1. Neuroscience

Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe

  1. Lucija Rapan  Is a corresponding author
  2. Sean Froudist-Walsh
  3. Meiqi Niu
  4. Ting Xu
  5. Ling Zhao
  6. Thomas Funck
  7. Xiao-Jing Wang
  8. Katrin Amunts
  9. Nicola Palomero-Gallagher
  1. Institute of Neuroscience and Medicine INM-1, Research Centre Jülich, Germany
  2. Center for Neural Science, New York University, United States
  3. Bristol Computational Neuroscience Unit, Faculty of Engineering, University of Bristol, United Kingdom
  4. Center for the Developing Brain, Child Mind Institute, United States
  5. C. & O. Vogt Institute for Brain Research, Heinrich-Heine-University, Germany
https://doi.org/10.7554/eLife.82850
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Cite this article
  1. Lucija Rapan
  2. Sean Froudist-Walsh
  3. Meiqi Niu
  4. Ting Xu
  5. Ling Zhao
  6. Thomas Funck
  7. Xiao-Jing Wang
  8. Katrin Amunts
  9. Nicola Palomero-Gallagher
(2023)
Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe
eLife 12:e82850.
https://doi.org/10.7554/eLife.82850
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21 figures, 5 tables and 1 additional file

Figures

Figure 1
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Schematic drawing of the medial, lateral, and orbital surfaces of the macaque prefrontal cortex depicting parcellations according to (A) Walker, 1940, and (B) Carmichael and Price, 1994.

Macroanatomical landmarks are marked with red dashed lines; cgs, cingulate sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; ros, rostral orbital sulcus; sas, superior arcuate sulcus.

Figure 2 with 2 supplements
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Position and extent of the prefrontal areas on the medial, lateral, and orbital views of the Yerkes19 surface.

The files with the parcellation scheme are available via EBRAINS platform of the Human Brain Project (https://search.kg.ebrains.eu/instances/Project/e39a0407-a98a-480e-9c63-4a2225ddfbe4) and the BALSA neuroimaging site (https://balsa.wustl.edu/study/7xGrm). Macroanatomical landmarks are marked in red letters, while black dashed lines mark fundus of sulci. arcs, spur of the arcuate sulcus; cgs, cingulate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; lf, lateral fissure; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 2—figure supplement 1
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Macroanatomical landmarks (sulci labelled in red letters and dimples in green) shown on the lateral surface of the two related species of macaque monkey used in the present architectonic analyses.

Photographs of two of the postmortem brains used in this study. Brain ID DP1. (A) Macaca mulatta, and brain ID 11530 (B) Macaca fascicularis. Average surface representations of the Yerkes19. (C) Macaca mulatta template brains. arcs, spur of the arcuate sulcus; asd, anterior supracentral dimple; aspd, anterior superior principal dimple; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; pspd, posterior superior principal dimple; sas, superior arcuate sulcus; spcd, superior precentral dimple.

Figure 2—figure supplement 2
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2D flat map, based on the macroanatomical landmarks of every 40th section, displays orbital, medial, and dorsolateral hemispheric views with all defined areas within the macaque frontal lobe.

Areas are labelled on the left hemisphere, that is, prefrontal areas in black and previously mapped (pre)motor areas (Rapan et al., 2021) in grey. Due to limited space on the map, we used white arrows to mark anterior and posterior subdivisions of 46. Dashed yellow line on the hemispheres represents the midline, which separates medial and dorsolateral cortex. Black full lines mark the fundus of sulci. Macroanatomical landmarks are marked on the right hemisphere; arcs, spur of the arcuate sulcus; asd, anterior supracentral dimple; aspd, anterior superior principal dimple; cgs, cingulate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ipd, inferior principal dimple; lf, lateral fissure; lorb, lateraral orbital sulcus; morb, medial orbital sulcus; ps, principal sulcus; pspd, posterior superior principal dimple; sas, superior arcuate sulcus; spcd, superior precentral dimple.

Figure 3
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Quantitative analysis of the cytoarchitecture of Walker’s area 10 (Walker, 1940).

(A) Position and extent of subdivisions of Walker’s area 10 within the hemisphere are displayed on orbital, lateral, and medial views of the Yerkes19. Macroanatomical landmarks are marked in red letters. (B) High-resolution photomicrographs show cytoarchitectonic features of areas 10d, 10md, 10mv, and 10o. Each subdivision is labelled by a coloured dot, matching the colour of the depicted area on the 3D model. (C) We confirmed cytoarchitectonic borders by a statistically testable method, where the Mahalanobis distance (MD) was used to quantify differences in the shape of profiles extracted from the region of interest. Profiles were extracted between outer and inner contour lines (yellow lines drawn between layers I/II and VI/white matter, respectively) defined on grey-level index (GLI) images of the histological sections (left column). Pink lines highlight the position of the border for which statistical significance was tested. The dot plots (right column) reveal that the location of the significant border remains constant over a large block size interval (highlighted by the red dots). (a) depicts analysis of the border between areas 10d and a46d (profile index 23); (b) depicts analysis of the border delineating dorsally located subdivisions, 10d and10md (profile index 48), as well as the medial border segregating dorsal and ventral subdivision, 10md and 10mv (profile index 127); and (c) depicts analysis of the borders between ventrally positioned subdivisions of the frontal polar region, 10mv and 10o (profile index 38) and 10o and 11m (profile index 81). Scale bar 1 mm. Roman numerals indicate cytoarchitectonic layers. arcs, spur of the arcuate sulcus; cgs, cingulate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 4 with 2 supplements
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Cytoarchitecture of orbitofrontal areas.

(A) Position and extent of the orbitofrontal areas within the hemisphere are displayed on orbital, lateral, and medial views of the Yerkes19. Macroanatomical landmarks are marked in red letters. (B) High-resolution photomicrographs show cytoarchitectonic features of orbitofrontal 14r, 14c, 11m, 11l, 12r, 12m, 12l, 12o, 13b, 13a, 13m, and 13l. Each subdivision is labelled by a coloured dot, matching the colour of the depict area on the 3D model. Scale bar 1 mm. Roman numerals (and letters) indicate cytoarchitectonic layers. arcs, spur of the arcuate sulcus; cgs, cingulate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 4—figure supplement 1
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Statistically testable borders (pink lines) confirmed by the quantitative analysis for the rostral orbital and ventrolateral areas 14r, 13b, 11m, 11l, 12m, and 12r.

(a) Border between 14r and 10mv (profile index 55); (b) border between 14a and 13b (profile index 28); (c) border between 13b and 11m (profile index 38); (d) borders between 11m and 11l (profile index 110) and 11l and 12m (profile index 28); (e) border between 12m and 12r (profile index 43); and (f) border between 124 and a46v (profile index 31). For details see Figure 3.

Figure 4—figure supplement 2
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Statistically testable borders (pink lines) confirmed by the quantitative analysis for the caudal orbital and ventrolateral areas 14c, 13a, 13m, 13l, and 12o.

(a) Border between 25 and 14c (profile index 26); (b) border between 14c and 13a (profile index 22); (c) border between 13a and 13m (profile index 40); (d) border between 13m and 13l (profile index 59); (e) border between 13l and 12o (profile index 56); and (f) border between 12o and 12l (profile index 76). For details see Figure 3.

Figure 5
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Quantitative analysis of the cytoarchitecture of Walker’s area 9 (Walker, 1940).

(A) Position and extent of the rostral medial and dorsolateral prefrontal areas within the hemisphere are displayed on lateral and medial views of the Yerkes19. Macroanatomical landmarks are marked in red letters. (B) High-resolution photomicrographs show cytoarchitectonic features of areas 9m, 9d, and 9l. Each subdivision is labelled by a coloured dot, matching the colour of the depict area on the 3D model. (C) We confirmed cytoarchitectonic borders by statistically testable method (for details see Figure 3). (a) depicts analysis of the borders between area a46d and 9l (profile index 122), as well as 9l and 9d (profile index 44); (b) depicts analysis of the border between dorsal and medial subdivision, 9d and 9m (profile index 44); and (c) depicts analysis of the border distinguishing medial subdivision 9m from cingulate cortex, area 24 (profile index 35). Scale bar 1 mm. Roman numerals (and letters) indicate cytoarchitectonic layers. arcs, spur of the arcuate sulcus; cgs, cingulate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 6
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Quantitative analysis of the cytoarchitecture of Walker’s area 8B (Walker, 1940).

(A) Position and the extent of the caudal medial and dorsolateral prefrontal areas within the hemisphere are displayed on lateral and medial views of the Yerkes19. Macroanatomical landmarks are marked in red. (B) High-resolution photomicrographs show cytoarchitectonic features of areas 8B (8Bm, 8Bd, 8Bs) and 8A (8Ad, 8Av). Each subdivision is labelled by a coloured dot, matching the colour of the depict area on the 3D model. (C) We confirmed cytoarchitectonic borders of new 8B subdivisions by statistically testable method (for details see Figure 3). (a) depicts analysis of the border that separates new subdivisions 8Bs from neighbouring area 8Ad (profile index 25); (b) depicts analysis of the borders which delineate area 8Bd from surrounding areas 8Bs and 8Bm (profile index 69), as well as 8Bd and 8Bm (profile index 129); and (c) depicts analysis of the border distinguishing medial subdivision 8Bm from cingulate cortex, area 24 (profile index 37). Statistically testable borders for area 8Ad (adjacent to p46d) shown in Figure 7—figure supplement 2 and for area 8Av borders can be seen in the Figure 8—figure supplement 2. Scale bar 1 mm. Roman numerals (and letters) indicate cytoarchitectonic layers. arcs, spur of the arcuate sulcus; cgs, cingulate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 7 with 2 supplements
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Cytoarchitecture of Walker’s area 46 (Walker, 1940).

(A) Position and the extent of areas located within and around the ps, are displayed on lateral view of the Yerkes19. Additionally, schematic drowning demonstrates how identified subdivisions are labelled with letters highlighted in red. Macroanatomical landmarks are marked in red letters. Black line indicates fundus, black dotted line marks border between shoulder and fundus region, and red dotted line separates anterior and posterior portion of sulcus. (B) High-resolution photomicrographs show cytoarchitectonic features of anterior areas of 46 (a46d, a46df, a46vf, a46v) and posterior ones (p46d, p46df, p46vf, p46v), separated by red dashed line. Each subdivision is labelled by a coloured dot, matching the colour of the depict area on the 3D model. Scale bar 1 mm. Roman numerals indicate cytoarchitectonic layers. arcs, spur of the arcuate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 7—figure supplement 1
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Statistically testable borders (pink lines) confirmed by the quantitative analysis for the rostral region of the ps, occupied by the anterior subdivisions of area 46; a46d, a46df, a46vf, and a46v.

(a) Border between 9l and a46d (profile index 122); (b) borders between a46d and a46df (profile index 16) and a46df and a46vf (profile index 111); (c) border between ap46vf and a46v (profile index 38); and (d) border between a46v and 12l (profile index 35). For details see Figure 3.

Figure 7—figure supplement 2
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Statistically testable borders (pink lines) confirmed by the quantitative analysis for the caudal region of the ps, occupied by the posterior subdivisions of area 46; p46d, p46df, p46vf, and p46v.

(a) Border between 8Ad and p46d (profile index 42); (b) border between p46d and p46df (profile index 20); (c) borders between p46df and p46vf (profile index 39) and p46vf and p46v (profile index 124); and (d) border between p46v and 8Av (profile index 19). For details see Figure 3.

Figure 8 with 2 supplements
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Cytoarchitecture of areas 44 and 45.

(A) Position and the extent of the posterior ventrolateral areas within the hemisphere are displayed on lateral view of the Yerkes19. Macroanatomical landmarks are marked in red letters. (B) High-resolution photomicrographs show cytoarchitectonic features of areas 44 and 45 (45A, 45B). Each subdivision is labelled by a coloured dot, matching the colour of the depict area on the 3D model. Scale bar 1 mm. Roman numerals indicate cytoarchitectonic layers. arcs, spur of the arcuate sulcus; cs, central sulcus; ias, inferior arcuate sulcus; ps, principal sulcus; sas, superior arcuate sulcus.

Figure 8—figure supplement 1
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Statistically testable borders (pink lines) confirmed by the quantitative analysis for the caudal ventrolateral area 12l and dorsally adjacent area 45A.

(a) Border between p46v and 45A (profile index 28); (b) border between 45A and 12l (profile index 44); and (c) border between 12l and 12o (profile index 26). For details see Figure 3.

Figure 8—figure supplement 2
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Statistically testable borders (pink lines) confirmed by the quantitative analysis for the caudal ventrolateral cortex; areas 8Av, 45B, and 44.

(a) Border between p46v and 8Av (profile index 19); (b) border between 8Av and 45B (profile index 30); (c) border between 45B and 44 (profile index 39); and (d) border between 44 and F5 (prolfile index 59). For details see Figure 3.

Figure 9 with 3 supplements
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Exemplary sections depicting the distribution of kainate, M2 and 5-HT1A receptors in coronal sections through a macaque hemisphere.

The colour bar, positioned left to the autoradiographs, codes receptor densities in fmol/mg protein, and borders are indicated by black lines. The four schematic drawings at the top represent the distinct rostro-caudal levels and show the position of all prefrontal areas defined. C, caudal; D, dorsal; R, rostral; V, ventral.

Figure 9—figure supplement 1
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Exemplary sections depicting the distribution of the remaining receptor types, that is, of glutamate (AMPA, kainate, NMDA) and gamma-aminobutyric acid (GABA) (GABAA, GABAB, GABAA-associated benzodiazepine binding sites – BZ) receptors, in coronal sections through a macaque hemisphere.

The colour bar positioned left to the autoradiographs codes values of receptor densities in fmol/mg protein, and borders are indicated by the black lines.

Figure 9—figure supplement 2
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Exemplary sections depicting the distribution of the remaining receptor types, that is, acetylcholine (M1, M2, M3) and noradrenalin (α1, α2) receptors in coronal sections through a macaque hemisphere.

The colour bar positioned left to the autoradiographs codes values of receptor densities in fmol/mg protein, and borders are indicated by the black lines.

Figure 9—figure supplement 3
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Exemplary sections depicting the distribution of the remaining receptor types, that is, serotonin (5HT2) and dopamine (D1) receptors in coronal sections through a macaque hemisphere.

The colour bar positioned left to the autoradiographs codes values of receptor densities in fmol/mg protein, and borders are indicated by the black lines.

Figure 10 with 1 supplement
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Normalized receptor fingerprints of the frontopolar and orbital areas.

Black dotted line on the plot represents the mean value over all areas for each receptor. Receptors displaying a negative z-score are indicative of absolute receptor densities which are lower than the average of that specific receptor over all examined areas. The opposite is true for positive z-scores. Labelling of different receptor types, as well as the axis scaling, is identical for each area plot, which is specified in the polar plot on the top of the figure.

Figure 10—figure supplement 1
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Receptor fingerprints of the frontopolar and orbital areas.

Absolute receptor densities are given in fmol/mg protein. The positions of the different receptor types and the axis scaling are identical in all areas, and specified in the polar plot on the top of the figure.

Figure 11 with 1 supplement
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Normalized receptor fingerprints of the medial, dorsolateral, lateral, and ventrolateral areas.

Black dotted line on the plot represents the mean value over all areas for each receptor. Receptors displaying a negative z-score are indicative of absolute receptor densities which are lower than the average of that specific receptor over all examined areas. The opposite is true for positive z-scores. Labelling of different receptor types, as well as the axis scaling, is identical for each area plot, which is specified in the polar plot on the top of the figure. Due to the low receptor densities measured in area 8Av, scaling for its fingerprint is adjusted and shown directly on the corresponding polar plot.

Figure 11—figure supplement 1
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Receptor fingerprints of the medial, dorsolateral, lateral, and ventrolateral areas.

Absolute receptor densities are given in fmol/mg protein. The positions of the different receptor types and the axis scaling are identical in all areas, and specified in the polar plot on the top of the figure.

Figure 12
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Schematic summary of the functional connectivity analysis between subdivisions of areas 10, 14, 11, 13, and 12.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain regions are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, and temporal cortex (TC) in light blue.

Figure 13
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Schematic summary of the functional connectivity analysis between subdivisions of areas 9 and 8B.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain region are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, motor cortex (MC) in dark green, somatosensory cortex (SSC) in orange, parietal cortex (PC) in red, occipital cortex (OCC) in purple, and temporal cortex (TC) in light blue.

Figure 14
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Schematic summary of the functional connectivity analysis between subdivisions of areas 46, rostral areas ‘a46,’ and caudal ones ‘p46’.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain region are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, motor cortex (MC) in dark green, somatosensory cortex (SSC) in orange, parietal cortex (PC) in red, occipital cortex (OCC) in purple, and temporal cortex (TC) in light blue.

Figure 15
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Schematic summary of the functional connectivity analysis between subdivisions of areas 8A and 45, and area 44.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain region are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, motor cortex (MC) in dark green, somatosensory cortex (SSC) in orange, parietal cortex (PC) in red, occipital cortex (OCC) in purple, and temporal cortex (TC) in light blue.

Figure 16
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Schematic summary of the functional connectivity analysis between subdivisions of premotor areas F7 and F2, and areas F3 and F6.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain region are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, motor cortex (MC) in dark green, somatosensory cortex (SSC) in orange, parietal cortex (PC) in red, occipital cortex (OCC) in purple, and temporal cortex (TC) in light blue.

Figure 17
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Schematic summary of the functional connectivity analysis between subdivisions of premotor areas F5 and F4.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain region are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, motor cortex (MC) in dark green, somatosensory cortex (SSC) in orange, parietal cortex (PC) in red, occipital cortex (OCC) in purple, and temporal cortex (TC) in light blue.

Figure 18
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Schematic summary of the functional connectivity analysis between subdivisions of primary motor areas 4.

Legend shows the strength of the functional connectivity coefficient (z) is coded by the appearance (wider-thinner-doted) of the connecting arrows. Areas related to different brain region are marked on the scheme with distinct colours; prefrontal cortex (PFC) in light yellow, cingulate cortex (CC) in pink, premotor cortex (PMC) in light green, motor cortex (MC) in dark green, somatosensory cortex (SSC) in orange, parietal cortex (PC) in red, occipital cortex (OCC) in purple, and temporal cortex (TC) in light blue.

Figure 19
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Receptor-driven hierarchical clustering of the receptor fingerprints in the macaque frontal lobe.

The analyses include 33 of the 35 areas identified in this study (for areas 14c and 13a was not possible to extract receptor densities due to technical limitations), as well as 16 areas of the primary motor and premotor cortex identified in a previous study (Rapan et al., 2021) carried out on the same monkey brains. Above the hierarchical dendrogram, the extent and location of the five clusters are depicted on the medial, lateral, and orbital surface of the Yerkes19 atlas. Clusters are colour coded based on the corresponding colour on the dendrogram.

Figure 20
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Principal component analysis (variance 79.8%) of the receptor fingerprints, where the k-means analysis showed five as the optimal number of clusters.
Author response image 1
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Tables

Table 1
A list of cortical areas identified by the different authors (Walker, 1940; Petrides and Pandya, 1994; Petrides and Pandya, 2002; Preuss and Goldman-Rakic, 1991; Morecraft et al., 2012; Caminiti et al., 2017), whose maps were used as references for the present analysis, compared to areas identified by Rapan and colleagues.

‘a46’, areas a46d, a46df, a46vf, a46v; ‘p46’, areas p46d, p46df, p46vf, p46v; ‘p46d’, areas p46d, p46df; ‘p46v’, areas p46v, p46vf.

Walker vs.RapanPreuss & Goldman-Rakic vs.RapanCarmichael & Price vs.Rapan
1010d1010d10m10d
10md10md10md
10mv10mv10mv
10o10o10o10o
Rostral part of 'a46', 11m, 14r, 13bRostral part of a46d and a46v
99d9d9dn.a.
9l9l
9m9m9m
8B8Bd8Bd8Bdn.a.
8Bs8Bs
8Bm8Bm8Bm
Caudal part of 9d, 9l, and 9mCaudal part of 9d, 9l, and 9m
8A8Ad8Ar8Ad, 8Av, 45A, caudal part of 'p46'n.a.
8Av8Am8Ad
Caudal part of 'p46'8Ac8Av
46a46'46ra46df, a46vfn.a.
p46'46dra46d, p46d, ventral part of 9l
Dorsal part of 12r; ventral part of 9l46vra46v, p46v, dorsal part of 12r
Rostroventral part of 8Ad; rostrodorsal part of 45A46da46df, p46df
46va46vf, p46vf
4545A4545B, 44n.a.
45B
Rostroventral part of 8Av
n.a.n.a.n.a.
1212r12vl12r12r12r
12m12l12m12m, 12o
12lRostral part of 45A12l12l
12o12o12o
Part of 45A; 13l
1313m13M13m13b13b
13l13L13l13a13a
13m13m
13l13l
1111m1111m11m11m
11l11l11l11l
Part of12m, ventral part of 12l
1414r14A14r, 10o, 10mv, 11m, 13b14r14r
14c14M14r, 14c14c14c
Part of 11m; 13b, 13a14L14r, 14c, 13b, 13a
Petrides & Pandya vs.RapanMorecraft vs.RapanCaminiti vs.Rapan
1010d1010d1010d
10md10md10md
10mv10mv10mv
10o10o10o
Rostral part of a46d and a46v; ventral part of 12rRostral part of a46d and a46vRostral part of a46d and a46v
99d99d9l9d
9l9l9l
9m9m9m9m9m
8B8Bd8Bd8Bd8B8Bd
8Bs8Bs8Bs
8Bm8Bm8Bm8Bm
Caudal part of 9d, 9l, and 9mCaudal part of 9d, 9l, and 9mCaudal part of 9d, 9l, and 9m
8Ad8Ad8Ad8Ad8Ad8Ad
8Av8Av8Av8Av8Av8Av
Caudal part of 'p46'Caudal part of 'p46'Caudal part of 'p46'
46a46'46a46'46dra46d, a46df
9/46dp46d'9/46dp46d'46vra46v, a46vf
9/46vp46v'9/46vp46v'46dcCaudal part of a46d and a46df, 'p46d'
r46vcCaudal part of 'a46v', rostral part of 'p46v'
c46vcp46v, p46vf
45A45A4545A45A45A
45B45B45B45B
44444444, F5sn.a.
47/1212r47/1212rr12r12r
12l12li12r12r
12mc12r12r, rostral part of 12l and 45A
12o12l12l
12m12m, 12o
12o12o
1313mn.a.13a/13b13a, 13b
13l13m/13l13m, 13l
1111l, part of 12r and 12mn.a.11m11m
11l11l, 11m
1414r1414r1414r
14c14c14c
Caudal part of 10mv; 13a, 13bCaudal part of 10mv10mv
Table 2
Prominent cytoarchitectonic features highlighted for all 35 identified prefrontal areas.
AreaLayer IVCytoarchitecture
10dGranularSmall-size pyramids in III/V; dense granular layers II/IV
10mdWide, pale layer V
10mvProminent middle-size pyramids in V
10oProminent layer II
14rDysgranularwell-developed layer II; columnar pattern in IV-V
14cAgranularPale layer III
11mGranularSublamination of V (Va/Vb); cell clusters in Va
11lSublamination of V (Va/Vb)
13bGranularColumnar pattern in IV-V
13aDysgranularSublamination of V (Va/Vb)
13mSublamination of V (Va/Vb); layer Va wider than Vb
13lSublamination of V (Va/Vb); both layers of comparable width
12rDysgranularNo sublamination of V
12mGranularSublamination of V (Va/Vb)
12lSublamination of V (Va/Vb)
12oDysgranulaNo sublamination of V
9mGranularSublamination of V (Va/Vb)
9dGradient in cell-size within III; sublamination of V (Va/Vb);
pale layer Vb is wider in 9d than 9l
9lGradient in cell size within III; sublamination of V (Va/Vb)
a46dGranularScattered middle-sized pyramids in upper layer VWell-developed layer II
a46dfScattered middle-sized pyramids in lower layer III
a46vfScattered middle-sized pyramids in layer III
a46vProminent layer II, but not as in a46d
p46dGranularCells more uniform in size throughout the cortexWell-developed layer II; densely packed cells in layer III
p46dfDensely packed cells in layer III; scattered middle-sized pyramids in lower layer III
p46vfScattered middle-sized pyramids in layer III
p46vProminent layer II, but not as in p46d
8BmDysgranularLayer VI pale compared to dorsal subdivisions
8BdDark, prominent layer II
8BsSmall size pyramids in III and V compared to 8Bd
8AdGranularUpper layer III pale
8AvLower layer III pale; highly granular cortex
45AGranularMiddle-sized pyramids in layer III
45BLayer IV less developed
44DysgranularFew larger pyramids scattered in layer V
Table 3
Absolute receptor densities (mean ± SD) in fmol/mg protein.

BZ, GABAA-associated benzodiazepine binding sites.

AreaAMPAKainateNMDAGABAAGABABBZM1M2M3α1α25-HT1A5-HT2D1
10d
SD		591
161		858
116		1430
260		1697
162		1970
542		2151
829		995
230		141
35		880
117		507
75		337
68		623
169		340
75		93
20
10md
SD		586
106		895
90		1470
177		1651
168		2095
495		2307
783		1012
274		154
45		856
112		494
48		327
48		628
151		357
60		90
20
10mv
SD		628
130		903
66		1612
151		1680
199		2254
606		2451
839		1063
332		145
35		894
124		471
94		334
56		666
214		320
67		86
18
10o
SD		569
76		909
50		1523
190		1723
160		2336
612		2327
774		1068
313		150
45		923
105		470
76		342
76		682
233		350
59		82
12
14r
SD		470
81		818
107		1442
255		1427
162		2482
424		1715
542		921
385		134
35		833
118		497
109		297
95		583
119		323
44		86
15
11m
SD		604
100		771
65		1585
139		1762
142		2476
466		1975
218		1094
200		159
64		965
132		473
50		342
40		549
167		357
60		92
27
11l
SD		623
111		807
123		1562
113		1876
235		2644
478		2066
247		1050
228		159
54		944
101		462
46		351
45		529
116		357
51		96
29
13b
SD		489
44		820
103		1548
223		1615
120		2311
452		1901
431		1039
263		166
57		897
104		480
73		350
75		562
206		355
57		93
22
13m
SD		753
67		856
111		1499
122		1622
126		1908
429		1864
269		1059
121		206
94		918
130		485
21		417
21		527
138		357
50		78
11
13l
SD		713
95		756
60		1498
187		1683
180		2057
240		2052
303		1054
148		223
78		826
108		461
15		404
26		460
107		351
43		70
4
12r
SD		659
122		854
120		1406
121		1843
283		2412
312		1991
307		1026
301		180
72		922
96		439
38		306
52		540
88		350
51		86
9
12m
SD		598
136		799
55		1533
175		1792
246		2222
353		1873
421		1152
262		202
74		918
108		481
48		379
71		504
103		354
45		86
22
12l
SD		630
112		840
73		1400
126		1494
221		2010
483		1789
417		824
347		182
75		780
132		491
82		320
43		531
163		351
48		71
6
12o
SD		670
165		817
97		1527
158		1579
267		2142
414		2102
436		888
174		209
64		832
149		484
32		401
66		541
87		384
61		89
20
9m
SD		607
125		818
84		1224
252		1460
352		2048
235		1864
449		868
196		168
33		760
79		508
50		307
49		629
136		359
55		89
22
9d
SD		584
154		766
72		1341
206		1633
338		2312
235		2081
478		1050
177		176
34		841
80		515
40		355
59		642
81		362
61		92
24
9l
SD		554
151		711
56		1311
230		1582
324		2173
260		1972
464		1029
143		164
31		822
91		497
38		361
47		594
64		366
54		67
21
a46d
SD		527
138		810
81		1247
197		1609
253		1993
189		1821
349		981
234		187
40		819
114		462
68		318
65		521
86		354
66		90
26
a46df
SD		559
126		667
44		1348
124		1663
219		2071
170		1898
444		1083
160		176
45		860
79		478
60		384
61		466
94		355
80		94
29
a46vf
SD		619
126		679
81		1427
102		1752
297		2291
280		1873
352		1124
161		180
47		894
94		484
47		395
39		497
88		376
76		93
30
a46v
SD		502
67		808
61		1339
167		1614
281		2068
200		1908
406		1017
235		187
52		856
85		440
52		319
35		496
79		349
58		87
17
p46d
SD		563
103		785
50		1187
318		1449
259		1934
231		1786
286		889
257		185
48		771
84		439
70		300
30		484
77		364
35		81
29
p46df
SD		592
102		692
40		1305
254		1649
268		2049
177		1978
256		1000
241		176
43		812
84		453
78		388
47		478
86		373
42		85
22
p46vf
SD		613
115		671
71		1369
225		1726
315		2295
315		2138
383		998
230		163
41		834
115		467
74		395
67		528
107		381
48		88
24
p46v
SD		519
49		758
67		1241
207		1444
279		1956
213		1814
284		810
294		170
34		783
74		416
88		321
43		461
98		361
43		81
23
8Bm
SD		528
136		731
128		1018
438		1216
217		1888
267		1958
236		806
173		178
31		667
87		472
70		273
49		508
80		351
32		83
27
8Bd
SD		481
92		641
106		973
346		1195
151		1896
173		2136
385		832
131		195
41		680
92		466
73		263
70		437
89		362
47		89
28
8Bs
SD		494
99		570
54		1047
348		1232
209		1901
389		1931
134		831
117		164
47		682
117		436
75		304
67		484
106		356
56		88
23
8Ad
SD		528
115		694
65		1108
322		1219
200		1972
143		1795
301		870
227		158
37		685
139		438
67		272
36		450
82		359
43		82
29
8Av
SD		440
94		591
102		1017
264		1205
202		1703
264		1807
369		708
268		163
36		603
174		347
112		257
64		262
109		323
67		79
25
45A
SD		550
97		733
61		1235
165		1461
186		1846
280		1810
378		880
244		168
52		734
62		422
106		321
47		394
126		358
47		75
19
45B
SD		601
150		588
54		1310
271		1472
286		1955
301		1911
249		972
317		147
29		705
120		442
65		372
75		499
166		378
58		88
30
44
SD		595
162		592
86		1310
277		1520
220		2065
233		1756
294		957
339		154
22		697
164		475
79		402
70		638
253		385
57		93
27
Table 4
FDR-corrected p-values for the post hoc tests (i.e. third-level tests; p-values were corrected for 258 comparisons per receptor type).

No p-values are provided for the M1, M2, 5-HT2, or D1 receptors because they did not reach the level of significance in the second-level test. Green background highlights significant pairs of adjacent prefrontal areas in the macaque brain. *p<0.05, **p<0.01, ***p<0.001.


AMPAKainateNMDAGABAᴀGABABBZM3α1α25-HT1A
10d - 10md0.93930.55910.80280.87760.69760.78710.75530.91040.8660.9753
10d - 9d0.90410.11420.57210.83640.14130.87280.61350.91040.56920.9081
10d - 9l0.6180.0091**0.43290.58710.44740.72770.41730.95490.46030.746
10d - a46d0.34720.44350.1940.70850.97110.31490.38450.55710.69290.1842
10md - 10mv0.63040.88670.30330.94070.49080.84150.5860.75540.84350.7195
10md - 9m0.82310.15080.0461*0.18260.87010.12420.14560.83130.54170.9816
10mv - 10o0.43910.98010.54580.80640.78720.85870.74410.99730.82760.9081
10mv - 14r0.0386*0.1490.21670.13050.35290.0291*0.35220.77520.24440.3143
10o - 11m0.70180.0056**0.66760.84250.52910.29960.53960.95490.99360.0666
10o - 14r0.1680.12270.55250.0366*0.57510.0291*0.17930.76450.14710.2115
11l - 11m0.82070.51260.89310.45190.48320.87210.78070.91040.78810.8618
11l - 12m0.82070.96660.92710.70450.0580.74090.79640.80850.38540.8686
11l - 12r0.58480.37270.22910.89320.27390.87210.74460.76450.13250.917
11l - 13l0.24080.67320.92230.48660.05230.97660.28140.95490.14270.7352
11l - 13m0.10050.41050.92560.30350.0104*0.86780.94870.76450.07810.9081
11m - 13b0.09880.39980.80280.30630.45930.87280.29910.95490.84030.917
11m - 13l0.15930.98010.82610.89110.2080.86520.190.97950.09250.6198
11m - 13m0.060.16840.82610.6980.05540.97660.79430.85410.0465*0.997
11m - 14r0.06880.49280.28950.0159*0.98090.4890.0347*0.8120.1490.8153
12l - 12o0.73960.72210.54770.77850.71170.54490.5910.93380.0323*0.9837
12l - 12r0.74230.840.98080.0261*0.08240.75230.06130.38640.64950.9869
12l - 45A0.27790.07730.21520.87290.49240.99840.56060.1480.92310.0933
12m - 12o0.43910.86640.92230.18510.78510.73130.23350.99730.63060.7877
12m - 12r0.41910.37350.34650.83260.49360.87210.96020.51040.0176*0.7772
12m - 13l0.17420.72070.98670.77850.76490.74960.42950.9290.50690.8618
12o - 12r0.96690.51440.47820.09230.25830.85870.23350.55750.004**0.9881
12o - 13l0.57360.60210.96490.53060.94290.99010.90490.9290.81280.6789
12r - a46v0.0151*0.37430.63930.09620.08240.87380.34150.99730.70230.6442
12r - p46v0.0427*0.06590.22460.0032**0.019*0.74090.0347*0.72530.66340.3438
13b - 14r0.85360.9730.46540.21720.49360.72770.3390.880.10520.9081
13l - 13m0.76240.29090.99790.85630.74520.85870.42980.85650.83540.6937
44A - 45B0.94160.96480.98080.84250.6770.84150.9330.67270.44470.089
45A - 45B0.57140.0122*0.62780.970.75930.87210.73630.79020.12750.2574
45A - 8Av0.09880.0062**0.0950.12190.52910.99280.0476*0.08570.04010.0853
45A - p46v0.72740.69560.93630.96040.67920.99010.48610.95490.96860.4794
45B - 8Av0.0335*0.98010.0327*0.09140.31290.87210.17540.0238*0.0004***0.0016**
8Ad - 8Av0.20090.0487*0.54580.98520.19330.98970.24120.0155*0.69290.0073**
8Ad - 8Bs0.71420.0183*0.71490.94070.82090.78360.98330.99780.28070.7062
8Ad - p46d0.61850.07050.55460.1230.91520.99840.20240.97950.3580.7062
8Av - p46v0.26670.0009***0.07260.10470.20990.99150.0036**0.10380.0344*0.0043**
8Bd - 8Bm0.61650.12260.79360.91940.96980.74090.90380.9370.84030.4665
8Bd - 8Bs0.86840.22130.60660.86630.9680.73860.96020.70480.22970.6243
8Bd - 9d0.12130.0168*0.0031**0.0011**0.0469*0.95570.0155*0.34770.0044**0.004**
8Bm - 9m0.27440.12020.13030.1150.51710.90710.18630.56630.28680.1364
8Bs - 9l0.3850.0058**0.0364*0.0083**0.20990.97660.0362*0.19570.0840.1598
9d - 9l0.69670.32210.85160.76570.59230.85870.79640.80850.86020.6144
9d - 9m0.77040.35510.38810.21720.20990.66360.20480.93840.11210.9095
9l - a46d0.72460.0540.65530.89080.42260.75440.96020.57260.15950.3769
a46df - a46d0.68010.004**0.46990.77050.78080.87280.56210.8330.0257*0.5572
a46df - a46vf0.36880.84650.57640.58430.31290.98570.62790.95490.7470.7573
a46df-p46df0.67140.65740.78150.96120.95190.87210.5280.69640.92080.9138
a46d-p46d0.64340.66480.68310.30380.85040.97810.52830.70530.59330.7062
a46vf - a46v0.06880.0105*0.53490.34640.30660.97660.58950.44810.0101*0.9936
a46vf - p46vf0.93930.90030.68640.91460.9680.4890.4020.79020.99480.7508
a46v - p46v0.85360.39580.52190.27310.6770.87210.2870.70480.95040.7352
p46df - p46d0.70610.07240.38350.19530.6380.72770.57810.83860.003**0.9546
p46df - p46vf0.79530.71990.66010.69340.2260.75010.77680.86380.83260.6022
p46vf - p46v0.17420.09820.38240.05630.07460.34280.46630.31930.0146*0.4608
Table 5
Receptor labelling protocols.

Square brackets indicate substances that are only included in the buffer solution for the main incubation.

TransmitterReceptorMechanismoutcomeLigand(nM)PropertyDisplacer(μM)Incubation bufferPre- incubationMain incubationFinal rinsing
GlutamateAMPAExcitatory
Ionotropic		[3H]-AMPA
(10)		AgonistQuisqualate
(10)		50 mM Tris-acetate (pH 7.2) [+100 mM KSCN]3 × 10 min,
4°C		45 min, 4°C1. 4 × 4 s
2. Acetone/glutaraldehyde (100 ml + 2,5 ml), 2 × 2 s, 4°C
NMDAExcitatory
Ionotropic		[3H]-MK-801
(3.3)		Antagonist(+)MK-801 (100)50 mM Tris-acetate (pH 7.2) + 50 μM glutamate [+30 μM glycine +50 μM spermidine]15 min, 4°C60 min, 22°C1. 2 × 5 min, 4°C
2. Distilled water, 1 × 22°C
KainateExcitatory
Ionotropic		[3H]-Kainate
(9.4)		AgonistSYM 2081
(100)		50 mM Tris-acetate (pH 7.1) [+10 mM Ca2+-acetate]3 × 10 min,
4°C		45 min, 4°C1. 3 × 4 s
2. Acetone/glutaraldehyde (100 ml + 2.5 ml), 2 × 2 s, 22° C
GABAGABAAInhibitory
Ionotropic		[3H]-Muscimol
(7.7)		AgonistGABA
(10)		50 mM Tris-citrate (pH 7.0)3 × 5 min,
4°C		40 min, 4°C1. 3 × 3 s, 4°C
2. Distilled water, 1 × 22°C
GABABInhibitory
Metabotropic		[3H]-CGP 54626
(2)		AntagonistCGP 55845
(100)		50 mM Tris-HCl (pH 7.2) + 2.5 mM CaCl23 × 5 min,
4°C		60 min, 4°C1. 3 × 2 s, 4°C
2. Distilled water, 1 × 22°C
GABAA/BzInhibitory
Ionotropic		[3H]-Flumazenil
(1)		AntagonistClonazepam (2)170 mM Tris-HCl (pH 7.4)15 min, 4°C60 min, 4°C1. 2 × 1 min, 4°C
2. Distilled water, 1 × 22°C
AcetylcholineM1Excitatory
Metabotropic		[3H]-Pirenzepine
(1)		AntagonistPirenzepine
(2)		Modified Krebs buffer
(pH 7.4)		15 min, 4°C60 min, 4°C1. 2 × 1 min, 4°C
2. Distilled water, 1 × 22°C
M2Inhibitory
Metabotropic		[3H]-Oxotremorine-M
(1.7)		AgonistCarbachol
(10)		20 mM HEPES-Tris (pH 7.5) + 10 mM MgCl2 + 300 nM pirenzepine20 min, 22°C60 min, 22°C1. 2 × 2 min, 4°C
2. Distilled water, 1 × 22°C
M3Excitatory
Metabotropic		[3H]–4-DAMP
(1)		AntagonistAtropine sulfate
(10)		50 mM Tris-HCl (pH 7.4) + 0.1 mM PSMF +1 mM EDTA15 min, 22°C45 min, 22°C1. 2 × 5 min, 4°C
2. Distilled water, 1 × 22°C
Noradrenalineα1Excitatory
Metabotropic		[3H]-Prazosin
(0.2)		AntagonistPhentolamine mesylate
(10)		50 mM Na/K-phosphate buffer (pH 7.4)15 min, 22°C60 min, 22°C1. 2 × 5 min, 4°C
2. Distilled water, 1×
22°C
α2Inhibitory
Metabotropic		[3H]-UK 14,304
(0.64)		AgonistPhentolamine mesylate
(10)		50 mM Tris-HCl + 100 μM MnCl2 (pH 7.7)15 min, 22°C90 min, 22°C1. 5 min, 4°C
2. Distilled water, 1×
22°C
Serotonin5-HT1AInhibitory
Metabotropic		[3H]–8-OH-DPAT
(1)		Agonist5-Hydroxy- tryptamine, (1)170 mM Tris-HCl (pH 7.4) [+4 mM CaCl2
+ 0.01% ascorbate]		30 min, 22°C60 min, 22°C1. 5 min, 4°C
2. Distilled water, 3×
22°C
5-HT2Excitatory
Metabotropic		[3H]-Ketanserin
(1.14)		AntagonistMianserin
(10)		170 mM Tris-HCl (pH 7.7)30 min, 22°C120 min, 22°C1. 2 × 10 min, 4°C
2. Distilled water, 3 × 22°C

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  1. Lucija Rapan
  2. Sean Froudist-Walsh
  3. Meiqi Niu
  4. Ting Xu
  5. Ling Zhao
  6. Thomas Funck
  7. Xiao-Jing Wang
  8. Katrin Amunts
  9. Nicola Palomero-Gallagher
(2023)
Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe
eLife 12:e82850.
https://doi.org/10.7554/eLife.82850