Abstract

Recent studies have revealed a marked degree of variation in the pyramidal cell phenotype in visual, somatosensory, motor and prefrontal cortical areas in the brain of different primates, which are believed to subserve specialized cortical function. In the present study we carried out comparisons of dendritic structure of layer III pyramidal cells in the anterior and posterior cingulate cortex and compared their structure with those sampled from inferotemporal cortex (IT) and the primary visual area (V1) in macaque monkeys. Cells were injected with Lucifer Yellow in flat-mounted cortical slices, and processed for a light-stable DAB reaction product. Size, branching pattern, and spine density of basal dendritic arbors was determined, and somal areas measured. We found that pyramidal cells in anterior cingulate cortex were more branched and more spinous than those in posterior cingulate cortex, and cells in both anterior and posterior cingulate were considerably larger, more branched, and more spinous than those in area V1. These data show that pyramidal cell structure differs between posterior dysgranular and anterior granular cingulate cortex, and that pyramidal neurons in cingulate cortex have different structure to those in many other cortical areas. These results provide further evidence for a parallel between structural and functional specialization in cortex.

Introduction

The mammalian cerebral cortex is composed of many different areas, some of which, such as the primary sensory areas, are widely believed to have been present in ancestral mammals, whereas others, such as sensory association and granular prefrontal areas, are thought to have evolved more recently (for reviews, see Preuss, 2000; Allman et al., 2001; Kaas and Collins, 2001; Northcutt, 2002; Kaas and Preuss, 2003; Elston, 2003a). Various theories exist for how new cortical areas may have evolved (e.g. Sanides, 1970; MacLean, 1989; Gould, 2002). Most of these theories assume that expansion of cortex allowed the evolution of more sophisticated, and/or cognate, processing. Many believe that this expansion occurred through the addition of more of the same basic repeated unit of cortex (Creutzfeldt, 1977; Mountcastle, 1978; Szentagothai, 1978; Rockel et al., 1980; Eccles, 1984; Douglas et al., 1989; Churchland and Sejnowski, 1992; Hendry and Calkins, 1998; Jerison, 2001), while others suggested that circuit specialization may have occurred during cortical expansion (Kaas, 2000; Rakic and Kornack, 2001; Elston, 2002, 2003a).

The results of recent studies of pyramidal cell structure provide evidence for the latter hypothesis: there is marked variation in the structure of pyramidal cells, the most ubiquitous neuron in cortex, between different cortical areas (Lund et al., 1993; Elston et al., 1999a, b; Jacobs et al., 2001). In macaque, marmoset and owl monkeys there is a progressive increase in the complexity of pyramidal cell structure through the primary visual area (V1), the second visual area (V2), and inferotemporal (IT) cortex (Elston and Rosa, 1998; Elston et al., 1999a,b; Elston, 2003b). Likewise, pyramidal cells in visual areas of the parietal lobe have more complex structure than those in V1 or V2 (Elston and Rosa, 1997; Elston et al., 1999b). There is also a progressive increase in the complexity of pyramidal cell structure through somatosensory areas 3b, 5 and 7 (Elston and Rockland, 2002). Granular prefrontal cortex (gPFC) in higher primates, which has undergone dramatic expansion (Brodmann, 1913; for a translation, see Elston and Garey, 2004), is composed of highly branched and spinous pyramidal cells: macaque prefrontal pyramidal cells have, on average, over 16 times more dendritic spines than those in its V1 and those in human prefrontal cortex have 23 times more spines than those in macaque V1 (Elston, 2000; Elston et al., 2001). As each dendritic spine receives at least one excitatory input (for reviews, see Harris, 1999; Elston and DeFelipe, 2002), regional differences in the number of spines in the dendritic arbours of neurons suggest that they integrate different numbers of inputs. It has been argued that regional specializations in pyramidal cell structure reflect fundamental differences in patterns in cortical circuitry, which shape its functional abilities (for reviews, see Elston, 2002, 2003a; Jacobs and Scheibel, 2002). Here we focus on pyramidal cell structure in anterior and posterior cingulate areas of the macaque monkey in a bid to gather more information regarding the underlying trends that result in specialization of the pyramidal cell phenotype and how they relate to cortical function.

Materials and Methods

Methods of perfusion, slice preparation, cell injection, classification, morphological and statistical analysis have been detailed in previous studies (Buhl and Schlote, 1987; Elston et al., 1997). Two male Macaca fasicularis (four and a half years old) and a single male M. mulatta (unknown age) were used in the present study. The animals were deeply anaesthetized with sodium pentobarbitol, perfused intracardially with physiological saline, followed by a solution of 4% paraformaldehyde in 0.1 mol/l phosphate buffer (pH 7.2). The protocol for these experiments was in accordance with those endorsed by the NIH (publication No. 86-23, revised 1985) and was approved by the University of Queensland and RIKEN Animal Ethics Committees.

Tissue was taken from the caudal region of the cingulate gyrus (corresponding to Brodmann's area 23), the rostral portion of the cingulate gyrus (corresponding to Brodmann's area 24), the rostral third of the ventral bank of the superior temporal sulcus (IT; cytoarchitectural area TEa of Seltzer and Pandya, 1978; TEad(s) of Yukie, 1997; PIT of Felleman and Van Essen, 1991) and the occipital operculum (V1 or area 17 of Brodmann) of the left hemisphere (Fig. 1). Blocks were prepared as flattened specimens by ‘unfolding’ the tissue, removing the white matter and postfixing between glass slides. Sections (250 μm, tangential to the cortical surface) were cut with the aid of a vibratome and prelabelled with the fluorescent dye 4,6 diamidino-2-phenylindole (DAPI; Sigma D9542). Individual cell bodies can be visualized in DAPI labelled tissue with the aid of UV excitation. Differences in neuronal packing density and cell type can be identified in DAPI-labelled sections in much the same way as in preparations labelled for Nissl-substance or thionin (see Fig. 3 of Elston and Rosa, 1997). Distinction was easily made in granular cortex between the cell dense layer IV and adjacent supra- and infragranular layers by (i) calculating the depth of the series of 250 μm tangential sections (from cortical surface to white matter) and comparing with that in adjacent tissue cut in the transverse plane and (ii) studying the morphology of injected neurons (spiny stellate cells are restricted to layer IV and are rarely present in supra- and infragranular layers). [Here we use the terminology of Hassler (1966) in preference to that of Brodmann (1909; translated by Garey, 1994) for reasons outlined in Elston and Rosa (1997) and Casagrande and Kaas (1994).] In the case of posterior dysgranular cingulate cortex, we calculated from our own preparations, and previous studies (e.g. Figure 3 of Nimchinsky et al., 1996), that the base of layer III is located approximately half way between the cortical surface and the white matter, corresponding to our third successive 250 μm tangential section.

Figure 1.

Schematic showing the regions of cortex from which tissue was sampled. Tissue was taken from the caudal region of the cingulate gyrus (Post Cing), the rostral region of the cingulate gyrus (Ant Cing), the rostral third of the ventral bank of the superior temporal sulcus (IT; cytoarchitectural area TEa of Seltzer and Pandya, 1978; TEad(s) of Yukie, 1997; PIT of Felleman and van Essen, 1991) and the occipital operculum (V1, or area 17 of Brodmann). In the case of cingulate cortex, neurons were injected as close to incisions made and the anterior and posterior extremities of the corpus callosum (dashed lines) as possible.

Figure 1.

Schematic showing the regions of cortex from which tissue was sampled. Tissue was taken from the caudal region of the cingulate gyrus (Post Cing), the rostral region of the cingulate gyrus (Ant Cing), the rostral third of the ventral bank of the superior temporal sulcus (IT; cytoarchitectural area TEa of Seltzer and Pandya, 1978; TEad(s) of Yukie, 1997; PIT of Felleman and van Essen, 1991) and the occipital operculum (V1, or area 17 of Brodmann). In the case of cingulate cortex, neurons were injected as close to incisions made and the anterior and posterior extremities of the corpus callosum (dashed lines) as possible.

Neurons were injected with a continuous current (up to 1000 nA) until the individual dendrites of each cell could be traced to abrupt distal tips and the dendritic spines were easily visible. Following cell injection the tissue was processed with an antibody to Lucifer Yellow (LY), at a concentration of 1:400 000 in stock solution [2% bovine serum albumin (Sigma A3425), 1% Triton X-100 (BDH 30632), 5% sucrose in 0.1 mol/l phosphate buffer]. Anti-LY was detected by a species-specific biotinylated secondary antibody (Amersham RPN 1004; 1:200 in stock solution for 2 h) followed by a biotin–horseradish-peroxidase complex (1:200 in 0.1 mol/l phosphate buffer; Amersham RPN1051). Labelling was revealed using 3,3′-diaminobenzidine (DAB; 1:200 in 0.1 mol/l phosphate buffer; Sigma D 8001) as the chromogen. This method allowed reconstruction of cell morphology in fine detail, including the identification of individual dendritic spines (Fig. 2). In addition, we were able to determine which cells were completely filled and exclude those that were only partially filled. Neurons were drawn with the aid of a camera lucida attached to a Zeiss Axioplan microscope (40× objective). The size of the basal dendritic arbours was determined by calculating the area contained within a polygon that joined the outermost distal tips of the dendritic arbour (using features of NIH image software; NIH Research Services, Bethesda, MD; see Elston and Rosa, 1997). Branching patterns were determined by Sholl analyses (Sholl, 1953), using a 25 μm incremental increase in the radii of successive concentric circles. Spines were drawn at high power (100× oil immersion objective) and were counted as a function of distance from the cell body to the distal tips of the dendrites. The density of spines was determined per 10 μm dendritic segment (e.g. Eayrs and Goodhead, 1959). All spine types, including sessile and pedunculate (Jones and Powell, 1969), were included in the spine counts but no distinction was made between them. Correction factors used in other studies when quantifying spines (e.g. Feldman, 1984) were not used in the present study as the DAB reaction product is more transparent than the Golgi precipitate, allowing the visualization of spines that issue from the underside of dendrites. All spine data were obtained from a single case (MF2) in which we sampled the greatest number of cells. Cell bodies were drawn with the aid of a Zeiss 100× oil-immersion lens and their areas determined by tracing the outermost perimeter, whilst changing focal plane, and using standard features of NIH Image. Statistical analysis was performed using SPSS (SPSS Inc., Chicago, IL).

Figure 2.

Photomicrographs of layer III pyramidal cells injected with Lucifer Yellow and processed for a DAB (3,3′-diaminobenzidine) reaction product. (AD) Low power micrographs illustrating the gross structure of individually injected cells in inferotemporal (A, B), and anterior (C) and posterior (D) cingulate cortex. Higher power photomicrographs of the proximal dendrites of cells in anterior (E) and posterior (F) cingulate cortex and inferotemporal cortex (G, H) reveal differences in the diameter of the basal dendrites and the density of dendritic spines. Scale bars = 200 μm (AD) and 50 μm (EH).

Figure 2.

Photomicrographs of layer III pyramidal cells injected with Lucifer Yellow and processed for a DAB (3,3′-diaminobenzidine) reaction product. (AD) Low power micrographs illustrating the gross structure of individually injected cells in inferotemporal (A, B), and anterior (C) and posterior (D) cingulate cortex. Higher power photomicrographs of the proximal dendrites of cells in anterior (E) and posterior (F) cingulate cortex and inferotemporal cortex (G, H) reveal differences in the diameter of the basal dendrites and the density of dendritic spines. Scale bars = 200 μm (AD) and 50 μm (EH).

Results

Fifty-six layer III pyramidal cells in anterior cingulate and 64 layer III pyramidal cells in posterior cingulate were compared with 67 layer III pyramidal cells in IT and 53 cells in V1 sampled from the same hemispheres of two M. fasicularis monkeys. An additional 39 cells were sampled from anterior cingulate and 53 from posterior cingulate cortex from a single M. mulatta monkey. Only cells that had an unambiguous apical dendrite, had their complete basal dendritic arbours contained within the section and were well filled were included for analysis. Data are presented as individual cases.

Pyramidal Neurons in M. fasicularis

Basal Dendritic Arbour Size

The size of the basal dendritic arbours of pyramidal cells in anterior cingulate were larger (>50%) than those in posterior cingulate (Table 1; Figs 3 and 4). Moreover, cells in both anterior and posterior cingulate were larger than those in IT and V1 (Table 1; Figs 3 and 4). A one way analysis of variance (ANOVA) revealed significant differences (P < 0.001) in the sizes of the basal dendritic arbours of pyramidal cells these four cortical areas in both MF1 [F(3,103) = 115.1] and MF2 [F(3,129) = 117.2]. Post hoc Scheffe tests revealed significant differences (P < 0.05) in the size of the basal dendritic arbors of layer III pyramidal cells between cingulate (anterior and posterior) cortex and both IT and V1 in both cases MF1 and MF2.

Figure 3.

Skeletonized drawings of layer III pyramidal cells in anterior and posterior cingulate (Ant Cing and Post Cing, respectively), as well as inferotemporal cortex (IT) and the primary visual area (V1) of M. fasicularis. Illustrated cells were selected as they had basal dendritic arbors of a size similar to the mean in each case (MF1 and MF2). In addition to the difference in the size of the basal dendritic arbors, there are notable differences in the branching patterns of the dendrites. Scale bar = 50 μm.

Figure 3.

Skeletonized drawings of layer III pyramidal cells in anterior and posterior cingulate (Ant Cing and Post Cing, respectively), as well as inferotemporal cortex (IT) and the primary visual area (V1) of M. fasicularis. Illustrated cells were selected as they had basal dendritic arbors of a size similar to the mean in each case (MF1 and MF2). In addition to the difference in the size of the basal dendritic arbors, there are notable differences in the branching patterns of the dendrites. Scale bar = 50 μm.

Figure 4.

Frequency histograms of the size of the basal dendritic arbours of layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis (cases MF1 and MF2).

Figure 4.

Frequency histograms of the size of the basal dendritic arbours of layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis (cases MF1 and MF2).

Table 1

Size of the basal dendritic arbors of layer III pyramidal cells in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and the primary visual area (V1) [mean × 103 ± SEM × 103 (n = number of cells included for analysis)]


 
Ant Cing
 
Post Cing
 
IT
 
V1
 
MF1 208.9 ± 9.66 (28) 136.7 ± 4.91 (26) 124.5 ± 4.00 (31) 42.76 ± 1.70 (22) 
MF2 165.3 ± 8.24 (28) 140.1 ± 4.54 (38) 130.5 ± 2.96 (36) 44.14 ± 1.52 (31) 
R51
 
179.5 ± 6.36 (39)
 
123.8 ± 3.03 (53)
 

 

 

 
Ant Cing
 
Post Cing
 
IT
 
V1
 
MF1 208.9 ± 9.66 (28) 136.7 ± 4.91 (26) 124.5 ± 4.00 (31) 42.76 ± 1.70 (22) 
MF2 165.3 ± 8.24 (28) 140.1 ± 4.54 (38) 130.5 ± 2.96 (36) 44.14 ± 1.52 (31) 
R51
 
179.5 ± 6.36 (39)
 
123.8 ± 3.03 (53)
 

 

 

Branching Patterns of the Basal Dendritic Arbours

Pyramidal cells in anterior cingulate had more branches in their basal dendritic arbours than those in posterior cingulate (Fig. 5). In addition, pyramidal cells in both anterior and posterior cingulate had more branches than those in IT and V1 (Fig. 5; Table 2). Analysis of variance revealed these differences to be significant [P < 0.001; MF1, intercept F(1,118) = 2558, cortical area F(3,118) = 99.16; MF2, intercept F(1,131) = 2826, cortical area F(3,131) = 98.63]. Post hoc Scheffe tests revealed that, in both MF1 and MF2 monkeys, cells in anterior cingulate were significantly more branched than those in IT. In addition, those in both anterior and posterior cingulate were significantly more branched than those in V1 (P < 0.05).

Figure 5.

Graphs of the branching patterns of the basal dendritic arbours of layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis (cases MF1 and MF2).

Figure 5.

Graphs of the branching patterns of the basal dendritic arbours of layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis (cases MF1 and MF2).

Table 2

Branching patterns of the basal dendrites of layer III pyramidal cells, as determined by Sholl analysis with concentric circles of progressively larger radii (25 μm increments) centred on the soma that were sampled in anterior and posterior cingulated cortex (A Cing and P Cing, respectively), inferotemporal cortex (IT) and the primary visual area (V1)

MF1
 
25 μm
 
50 μm
 
75 μm
 
100 μm
 
125 μm
 
150 μm
 
175 μm
 
200 μm
 
225 μm
 
250 μm
 
275 μm
 
300 μm
 
A Cing 13.04 ± 2.8 27.19 ± 4.6 31.65 ± 4.3 29.58 ± 5.1 25.92 ± 4.3 21.96 ± 4.2 15.23 ± 4.9 10.85 ± 5.8 7.23 ± 5.0 3.73 ± 3.2 1.69 ± 2.5 0.77 ± 1.5 
P Cing 14.77 ± 3.3 29.56 ± 4.3 30.86 ± 4.1 28.19 ± 5.1 23.98 ± 5.4 19.4 ± 6.3 13.95 ± 7.4 8.58 ± 6.9 4.86 ± 5.8 2.07 ± 3.7 0.88 ± 1.9 0.33 ± 0.9 
IT 14.55 ± 3.6 29.58 ± 4.2 31.19 ± 4.2 27.32 ± 4.9 22.52 ± 4.5 15.29 ± 4.8 7.16 ± 5.1 2.55 ± 3.7 0.23 ± 0.7 0.06 ± 0.2 
V1 14.95 ± 3.4 18 ± 3.4 12.86 ± 3.8 7.55 ± 3.8 1.14 ± 2.3 
MF2             
A Cing 13.68 ± 3.3 31.68 ± 6.2 36.68 ± 8.8 33.21 ± 8.4 29.36 ± 7.5 22.96 ± 7.4 15.57 ± 7.0 8.86 ± 5.8 4.00 ± 3.8 1.21 ± 1.8 0.43 ± 1.0 0.11 ± 0.3 
P Cing 15.00 ± 3.2 30.20 ± 4.3 30.67 ± 5.8 27.15 ± 6.3 22.41 ± 5.8 16.87 ± 5.6 9.97 ± 5.4 3.28 ± 3.4 0.62 ± 1.3 0.10 ± 0.4 
IT 13.56 ± 2.8 28.56 ± 2.8 30.64 ± 4.0 27.72 ± 5.0 22.72 ± 4.4 16.69 ± 4.2 9.47 ± 4.7 2.81 ± 3.0 0.31 ± 0.7 0.06 ± 0.2 
V1 15.97 ± 3.1 22.19 ± 4.0 17.09 ± 4.1 8.63 ± 5.2 1.53 ± 3.7 0.31 ± 1.8 0.06 ± 0.4 
R51             
A Cing 12.68 ± 3.1 27.2 ± 4.2 30.7 ± 5.9 29.46 ± 6.6 25.68 ± 6.5 21.04 ± 5.8 15.06 ± 5.3 8.56 ± 4.8 3.78 ± 3.3 1.46 ± 1.9 0.5 ± 1.0 0.12 ± 0.3 
P Cing
 
15.09 ± 3.0
 
27.19 ± 4.4
 
28.76 ± 5.6
 
25.73 ± 5.7
 
20.97 ± 5.9
 
14.48 ± 6.0
 
7.44 ± 5.1
 
1.59 ± 2.2
 
0.10 ± 0.3
 
0.02 ± 0.1
 
0
 
0
 
MF1
 
25 μm
 
50 μm
 
75 μm
 
100 μm
 
125 μm
 
150 μm
 
175 μm
 
200 μm
 
225 μm
 
250 μm
 
275 μm
 
300 μm
 
A Cing 13.04 ± 2.8 27.19 ± 4.6 31.65 ± 4.3 29.58 ± 5.1 25.92 ± 4.3 21.96 ± 4.2 15.23 ± 4.9 10.85 ± 5.8 7.23 ± 5.0 3.73 ± 3.2 1.69 ± 2.5 0.77 ± 1.5 
P Cing 14.77 ± 3.3 29.56 ± 4.3 30.86 ± 4.1 28.19 ± 5.1 23.98 ± 5.4 19.4 ± 6.3 13.95 ± 7.4 8.58 ± 6.9 4.86 ± 5.8 2.07 ± 3.7 0.88 ± 1.9 0.33 ± 0.9 
IT 14.55 ± 3.6 29.58 ± 4.2 31.19 ± 4.2 27.32 ± 4.9 22.52 ± 4.5 15.29 ± 4.8 7.16 ± 5.1 2.55 ± 3.7 0.23 ± 0.7 0.06 ± 0.2 
V1 14.95 ± 3.4 18 ± 3.4 12.86 ± 3.8 7.55 ± 3.8 1.14 ± 2.3 
MF2             
A Cing 13.68 ± 3.3 31.68 ± 6.2 36.68 ± 8.8 33.21 ± 8.4 29.36 ± 7.5 22.96 ± 7.4 15.57 ± 7.0 8.86 ± 5.8 4.00 ± 3.8 1.21 ± 1.8 0.43 ± 1.0 0.11 ± 0.3 
P Cing 15.00 ± 3.2 30.20 ± 4.3 30.67 ± 5.8 27.15 ± 6.3 22.41 ± 5.8 16.87 ± 5.6 9.97 ± 5.4 3.28 ± 3.4 0.62 ± 1.3 0.10 ± 0.4 
IT 13.56 ± 2.8 28.56 ± 2.8 30.64 ± 4.0 27.72 ± 5.0 22.72 ± 4.4 16.69 ± 4.2 9.47 ± 4.7 2.81 ± 3.0 0.31 ± 0.7 0.06 ± 0.2 
V1 15.97 ± 3.1 22.19 ± 4.0 17.09 ± 4.1 8.63 ± 5.2 1.53 ± 3.7 0.31 ± 1.8 0.06 ± 0.4 
R51             
A Cing 12.68 ± 3.1 27.2 ± 4.2 30.7 ± 5.9 29.46 ± 6.6 25.68 ± 6.5 21.04 ± 5.8 15.06 ± 5.3 8.56 ± 4.8 3.78 ± 3.3 1.46 ± 1.9 0.5 ± 1.0 0.12 ± 0.3 
P Cing
 
15.09 ± 3.0
 
27.19 ± 4.4
 
28.76 ± 5.6
 
25.73 ± 5.7
 
20.97 ± 5.9
 
14.48 ± 6.0
 
7.44 ± 5.1
 
1.59 ± 2.2
 
0.10 ± 0.3
 
0.02 ± 0.1
 
0
 
0
 

Data are averaged for all neurons in each cortical area (mean ± SEM). The peak dendritic branching complexity is highlighted in bold; n is the same as for Table 1.

Spine Densities of the Basal Dendrites

In order to determine possible differences in the density and distribution of dendritic spines we drew and tallied >16 000 spines from 20 horizontally projecting basal dendrites of different neurons in each cortical area. From Figure 6 it is clear that the density of spines varied markedly for pyramidal cells in the different areas. Pyramidal cells in anterior cingulate had higher average peak spine density than those in posterior cingulate (Fig. 6; Table 3). The average peak spine density of cells in IT was similar to that in our previous studies (Elston et al., 1999a), being greater than that of cells in cingulate cortex (Fig. 6; Table 3). The average peak spine density of cells in V1 was similar to that reported in our previous studies (Elston and Rosa, 1997, 1998), being considerably lower than that in the other cortical areas (Fig. 6; Table 3). A repeated measures ANOVA (cortical area × distance from soma × spine density), revealed a significant difference in the distribution of spines [intercept F(1,76) = 1463, cortical area F(3,76) = 93.3; P < 0.001]. Post hoc Scheffe tests revealed all between area comparisons to be significantly different (P < 0.05), except that between area 24 and IT. By combining data from the Sholl analyses with that of spine densities we were able to determine an estimate for the total number of dendritic spines in the basal dendritic arbour of the ‘average’ pyramidal neuron in each area (see Elston, 2001). The ‘average’ neuron in anterior cingulate had considerably more spines in its basal dendritic arbour than that in posterior cingulate (6825 and 4357 spines, respectively). The ‘average’ cell in IT had 6170 spines, whereas that in V1 had 855 spines in its basal dendritic arbour.

Figure 6.

Frequency histograms of the size of the somata of layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis (cases MF1 and MF2).

Figure 6.

Frequency histograms of the size of the somata of layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis (cases MF1 and MF2).

Table 3

Spine density per 10 μm of horizontally projecting dendrites, as a function of distance from the cell body to the distal tips of the dendrites, of neurons sampled in anterior and posterior cingulate cortex (A.Cing and P.Cing, respectively), inferotemporal cortex (IT) and the primary visual area (V1)

MF2
 
0–10 μm
 
11–20 μm
 
21–30 μm
 
31–40 μm
 
41–50 μm
 
51–60 μm
 
61–70 μm
 
71–80 μm
 
81–90 μm
 
91–100 μm
 
101–110 μm
 
111–120 μm
 
121–130 μm
 
131–140 μm
 
141–150 μm
 
151–160 μm
 
161–170 μm
 
171–180 μm
 
181–190 μm
 
191–200 μm
 
201–210 μm
 
211–220 μm
 
221–230 μm
 
231–240 μm
 
241–250 μm
 
251–260 μm
 
261–270 μm
 
271–280 μm
 
281–290 μm
 
291–300 μm
 
A Cing 0.05 0.9 ± 0.31 4.75 ± 0.99 11.1 ± 0.93 12.95 ± 0.93 15.6 ± 1.06 18.3 ± 1.02 17.0 ± 0.88 16.4 ± 0.87 18.1 ± 1.13 17.3 ± 1.04 17.7 ± 0.83 15.8 ± 0.98 14.1 ± 1.15 14.2 ± 1.35 12.0 ± 1.10 11.6 ± 1.45 9.6 ± 1.51 8.4 ± 1.26 7.7 ± 1.31 7.7 ± 1.27 4.95 ± 1.02 3.3 ± 0.99 1.4 ± 0.61 0.95 ± 0.65 0.6 ± 0.42 0.5 ± 0.5 
P Cing 1.05 ± 0.37 4.7 ± 0.68 9.65 ± 0.76 12.1 ± 0.68 13.1 ± 0.74 12.4 ± 1.03 14.2 ± 0.73 13.8 ± 0.72 14.9 ± 0.85 14.8 ± 0.86 13.0 ± 0.57 12.8 ± 0.81 13.0 ± 0.80 11.5 ± 0.50 11.1 ± 0.65 9.0 ± 0.99 6.9 ± 1.07 5.4 ± 1.22 3.3 ± 0.96 0.8 ± 0.53 0.6 ± 0.6 0.55 ± 0.55 0.6 ± 0.6 0.45 ± 0.45 0.5 ± 0.5 
IT 2.85 ± 0.64 9.65 ± 1.14 15.0 ± 1.13 17.2 ± 0.95 18.1 ± 1.02 18.6 ± 0.79 18.8 ± 0.92 21.2 ± 0.93 19.7 ± 0.76 18.1 ± 0.79 20.2 ± 1.33 19.0 ± 1.02 15.8 ± 0.79 16.2 ± 0.77 13.7 ± 0.68 13.7 ± 0.68 12.5 ± 1.01 10.1 ± 1.32 8.2 ± 1.30 1.25 ± 0.87 0.85 ± 0.85 
V1
 
0
 
1.15 ± 0.23
 
4.9 ± 0.42
 
6.1 ± 0.34
 
7.5 ± 0.42
 
6.95 ± 0.41
 
6.8 ± 0.52
 
7.1 ± 0.29
 
6.1 ± 0.42
 
5.55 ± 0.37
 
4.4 ± 0.59
 
0.95 ± 0.48
 
0.2 ± 0.2
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
MF2
 
0–10 μm
 
11–20 μm
 
21–30 μm
 
31–40 μm
 
41–50 μm
 
51–60 μm
 
61–70 μm
 
71–80 μm
 
81–90 μm
 
91–100 μm
 
101–110 μm
 
111–120 μm
 
121–130 μm
 
131–140 μm
 
141–150 μm
 
151–160 μm
 
161–170 μm
 
171–180 μm
 
181–190 μm
 
191–200 μm
 
201–210 μm
 
211–220 μm
 
221–230 μm
 
231–240 μm
 
241–250 μm
 
251–260 μm
 
261–270 μm
 
271–280 μm
 
281–290 μm
 
291–300 μm
 
A Cing 0.05 0.9 ± 0.31 4.75 ± 0.99 11.1 ± 0.93 12.95 ± 0.93 15.6 ± 1.06 18.3 ± 1.02 17.0 ± 0.88 16.4 ± 0.87 18.1 ± 1.13 17.3 ± 1.04 17.7 ± 0.83 15.8 ± 0.98 14.1 ± 1.15 14.2 ± 1.35 12.0 ± 1.10 11.6 ± 1.45 9.6 ± 1.51 8.4 ± 1.26 7.7 ± 1.31 7.7 ± 1.27 4.95 ± 1.02 3.3 ± 0.99 1.4 ± 0.61 0.95 ± 0.65 0.6 ± 0.42 0.5 ± 0.5 
P Cing 1.05 ± 0.37 4.7 ± 0.68 9.65 ± 0.76 12.1 ± 0.68 13.1 ± 0.74 12.4 ± 1.03 14.2 ± 0.73 13.8 ± 0.72 14.9 ± 0.85 14.8 ± 0.86 13.0 ± 0.57 12.8 ± 0.81 13.0 ± 0.80 11.5 ± 0.50 11.1 ± 0.65 9.0 ± 0.99 6.9 ± 1.07 5.4 ± 1.22 3.3 ± 0.96 0.8 ± 0.53 0.6 ± 0.6 0.55 ± 0.55 0.6 ± 0.6 0.45 ± 0.45 0.5 ± 0.5 
IT 2.85 ± 0.64 9.65 ± 1.14 15.0 ± 1.13 17.2 ± 0.95 18.1 ± 1.02 18.6 ± 0.79 18.8 ± 0.92 21.2 ± 0.93 19.7 ± 0.76 18.1 ± 0.79 20.2 ± 1.33 19.0 ± 1.02 15.8 ± 0.79 16.2 ± 0.77 13.7 ± 0.68 13.7 ± 0.68 12.5 ± 1.01 10.1 ± 1.32 8.2 ± 1.30 1.25 ± 0.87 0.85 ± 0.85 
V1
 
0
 
1.15 ± 0.23
 
4.9 ± 0.42
 
6.1 ± 0.34
 
7.5 ± 0.42
 
6.95 ± 0.41
 
6.8 ± 0.52
 
7.1 ± 0.29
 
6.1 ± 0.42
 
5.55 ± 0.37
 
4.4 ± 0.59
 
0.95 ± 0.48
 
0.2 ± 0.2
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 
0
 

Data are averaged over 20 randomly selected dendrites of different neurons in each cortical area (mean ± SEM).

Somal Areas

Cell bodies were drawn in the plane tangential to the cortical surface, and plotted in Figure 7. In contrast to the size of the basal dendritic arbours, the somata of cells in layer III of anterior cingulate were, on average, smaller than those in posterior cingulate (Table 4). In addition, somata in both regions of the cingulate cortex were larger than those in IT and V1 (Table 4). Statistical analysis of the size of the cell bodies revealed significant differences between anterior and posterior cingulate areas [repeated measures ANOVAs: MF1, F(3,106) = 53.0, MF2, F(3,132) = 128; P < 0.001] and these cells were significantly different to those in IT and V1 (P < 0.05).

Figure 7.

Graph of the spine density along the basal dendritic arbours of 20 horizontally projecting basal dendrites of different layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis.

Figure 7.

Graph of the spine density along the basal dendritic arbours of 20 horizontally projecting basal dendrites of different layer III pyramidal neurons in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and primary visual area (V1) of M. fasicularis.

Table 4

Size of the cell bodies of layer III pyramidal cells in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively), inferotemporal cortex (IT) and the primary visual area (V1) [mean ± SD (n)]


 
Ant Cing
 
Post Cing
 
IT
 
V1
 
MF1 276.1 ± 13.0 (28) 278.0 ± 8.59 (26) 219.6 ± 7.36 (31) 123.9 ± 5.33 (22) 
MF2 295.0 ± 6.65 (28) 346.4 ± 10.7 (38) 239.3 ± 4.44 (36) 146.6 ± 5.40 (31) 
R51
 
217.3 ± 8.66 (39)
 
235.5 ± 10.5 (53)
 

 

 

 
Ant Cing
 
Post Cing
 
IT
 
V1
 
MF1 276.1 ± 13.0 (28) 278.0 ± 8.59 (26) 219.6 ± 7.36 (31) 123.9 ± 5.33 (22) 
MF2 295.0 ± 6.65 (28) 346.4 ± 10.7 (38) 239.3 ± 4.44 (36) 146.6 ± 5.40 (31) 
R51
 
217.3 ± 8.66 (39)
 
235.5 ± 10.5 (53)
 

 

 

Pyramidal Neurons in M. mulatta

In agreement with our findings in M. fasicularis, we found that the basal dendritic arbours of pyramidal cells in anterior cingulate of M. mulatta were larger than those in posterior cingulate (Fig. 8; Table 1). A Mann–Whitney U-test revealed the difference to be significant (P < 0.001; kurtosis = 0.39, skew = 0.753). Moreover, we found that pyramidal cells in anterior cingulate of M. mulatta had more dendritic branches than those in posterior cingulate (Fig. 8; Table 3). A repeated measures ANOVA revealed the difference to be significant [P < 0.001; intercept F(1,111) = 2472, cortical area F(1,111) = 29.8; P < 0.05]. As in M. fasicularis, we found that the size of the somata in anterior cingulate of M. mulatta were, on average, smaller than those in posterior cingulate (Fig. 8; Table 4). However, an unpaired t-test revealed no significant difference between the two groups [t(90) = 1.27; P = 0.2075; kurtosis = 0.0397, skew = 0.432].

Figure 8.

Graphs illustrating data of the size (A, B) and branching pattern (C) of the basal dendritic arbours of layer III pyramidal cells, as well as the size of their somata (D, E), that were sampled in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively) of a single M. mulatta.

Figure 8.

Graphs illustrating data of the size (A, B) and branching pattern (C) of the basal dendritic arbours of layer III pyramidal cells, as well as the size of their somata (D, E), that were sampled in anterior and posterior cingulate cortex (Ant Cing and Post Cing, respectively) of a single M. mulatta.

Discussion

In the present study we found that pyramidal cells within the cingulate cortex in both M. fascicularis and M. mullata differed in structure, those in anterior cingulate being larger and more branched and more spinous than those in posterior cingulate. Moreover, cells in anterior cingulate, but not posterior cingulate, are more spinous than those in IT. Pyramidal cells in both anterior and posterior cingulate cortex, as well as those in IT cortex, are considerably larger, more branched and more spinous than those in V1. Comparison of these data across seven different macaque monkeys reveals that the interindividual differences in pyramidal cell structure for any given cortical area are relatively small compared with the interareal differences reported in each animal (Table 5; for a discussion, see Elston et al., 1999b; Elston and Rockland, 2002). These data show that the size, branching complexity and spine density of the basal dendritic arbors of pyramidal neurons, differs between cytoarchitectonically distinct regions of cingulate cortex, and that these cells show markedly different structure to those in many other cortical areas.

Table 5

Summary of animals in which data has been sampled from anterior and posterior cingulate cortex (AC and PC, respectively), inferotemporal cortex (IT) and the primary visual area (V1)

Animal
 
Cortical areas
 
Age
 
Sex
 
No. of cells
 
DM4 ITa 18 months Male 21 
RM12 V1b 28 months Male 143 
RM13 V1c 20 months Male 26 
R51d PC, AC Unknowne Male 92 
mfII ITa 11 years Male 29 
MF1 PC, AC, IT, V1 4½ years Male 107 
MF2 PC, AC, IT, V1 4½ years Male 133 

 

 

 
Total
 
551
 
Animal
 
Cortical areas
 
Age
 
Sex
 
No. of cells
 
DM4 ITa 18 months Male 21 
RM12 V1b 28 months Male 143 
RM13 V1c 20 months Male 26 
R51d PC, AC Unknowne Male 92 
mfII ITa 11 years Male 29 
MF1 PC, AC, IT, V1 4½ years Male 107 
MF2 PC, AC, IT, V1 4½ years Male 133 

 

 

 
Total
 
551
 
a

Corresponds to area TE.

b

Data sampled from the blobs and interblobs of middle and upper layer III.

c

Data sampled from the sublamina IIIc.

d

Macaca mulatta.

e

Animal caught in the wild.

Structure and Function in Cingulate Cortex

A study of the literature reveals little agreement regarding functions performed in anterior and posterior cingulate cortex. Various authors have attributed higher cognitive and emotional functions to the anterior cingulate cortex and vegetative functions to posterior cingulate cortex (Goldman-Rakic, 2000; Passingham, 2000; Allman et al., 2001) whereas others have claimed the reverse (e.g. Baleydier and Mauguiere, 1980). Indeed, there are many differences in opinion regarding the evolution and function of cingulate cortex (for reviews, see Sanides, 1970; Baleydier and Mauguiere, 1980; MacLean, 1989; Allman et al., 2001). In a recent series of studies in which cortical activity was recorded in awake behaving monkeys by fMRI, Dreher and colleagues revealed that anterior cingulate, unlike posterior cingulate, is often co-activated with granular prefrontal cortex (gPFC) during cognitive tasks (Dreher and Berman, 2002; Dreher and Grafman, 2003). Our results show that the size, branching pattern and spine density along the dendrites of the pyramidal cells in anterior cingulate is considerably higher than that in posterior cingulate cortex. Moreover, pyramidal cell structure in anterior cingulate cortex more closely approximates that seen for cells sampled from gPFC of the same hemisphere, than do those in posterior cingulate (unpublished observations).

As reviewed elsewhere, these different aspects of pyramidal cell microanatomy may influence different aspects of cellular, and systems, function (Segev and Rall, 1998; Koch, 1999; Mel, 1999; Spruston et al., 1999; Häusser et al., 2000; Segev et al., 2001; Elston, 2002, 2003a; Häusser and Mel, 2003). Briefly, the size of the arbour influences sampling geometry: the relationship between the size of the dendritic arbour and the arborization pattern of axons from which they sample inputs determines the degree of convergence/divergence (Malach, 1994). The branching structure influences the potential for compartmentalization of processing within the arbours of pyramidal cells, which reportedly endows more branched cells with greater functional capability (Poirazi and Mel, 2000). The branching structure and spine density influence the total number of putative excitatory inputs sampled by cells. That pyramidal cells in anterior cingulate cortex have more complex structure than those in posterior cingulate cortex but less complex structure than those in granular prefrontal cortex (cf. Elston, 2000) suggests that patterns of intrinsic connectivity and, hence, the functional capabilities, of circuitry in the anterior cingulate is intermediate between the posterior cingulate and gPFC.

Specialization in Pyramidal Cell Structure in Cingulate Cortex

The present data confirm and extend previous findings of regional variation in pyramidal cell structure in primate cingulate cortex (Nimchinsky et al., 1996, 1997). Moreover, direct comparison of layer III pyramidal cells sampled in cingulate cortex with those sampled in V1 of the same hemisphere revealed that those in anterior cingulate are, on average, at least eight times more spinous than those in V1. Comparison of the present data with those of previous studies reveals that layer III pyramidal cells in cingulate (both anterior and posterior) are characterized by more complex structure than those in primary somatosensory and auditory areas (cf. Elston and Rockland, 2002; Elston et al., 2002). In addition, layer III pyramidal cells in cingulate cortex are more spinous than those in many association areas. For example, they are more branched and more spinous than those in the lateral intraparietal area (LIP), cytoarchitectonic area 7a and the fourth visual area (cf. Elston and Rosa, 1997, 1998). However, the relative structural complexity of pyramidal cells in cingulate cortex depends on where in cingulate cortex the cells are located. In future studies it will be interesting to study pyramidal cell structure in that part of cingulate cortex that occupies the medial wall of the frontal lobe (anterior to the commisure, e.g. Brodmann's area 32 or area MF of Preuss and Goldman-Rakic, 1991) to determine how they compare with those sampled here and those in gPFC.

Our sincerest thanks to Professor Kathleen Rockland for hosting the experiments performed in M. mulatta and for suggestions to improve a previous version of this manuscript. Thanks also go to Alejandra Elston for cell reconstruction and Laura Ferris for help with preparing the figures. G.N.E. was supported by grants from the National Health and Medical Research Council of Australia, the Clive and Vera Ramaciotti Foundation and the McDonnell Foundation. Collaborative work was supported by research funds from the RIKEN Brain Science Institute and the Spanish Ministry of Science and Technology (DGCYT PM99-0105 and BFI 2003-02745). R.B.-P. was supported by a fellowship from the Comunidad Autonoma de Madrid (01/0782/2000).

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Author notes

1Vision, Touch and Hearing Research Centre, Department of Physiology and Pharmacology, School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia and 2Instituto Cajal (CSIC), Avda Dr Arce, 37, 28002, Madrid, Spain