. The caudal lateral grasping network input channel occupies a caudal and ventral putaminal zone extending from about 5 mm to about 8 mm caudal to the AC. This zone was consistently involved by focal projections originating from all the areas of the lateral grasping network of the present study, except for F5p.

Figure 14.

Composite views of the distribution of the striatal focal projections from VLPF (green lines), PMv (red lines), and IPL (blue lines) hand-related areas obtained by warping the focal projections observed in each individual case to template 1-mm-thick coronal and 2-mm-thick oblique sections. The sections were taken at the levels indicated in the 3D reconstructions of the striatum shown in the right part of the figure. Overlap of the focal projections from 3 and 2 regions is shown in darker and lighter orange, respectively. In the upper part, arrows indicate the sources of projections, identified in the present study, to the 2 input channels. Dashed arrows indicate possible additional source of projections, based on other studies (Yeterian and Pandya 1993; Webster et al. 1993; Cheng et al. 1997). Abbreviations as in Figures 2 and 3.

Figure 14.

Composite views of the distribution of the striatal focal projections from VLPF (green lines), PMv (red lines), and IPL (blue lines) hand-related areas obtained by warping the focal projections observed in each individual case to template 1-mm-thick coronal and 2-mm-thick oblique sections. The sections were taken at the levels indicated in the 3D reconstructions of the striatum shown in the right part of the figure. Overlap of the focal projections from 3 and 2 regions is shown in darker and lighter orange, respectively. In the upper part, arrows indicate the sources of projections, identified in the present study, to the 2 input channels. Dashed arrows indicate possible additional source of projections, based on other studies (Yeterian and Pandya 1993; Webster et al. 1993; Cheng et al. 1997). Abbreviations as in Figures 2 and 3.

Organization of the Corticostriatal Projections and Input Channels in the Motor Putamen

Cortical projections are the major source of input to the basal ganglia. As these projections represents the first step in the transposition of the functional cortical map onto this structure, detailed knowledge of their organization is fundamental for determining the nature of the information that is conveyed and integrated through the various basal ganglia-thalamocortical loops.

Virtually all cortical areas project to the striatum and their terminal fields are typically heterogeneous, consisting of dense patches of terminals surrounded by more sparse terminals, which in the frontal plane tend to form diagonal band (see, e.g., Selemon and Goldman-Rakic 1985; Parent and Hazrati 1995).

Early studies, based on fiber degeneration techniques, described a topographic organization of corticostriatal projections in which each cortical area projects to its nearest part of the striatum (Kemp and Powell 1970). Subsequent studies, based on anterograde neural tracers, showed that corticostriatal projections are much more extensive in the anteroposterior dimension (Goldman and Nauta 1977; Yeterian and Van Hoesen 1978; Van Hoesen et al. 1981). Furthermore, Yeterian and Van Hoesen (1978) first proposed that cortical areas having reciprocal cortico-cortical connections share common zones of termination in the striatum. Indeed, evidence from dual-tracer experiments showed overlap of terminal fields from tightly or even relatively weakly connected areas (e.g., Parthasarathy et al. 1992; Flaherty and Graybiel 1993). However, overlap of cortical terminal fields in the striatum cannot be predicted simply based on cortical connectivity patterns, as in some cases terminal fields from interconnected areas are simply interdigitated or even segregated (e.g., Selemon and Goldman-Rakic 1985). Based on a large number of tracer injections in different prefrontal (orbitofrontal, ventromedial, and dorsolateral), rostral cingulate, and dorsal premotor (PMd) areas, Haber et al. (2006) and Calzavara et al. (2007) observed, mostly in the rostral part of the caudate, interweaving and convergence of focal projections from areas of the same or even of different (e.g., rostral PMd and area 9) domains, providing an anatomical substrate for integration between different processing circuits (see Haber 2010). Furthermore, diffuse projections from one area could overlap with focal projections of another area, providing an anatomical substrate for modulation of signals broadcasted by focal projections (see Haber 2010).

Accordingly, based on the organization of corticostriatal projections, different striatal zones, or input channels (Strick et al. 1995), can be specified by convergence of specific subsets of cortical inputs reflecting the parallel output organization of the striatum (Parthasarathy et al. 1992; Middleton and Strick 2000).

These general principles apply also to the organization of the corticostriatal projections from the various corticospinal frontal and cingulate motor areas to the motor putamen. Specifically, projection fields from M1 and the supplementary motor area (SMA), which are tightly interconnected, are largely segregated, at least in their focal projections, involving mostly the lateral and the medial part of the motor putamen, respectively (Strick et al. 1995; Inase et al. 1996; Takada et al. 1998). However, projections from PMv and PMd cortex, though segregated, appear to partially overlap with those from the SMA (Takada et al. 1998). Furthermore, the projections from the caudal cingulate motor area appear to partially overlap with those from M1 (Takada et al. 2001). Altogether, these data suggest that in the motor putamen there are different input channels specified by convergence of specific subsets of motor areas. In agreement with these observations, the present study showed extensive focal projections in the motor putamen after tracer injections in the 2 PMv areas F5p and F5a. These focal projections, as previously observed by Takada et al. (1998), were located mostly in the medial part of the putamen, which corresponds to the location of the SMA projection field (Strick et al. 1995; Inase et al. 1996; Takada et al. 1998). Furthermore, they were also observed more laterally and ventrally, in a location that is ventral to the M1-recipient one, similar to what observed by Strick et al. (1995).

The present study also showed that these PMv focal projections involve a more rostral and, in the case of F5a, a caudo-ventral zone—the rostral and caudal lateral grasping network input channels, respectively—which both appear to share common projections from hand-related VLPF and IPL areas. Accordingly, the PMv focal projections could partially overlap in different zones of the striatum with focal projections of different cortical areas, thus taking part to different input channels. Our data mostly based on tracer injections in different subjects can only strongly suggest partial overlap or at least interweaving of the focal projections from the studied areas in these 2 input channels. However, this possibility appears even more likely considering that the relative narrowness of our tracer injections, the slight variability in the location of the patches of focal projections observed even after different tracer injections in the same area and the common observation that larger is the injection site, more extensive is the striatal terminal field (e.g., Parthasarathy et al. 1992; Flaherty and Graybiel 1994; Takada et al. 1998), suggest that focal projections observed in our study represent an underestimate of the entire striatal territory devoted to each cortical area. Furthermore, in our cases of multiple anterograde tracers injections (Cases 62l and 30l), the distribution of the focal projections observed in both the rostral and the caudal lateral grasping network input channels after injections in the VLPF and the IPL hand-related regions and in F5a, provided direct evidence for partial overlapping and interweaving of the striatal projections from the different cortical regions composing the lateral grasping network.

Connectional Specificity of the Rostral and Caudal Lateral Grasping Network Input Channels

The present data leave open the possibility that other areas, more or less directly involved in cortical control of grasping, project to the 2 above described input channels. However, a careful examination of the available data on the organization of corticostriatal projections strongly suggests a relatively high degree of specificity of the subset of inputs to these 2 putaminal zones.

Indeed, caudal VLPF eye-related areas, even those (caudal 12r and caudal 46vc) located just caudal to the hand-related VLPF fields, mostly project to the caudate body (Borra et al. 2015), which is the input zone of the so-called oculomotor basal ganglia circuit (e.g., Alexander et al. 1986; Hikosaka et al. 1989), whereas more rostral VLPF areas (personal observations) or dorsolateral prefrontal areas (Yeterian and Pandya 1991; Ferry et al. 2000; Haber et al. 2006; Calzavara et al. 2007) mostly project more rostrally and dorsally in the putamen and/or to the caudate head and rostral body.

Furthermore, both the rostral and the caudal lateral grasping network input channels appear to be skipped or only marginally involved by the projections from the various frontal and cingulate motor areas. Specifically, the 2 PMd areas F2 and F7 and area F6 (pre-SMA) appear to project dorsally to the rostral lateral grasping network input channel (Takada et al. 1998; Inase et al. 1999; Tachibana et al. 2004; Calzavara et al. 2007). This appears to be true also for the projections from the rostral and the caudal cingulate motor areas, at least considering only their focal projections (Takada et al. 2001). In contrast, terminal fields from M1 and SMA are located mostly caudal to the rostral lateral grasping network input channel and dorsal to the caudal one (Liles and Updyke 1985; Inase et al. 1996, 1999; Takada et al. 1998).

Finally, previous studies on corticostriatal projections from posterior parietal areas showed projection to the location of both the lateral grasping network input channels only after injections in the rostral part of the IPL, likely involving PFG and, possibly, AIP, but not after tracer injections in caudal IPL or superior parietal areas (Cavada and Goldman-Rakic 1991; Yeterian and Pandya 1993). Accordingly, these 2 input channels do not appear to be targeted by projections from PMd and caudal superior parietal areas forming parietofrontal circuits involved in online control of reaching and grasping movements (Raos et al. 2004; Fattori et al. 2012). Some labeling in correspondence or close to both the 2 input channels was observed by Yeterian and Pandya (1993) after a large tracer injection in the lateral part of the parietal operculum, likely partially involving area SII. Thus, it is possible that area SII, which is tightly connected to all the areas under study (Rozzi et al. 2006; Borra et al. 2008, 2011; Gerbella et al. 2011; Gerbella, Borra, Tonelli, et al. 2013) is an additional source of projections to these 2 putaminal zones. Focal projections in the proximity of, or marginally overlapping with, the caudal lateral grasping network input channel were observed after tracer injections in inferotemporal areas TE and TEO (Webster et al. 1993; Cheng et al. 1997). Interestingly, AIP and i12r are robustly connected to a specific sector of area TEa/m located in the lower bank of the superior temporal sulcus. Thus, it is possible that this inferotemporal sector is an additional source of projections to this caudal input channel, which, however, needs empirical demonstration.

Correlation with Functional Data

The differentiation of the motor putamen in distinct input channels provides the substrate for a parallel processing of different aspects of motor control through the basal ganglia circuitry. Indeed, electrophysiological data showed, in the lateral part of the putamen, movement-related neural activity closely resembling that of agonist muscles (Liles 1983; Alexander and Crutcher 1990). In contrast, neurons in the medial putamen are active during the preparatory activity, or in relation to complex movements (Liles 1983; Alexander and Crutcher 1990). Furthermore, microstimulation appears to be much more effective in evoking body movements when applied in the lateral than in the medial part of the putamen (Nambu et al. 2002). The present study provides evidence for 2 additional striatal input channels characterized by rather specific subsets of cortical input from hand-related VLPF, PMv, and IPL areas. Indeed, hand-related neural activity was recorded even rostral to the microexcitable motor putaminal region, likely in the location of the rostral grasping zone (Crutcher and DeLong 1984; Alexander and DeLong 1985). In the light of the well-established role of the basal ganglia in action selection and motor learning (DeLong and Wichmann 2009), future studies will clarify the possible contribution of these newly identified hand-related striatal zones to the neural mechanisms for controlling purposeful hand actions. Our connectional data indicate that input from F5p, which is the only node of the network connected to both the primary motor area and the spinal cord, distinguish the rostral from the caudal input channel. Furthermore, it is possible that the caudal, but not the rostral input channel is a target of projections from higher order ventral visual stream areas involved in object recognition (see, e.g., Tanaka 1996). Accordingly, it seems conceivable that these 2 hand-related input channels are differentially involved in selecting and generating hand actions based on object properties, contextual information, and behavioral goals.

Interestingly, our data also showed focal projections to the lateral part of the caudate body from all the studied areas, more extensive from VLPF and more restricted from PMv and IPL, which in Case 62 overlapped in correspondence of the AP level of the AC. Thus, these focal projections could involve the caudate sector targeted by projections from oculomotor frontal and parietal areas (Selemon and Goldman-Rakic 1985; Stanton et al. 1988; Shook et al. 1991; Parthasarathy et al. 1992; Cui et al. 2003; Borra et al. 2015), hosting neurons displaying saccade-related activity (Hikosaka et al. 1989), and considered to be the striatal region engaged in the “oculomotor” basal ganglia circuit (Alexander et al. 1986). In a previous study, we found that VLPF, PMv, and IPL areas of the lateral grasping network are a source of corticotectal projections (Borra et al. 2014). These projections could broadcast to this oculomotor structure information related to hand action goals and object affordances extraction and selection for the eye–hand coordination necessary for appropriate hand–object interactions. The projections to the caudate body observed in the present study could represent a further possible substrate for the contribution of this information to oculomotor control.

Final Considerations

To our knowledge, the present study is the first in providing evidence for partial overlap in specific striatal zones of projections from multiple, even remote, areas taking part in a large-scale functionally specialized cortical network. This complex connectional organization raises the question of how information from these input channels is then conveyed back to the cortical level through the basal ganglia-thalamocortical circuitry. The internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), which are the major output stations of the basal ganglia, are organized in largely segregated output channels each of them projecting via the thalamus to a specific cortical area (Middleton and Strick 2000; Kelly and Strick 2004). Output channels projecting to PMv areas and to area 46 are located in different parts of the GPi, whereas those projecting to areas 12 and AIP were identified in different parts of the SNr (Middleton and Strick 2002; Kelly and Strick 2004; Clower et al. 2005). Striatal cells projecting to different output channels directed to closely related cortical areas can be intermingled (Saga et al. 2011). Furthermore, different striatal zones where projections from single body part representations of M1 and S1 converge, can in turn project to the same output channel (Flaherty and Graybiel 1994). Finally, restricted striatal zones or even individual striatal neurons appear to project in different parts of both the GPi and the SNr (Hedreen and DeLong 1991; Parent and Hazrati 1994; Lévesque and Parent 2005). Thus, it is possible that the output from the various hand-related input channels could be conveyed back to all, or part, of the areas of the lateral grasping network in the framework of a closed loop organization. If this is the case, then the present data favor a model of cortical-basal ganglia connectivity in which signals from a given area are first sent to different striatal zones, where they are integrated with signals from other functionally related areas, and then reconverge to the output channel projecting back to the same area.

In recent years, several human studies based on magnetic resonance connectional techniques have suggested, although with their limitations in terms of spatial resolution, overlap of corticostriatal projections from different cortical region (Draganski et al. 2008; Choi et al. 2012) or from functionally related areas (Oguri et al. 2013; Jung et al. 2014). Furthermore, functional imaging evidence in humans showed differential involvement of rostral versus caudal putamen in different aspects of hand actions planning and execution, suggesting that the cortical grasping network should be expanded to include the basal ganglia (see Prodoehl et al. 2009). The present data providing higher resolution views of the possible convergence of corticostriatal projections from different anatomically or functionally related areas could be very helpful for the interpretation of the above-mentioned human data. Furthermore, they provide additional insight on the neural substrate for the contribution of the basal ganglia to the generation and control of hand actions which could be useful for the interpretation of functional and clinical observations in humans.

Supplementary Material

Supplementary material can be found at: http://www.cercor.oxfordjournals.org/.

Funding

The work was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (grant number: PRIN 2010, 2010MEFNF7_005), European Commission Grant Cogsystems FP7–250013, and Interuniversity Attraction Poles (IAP) P7/11.

Notes

Conflict of Interest: None declared.

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