ipsilateral connections of the anterior cingulate cortex with the frontal and medial temporal...

E L S E V I E R Neuroscience Research 21 (1994) 19-39

NEUROSCIENCE RESEARCH

Ipsilateral connections of the anterior cingulate cortex with the frontal and medial temporal cortices in the macaque monkey

• . , a a T o m i o A n k u m , H i r o k o S a k o , A k i r a M u r a t a h

aDepartment of Anatomy, Nihon University, School of Medicine, 30-1 Oyaguchi-Kamimachi, ltabashi-ku, Tokyo 173, Japan bDepartment of Physiology, Nihon University, School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173, Japan

Received 25 May 1994; revision received 8 August 1994; accepted 15 August 1994

Abstract

The present study was attempted to study ipsilateral corticocortical connections of the anterior part (area 24) of the cingulate cortex of the macaque monkey by means of wheat germ agglutinin-conjugated peroxidase (WGA-HRP) method. In 2 out of 4 Japanese monkeys (Macacafuscata) that were injected with WGA-HRP into the anterior part of the cingulate cortex, the sites of injection were successfully localized within the cortical regions corresponding to areas 24a and 24b. The results obtained from these monkeys indicate that areas 24a and 24b in the anterior part of the cingulate cortex are reciprocally connected with the prefrontal, premotor, and motor cortical regions, and also with the medial temporal cortical regions. Areas 24a and 24b were strongly connected with the lateral and medial prefrontal cortices and area 6a/3 of the premotor cortex, moderately with the remaining premotor cortex, and weakly with the motor cortex. In the medial temporal cortex, areas 24a and 24b were strongly connected with the prosubiculum, entorhinal cortex (area 28), and perirhinal cortex (areas 35 and 36), and weakly with areas TF and TH of the parahippocampal gyrus, throughout their rostrocaudal extent. In addition, areas 24a and 24b projected to the molecular layer of the CAI subfield of Ammon's horn and the external pyramidal layer of the presubiculum. Our findings suggest that areas 24a and 24b of the anterior cingulate cortex may constitute relays in the reciprocal pathways between the prefrontal cortex and the hippocampal, entorhinal and/or perirhinal cortical regions.

Keywords." Prefrontal cortex; Premotor cortex; Entorhinal cortex; Perirhinal cortex; Prosubiculum

Abbreviations a, alveus; AC, anterior commissure; Amy, amygdala; BL, basolateral nucleus of amygdala; CA, commissura anterior; CAI-3, Cornu Ammonis I-3; Cad, caudate nucleus; Cal, calcarine sulcus; CC, corpus callosum; Ci, cingulate sulcus; CS, central sulcus; DG, dentate gyrus; F, fornix; H, hippocampus; HF, hippocampal fissure; IA, inferior arcuate sulcus; IP, intraparietal sulcus; IPS, intraparietal sulcus; LF, lateral fissure; LGB, lateral geniculate body; LO, lateral orbital sulcus; LS, lunate sulcus; m, molecular layer; MGB, medial geniculate body; MO, medial orbital sulcus; MTS, middle temporal sulcus; o, stratum oriens; OC, optic chiasma; OFO, orbitofrontal opercular area; OT, optic tract; OTS, occipitotemporal sulcus; PALL, periallocortex; PO, parietooccipital sulcus; PRCO, precentral opercular area; PRCS, sulcus precentralis superior; PreS, presubiculum; Pro, proisocortex; ProS, prosubiculum; PS, principal sulcus; Pul, pulvinar; Pul. inf; inferior pulvinar nucleus; Put, putamen: py, pyramidal layer; r, stratum radiatum; Ro, rostral sulcus; RS, rhinal sulcus; S, subiculum; SA, superior arcuate sulcus; SG, subgenual sulcus; SMA, supplementary motor area; STS, superior temporal sulcus; V, lateral ventricle.

* Corresponding author, Tel.: +81 3 3972 8111; Fax: +81 3 3972 8292.

1. Introduction

The purpose of the present study was to gain insight into the anatomical relationship between the frontal cortex, the anterior cingulate cortex (area 24), and the me-

dial temporal cortex in the brain of the macaque monkey. Such anatomical knowledge should contribute to the analysis of the neural mechanisms of space and working memory in the prefrontal cortex (Fuster, 1991; Goldman-Rakic and Friedman, 1991; Friedman and Goldman-Rakic, 1994).

Most studies on connections between the frontal cortex and the anterior cingulate cortex in the macaque monkey have been done by injecting anterograde and retrograde tracers or by making a lesion in the prefrontal cortex (Mettler, 1935; Adey and Meyer, 1952; Nauta, 1964; Pandya and Kuypers, 1969; Pandya and Vignolo, 1971; Pandya et al., 1971; Leichnetz and Astruc,

0168-0102/94/$07.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0168-0102(94)00825-Z

20 T. Arikuni et al. / Neurosci. Re,~, 21 (1994) t 9 - 3 9

1975a,b, 1976; van Hoesen et al., 1975; Goldman and Nauta, 1977; Pritzel and Markowitsch, 1982; Goldman- Rakic et al., 1984; Kawamura and Naito, 1984; Barbas and Mesulam, 1985; Hiierta et al., 1987; Selemon and Goldman-Rakic, 1988; Lu and Strick, 1990; Deacon. 1992), in the premotor cortex (Arikuni et al.. 1980: Jiirgens, 1984; Markowitsch et al., 1985; Matelli et al., 1986; Luppino et al., 1990), or in the motor cortex (Muakkassa and Strick, 1979; Leichnetz, 1986; Dum and Strick, 1991; Shima et al., 1991; Morecraft and van Hoesen, 1992; Stepniewska et al., 1993). These studies showed that there are reciprocal connections between the anterior cingulate cortex and the frontal cortex in the monkey. In some studies, after tracers were injected into cytoarchitecturally defined frontal regions, labeled cells and terminals were charted on a map of the monkey brain (Jacobson and Trojanowski, 1977; Barbas and Mesulam, 1981; Barbas and Pandya, 1987, 1989; Arikuni et al., 1988; Barbas, 1988; Preuss and Goldman- Rakic, 1989; Bates and Goldman-Rakic, 1990). These studies revealed that certain cytoarchitectural regions of the frontal cortex, such as areas 10, 9, 46, 8, 12, and 11, are reciprocally connected with the anterior cingulate cortex.

According to studies on connections between the anterior cingulate cortex and the medial temporal cortex in the monkey (Vogt et al., 1979; Pandya et al., 1981; Jiirgens, 1984; Markowitsch et al., 1985; Insausti et al., 1987; Suzuki and Amaral, 1990; Martin-Elkins and Horel, 1992), the anterior cingulate cortex sends efferent to the entorhinal cortex (area 28), area 36 of the perirhinal cortex, areas TF and TH of the parahippocampal gyms, the CA I subfield of Ammon's horn, and areas TEl and TE2 of the inferotemporal cortex; and it receives afferent from areas TF and TH and the subiculum. According to studies by Rosene and van Hoesen (1977), Yukie and Iwai (1988), and Martin- Elkins and Horel (1992), the entorhinal cortex projects to the dentate gyrus, with reciprocal connection with the subiculum, and the CA1 subfield is reciprocally connected with areas TE and TF.

Taken together with the foregoing studies of fronto- cingulate connections, the anterior cingulate cortex ap- pears to constitute a relay in the transcortical routes that connect the frontal cortex with the hippocampal formation. The previous studies on the connections of the anterior cingulate cortex, however, have not paid much attention to the cytoarchitectural subdivisions of the anterior cingulate cortex. Thus, in the present study, we injected WGA-HRP into area 24 of the anterior cingulate cortex in Japanese macaques and analyzed the distribution and laminar pattern of retrogradely labeled cells and anterogradely labeled terminals in the prefrontal, premotor, motor, and medial temporal cortices on the ipsilateral side. A preliminary report of some of

these results has been presented elsewhere (Arikuni et al., 1991).

2. Materials and methods

The experiments were performed on four Japanese monkeys (Macaca fuscata) of 2.0-5.0 kg. The animals were anesthetized initially with Ketaral (5 mg/kg i.p.) and then with pentobarbital sodium (35 mg/kg i.v.), and mounted on a stereotaxic apparatus. The procedure for injection of WGA-HRP was performed aseptically. Prior to surgery, to reduce brain volume, a small amount of cerebrospinal fluid was drained via an epi- dural catheter inserted into the fourth ventricle, and a solution of mannitol (2.0-3.5 g/kg) was administered via a venous catheter attached to the small saphenous vein, which was also used for administration of an additional dose of pentobarbital sodium when necessary.

A large portion of the frontal bones was removed. The dura mater over the frontal cortex on both sides was transversely cut away from the superior sagittal vein at the level of intended injection of WGA-HRP. The superior sagittal vein was sutured at two points, rostral and caudal to the level of intended injection of WGA-HRP, and then it was cauterized at the midpoint with a bipolar coagulator. The right bridge vein was usually cauterized. The falx cerebri was cut downward from the cauterized part of the superior sagittal vein, and the anterior cingulate cortex including the intended site of injection was exposed. To allow better visualization of the medial surface of the anterior cingulate cortex on the injection side, the cerebral hemisphere contralateral to the injection was gently retracted with a surgical spatula.

A single injection of WGA-HRP was given with a glass pipette with a tip diameter of 100 #m, The pipettes were filled with a solution of 10% WGA-HRP in saline. We inserted a pipette into area 24 on the medial surface of the anterior cingulate cortex, tilting it appropriately to avoid involvement of the overlying supplementary motor area. Then, 0.5-1.5 tA of WGA-HRP solution was injected under air pressure and the pipette was kept in place for 5 min. The cut ends of the dura mater were then tightly sutured together and the excised frontal bone flaps were glued to the skull.

After a survival period of 2 days, the animals were deeply anesthetized with pentobarbital sodium and per- fused through the ascending aorta with 300 ml of 0.01 M phosphate buffer (pH 7.4), and then with 2000 ml of fixative (1.25% glutaraldehyde, 1.0% paraformaldehyde, and 0.1 M phosphate buffer pH 7.4). The brains were removed immediately and, after photographs had been taken of the external surface of each brain, they were stored overnight in 20% sucrose in phosphate buffer (pH 7.4) at 4°C. In cases 900517, 901113, and 900803, the cerebral hemispheres ipsilateral to the injection site were

T. Arikuni et a l . / Neurosci. Res. 21 (1994) 19-39 21

cut transversely at 50-/~m thickness on a freezing microtome. Two series of every fourth section were col- lected and processed by the tetramethylbenzidine method of Mesulam (1978). One series of sections was left unstained, and the other series was counter-stained with 1% neutral red. In case 910226, a block containing area 46 from the ipsilateral hemisphere was cut off to ex- amine columns of HRP-labeled cells, and some tissues of the ipsilateral prefrontal cortex were, therefore, lost. This block and the remaining part of the ipsilateral hemisphere were treated in the same way. This particu- lar procedure resulted in limited data in this case.

Sections were studied under the light microscope with bright- and dark-field illumination. The area containing dark reaction products (injection core) and the less densely labeled area around it (halo of injection) were considered as the site of injection. Since HRP-labeled cells and terminals were colocalized everywhere in the cortex, apart from the presubiculum, only HRP-labeled cells were plotted as dots on the outlines of the brain. Cortical designations of the brain of the macaque monkey were based on the work of Brodmann (1925), Vogt and Vogt (1919), and Walker (1940). Cytoarchitectural subdivisions of area 24 were those referred to in the works of Vogt et al. (1987) and Matelli et al. (1991). Borders of the perirhinal cortex and prosubiculum were based on studies by Amaral et al. (1987) and Lorente de N5 (1934), respectively. In the present experiments borders of some cytoarchitectural areas were different from standard maps of the macaque brain. This is due to individual differences of Japanese macaques.

3. Results

3.1. The sites of injection WGA-HRP was injected into cytoarchitecturally

defined regions of area 24 on the medial surface of the anterior cingulate cortex. Therefore, a brief description of cytoarchitecture and borders of subdivisions of area 24 in the brain of the Japanese macaque is appropriate here. Area 24, which lacks layer IV, is located in the anterior portion of the cingulate cortex in the macaque monkey, and it is cytoarchitecturally subdivided into areas 24a, 24b, 24c, and 24d (Matelli et al., 1991). Area 24a shows the fusion of layers V and VI and occupies the lower part of the medial surface of the anterior cingulate cortex. In area 24b, layer V is clearly separated from layer VI. Area 24b lies above area 24a and extends over the medial part of the ventral bank of the cingulate sulcus. Areas 24c and 24d have a broad layer III and oc- cupy the depth of the ventral and dorsal banks and fundus of the cingulate sulcus. Area 24c is located rostrally to area 24d and is richer in large cells in layer V than area 24d. The border between areas 24c and 24d corresponds approximately to the level at which area 6aa

is replaced by area 6a/~. Area 24d continues caudally to area 23 at the level at which area 6aot changes to area 4a. Area 32 that was divided by Pandya et al. (1981) is located immediately rostral to area 24 and has a poorly developed layer IV and undifferentiated layers V and VI.

3.1.1. Case 900517. The center of injection site was located in the rostral portion of area 24 of the anterior cingulate cortex at the level behind the genu of the corpus callosum on the right hemisphere, and the injection site extended about 4 mm rostrocaudally (Figs. I B, 2). The injection was confined to areas 24a and 24b on the medial surface of the anterior cingulate cortex (Fig. I A). There was no diffusion of the tracer into the cingulum bundle or the underlying corpus callosum.

3.1.2. Case 910226. The injection site was small and localized within areas 24a and 24b of the anterior cingulate cortex at the level of the genu of the corpus callosum on the right hemisphere. It was located a little more caudally than that in case 900517.

3.1.3. Case 901113. The injection site was centered in the rostral portion of area 24 on the left hemisphere at the level of the rostral pole of the putamen, extending about 4 mm rostrocaudally (Fig. 4). It was located more caudally than that in case 900517 and involved areas 24a and 24b. It encroached on the infragranular layers of area 24c on the ventral bank of the cingulate sulcus. At the center of the injection site, the tip of the injection pipette reached the cingulum bundle and the tracer was also deposited in the cingulum bundle and on part of the corpus callosum.

3.1.4. Case 900803. The center of the injection site was located in the caudal portion of the anterior cingulate cortex at the level of the anterior commissure, and the injection site extended about 8 mm rostrocaudally (Figs. ID, 6). The injection site involved areas 24a and 24b on the medial surface of the caudal part of the anterior cingulate cortex and encroached on the infragranular layers of part of area 24d on the ventral bank of the cingulate sulcus (Fig. IC). There was slight damage to tissue in area 24a at the site of the pipette tip (circular lesion in frontal section; Fig. 1C), and there was diffusion of the tracer into the cingulum bundle and callosal fibers.

3.2. Distribution of HRP-labeled cells and terminals & the frontal and medial temporal cortices in cases 900517 and 910226

In cases 900517 and 910226, the injection sites were localized within areas 24a and 24b in the rostral part of the anterior cingulate cortex and in both cases the patterns of cortical and laminar distribution of HRP- labeled cells and terminals were similar. Therefore, we will describe the findings obtained from case 900517 as a representative. Areas 24a and 24b of the anterior

22 Z Arikuni et al . / Neurosci. Res. 21 (1994) 19-39

A 90051 7 g 45 4o 30 25 c lO

4s ;0 a0 2~ 20 $3 30 20 10 2

c s

I t 20 43 30 ,.~u

900803 2o, ,o ,o D

10 ~ ~ c ~

20 30 4b t ~0 10 20 30 40 50

PS SA " ~ IP

- ' I t ~

................ 30 40 50

Fig. 1. Low-power photomicrographs of frontal sections through the core of injection sites, diagrams of monkey brains showing locations of sites of injections of WGA-HRP and the frontal sections used in Figs. 2, 3, 6, and bright-field photomicrographs of frontal sections of the frontal and medial temporal cortices, showing laminar pattern of labeled cells. (A) A photomicrograph showing the injection site in areas 24a and 24b in case 900517. a, b, and c indicate areas 24a, 24b, and 24c, respectively. Short bars indicate cytoarchitectural borders. These conventions also apply to Fig. IC. (B) Diagrams of brain in case 900517. The injection site is depicted in black on the medial view of monkey brain. Arrows and numbers on the medial and dorsolateral views of the brain indicate distances in mm from the frontal pole, These conventions also apply to Fig. tD. (C) A photomicrograph showing the injection site in case 900803. d indicates area 24(t. (D) Diagrams of brain in case 900803. (E) A bright-field photomicrograph showing labeled cells in area 46 on the ventral bank of the principal sulcus in case 900517. (F) A bright-field photomicrograph showing labeled cells in layer V in area 28 on the gyral surface of the entorhinal cortex in case 901113. An asterisk indicates lamina dissecans, that is, layer IV. (G) A bright-field photomicrograph showing labeled cells in the prosubiculum and the CAI subfield of Ammon's horn in case 900803. Arrows indicate labeled cells in the CA i subfield. In the prosubiculum, pyramidal cells of the upper part of the pyramidal layer are smaller than those of the lower part of the pyramidal layer. An arrowhead indicates cytoarchitectural border between the CAI subfield and the prosubiculum.

T. Arikuni et al./Neurosci. Res. 21 (1994) 19-39 23

cingulate cortex were strongly interconnected with the rostral regions of the lateral and medial prefrontal cortices and area 6aft of the premotor cortex, moderately with the remaining regions of the premotor cortex, and weakly with the motor cortex (Fig. 2).

3.2.1. Frontal cortical regions. At the frontal pole, labeled cells and terminals were present in the mediodorsal part of area 10. The labeled cells were densely distributed in layers V and VI, but less densely in layers II and III. In area 9, labeled cells and terminals were present mainly on the medial surface of the hemisphere. The labeled cells were distributed in layers II, III, V, and VI with the same density, and the labeled terminals were distributed over all cortical layers with a lower density in layer IV. There were a few labeled cells in area 8B adjacent to the beginning of the superior arcuate sulcus.

There was a dense labeling in the rostral part of area 46 along the principal sulcus on the lateral prefrontal cortex. Almost no labeling was found in area 46 on the ventral bank of the caudal portion of the principal sulcus. This pattern of distribution of labeled cells and terminals in area 46 suggests that the rostral potion of areas 24a and 24b are strongly connected with the rostral portion of area 46, but only weakly with its caudal portion. The labeled cells were densely distributed in layers II and III with a lower density in layers V and VI (Fig. 1E), and the labeled terminals were distributed in all cortical layers with a lower density in layer IV. In area 12, which lies ventral to area 46 and extends ventrally into the lateral part of the orbitofrontal cortex, labeling was mostly confined to the orbital part. A number of labeled cells and terminals were seen throughout area 8A, while a few labeled cells were scattered in area 45 on the fundus of the inferior arcuate sulcus. Most of the labeled cells were located in layer III, with some in layers V and VI (Fig. 5A), and the labeled terminals were distributed in all cortical layers.

Area 32 extends over the medial surface of the hemisphere from the cingulate sulcus to the rostral sulcus or the subgenual sulcus. There was dense labeling throughout area 32. The labeled cells were located uniformly in layers III, V and VI, and the labeled terminals were seen in all cortical layers. In area 25, there was dense labeling in its caudal part.

Labeling in the orbitofrontal cortex was not as dense as that in the lateral prefrontal cortex or the medial prefrontal cortex. There were scattered labeled cells in areas 11, 12, 13, and 14, PALL, and Pro. The labeled cells were located mainly in layer III , and the labeled terminals were distributed in all cortical layers.

In the premotor cortex, the most dense labeling was found in area 6a~3 in the superior premotor area over its rostrocaudal extent and dense labeling was seen in area 6b in the depths of the posterior bank of the inferior arcuate sulcus. In addition, there was sparse labeling in the

rostral part of area 6aa in the superior premotor area and area 6ba in the inferior premotor area. In the superior premotor area, labeled cells were located in layers II, III, V, and VI with a lower density in the lower part of layer III (III B), and labeled terminals were distributed in all cortical layers with a lower density in the lower part of layer III (See Fig. 7B). There was dense labeling throughout the supplementary motor area. The labeling was denser in the rostral than in the caudal part of the supplementary motor area.

The motor cortex is subdivided cytoarchitecturally into areas 4a, 4b, and 4c (Vogt and Vogt, 1919). Label- ing in the motor cortex was not as dense as that in the prefrontal cortex or the premotor cortex. A small number of labeled cells and terminals were present in areas 4a and 4b, with none in area 4c. In area 4a, labeling wag present in the caudal part of the ventral bank of the superior precentral sulcus. In area 4b labeling was confined to the crown of the anterior bank of the central sulcus, corresponding to the hand area as physiologically defined. Most labeled cells were located in layer II and in the upper part of layer III, with some scattered in layers V and VI. The labeled terminals were distributed in all cortical layers.

3.2.2. Medial temporal cortical regions. Our results revealed that areas 24a and 24b were extensively interconnected with the prosubiculum of the hippocampal formation, the entorhinal cortex (area 28), the perirhinai cortex (areas 35 and 36), and areas TF and TH (Fig. 3). In addition, areas 24a and 24b projected to the molecular layer of the CA1 subfield of Ammon's horn and to the external lamina of the presubiculum.

HRP-labeled cells and terminals were distributed in the ipsilateral entorhinal cortex (area 28 of Brodmann) at rostrocaudal levels from the beginning of the rhinal sulcus to its disappearance. They were present mainly in area 28 on the medial bank of the rhinal sulcus. The labeled cells were located in layer V and the labeled terminals were distributed in all cortical layers. No labeled cells or terminals were found in the olfactory field of the entorhinal cortex, which lies in the medial part of area 28 ventral to the amygdala (Amaral et al., 1987).

The perirhinal cortex extends laterally from the lateral bank of the rhinal sulcus to the middle temporal sulcus. This region is subdivided cytoarchitecturally into areas 35 and 36 (Amaral et al., 1987); in area 35, layer IV is a cell-free zone and in area 36, layer IV is composed of granular cells and large cells. A large number of labeled cells were present in area 35 over its entire rostrocaudal extent and some were present in area 36 on the lateral bank of the rhinal sulcus at the level of the caudal end of the rhinal sulcus. The labeled cells were distributed densely in layer V and less densely in the lower part of layer III. It is noteworthy that, as shown in Figs. 3, 5, 6B, and 7C, labeled cells in layer V in areas 35 and 36 were continuous with labeled cells in layer V of area 28.

24 T Arikuni et aL /Neurosci. Res. 21 (1994) 19-39

The labeled terminals were distributed in all cortical

layers with the highest density in layer IV.

The parahippocampal gyrus is composed of areas TH and T F (Zola-Morgan et al., 1993), located posterior to

areas 28 and 36. Labeled cells and terminals were seen in areas T F and TH over their entire rostrocaudal ex-

tent, although the most caudal part of area TH was devoid of labeling. Most of the labeled cells were located

900517 8 10

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14 9 16 9 ~ ,6

s' l v - ~ / " . ~.+U ~_.~J A . , / '= " : ': , , ,

20 ,, ~'~ r

C I . - , ' 24 ~

32

Ro L~ w

• ~ . . ~ 14

2 2 ~,~ 2 4 ~ s.~

c, g ~ . ~ ~ / / / L " x " c,-

ICC ~ ~ i t "

i PALL 1 13

Fig. 2. Distribution of labeled cells in the frontal cortex in case 900517. Frontal sections of the frontal cortex were taken at the indicated distances on the dorsolateral and medial views of the brain of Fig. lB. Dots indicate labeled cells. The hatched area shows injection site. Numbers at the upper left of each section indicate distances in mm from the frontal pole. Arrowheads or arrows indicate cytoarchitectural borders. Dashed lines show regions of damaged or lost tissue. These conventions also apply to the subsequent figures.

T. Arikuni et aL / NeuroscL Res. 21 (1994) 19-39

900517

26 : ~ ~ " , p ~ P

...;:.~

3 0 A 61,~

,~UlA

Ci

q

\ \ ,o

~ LF

40 ~p.es~LL

LF

STS

S

Fig. 2 (continued).

25

in layer V and some were scattered in layer III. The labeled terminals were distributed in all cortical layers.

Area 29 consists of supracallosal, retrosplenial, and temporal parts, and the temporal part of area 29 is further subdivided into areas 29 m and 29 1 (Insausti et al., 1987). Of those subfields, only area 29 1 contained HRP- labeled terminals in layer I. No labeled cells were found in area 29.

We identified the medial bank of the rostral part of the occipitotemporal sulcus as area TE, because it had layers V and VI that were slightly different from those of area TF and a better developed layer IV. Suzuki and Amaral (1990) designated this region as a transition zone between area TF and area TE. A moderate number of labeled cells and terminals were seen in area TE on the medial and lateral banks of the beginning of the oc-

26 7~ Arikuni et aL /Neurosci. Res. 21 (1994) 19-39

cipitotemporal sulcus. The labeled cells were distributed in layers III and V, and the labeled terminals were present in all cortical layers with a lower density in layer IV.

The prosubiculum of the hippocampal formation in the macaque monkey was defined as a region between the CA1 subfield of Ammons horn and the subiculum (Lorente de N6, 1934). The prosubiculum lacks the

stratum radiatum, and it contains smaller pyramidal cells in the upper part of the pyramidal layer as compared with those in the CA1 subfield and the subiculum. A considerable number of labeled cells were found in the pyramidal layer of the prosubiculum over its entire rostrocaudal extent (Figs. 3, 7D). As shown in frontal sections at the level 8 to 12 mm from the temporal pole

900517

6

14

/ . / ~ sTs

36 16

8 ~ • "' ms

STS " ' " " • . . .

36

18 STS

l0

36

12

Amy : . ~ ':" STS

36

Fig. 3. Distribution of labeled cells in the medial temporal cortex in case 900517. Frontal sections were taken at the indicated distances in mm from the temporal pole at the upper right or left of each section.

71 Arikuni et al. INeurosci. Res. 21 (1994) 19-39 27

900517 ( ~ ~ 22

23

r~

° ~ 2 4 o

( -

TE-"--%TS~__

T E O T S

Fig, 3 (continued).

in Fig. 3, a few labeled cells were scattered in a region immediately ventral to the white matter under the amygdala. This labeled region was identified as the most rostral part of the prosubiculum. In the prosubiculum, the labeled cells were more numerous in the caudal part of it than in its rostral part. Some labeled cells were also found in the pyramidal layer of the CA 1 subfield of Am- mon's horn adjacent to the prosubiculum. The labeled terminals were densely distributed in the molecular and pyramidal layers of the prosubiculum and in the molecular layer of the CA1 subfield (Fig. 7D). In this case, no labeled cells or terminals were seen in the subiculum.

HRP-labeled terminals were always present in the external pyramidal lamina of the presubiculum over its

entire rostrocaudal extent, but not in the internal pyramidal lamina. This supports an early report of Adey and Meyer (1952) that ablation of the anterior cingulate cortex produced terminal degeneration in the small-celled zone of layers II and III in the presubiculum of the monkey. No labeled cells were found in the presubiculum.

3.3. Distribution of HRP-labeled cells and term&als in the frontal and medial temporal cortices in case 901113

In case 901113, the injection site was not confined to areas 24a and 24b at the level of the genu of the corpus callosum, and included a part of area 24c on the ventral bank of the cingulate sulcus, the cingulum bundle, and a part of the corpus callosum (Fig. 4). It is possible that

28 T. Arikuni et al. I Neurosci. Res. 21 (1994) 19-39

901113 sA " 24

"I i~ A

SA, ~ 26 . f"

LI

, . , 2 8 °.o :. 30

6a~ S

24

LF

STS

Fig. 4. Distribution of labeled cells in the frontal cortex in case 901113. Frontal sections were taken at the indicated distances in mm from the frontal pole at the upper right of each section. The injection site is shown in black.

T. Arikuni et a l . / Neurosci. Res. 21 (1994) 19-39 29

901113

2 ,o 4 , , s

,ps#~

10 8 ?L.

RO ~,4

15 12 14 ,,

~ C

p ~ PS 46 ' 9

18 8B "->z:.:'

61 '~ .~.~r : ' .": .~ ~ ' :' / SMA

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CC

12 CL 32

SG /.

20 ' " 22

16

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12 ]

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46 SMA

Fig. 4 (continued).

labeling was the results of uptake of HRP not only from rostral areas 24a and 24b, but also from the rostral area 24c, the cingulum bundle fibers that pass from the prefrontal cortex to the posterior cingulate cortex or vice versa, or from the callosal fibers that innervate the contralateral frontal cortex (Nauta, 1964; Pandya, 1985: Barbas and Pandya, 1991; Insausti et al., 1992). In fact,

labeled cells and terminals in case 901113 were distributed more densely and broadly in the frontal and medial temporal cortices than those in case 900517 (Figs. 4, 5).

3.3.1. Frontal cortical regions. Labeled cells and terminals were densely distributed throughout areas 10, 9, and 8B. In these areas, labeled cells were equally densely

30 7: Arikuni et al. / Neurosci. Res. 21 (1994) 19-39

located in layers III, V, and VI, and labeled terminals were distributed in all cortical layers with a lower density in layer IV. There was dense labeling in area 46 along the principal sulcus of the prefrontal cortex. However, there was a paucity of labeled cells and terminals in area

46 on the ventral and dorsal banks of the principal sulcus at levels of 15 to 20 mm from the frontal pole. Supposing that, in this case, dense labeling in area 46 on the caudal part of the principal sulcus was due to spreading of WGA-HRP in catlosal fibers, findings from

901 1 13 18

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12 20 36 35

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8 ' 28

22 36 14 ~ "~ ~ .~r~..

s 36

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STS

36 35

Fig. 5. Distribution of labeled cells in the medial temporal cortex in case 901113. Frontal sections were taken at the indicated distances in mm from the temporal pole at the upper left of each section.

T. Arikuni et aL/NeuroscL Res. 21 (1994) 19-39 31

901113

26 32

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this case would suggest that the rostral region of area 46 is strongly connected with areas 24a and 24b of the anterior cingulate cortex. In this case, area 46 on the dorsal bank of the principal sulcus was densely labeled, as compared to case 900517.

In area 12, labeled cells and terminals were distributed in its entire region with a higher density in its rostral region, although labeling was less dense than in areas 46, 9, and 8B. A large number of labeled cells and terminals were present throughout area 8A, but only small numbers were present in area 45 on the shoulder of the anterior bank of the inferior arcuate sulcus. As in case

(continued).

900517, dense labeling was seen throughout area 32 and labeling in the orbitofrontal cortex was less dense than that in the lateral or medial prefrontal cortices, apart from area 13. In area 13, there was a number of labeled cells and terminals. Unlike area 25 in case 900517, area

25 was devoid of label. As in case 900517, the densest labeling was noted in

area 6a~ in the superior premotor cortex, while labeling was least dense in areas 6aa and 6bct in the premotor cortex around the arcuate spur. In addition, a considerable number of labeled cells and terminals were present in area 6b/~ on the gyral surface behind the most

32 T Arikuni et al. I Neurosci, Res. 21 (1994) 19-39

la tera l par t o f the in fe r io r a r cua t e sulcus and in a reas

P R C O and O F O in the in fe r io r p r e m o t o r area. T h e r e

were labe l ing in the s u p p l e m e n t a r y m o t o r a rea ad jacen t

to the c ingula te sulcus at the level o f a rea 6a/~. In con-

trast to case 900517, no labeled cells o r t e rmina l s were

seen in the m o t o r cor tex.

3.3.2. Media l temporal cortical regions. As in case

900517, labeled cells and t e rmina l s were d i s t r ibu ted in

A 900803 B

64 r 24 36

45 ( ~ ~ ~ i " ; f : ' J 2 4 ""'~: ""

"~ C[ 4

4a 44

23

z / 23

TE TF

TE

27

Fig. 6. Distribution of labeled cells in case 900803. (A) Distribution of labeled cells in the frontal cortex. Frontal sections were taken at the indicated distances in mm on the dorsolateral and medial views of the brain of Fig. 1D. (B) Distribution of labeled cells in the medial temporal cortex. Numbers at the upper right of each section indicate distances in mm from the temporal pole.


area 28 over its entire rostrocaudal extent with the ex- ception of the olfactory field of area 28. Fig. 1F shows labeled cells in layer V in area 28 on the gyral part of the entorhinal cortex. There were a number of labeled cells and terminals in the perirhinal cortex (areas 35 and 36): they were confined to the lateral bank of the rhinal sulcus at its rostral level, while they were present both in the lateral bank of the rhinal sulcus and in the gyral part of the perirhinal cortex at its caudal level. Such labeling in the gyral part of the perirhinal cortex (area 36) was not seen in case 900517. Strong labeling was seen in the rostral part of area TF, while weak labeling was seen in area TH adjacent to area TF.

Area 29 1 contained only HRP-labeled terminals in all cortical layers. In case 901113, however, large numbers of labeled cells and terminals were also found in the retrosplenial part of area 29, which corresponds to the caudomedial lobule of Goldman-Rakic et al. (1984). A moderate number of labeled cells and terminals were distributed widely in area TE on the medial and lateral banks of the beginning of the occipitotemporal sulcus.

As in case 900517, a considerable number of labeled cells were present in the pyramidal layer of the prosubiculum over its entire rostrocaudal extent (Fig. 7E), and some labeled cells were found in the pyramidal layer of the CA1 subfield of Ammon's horn, Besides, there were a few labeled cells in the lower part of the pyramidal layer of the subiculum. Fig. 7E exhibits labeled terminals in the molecular and pyramidal layers of the prosubiculum and in the molecular layer of CA I subfield of Ammon's horn. In the presubiculum, only labeled terminals were found in the external pyramidal lamina.

3.4. Distribution of HRP-labeled cells and terminals in the frontal and medial temporal cortices in case 900803

In case 900803, the injection site involved not only caudal areas 24a and 24b at the level of the anterior commissure, but also area 24d, the cingulum bundle, and the corpus callosum (Figs. I C, D, 6A). Hence, connections observed in this case might include connections between the frontal cortex and area 24d, the posterior cingulate cortex, the retrosplenial cortex, or the contralateral frontal cortex, in addition to the connections between the frontal cortex and areas 24a and 24b. Since the injection site of this case included the caudal area 24a and 24b, we will briefly describe the results of this case for comparison purpose (Fig. 6).

3.4.1. Frontal cortical regions. Among the three major subdivisions of the prefrontal cortex, the lateral prefrontal cortex was the most densely and the most extensively labeled (Fig. 6A). In area 46, labeled cells and terminals were present in area 46 on the dorsal and ventral banks of the principal sulcus along its rostrocaudal extent. No iabeling was found in the most caudal part of area 46 ventral to the principal sulcus. Area 8A was densely and

extensively labeled, while area 45 was weakly labeled in the fundus of the rostral part of the inferior arcuate sulcus. Labeling in area 32 of the medial prefrontal cortex was not as dense as in cases 900517 and 901113. As in case 901113, labeling in the orbitofrontal cortex was weak, although area 11 and the rostral part of area 13 contained a large number of labeled cells and terminals.

Relatively dense labeling was found in area 6aa in the superior premotor area and the ventral bank of the arcuate spur, as compared to that in cases 900517 and 901113. There was also dense labeling in area 6a/3 in the superior premotor area (Fig. 7B). As in case 901113, areas PRCO and OFO in the inferior premotor area were densely labeled. There was heavy labeling throughout the supplementary motor area, perhaps due to the spread of HRP into callosal fibers. Sparse labeling was seen in area 4a on the medial surface of the hemisphere as well as in areas 4a and 4b on the lateral surface of the hemisphere.

3.4.2. Medial temporal cortical regions. Labeled cells and terminals were present in area 28 (the entorhinal cortex) on the medial bank of the rhinal sulcus (Fig. 7C) and on the gyral part of the entorhinal cortex over its entire rostrocaudal extent, but not in the olfactory field of the entorhinal cortex. A large number of labeled cells were seen throughout the perirhinal cortex (areas 35 and 36). Labeling was denser in the rostral part of area TF than in its caudal part: area TF was devoid of label in its most caudal part. In area TH, labeling was seen only in its rostral part. Area 291 contained only labeled terminals in all cortical layers. A large number of labeled cells and terminals were also present in the retrosplenial part of area 29. A small number of labeled cells and terminals were seen in area TE on the medial and lateral banks of the beginning of the occipitotemporal sulcus.

Labeled cells were distributed in the pyramidal layer of the prosubiculum over its entire rostrocaudal extent, with their numbers waxing and waning (Fig. 1G). Some labeled cells were found in the pyramidal layer of the CA1 subfield of Ammon's horn (Fig. IG) and a few in the lower part of the pyramidal layer of the subiculum. Labeled terminals were present in the molecular and pyramidal layers of the prosubiculum and in the molecular layer of the CA1 subfield of Ammon's horn. In the presubiculum, labeled terminals were seen only in the external pyramidal lamina over its entire rostrocaudal extent.

4. Summary of the present findings.

4.1. Frontal cortical regions The rostral regions of the lateral and medial prefron-

tal cortices and area 8A were strongly connected with subfields 24a and 24b of area 24. Area 6a/3 of the superi- or premotor cortex was strongly connected with the rostral portion of areas 24a and 24b, while area 6at~ of

34 T. Arikuni et at./Neurosci. Res. 21 (1994) 19-39

Fig. 7. Dark-field photomicrographs of frontal sections of various regions of the frontal and medial temporal cortices, showing laminar pattern of labeled cells and terminals. (A) Area 8A in case 900517. (B) Area 6a/3 in case 900803. Labeled cells are less dense in the lower part of layer IlI (IIIB). (C) Areas 28, 35, and 36 in case 900803. (D) Labeled terminals in the molecular layer of the prosubiculum and CAI subfield of Ammon's horn in case 900517. A white arrow shows a labeled cell in the prosubiculum. (E) Labeled cells and terminals in the prosubiculum and CA1 subfield of Ammon's horn at the level of the lateral geniculate body in case 901113. White triangles indicate cytoarchitectural borders.

T. Arikuni et al . / Neurosci. Res. 21 (1994) 19-39 35

the superior premotor cortex was strongly connected with the caudal portion of area 24, including areas 24a and 24b. Areas 4a and 4b of the motor cortex were weakly connected with areas 24a and 24b. In the frontal cortex, labeled cells were more densely distributed in layer III than in layers V and VI, and labeled terminals were seen in all cortical layers with a lower density in layers IV or IIIB.

4.2. Medial temporal cortical regions Large numbers of labeled cells and terminals were

present in the entorhinal cortex (areas 28), perirhinal cortex (areas 35 and 36), and areas TF and TH throughout their rostrocaudal extent; The labeled cells were located mainly in layers III and V, with the excep- tion of area 28 in which labeled cells were located in layer V: The labeled terminals were seen in all cortical layers, with a relatively low density in layer IV. In the hippocampal formation, the prosubiculum contained some labeled cells in the pyramidal layer and labeled terminals in the molecular and pyramidal layers. The CA 1 subfield of Ammon's horn contained a few labeled cells in the pyramidal layer and labeled terminals in the molecular layer. In the presubiculum, only labeled terminals were present in the external pyramidal lamina.

5. Discussion

Recent studies with retrograde tracers have provided connections between cytoarchitecturally defined subdivisions of the prefrontal cortex and area 24 of the anterior cingulate cortex. This knowledge is indispens- able for an understanding of the functional heterogeneity of the prefrontal cortex in the macaque monkey (Rosenkilde, 1979). Injection of HRP into the principal sulcal region (Barbas and Mesulam, 1985) revealed that the ventral bank (ventral area 46) of the principal sulcus is more heavily innervated by the anterior cingulate cortex than the dorsal bank of the principal sulcus (dorsal area 46), and that area 10 receives fewer projections from the anterior cingulate cortex. However, such topography of the connections was not shown in this study in terms of anatomical relationship between areas 24a and 24b and the prefrontal cortex. In contrast, our results demonstrated that area 10 in the rostral part of the prefrontal cortex was predominantly connected with the anterior cingulate cortex. Vogt and Pandya (1987) reported that subfields 24a and 24b of area 24 receive afferent from areas 9, 46, and 12 in the lateral prefrontal cortex and area 11 in the orbitofrontal cortex, whereas subfields 24c and d of area 24 receive afferent from areas 46 and 12 in the lateral prefrontal cortex, and they con- cluded that the main target of areas 24c and d is the lateral prefrontal cortex and that the main target of areas 24a and 24b is the orbitofrontal cortex. The present

study provides no information on this issue, because in no case was injection limited to area 24c or 24d.

Since areas 8A and 45 include the frontal eye field (Bruce et al., 1985; Huerta et al., 1986; Stanton et al., 1989; Gottlieb et al., 1993), these cortical regions have been extensively studied by anatomists and physiologists. Degeneration studies showed that areas 8A and 45 project to area 24 of the cingulate cortex (Pandya and Kuypers, 1969; Pandya and Vignolo, 1971), whereas autoradiographic studies failed to show a projection from area 8 to area 24 (Vogt and Pandya, 1987; Barbas and Pandya, 1989). Although several studies involving injection of HRP into the frontal eye field confirmed projection from area 8A to the anterior cingulate cortex (Baleydier and Mauguiere, 1980; Jtirgens, 1983; Arikuni et al., 1988; Bates and Goldman Rakic, 1990), Stanton et al. (1993) argued, from their autoradiographic study of the frontal eye field, that projection from area 8A to area 24 demonstrated with HRP was due to spreading of HRP into areas 46 or 12 adjacent to area 8A. In this regard, our study demonstrated that area 8A projects heavily to areas 24a and 24b, whereas area 45 projects to areas 24a and 24b to a lesser extent.

With respect to efferent from area 24 to areas 8A or 45, some researchers reported that area 24 projects to area 8A (Pandya et al., 1981; Barbas and Mesulam, 1981; H~ierta et al., 1987). Other researchers exhibited that area 24 projects more heavily to area 8A than to area 45 (Jacobson and Trojanowski, 1977; Barbas, 1988; Bates and Goldman-Rakic, 1990; Watanabe Sawaguchi et al., 1991). The latter results were supported by the present study. The reciprocal connection between the frontal eye field and area 24 of the anterior cingulate cortex may correspond to the anatomical substrate for voluntary saccade during which the anterior cingulate cortex is activated in humans (Petit et al., 1993).

Previous studies using various techniques showed that a reciprocal connection exists between the premotor cortex and the anterior cingulate cortex (Adey and Meyer, 1952; Pandya and Kiiypers, 1969; Pandya et al., 1981; Mufson and Pandya, 1984; Markowitsch et al., 1985). This connection has been also investigated in terms of cytoarchitecturally or physiologically defined subdivisions of the premotor cortex. Area 6a~ of the superior premotor area receives afferent from the upper and lower banks of the cingulate sulcus (Arikuni et al., 1980), cingulate motor area (Luppino et al., 1990), caudal portion of areas 24a, 24b, and 24c (Barbas and Pandya, 1987), or the anterior cingulate cortex (Watanabe-Sawaguchi et al., 1991), and it sends efferent to area 24 (Baleydier and Mauguiere, 1980). Area 6aa of the superior premotor area receives afferent from the caudal portion of area 24c (Barbas and Pandya, 1987), and it sends efferent to the anterior cingulate gyrus

36 T. Arikuni et al./Neurosci. Res. 21 (1994) 19-39

(Pandya and Vignolo, 1971). Area 6b of the inferior premotor area receives afferent from the upper and lower banks of the anterior cingulate sulcus (Arikuni et al., 1980; Matelli et al., 1986; Watanabe-Sawaguchi et al., 1991; Deacon, 1992), and it sends efferent to area 24 (Pandya and Vignolo, 1971; Jfirgens, 1983). Our study confirmed the previously reported reciprocal connections of area 24 with various cytoarchitectural subdivisions of the premotor cortex and, furthermore, it produced that subfields 24a and 24b of the rostral area 24 are most strongly connected with area 6a13.

In recent physiological studies of the anterior cingulate cortex, firing of movement related neurons was recorded from the dorsal and ventral banks of the anterior cingulate sulcus (Lu and Strick, 1990; Shima et al., 1991), and motor responses were elicited by microstimulation of areas 24c or 24d on the dorsal and ventral banks of the anterior cingulate sulcus, referred to as the cingulate motor area (Luppino et al., 1991). With respect to anatomical substrates for these motor responses, it has been demonstrated that the cingulate motor area has neurons that project to the spinal cord (Dum and Strick, 1991) or the motor cortex ( Muak- kassa and Strick, 1979; Leichnetz, 1986; Vogt and Pan- dya, 1987; Dum and Strick, 1991; Stepniewska et al., 1993). Therefore, it is hard to explain the labeling of the motor cortex in the present study since sites of HRP injection were located in areas 24a and 24b on the medial surface of the anterior cingulate cortex. However, in recent studies, Morecraft and van Hoesen (1992) and Tokuno and Tanji (1993) reported that the most medial part of the ventral bank of the anterior cingulate sulcus contained some labeled neurons after injection of fluorescent dye into the motor cortex in the monkey, although in a similar study Darian-Smith et al. (1993) found no labeled neurons there. Hence, sparse labeling in areas 4a and 4b in the present study may have been due to involvement of injected WGA-HRP in the medial part of the ventral bank of the cingulate sulcus. This means that the upper portion of area 24b is weakly connected with the motor cortex.

In the present study, large numbers of labeled cells and terminals were distributed in area 28 over its entire rostrocaudal extent. Pandya et al. (1981), using autoradiographic technique, reported that area 24 projects to area 28. Insausti et al. (1987) found, from retrograde experiments on the entorhinal cortex, that area 24 projects heavily to the entorhinal cortex, with the excep- tion of the olfactory field (Eo) of the entorhinal cortex (Amaral et al., 1987). Our findings were in agreement with these previous studies and, furthermore, revealed that neurons in layer V of Cajal or layer 1V of Lorente de N6 (1933) in area 28 project to areas 24a and 24b of the anterior cingulate cortex.

In the present study, a number of HRP-labeled cells and terminals were distributed in the perirhinal cortex

(areas 35 and 36) over its entire rostrocaudal extent. Data on connections between the anterior cingulate cortex and the perirhinal cortex are limited. Martin-Elkins and Horel (1992) injected WGA-HRP into area 36 of the monkey brain and observed retrogradely labeled cells in area 24 of the cingulate gyrus. Musil and Olson (1988) injected fluorescent dye into the anterior cingulate cortex of the cat and found retrogradely labeled cells in areas 35 and 36. Thus, area 24 of the anterior cingulate cortex makes reciprocal connections with the perirhinal cortex. Our findings confirmed these previous reports and, further, specified laminar sources of connections between area 24 and the perirhinal cortex, that is, neurons in layers III and V in the perirhinal cortex project to areas 24a and 24b.

It has been shown that areas TF and TH of the parahippocampal gyrus project to area 24 of the anterior cingulate gyrus in the monkey (Vogt et al., 1979; Vogt and Pandya, 1987: Martin-Elkins and Horel, 1992). The projections from area TF or area TH to area 24 were confirmed by the present study and a reciprocity of connections of area 24 with area TF or area TH was newly found. In addition, our retrograde experiments demonstrated that area TE on the medial bank of the rostral part of the occipitotemporal sulcus makes reciprocal connections with areas 24a and 24b.

Jfirgens (1983) observed labeled cells in the subiculum of monkeys after injection of HRP into the anterior cingulate gyrus at the level of the genu of the corpus callosum. Vogt and Pandya (1987) saw retrogradely labeled cells in the subiculum of monkeys after injection of HRP into areas 24a and 24b, but not in the CAI subfield of Ammon's horn. Musil and Olson (1988) also observed a few labeled cells in the subiculum of cats after injection of fluorescent dye into the anterior cingulate gyrus. In the present study, we found labeled cells throughout the prosubiculum with a few labeled cells in the CA I subfield of Ammon's horn and/or the subiculum. It seems there is a discrepancy between what we observed and the previous studies. It may be explain- ed if, in these previous studies, the prosubiculum was not clearly distinguished from the subiculum. In the present study, retrogradely labeled terminals were also seen in the molecular layers of the CA 1 subfield of Ammon's horn as well as in the prosubiculum, but not in the subiculum. It was reported that the CA1 subfield of Ammon's horn makes reciprocal connections with area TE of the inferotemporal cortex (Yukie and Iwai, 1988) and receives projections from area TH as well as the anterior cingulate gyrus (Suzuki and Amaral, 1990). Thus, in our opinion, some divisions of the association cortex, including the anterior cingulate cortex, send their axons to the CA1 subfield of Ammon's horn and prosubiculum of the hippocampal formation.

In conclusion, the present study has demonstrated that areas 24a and 24b of the anterior cingulate cortex


are strongly and reciprocally connected ipsilaterally with the lateral and medial prefrontal cortices and area 6aB of the superior premotor cortex and further with the medial temporal cortex, including the hippocampal formation. Thus, it is possible that areas 24a and 24b may constitute relays in the reciprocal pathways between the frontal cortical regions and the medial temporal cortical regions.

Acknowledgments

This study was supported in part by a Grant-in-Aid from the Human Frontier Science Program and a Grant-in-Aid by the Ministry of Education, Science and Culture of Japan.

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ipsilateral connections of the anterior cingulate cortex with the frontal and medial temporal...

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