1 Departments of Neurobiology and , 2 Neurological Surgery and Psychiatry, Center for the Neural Basis of Cognition, University of Pittsburgh School of Medicine, Pittsburgh, PA and Research Service, Department of Veterans Affairs Medical Center, Pittsburgh, PA, USA
Address correspondence to Peter L. Strick, Departments of Neurobiology, Neurological Surgery and Psychiatry, University of Pittsburgh, W1640 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA. Email: strickp{at}pitt.edu.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It has been proposed (Alexander et al., 1986) that the basal ganglia participate in five parallel segregated circuits with the cerebral cortex. Two of these circuits involved loops with skeletomotor and oculomotor areas of cortex: the primary motor cortex (M1) and the frontal eye field (FEF). The remaining three circuits were thought to target non-motor areas in the frontal lobe: dorsolateral prefrontal cortex, lateral orbitofrontal cortex and anterior cingulate cortex. Each of these cortical regions is thought to be involved in various aspects of cognitive behavior, including working memory, planning, attention and rule-based learning (Goldman-Rakic, 1987
; Funahashi et al., 1989
, 1993
, 1997
; Petrides, 1995
; Fuster, 1997
). Thus, Alexander et al. (Alexander et al., 1986
) suggested that some of the non-motor symptoms of basal-ganglia dysfunction are due to alterations in basal-ganglia output to these frontal areas.
The disynaptic nature of basal-gangliathalamocortical connections has made it difficult to define the specific cortical areas that are the target of basal-ganglia output and to evaluate the proposal of Alexander et al. (Alexander et al., 1986), but see Ilinsky et al. (Ilinsky et al., 1985
). We developed the use of herpes simplex virus type 1 (HSV1) as a retrograde transneuronal tracer in the central nervous system of primates to overcome this problem (Zemanick et al., 1991
; Strick and Card, 1992
; Hoover and Strick, 1993
, 1999
; Lynch et al., 1994
; Middleton and Strick, 1994
). In a preliminary study (Middleton and Strick, 1994
), we used this method to examine the dorsolateral prefrontal circuit and demonstrated that area 46 is the target of a distinct basal-gangliathalamocortical pathway from the internal segment of the globus pallidus (GPi). Observations from experiments with conventional tracers suggest that the output of the dorsolateral prefrontal circuit is not limited to area 46 (Goldman-Rakic and Porrino, 1985
; Ilinisky et al., 1985; Barbas et al., 1991
; Dermon and Barbas, 1994
; Middleton and Strick, 2001
). Therefore, in the present study, we examined the extent and organization of basal-ganglia output to five regions of prefrontal cortex: medial and lateral area 9 (areas 9m and 9l), dorsal and ventral area 46 (areas 46d and 46v) and lateral area 12 (area 12l).
Our major finding is that all of the prefrontal areas we examined are targets of basal-ganglia output. The neurons that project to each area are largely separate from those that project to the other prefrontal areas. Furthermore, the outputs to prefrontal areas as a whole are largely segregated from those to the motor areas of the cerebral cortex. Thus, the dorsolateral prefrontal circuit and the basal-ganglia outputs to prefrontal cortex are more extensive and topographically organized than previously suspected. This system forms a rich anatomical substrate for the basal ganglia to influence the cognitive operations of the frontal lobe.
Short reports of some of the results reported in this manuscript have appeared elsewhere (Middleton and Strick, 1994, 1997
, 2000
).
![]() |
Materials and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The procedures adopted for this study and the care provided experimental animals conformed to the regulations detailed in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All protocols were reviewed and approved by the relevant institutional animal care and use committees. The biosafety precautions taken during these experiments conformed to or exceeded the BSL-2 regulations detailed in Biosafety in Microbiological and Biomedical Laboratories (Health and Human Services Publication 93-8395). A detailed description of the procedures for handling virus and virus-infected animals is presented elsewhere (Strick and Card, 1992; Hoover and Strick, 1999
).
Injection Sites
Injections of HSV1 were made at multiple sites in areas 9, 46 and 12 of 13 hemispheres in 9 cebus monkeys (Cebus apella, see Table 1). These cytoarchitectonic fields have a relatively fixed relationship to various surface landmarks such as the principal and arcuate sulci, and the medial wall of the hemisphere. Therefore, the location of each injection site was guided by these features. Our injection sites were placed to avoid spread to either the FEF or the supplementary eye field (SEF) Tian and Lynch (1995, 1996).
|
To determine the origin of thalamic input to the cortical regions under analysis, we injected one or two fluorescent tracers [fast blue (FB), diamidino yellow (DY), rhodamine dextran (RD), or nuclear yellow (NY)] into different sites within areas 9, 46 and 12 [for a detailed description of these injection sites see Table 1 in Middleton and Strick (Middleton and Strick, 2001
)]. Multiple small injections of tracer were made in each cortical area (1035 injections, 0.10.25 µl/site to a total volume of 1.73.5 µl/area). To determine the origin of basal-ganglia input to prefrontal cortex, we used the McIntyre-B strain of HSV1 as a trans-synaptic tracer (Middleton and Strick, 2001
). This strain travels transneuronally in the retrograde direction in the central nervous system of primates (Zemanick et al., 1991
; Strick and Card, 1992
; Hoover and Strick, 1993
, 1999
; Strick et al., 1993
; Lynch et al., 1994
; Middleton and Strick, 1994
). Three different preparations of this virus were used. In four hemispheres, we injected McIntyre-B obtained from Dr David I. Bernstein, Gamble Institute of Medical Research, Cincinnati, OH; for method of preparation, see McLean et al. (McLean et al., 1989
). In nine hemispheres, we injected a preparation of McIntyre-B that had been passaged in African green monkey kidney (Vero) cells by Dr Richard D. Dix, Jones Eye Institute, Little Rock, AR or by Dr Jennifer H. LaVail, University of California San Francisco, San Francisco, CA; for method of preparation, see LaVail et al. (LaVail et al., 1997
). No substantial differences were observed in the overall patterns of labeling produced by these different preparations. Multiple small injections of virus were made into areas 9, 46 and 12 (1759 injections, 0.050.25 µl/site to a total volume of 2.15.0 µl/area).
Survival Period
After 5 days, each animal was deeply anesthetized (ketamine hydrochloride, 25 mg/kg, i.m.; pentobarbital sodium, 3640 mg/kg, i.p.) and transcardially perfused using a three-step procedure (Rosene et al., 1986). The perfusates included 0.1 M phosphate buffered saline (PBS), 4% (w/v) paraformaldehyde in PBS and 4% paraformaldehyde in PBS with 10% (v/v) glycerine. Following the perfusion, the brain was photographed, stereo-taxically blocked, removed from the cranium and stored in buffered 4% paraformaldehyde with 20% glycerine (4°C) for 47 days.
Histology
Blocks of neural tissue were frozen (Rosene et al., 1986) and serially sectioned in the coronal plane at a thickness of 50 µm. Every tenth section was counterstained with cresyl violet (Nissl stain) for cyto-architectonic analysis. To identify neurons labeled by virus transport, we processed free-floating tissue sections according to the avidin biotinperoxidase method (ABC; Vectastain, Vector Laboratories Inc., Burlingame, CA) using a commercially available antibody to HSV1 (Dako Corp., Carpinteria, CA; 1:2000 dilution). At least every other section from these animals was reacted. Sections were mounted onto gelatin-coated glass slides, air dried and then coverslipped with either Artmount or DPX.
Analytic Procedures
Tissue sections reacted for HSV1 were examined under bright-field, dark-field and polarized illumination. At least every fourth section was plotted through the injection site and at least every other section was plotted through the output nuclei of the basal ganglia. Data from all experiments were plotted using a PC-based charting system (MD2; Minnesota Datametrics Inc., St Paul, MN). This system uses optical encoders to sense xy movements of the microscope stage and stores the coordinates of charted structures (e.g. section outlines, injection site zones and labeled neurons). Digital images of selected structures were captured from the microscope using a video camera coupled to a high-resolution video processing board in a PC. Software written in the laboratory enabled us to generate high-resolution composites from multiple images.
Reconstruction of Injection Sites
Three concentric zones of labeling surrounded each virus injection site. Zone I contained the needle track and the highest density of viral staining and pathology. In some instances, the tissue in this zone disintegrated during tissue processing. Zone II contained a dense accumulation of infected neurons and glia, as well as a high degree of background staining. Zone III contained large numbers of labeled neurons, but little or no background staining. We included both zones I and II in our reconstructions of injection sites [Fig. 1; see also Figs 1 and 2
of Middleton and Strick (Middleton and Strick, 2001
)].
|
|
Distribution and Density of Basal Ganglia Labeling
The numbers of labeled neurons and their locations in the basal ganglia were recorded using the computer-based charting system described above. This information was used to estimate the relative density of neurons in GPi and SNpr that were labeled by virus transport from each cortical injection. The proportion of GPi and SNpr containing labeled neurons was then calculated using Cavalieris estimator (Rosen and Harry, 1990) as previously described (Middleton and Strick, 2001
).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Retrograde transneuronal transport of HSV1 from each subregion of prefrontal cortex consistently labeled second-order neurons in the output nuclei of the basal ganglia (GPi and/or SNpr). The numbers of labeled neurons, the ratio of GPi to SNpr labeled neurons and the topographic distribution of labeled neurons within the output nuclei varied with the injection site (see below). The vast majority of the GPi and SNpr neurons that were labeled through retrograde transneuronal transport had darkly stained cell somas that were spindle-shaped (Fig. 2). In many instances, well-stained dendrites radiated from each pole of the cell body, giving the labeled neurons a bipolar appearance. These morphological features are typical of GPi and SNpr neurons that project to the thalamus (Beckstead and Frankfurter, 1982
; Parent and Bellefeuille, 1982
; Zemanick et al., 1991
; Hoover and Strick, 1993
; 1999
; Middleton and Strick, 1994
, 1996
).
Inputs to Different Prefrontal
We have at least two cases for each of the five regions examined (Table 1). In general, virus injections into the same region in different animals produced comparable results. The only qualification to this general statement is that smaller injections of virus resulted in fewer numbers of labeled neurons. Our figures will illustrate data from one representative animal for each area examined. The quantitative descriptions will include data from all cases.
Area 9m
Injections of HSV1 into area 9m (n = 2) labeled an average of >700 neurons in GPi and 400 neurons in SNpr (Table 1). Over 75% of the labeled neurons in GPi and >90% of the labeled neurons in SNpr were found ipsilateral to the injection site. Neurons labeled following area 9m injections were found entirely within the rostral pole of GPi and were most concentrated within the rostral third of SNpr (Figs 36
). These labeled neurons were located dorsomedially within GPi and ventrolaterally in SNpr (Figs 36
). Twenty percent of the labeled neurons in GPi were found in its inner portion. Labeled neurons after area 9m injections occupied ~8% of the volume of GPi and 16% of the volume of SNpr. On single sections, the proportions of GPi and SNpr that contained labeled neurons were as high as 23 and 35% of the total cross-sectional area of these nuclei.
|
|
|
|
Injections of HSV1 into area 9l (n = 2) labeled an average of >700 neurons in GPi and 1200 neurons in SNpr (Table 1). Over 83% of the labeled neurons in GPi and >92% of the labeled neurons in SNpr were found ipsilateral to the injection site. Neurons labeled following area 9l injections were most concentrated within the rostral half of GPi and within the rostral half of SNpr. These labeled neurons were located dorsomedially in GPi and laterally in SNpr (Figs 36
). Fifty percent of the labeled neurons in GPi were found in its inner portion. Labeled neurons after area 9l injections occupied ~10% of the volume of GPi and 20% of the volume of SNpr. On single sections, the proportions of GPi and SNpr that contained labeled neurons were as high as 38 and 36% of these nuclei.
Area 46
Large injections of HSV1 into area 46 (n = 3) labeled an average of >360 neurons in GPi and 240 neurons in SNpr (Table 1). Over 95% of the labeled neurons in GPi and >92% of the labeled neurons in SNpr were found ipsilateral to the injection site. Neurons labeled following area 46 injections were most concentrated in the middle third of GPi and in a caudal segment of SNpr. These labeled neurons were located dorsally within GPi and dorsolaterally in SNpr (Figs 36
). Sixty percent of the labeled neurons in GPi were found in its inner portion. Labeled neurons after area 46 injections occupied ~9% of the volume of GPi and 7% of the volume of SNpr. On single sections, the proportions of GPi and SNpr that contained labeled neurons were as high as 29 and 22% of these nuclei.
Although large injections of virus into area 46 resulted in labeled neurons in both GPi and SNpr, more restricted injections of virus demonstrated the presence of a clear topography in the distribution of GPi and SNpr projections to this region of cortex. Labeled neurons were found mainly in GPi after virus injections into area 46d, whereas labeled neurons were found mainly in SNpr after virus injections into area 46v. These observations are consistent with our data on the organization of thalamic inputs to area 46d and 46v (Middleton and Strick, 2001). We found that VApc, a target of pallidal efferents, is a major source of input to area 46d. In contrast, VAmc and MDmf, targets of nigral efferents, are the major source of input to area 46v.
Area 12l
Virus injections into area 12l labeled very few neurons in GPi, <2 cells in any given section (Table 1). Those that were labeled were located ipsilateral to the injection site, in the inner portion of GPi (>90%). In contrast, the same injections labeled an average of >300 neurons in the SNpr. Approximately 95% of these neurons were located ipsilateral to the injection site. Within the SNpr, neurons labeled by area 12l injections were located predominantly in the caudal half of the nucleus, where they were densely clustered in a dorsomedial region (Figs 5 and 6
). Neurons labeled following injections into area 12l occupied ~7% of the volume of SNpr. On single sections, this proportion was as high as 14% of the nucleus.
General Pattern of Basal-ganglia Projections to Prefrontal Cortex
GPi
Overall, there were several trends in the pattern of GPi labeling produced by retrograde transneuronal transport of HSV1 from different areas of prefrontal cortex. First, dorsomedial areas of prefrontal cortex (areas 9m, 9l and 46d) receive more GPi input than ventral and lateral areas (areas 46v and 12l; Table 1, Figs 36
). Second, the origin of projections from GPi to different cortical areas is topographically organized. For example, GPi neurons labeled by virus injections into area 9m were located medial, dorsal and rostral to those labeled after injections into area 46d (Figs 36
). GPi neurons labeled after injections into area 9l were located between the area 9m and 46d populations. Regardless of the area injected, there was a tendency for the location of labeled neurons in GPi to be more ventral and lateral in rostral regions of the nucleus and to shift dorsally and medially at more caudal levels (Fig. 3
). Finally, the proportion of labeled neurons in the inner portion of GPi increased as the injection sites moved from dorsomedial to ventrolateral regions of prefrontal cortex. Similarly, the proportion of labeled neurons located ipsilateral to the injection site increased as the injection sites moved from dorsomedial to ventrolateral regions (Table 1
).
SNpr
The pattern of nigral projections to prefrontal cortex also could be characterized by a number of trends. First, areas 9m and 9l receive more nigral input than the other areas. However, the ratio of nigral to pallidal input is greater for ventrolateral regions of prefrontal cortex (areas 12l and 46v) than for dorsomedial regions (areas 9m, 9l and 46d; Table 1). Second, the origin of projections from SNpr to different cortical areas is topographically organized. For example, dorsomedial regions of prefrontal cortex (areas 9m and 9l) receive input from SNpr regions that are rostral to those that project to ventrolateral regions of prefrontal cortex (areas 12l and 46v; Figs 5 and 6
). Within the rostral portion of SNpr, neurons that project to area 9m are located ventral to those that project to area 9l (Figs 5 and 6
). Less distinct shifts in the origin of projections to areas 12l and 46v were present in the caudal portion of SNpr (Figs 5 and 6
).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Our findings further indicate that basal-ganglia output is not restricted to a single area of prefrontal cortex, but innervates multiple areas. Each of the prefrontal regions we examined received input from one or both output nuclei of the basal ganglia. Areas 12l and 46v received the vast majority of their input from SNpr, whereas area 46d received its input largely from GPi. Areas 9m and 9l received their input from both GPi and SNpr. This creates the anatomical substrate for the basal ganglia to have a broad influence over the diverse operations performed by prefrontal cortex. In this respect, basal-ganglia output differs from cerebellar projections to prefrontal cortex, which appear to be more focused on specific subfields of areas 46 and 9, i.e. areas 46d, 9l and 9m (Middleton and Strick, 2001).
Retrograde transneuronal transport of HSV1 provided us with the unique opportunity to examine the topographic organization of GPi and SNpr projections to prefrontal cortex. We found that the projection to an individual cortical area originates from a largely distinct cluster of neurons in the output nuclei. We have termed such clusters output channels (Hoover and Strick, 1993). Our evidence suggests that the output channels to different prefrontal areas are topographically organized. For example, entirely different portions of SNpr (the rostral and caudal thirds) project to areas 9m and 12l. Similarly, entirely different output nuclei (GPi and SNpr) project to adjacent portions of the same cytoarchitectonic field (areas 46d and 46v). Thus, there are clear examples where the output channels to nearby prefrontal areas display no overlap.
Within GPi, we observed a progressive medial to lateral shift in the location of neurons that projected to adjacent prefrontal areas (areas 9m, 9l and 46d). We estimate that the overlap in the output channels to these areas is in the range of 1015%. However, this comparison has obvious limitations because it is made between data from different animals. In addition, the overlap may represent regions where neurons at the borders of two different output channels are simply intermingled. The actual extent of overlap between adjacent channels remains to be determined using techniques capable of revealing multiple channels in a single animal. At this point, although the potential for some overlap exists, our results indicate that the output channels to different prefrontal areas display a marked degree of spatial organization.
Origin of basal-ganglia output to other cortical areas
An important issue about basal-ganglia loops with the cerebral cortex is the extent of segregation between motor and non-motor circuits. There is a growing body of data that can be used to evaluate this issue. Using methods identical to those of the present study, we have defined the origin of basal-ganglia projections to the face, arm and leg representations of the primary motor cortex, the arm representation of several pre-motor areas, the saccade region of the frontal eye field and area TE in inferotemporal cortex (Zemanick et al., 1991; Strick and Card, 1992
; Hoover and Strick, 1993
, 1999
; Lynch et al., 1994
; Middleton and Strick, 1994
, 1996
; Dum and Strick, 1999
; Akkal et al., 2001
). We found that all of these areas are the target of basal-ganglia output. This output appears to originate from regions of GPi and/or SNpr that are separate from those that project to prefrontal areas of cortex. For example, within GPi, the neurons in output channels that project disynaptically to motor areas of the cortex are generally located caudal to those in output channels that project to the prefrontal areas. At levels of GPi where both types of output channels are found, those that target motor areas are generally found ventral and lateral to those that target prefrontal cortex. Similar separations are found between the output channels in SNpr that project disynaptically to prefrontal areas and those that project to the face area of M1, the saccade region of the frontal eye field and area TE (Lynch et al., 1994
, Hoover and Strick, 1999
; Middleton and Strick, 2001
). The caution expressed above about data comparisons between animals also applies here. However, the existing data suggest that there is little overlap between the basal-ganglia output to pre-frontal cortex and that to the other cortical areas that have been examined.
The anatomical segregation seen in the outputs of these circuits is supported by the distribution of neurons with different response properties in the output nuclei of the basal ganglia. Specifically, the results of recording studies in GPi and SNpr show that neurons with activity related to motor aspects of behavior are located in regions of these output nuclei that are separate from those containing neurons with activity related to non-motor aspects of task performance (DeLong, 1971; DeLong et al., 1983
; Hikosaka and Wurtz, 1983
; Anderson and Horak, 1985
; Schultz, 1986
; Mink and Thach, 1991
; Hikosaka et al., 1993
; Handel and Glimcher 2000
). For example, earlier studies (Hikosaka and Wurtz, 1983
; Hikosaka et al., 1993
) recorded the activity of neurons in the SNpr of monkeys trained to perform an oculomotor spatial-delayed response task. The authors found a group of SNpr neurons with activity that was modulated during the delay period of the task. The location of many of these neurons appears to correspond to output channels in SNpr that project to prefrontal cortex. Indeed, the response properties of these SNpr neurons appear to be very similar to those of neurons in area 46, a potential target of this nigral channel (Funahashi et al., 1989
, 1993
, 1997
). In contrast, the location of many purely saccade-related neurons appears to correspond to an output channel that projects to the saccade region of the FEF (Lynch et al., 1994
). Thus, neurons with cognitive or motor properties appear to be differentially located within SNpr channels that innervate prefrontal or motor areas of cortex.
A number of functional imaging studies provide further support for the differential involvement of specific output channels in cognitive components of task performance (Owen et al., 1996, 1998
; Jueptner et al., 1997a
,b
). For example, Jueptner and colleagues (Jueptner et al., 1997a
,b
) found that activation in rostrodorsal portions of the globus pallidus was enhanced during the learning of new movement sequences compared to the activation seen during the performance of highly practiced sequences. The same task comparisons also demonstrated enhanced activations in portions of areas 9 and 46, dorsolateral portions of the caudate and the ventral anterior nucleus of the thalamus. Thus, many of the brain regions thought to participate in basal-ganglia loops with areas 9 and 46 were specifically activated during a sequence-learning task in humans.
Perhaps the best evidence for the differential involvement of specific output channels in cognitive or motor components of behavior comes from numerous recent studies of the consequences of pallidal lesions (Bakay et al. 1992) that have been made in Parkinson patients to ameliorate some of their motor symptoms. In one of these studies, the cognitive and motor effects of pallidotomy were found to depend significantly on the location of the lesion (Lombardi et al., 2000
). Lesions located in the most anteromedial region of GPi, the likely origin of output channels to prefrontal cortex, produced the greatest degree of cognitive impairment. In contrast, lesions in the intermediate region of GPi, the likely origin of output channels to motor areas of cortex, led to maximal effects on motor performance, but produced little effect on cognition. These results indicate that the cognitive effects of pallidotomy can be dissociated from its motor effects. Furthermore, they provide a convincing demonstration of the functional segregation of motor and cognitive output channels in the human GPi.
It should be clear from our results that the output of the basal ganglia has the potential to have a substantial influence on processing in prefrontal cortex. This implies that basal-ganglia dysfunction, in addition to producing disorders of movement, should also provoke cognitive disorders. Although a complete review of the literature on this topic is beyond the scope of this report, it is important to note that patients with classical basal-ganglia disorders such as Huntingtons and Parkinsons diseases can display marked cognitive and neuropsychiatric symptoms. Furthermore, these symptoms can appear early in the course of these disorders when the pathology is largely confined to the basal ganglia. For example, in a recent study of patients with Huntingtons disease, 98% of the patients exhibited neuro-psychiatric symptoms (Paulsen et al., 2001). The cognitive decline associated with this disease, including impairments in visuospatial memory and executive functions, often precedes the onset of motor symptoms (Butters et al., 1978
; Heindel et al., 1989
; Jacobs et al., 1995
; Lawrence et al., 1996
). The diversity and range of frontal-lobe-like dysfunction seen in early and mid-stage Parkinsons and Huntingtons patients are not surprising given the broad extent of the prefrontal cortex that is a target of basal-ganglia output.
Finally, an interesting pattern has emerged from our analysis; namely, all those cortical areas that are the target of basal-ganglia output also project to the input stage of basal-ganglia processing (e.g., caudate-putamen). Furthermore, the parallel and segregated nature of output channels in the basal ganglia appears to a large extent be mirrored in the pattern of cortical inputs to this system. For example, efferents from prefrontal cortex mainly terminate in regions of the caudate that innervate pallidal and nigral output channels to prefrontal cortex, whereas efferents from the cortical motor areas terminate mainly in regions of the putamen that innervate pallidal output channels to the motor areas (Alexander et al., 1986; Hedreen and DeLong, 1991
; Yoshida et al., 1993
; Francois et al., 1994
). Thus, the basal ganglia appears to participate in multiple closed loops with a large number of cortical areas in the frontal lobe. Furthermore, the involvement of the basal ganglia in this type of circuit extends beyond the frontal lobe to include at least one area of inferotemporal cortex involved in higher-order visual processing (Middleton and Strick, 1996
).
Not all basal-ganglia operations fit this processing scheme. As noted above, there is evidence for overlap in the output channels to different cortical areas. Likewise, there is evidence for overlap in the striatal territories that receive inputs from different cortical areas (Parthasarathy et al., 1992; Takada et al., 1998
). Some cortical areas that project to the striatum do not appear to be the target of basal-ganglia output (e.g. primary somatic sensory cortex). In addition, some systems intrinsic to the basal ganglia appear to have a more global influence on basal-ganglia processing. None the less, the number and diversity of the output channels we have identified suggest that closed loop circuits with the cerebral cortex are a fundamental unit of basal-ganglia architecture.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex.Annu Rev Neurosci 9:357381.[ISI][Medline]
Anderson ME, Horak FB (1985) Influence of the globus pallidus on arm movements in monkeys. III. Timing of movement-related information.J Neurophysiol 54:433448.
Bakay RA, DeLong MR, Vitek JL (1992) Posteroventral pallidotomy for Parkinsons disease.J Neurosurg 77:487488.[ISI][Medline]
Barbas H, Pandya DN (1989) Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey.J Comp Neurol 286:353375.[ISI][Medline]
Barbas H, Haswell Henion TH, Dermon CR (1991) Diverse thalamic projections to the prefrontal cortex in the rhesus monkey.J Comp Neurol 313:6594.[ISI][Medline]
Beckstead RM, Frankfurter A (1982) The distribution and some morphological features of substantia nigra neurons that project to the thalamus, superior colliculus and pedunculopontine nucleus in the monkey.Neuroscience 7:23772388.[ISI][Medline]
Bhatia KP, Marsden CD (1994) The behavioural and motor consequences of focal lesions of the basal ganglia in man.Brain 117:859876.[Abstract]
Butters N, Sax D, Montgomery K, Tarlow S (1978) Comparison of the neuropsychological deficits associated with early and advanced Huntingtons disease.Arch Neurol 35:585589.[Abstract]
Cummings JL (1993) Frontal-subcortical circuits and human behavior.Arch Neurol 50:873880.[Abstract]
DeLong MR (1971) Activity of pallidal neurons during movement.J Neurophysiol 34:414427.
DeLong MR, Crutcher MD, Georgopoulos AP (1983) Relations between movement and single cell discharge in the substantia nigra of the behaving monkey.J Neurosci 3:15991606.[ISI][Medline]
Dermon CR, Barbas H (1994) Contralateral thalamic projections predominantly reach transitional cortices in the rhesus monkey.J Comp Neurol 344:508531.[ISI][Medline]
Dum RP, Strick PL (1999) Pallidal and cerebellar inputs to the digit representations of the lateral premotor areas.Soc Neurosci Abstr 25:1925.
Francois C, Yelnik J, Percheron G, Fenelon G (1994) Topographic distribution of the axonal endings from the sensorimotor and associative striatum in the macaque pallidum and substantia nigra.Exp Brain Res 102:305318.[ISI][Medline]
Funahashi S, Bruce CJ, Goldman-Rakic PS (1989) Mnemonic coding of visual space in the monkeys dorsolateral prefrontal cortex.J Neurophysiol 61:331349.
Funahashi S, Inoue M, Kubota K (1993) Delay-related activity in the primate prefrontal cortex during sequential reaching tasks with delay.Neurosci Res 18:171175.[ISI][Medline]
Funahashi S, Inoue M, Kubota K (1997) Delay-period activity in the primate prefrontal cortex encoding multiple spatial positions and their order of presentation.Behav Brain Res 84:203223.[ISI][Medline]
Fuster J (1997) The prefrontal cortex. New York: Raven.
Goldman-Rakic PS (1987) Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In: Handbook of physiology, Section 1, The nervous system (Plum F, ed.), vol. V, pp. 373413. Bethesda, MD: American Physiological Society.
Goldman-Rakic PS, Porrino LJ (1985) The primate mediodorsal (MD) nucleus and its projection to the frontal lobe.J Comp Neurol 242:535560.[ISI][Medline]
Handel A, Glimcher P (2000) Contextual modulation of substantia nigra pars reticulata neurons.J Neurophysiol 83:30423048.
Hedreen JC, DeLong MR (1991) Organization of striatopallidal, striato-nigral and nigrostriatal projections in the macaque.J Comp Neurol 304:569595.[ISI][Medline]
Heindel WC, Salmon DP, Shults CW, Walicke PA, Butters N (1989) Neuropsychological evidence for multiple implicit memory systems: a comparison of Alzheimers, Huntingtons, and Parkinsons disease patients.J Neurosci 9:582587.[Abstract]
Hikosaka O, Wurtz RH (1983) Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccades.J Neurophysiol 49:12301253.
Hikosaka O, Sakamoto M, Miyashita N (1993) Effects of caudate nucleus stimulation on substantia nigra cell activity in monkey.Exp Brain Res 95:457472.[ISI][Medline]
Hoover JE, Strick PL (1993) Multiple output channels in the basal ganglia.Science 259:819821.[ISI][Medline]
Hoover JE, Strick, PL (1999) The organization of cerebello- and pallido- thalamic projections to primary motor cortex: an investigation employing retrograde transneuronal transport of herpes simplex virus type 1.J Neurosci 19:14461463.
Ilinsky IA, Jouandet M, Goldman-Rakic PS (1985) Organization of the nigrothalamocortical system in the rhesus monkey.J Comp Neurol 236:315330.[ISI][Medline]
Jacobs DH, Shuren J, Heilman KM (1995) Impaired perception of facial identity and facial affect in Huntingtons disease.Neurology 45: 12171218.[Abstract]
Jueptner M, Frith CD, Brooks DJ, Frackowiak RS, Passingham RE (1997a) Anatomy of motor learning. II. Subcortical structures and learning by trial and error.J Neurophysiol 77:13251337.
Jueptner M, Stephan KM, Frith CD, Brooks DJ, Frackowiak RS, Passingham RE (1997b) Anatomy of motor learning. I. Frontal cortex and attention to action.J Neurophysiol 77:13131324.
Kemp JM, Powell TPS (1971) The connexions of the striatum and globus pallidus: synthesis and speculation.Phil Trans R Soc London Ser B 262:441457.[ISI][Medline]
LaVail JH, Topp KS, Giblin PA, Garner JA (1997) Factors that contribute to the transneuronal spread of herpes simplex virus.J Neurosci Res 49:485496.[ISI][Medline]
Lawrence AD, Sahakian BJ, Hodges JR, Rosser AE, Lange KW, Robbins TW (1996) Executive and mnemonic functions in early Huntingtons disease.Brain 119:16331645.[Abstract]
Lombardi WJ, Gross RE, Trepanier LL, Lang AE, Lozano AM, Saint-Cyr JA (2000) Relationship of lesion location to cognitive outcome following microelectrode-guided pallidotomy for Parkinsons disease: support for the existence of cognitive circuits in the human pallidum.Brain 123:746758.
Lynch JC, Hoover JE, Strick PL (1994) Input to the primate frontal eye field from the substantia nigra, superior colliculus, and dentate nucleus demonstrated by transneuronal transport.Exp Brain Res 100:181186.[ISI][Medline]
McLean JH, Shipley MT, Bernstein DI (1989) Golgi-like, transneuronal retrograde labelling with CNS injections of herpes simplex virus type 1.Brain Res Bull 22:867881.[ISI][Medline]
Middleton FA, Strick PL (1994) Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function.Science 266:458461.[ISI][Medline]
Middleton FA, Strick PL (1996) The temporal lobe is a target of output from the basal ganglia.Proc Natl Acad Sci USA 93:86838687.
Middleton FA, Strick PL (1997) New concepts about the organization of basal ganglia output.Adv Neurol 74:5768.[ISI][Medline]
Middleton FA, Strick PL (2000) Basal ganglia and cerebellar loops: motor and cognitive circuits.Brain Res Rev 31:236250.[ISI][Medline]
Middleton FA, Strick PL (2001) Cerebellar projections to the prefrontal cortex of the primate.J Neurosci 21:700712.
Mink JW, Thach WT (1991) Basal ganglia motor control: I. Nonexclusive relation of pallidal discharge to five movement modes.J Neurophysiol 65:273300.
Owen AM, Doyon J, Petrides M, Evans AC (1996) Planning and spatial working memory: a positron emission tomography study in humans.Eur J Neurosci 8:353364.[ISI][Medline]
Owen AM, Doyon J, Dagher A, Sadikot A, Evans AC (1998) Abnormal basal ganglia outflow in Parkinsons disease identified with PET. Implications for higher cortical functions.Brain 121:949965.[Abstract]
Parent A, Bellefeuille LD (1982) Organization of efferent projections from the internal segment of globus pallidus as revealed by fluorescence retrograde labeling method.Brain Res 245:201213.[ISI][Medline]
Parthasarathy HB, Schall JD, Graybiel AM (1992) Distributed but convergent ordering of corticostriatal projections: analysis of the frontal eye field and the supplementary eye field in the macaque monkey.J Neurosci 12:44684488.[Abstract]
Paulsen JS, Ready RE, Hamilton JN, Mega MS, Cummings JL (2001) Neuropsychiatric aspects of Huntingtons disease.J Neurol Neurosurg Psychiatry 71:310314.
Petrides M (1995) Impairments on nonspatial self-ordered and externally ordered working memory tasks after lesions of the mid-dorsal part of the lateral frontal cortex in the monkey.J Neurosci 15:359375.[Abstract]
Rogers D (1992) Motor disorder in psychiatry: towards a neurological psychiatry. Chichester: Wiley.
Rosen GD, Harry JD (1990) Brain volume estimation from serial section measurements: a comparison of methodologies.J Neurosci Methods 35:115124.[ISI][Medline]
Rosene DL, Roy NJ, Davis BJ (1986) A cryoprotection method that facilitates cutting sections of whole monkey brains for histological and histochemical processing without freezing artifact.Cytochemistry 34:13011315.
Schultz W (1986) Activity of pars reticulata neurons of monkey substantia nigra in relation to motor, sensory, and complex events.J Neurophysiol 55:660677.
Strick PL, Card JP (1992) Transneuronal mapping of neural circuits with alpha herpesviruses. In: Experimental neuroanatomy: a practical approach (Bolam JP, ed.), pp. 81101. Oxford: Oxford University Press.
Strick PL, Hoover JE, Mushiake H (1993) Evidence for output channels in the basal ganglia and cerebellum. In: Role of the cerebellum and basal ganglia in voluntary movement (Mano N, Hamada I, DeLong MR, eds), pp. 171180. Amsterdam: Elsevier.
Takada M, Tokuno H, Nambu A, Inase M (1998) Corticostriatal projections from the somatic motor areas in the frontal lobe of the macaque monkey: segregation versus overlap of input zones from the primary motor cortex, supplementary motor area, and the premotor cortex.Exp Brain Res 120:114128.[ISI][Medline]
Tian JR, Lynch JC (1995) Slow and saccadic eye movements evoked by microstimulation in the supplementary eye field of the cebus monkey.J Neurophysiol 74:22042210.
Tian JR, Lynch JC (1996) Functionally defined smooth and saccadic eye movement subregions in the frontal eye field of Cebus monkeys.J Neurophysiol 76:27402753.
Walker AE (1940) A cytoarchitectural study of the prefrontal area of the macaque monkey.J Comp Neurol 73:5986.
Yoshida S, Nambu A, Jinnai K (1993) The distribution of the globus pallidus neurons with input from various cortical areas in the monkeys.Brain Res 611:170174.[ISI][Medline]
Zemanick MC, Strick PL, Dix RD (1991) Transneuronal transport of herpes simplex virus type 1 in the primate motor system: transport direction is strain dependent.Proc Natl Acad Sci USA 88:80488051.[Abstract]