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Cerebral Cortex V 14 N 3 © Oxford University Press 2004; all rights reserved Cerebral Cortex March 2004;14:231–246; DOI: 10.1093/cercor/bhg123

The Parahippocampal Gyrus in the Baboon: Anatomical, Cytoarchitectonic and Magnetic Resonance Imaging (MRI) Studies

Xavier Blaizot1, Alino Martinez-Marcos1, Maria del Mar Arroyo-Jimenez1, Pilar Marcos1, Emilio Artacho-Pérula1, Monica Muñoz2, Chantal Chavoix3 and Ricardo Insausti1

1Laboratory of Human Neuroanatomy, Department of Health Sciences, School of Medicine, University of Castilla-La Mancha and Centro Regional de Investigaciones Biomedicas (CRIB), Albacete, Spain, 2Laboratory of Neuropsychology, NIMH, Bethesda, MD, USA and 3Université de Basse Normandie, CHU de Caen, France

The parahippocampal gyrus, located at the medial temporal lobe, is akey structure in declarative memory processing. We have analyzedthe general organization of the parahippocampal gyrus in the baboon,a nonhuman primate species relatively close to human. This region isrostrocaudally made up of the temporopolar, perirhinal, entorhinal(divided into seven subfields) and posterior parahippocampal (areasTH and TF) cortices. The basic analysis has been performed in threebrains, serially sectioned and stained with thionin, myelin stain,acetylcholinesterase and parvalbumin, to determine cytoarchitec-tonic boundaries. Borders of all subfields were charted onto cameralucida drawings, and two-dimensional maps of the surface andtopography of the parahippocampal gyrus were made. Finally, thelimits of each parahippocampal area were then transposed oncorresponding MR images (commonly used for in vivo PET orfunctional MRI activation studies) of two animals for precise identi-fication. The general cytoarchitectonic features of the baboonparahippocampal gyrus are similar to macaques, but the size oftemporopolar cortex and the laminar organization of perirhinal andposterior parahippocampal cortices resemble humans more thanmacaque species. In conclusion, the size and structure of the baboonparahippocampal cortex makes this species very appropriate forexperimental studies on memory function.

Keywords: entorhinal, functional neuroanatomy, magnetic resonance imaging, memory, monkey, perirhinal, posterior parahippocampal, temporal pole

IntroductionThe strategic importance of the medial temporal lobe in humanmemory mechanisms for facts and events (declarative memory)has been widely demonstrated, especially in neuropsycho-logical studies performed in amnesic subjects (Rempel-Cloweret al., 1996; Corkin et al., 1997; Mishkin et al., 1997; Reed andSquire, 1997) as well as in positron emission tomography (PET)and functional magnetic resonance imaging (fMRI) studies inhealthy subjects and Alzheimer’s disease patients (Roland andGulyas, 1995; Desgranges et al., 1998; Eustache et al., 2000;Rombouts et al., 2000). However, precise knowledge of theneuroanatomy of possible subdivisions of the parahippo-campal gyrus in the human brain is still unclear, thereby theanatomical systems of declarative memory lacking from charac-terization. It is now accepted that it is not only the hippo-campus that is the key structure in memory processing, butalso the surrounding areas (entorhinal, perirhinal and posteriorparahippocampal cortices) as well (for a review, see Fletcher et

al., 1997; Tulving et al., 1999). Their implication in memoryhas also been investigated in lesion and electrophysiologicalstudies in nonhuman primates (see for a review, see Squire andZola, 1996). Indeed, several studies based on the lesion of the

hippocampus and/or amygdala plus surrounding cortical areas,i.e. the entorhinal, perirhinal and/or posterior parahippo-campal cortices, all led to declarative memory impairment(Squire and Zola-Morgan, 1991; Suzuki et al., 1993; Alvarez et

al., 1995). Since research has focused on these brain areas, ithas been shown that bilateral lesions of cortex lying the rhinalsulcus (including the lateral entorhinal cortex and perirhinalcortex) lead to an impairment in visual recognition memorytests (Meunier et al., 1993; Gaffan, 1994; Chavoix et al., 2002).Lesions of perirhinal cortex alone are sufficient to producesevere memory impairment (Malkova et al., 2001; Millien et al.,2002), while lesions limited to the entorhinal cortex aloneresult in mild visual recognition memory deficit (Leonard et al.,1995). Concerning the posterior parahippocampal cortex,the few available reports suggest that this brain area wouldbe more involved in spatial than visual declarative memory(for a review, see Squire and Zola, 1996). Activation studiesperformed in the monkey with 2-deoxyglucose (2-DG) auto-radiography (Davachi and Goldman-Rakic, 2001) or 18F-fluorodeoxyglucose (18FDG) PET (Blaizot et al., 2000)methods also revealed the implication of perirhinal cortex inrecognition memory. It is interesting to note that patients withAlzheimer’s disease (AD), in whom declarative memorydeficits are predominant (for a review, see Eustache et al.,1994), the transentorhinal area of Braak and Braak (1985) is theearliest cortical area and the most affected by neurofibrillarytangles. In the same way, a recent study of this research teamrevealed an age-related progression of tau pathology inbaboon’s brains, thus providing a unique potential model ofneurodegenerative disorders afflicting the human brain, suchas AD (Schultz et al., 2000). Interestingly, we have recentlyshown in the baboon, that impairment in visual recognitionmemory observed after rhinal cortex lesion is correlated with adecrease in glucose consumption as measured by PET inseveral brain regions, also hypometabolic in AD (Blaizot et al.,2002). Taken together, these data do not only stress theimportance of the parahippocampal gyrus and especially therhinal cortex in memory, but also point out the need toelucidate the anatomy of this brain area to determine declar-ative memory at level systems. However, if experimental datahave revealed precious information about the role of themedial temporal lobe in memory, the extrapolation to humansis more difficult. Therefore it seems relevant to assess acomparative anatomical evaluation among primate species tobe used in neuroimaging techniques such as PET (Takechi et

al., 1997; Blaizot et al., 2000) or fMRI (Logothetis et al., 1999)that can be applied, as in humans, to nonhuman primates toperform activation studies. Note that performing activationstudies in nonhuman primates allow to assess plasticity ofmemory systems and synaptic reorganization after selective

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232 Neuroanatomy of the Parahippocampal Region in the Baboon • Blaizot et al.

brain lesions, which is not possible to perform in humans. Suchactivation studies require MRI as a morphological reference toidentify brain regions significantly activated during a cognitivetask, thereby making necessary to have the best anatomicalinterpretation of MRI images based on the histological correla-tion. Thus, the knowledge and use of the cytoarchitectonicdata to determine the limits of the parahippocampal areas onthe corresponding MR images of the same animal can be veryuseful to place approximately the limits of the parahippoc-ampal areas on primates’ MR images, without the need forhistological verification.

The purpose of the present study was to determine the struc-tural organization of the parahippocampal gyrus in the baboon,specifically aiming at the correlation of histological sectionsand MR images. The data are compared to those observed inmacaques and humans to see correspondence between thosethree primate species.

Materials and MethodsThree young-adult male Papio anubis baboons (14–16 kg) were usedin this study according to the European Union rules for care and useof laboratory animals (UE 86/609/CEE).

Experimental ProtocolTwo animals underwent a MRI examination for which the MR scan-ning methodology has been described elsewhere (for details, seeBlaizot et al., 1999). Briefly, the animals were premedicated with amixture of ketamine–xylazine (6–0.6 mg/kg i.m.), intubated and thenventilated with N2O/O2 (2:1 v/v). The anesthesia was completed withketamine–xylazine (3.20–0.32 mg/kg/40 min i.m.) plus enflurane(0.5–1.5%). The head of the baboon was placed in a non-ferro-magnetic stereotaxic frame with the animal in a sphinx position.Heart rate, arterial pressure, body temperature and end-tidal CO2 werecontinuously monitored.

MR ScanningMR scanning was performed using a GE Signa 1.5 T scanner with a12.7 cm (5 inch) general purpose receive-only surface coil. MR-T1-weighted images were obtained in the coronal plane using theinversion-recovery technique (TI = 600 ms, TE = 3.8 ms, TR = 15.8 ms,FOV = 18 cm, matrix = 256 × 256, thickness = 1.5 mm).

Histological ProcedureAnimals were deeply anesthetized with enflurane (0.5–2%) andN2O:O2 (2:1 v/v) plus atracurium (0.5 ml i.v.), and perfused trans-cardially after clamping the descending aorta. Blood was washed with500 ml of saline. Fixation started with a series of 1% paraformaldehydein 0.1 M phosphate buffer (4°C, pH 7.4) at rate of 250 ml/min for6 min, followed by 4% paraformaldehyde in 0.1 M phosphate buffer(4°C, pH 7.4) at the same rate for 15 min, and subsequently at 100 ml/min for 75 min. The series finalized with 5% sucrose in 0.2 M phos-phate buffer (4°C, pH 7.4) at rate of 100 ml/min for 30 min. Brainswere cut into five blocks along the rostrocaudal axis with thebaboon’s head fixed in the stereotaxic apparatus. Blocks were thenremoved and cryoprotected in 10% glycerol and 2% dimethylsulfoxidein 0.1 M phosphate buffer during 24 h followed by 20% glycerol in0.1 M phosphate buffer and 2% dimethylsulfoxide for 2 days. Theywere then sectioned coronally at 50 µm in a freezing, sliding micro-tome. One in five sections was immediately mounted onto gelatin-coated slides and stored for cytoarchitectonic analysis after thioninstaining. The adjacent section was also mounted and stained for thedemonstration of myelin series (modification of Heidenham stain;Hutchins and Weber, 1983). Additional series were prepared for thedemonstration of acetylcholinesterase by the method of Hedreen et al.

(1985). Immunohistochemical series were prepared for demonstra-tion of the calcium binding protein parvalbumin (Swant, Bellizona,Switzerland) at a working dilution of 1:10 000, revealed with 3,3′-diaminobenzidine (25 mg in 100 ml Tris–HCl, pH 7.4 and 0.002%

H2O2). Analysis was performed under a Leica Q500IW stereomicro-scope. Drawings of coronal sections every 1.25 mm apart from thebeginning of the temporal pole until the end of the posterior para-hippocampal cortex (average distance of 17.5 mm along the rostro-caudal axis). Boundaries of each parahippocampal area were firstdetermined under detailed microscopic analysis (Insausti et al., 1995)of thionin stained sections as well as in the additional histochemicaland immunohistochemical series. They were then charted on thesedrawings to appreciate the extent and topographical organization ofeach field in the parahippocampal gyrus. We performed a two-dimen-sional unfolded map based on unfolding the line corresponding tolayer IV or the interval between layers III and V (see Fig. 5), using thefundus of the rhinal sulcus at rostral level and the transition betweenareas TH and TF (Bonin and Bailey, 1947) more caudally as base line.The unfolding method has been described previously (Insausti andMuñoz, 2001); see also the method followed by Insausti et al. (1987a,Fig. 15), for additional details on the unfolding of the temporal pole.

Results

After a brief description of the topography of the entorhinal,perirhinal and posterior parahippocampal cortices (Fig. 1),cytoarchitectonic characteristics of these subfields, used fordelimitation, will be discussed and are shown in Figures 2 and3. MRI–histological correlations are presented in Figure 4, inwhich parahippocampal subfields are delimited on boththionin stained sections (represented as drawings) and T1-weighted MR images of the same animal. Finally, a two-dimen-sional reconstruction of the ‘unfolded’ parahippocampal gyrusis presented in Figure 5. Because of the very high similarity inthe parahippocampal gyrus between macaques and baboons,topography and cytoarchitectonics will be described using thesame terminology as used by Amaral et al. (1987) and Suzukiand Amaral (1994) for the macaque. Although cytoarchitec-tonic features of the parahippocampal region is quite similaracross species, we noticed differences on the general neuronalorganization, especially in the temporal pole, where neuronallayers are less defined in baboons compared to macaques.

Gross Anatomy of the Parahippocampal GyrusThe parahippocampal gyrus is a gross morphological term thatdescribes the ventromedial area of the temporal lobe. It iscomposed of three different cortical areas, namely entorhinal,perirhinal and posterior parahippocampal cortices (see Figs 1and 2).

We first observed several macroscopic characteristics in thebaboon: the anterior and dorsal extent of the rhinal sulcus islimited as compared to macaque in which it does extend as faras the dorsal aspect of the temporal pole. Additionally, in themacaque the course of the rhinal sulcus and the hippocampalfissure are roughly parallel; in contrast, in the baboon, thelarger extension to the entorhinal cortex forms an angle. Inthe human brain, the rhinal sulcus is rather short and almostperpendicular to the hippocampal fissure (Insausti et al.,1995). These characteristics also contribute to the expansionof the temporal pole in baboons as compared to macaques,although it remains smaller than in humans. Indeed, our calcu-lations from 2D unfolded maps measurements of each area inthe baboon, indicate that the temporal pole’s surface repre-sents ∼24% of the whole parahippocampal gyrus, while itrepresents 17% in macaques and 45% in humans (Burwell et al.,1996; data not shown).

The rostralmost portion is the temporal pole. It has beenpartitioned according to criteria described previously for

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Cerebral Cortex March 2004, V 14 N 3 233

Macaca fascicularis into areas 36pm and 36pl (Insausti et al.,1987b). Behind this region, area 35 of the perirhinal cortexoccupies the fundus of the rhinal sulcus as it comes around themedial aspect of the anterior temporal lobe (Fig. 1). Ventrallyand rostrally, area 35 borders laterally the rostral entorhinalcortex and medially area 36r of the perirhinal cortex. Area 35tapers off and finally disappears at the caudal part of theentorhinal cortex (at the beginning of the hippocampal fissureapproximately). Area 36 resembles more closely the lateraladjacent visual association area TE, especially at its caudal level

(36c) as it presents columnar organization. More caudally, atthe end of the rhinal sulcus, area 36 borders area TF of theposterior parahippocampal cortex.

The caudal part of the parahippocampal gyrus is formed byareas TH and TF of the posterior parahippocampal cortex, incaudal continuation with the entorhinal and perirhinal corticesrespectively. At the end of the rhinal sulcus, it lies beneath thebody and tail of the hippocampus. TH borders the subfield ECL

rostrally and area TF laterally (except for a short tongue ofparasubiculum, not included in the unfolded map of Fig. 5).

Figure 1. Localization of the entorhinal, perirhinal and posterior parahippocampal cortices, and their subdivisions on ventral and ventro-lateral views of a baboon’s brain.Abbreviations: EC, entorhinal cortex; EO, olfactive field of the entorhinal cortex; ER, rostral field of the entorhinal cortex; ELr, lateral rostral field of the entorhinal cortex; ELc, lateralcaudal field of the entorhinal cortex; EI, intermediate field of the entorhinal cortex; EC, caudal field of the entorhinal cortex; ECL, caudal limiting field of the entorhinal cortex; PC,perirhinal cortex; 35, Brodmann’s area 35; 36, Brodmann’s area 36; 36pm, 36 medial temporopolar; 36pl, 36 lateral temporopolar; 36r, 36 rostral; 36c, 36 caudal; PHP, posteriorparahippocampal cortex; TH and TF, posterior parahippocampal areas of Bonin and Bailey (1947); TE and TEO, visual associative areas of Bonin and Bailey ( 1947); PIR, piriform cortex;PAC, periamygdaloid cortex; STG, superior temporal gyrus; sts, superior temporal sulcus; amts, antero-medial temporal sulcus; H, hippocampus; A, amygdala; PrS, presubiculum;PaS, parasubiculum; S, subiculum; rs, rhinal sulcus; hp, hippocampal fissure.

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This latter is bordered laterally by the visual associative areasTE and more caudally TEO. Rostral to TF, lies the area 36c andcaudally is bordered by the visual area OA (Bonin and Bailey,1947) or V4 (Zeki, 1971).

Cytoarchitectony of the Parahippocampal Gyrus

Cytoarchitectonic Organization of the Entorhinal Cortex

The entorhinal cortex is located at the ventromedial part of thetemporal lobe. About one-half of the rostral extent of theentorhinal cortex lies under the amygdaloid complex, whilethe caudal half, starting at the hippocampal fissure, is associ-

ated with the uncal portion of the hippocampus. Theentorhinal cortex is bordered medially and rostrally by thevertical extension of the rhinal sulcus (Figs 1 and 2). Rostrallyand dorsally, the piriform and the periamygdaloid (area 51;Brodmann, 1909) cortices border the rostral entorhinal cortex.The posterior portion of this limit is indicated by a shallowgroove, the sulcus semiannularis, that separates theentorhinal and periamygdaloid cortices. Laterally, theentorhinal cortex extends as far as to the fundus of the rhinalsulcus, bordering area 35 rostrally and 36c caudally.

The baboon entorhinal cortex as in the fascicularis monkey(Amaral et al., 1987) can be partitioned into seven distinctsubfields, based on their cytoarchitectonic features. Thedistinction among subfields is based on the changing cytoarchi-tectonic features along the rostrocaudal and mediolateral axes,thus defining olfactory (EO), rostral (ER), intermediate (EI),caudal (EC) and caudal limiting (ECL) subfields. Those subfieldsare bordered laterally by two subfields, lateral rostral (ELr) andlateral caudal (ELc), both located at the medial bank of therostral half of the rhinal sulcus, up to the point where therhinal sulcus becomes shallow. Of all the subdivisions, EO is the

Figure 2. Series of photomicrographs (a–g) of coronal thionin-stained sections of theright hemisphere of a baboon used in this study. Boundaries were determinedmicroscopically (magnification ×1.6) from the cytoarchitectonic characteristics of eachsubarea and are represented by dark lines, from the temporal pole to the end of theposterior parahippocampal cortex. The nomenclature used to identify brain areas is thesame as used in Amaral et al. (1987). (h) Photomicrographs of coronal sections at twolevels of the medial temporal lobe of the baboon AB2 stained with (A) parvalbumin (atthe level of the posterior part of the amygdala) and (B) acetylcholinesterase (at thelevel between amygdala and hippocampus). On both images, transition between area35, and ELR and ELC, on one side, and 36r on the other side can be distinguished, as wellas between area 36 and TE can also be observed.

Figure 2. (b)

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only one characterized by its cytoarchitectonic features and itsconnectivity; as in the case of the M. fascicularis monkey it islikely that EO receives direct connections from the olfactorybulb as already described (Amaral et al., 1987; Insausti et al.,2002).

We recognize in the baboon six layers in the entorhinalcortex (Fig. 3a) following the scheme of layering described inmacaques by Amaral et al. (1987), who, in turn, followed theconcept of Lorente de Nó (1934). Although layers are desig-nated I–VI, they are not transposable to those of the neocortex.Layer I is a plexiform layer that tends to be thicker at posteriorlevels. Layer II is one of the most characteristic of theentorhinal cortex. It is a layer made up of cell aggregates(islands) of relatively large and darkly stained pyramidal andstellate cells. The islands are distributed all over the entorhinalcortex, although they tend to be thinner rostrally. There isusually an acellular gap between layers II and III that tends toincrease caudally. Layer III is made up of a relatively homo-genous population of medium-size pyramidal cells, with anincreasingly more columnar organization laterally as well as

caudally. In contrast, rostral and medial portions of theentorhinal cortex are characterized by the arrangement of layerIII pyramids into clusters. One of the most typical features ofthe entorhinal cortex is the absence of an internal granularlayer (layer IV), being replaced by a cell-sparse zone calledlamina dissecans, especially noticeable at mid-rostrocaudallevels. Layer V is made up of large and darkly stained pyramidalneurons; it merges with deep layer III at rostral levels, whilethey are separated by the lamina dissecans at mid and caudallevels. More caudally, layer V gets thicker and can be dividedinto three sublayers: Va, the most superficial, is made up of thelargest pyramidal neurons of the whole entorhinal cortex; Vb,the middle sublayer, contains a larger proportion of smallercells; and Vc contains only few neurons and looks like anacellular band. Layer VI is characterized by the presence ofpolymorphic neurons, easier to identify caudally. Interestingly,it does not present a coiled appearance in the baboon, incontrast to layer VI in the entorhinal cortex of the fascicularis

monkey, thereby being more akin to layer VI of the human

Figure 2. (c) Figure 2. (d)

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entorhinal cortex. In the same way, the border between layerVI and the white matter is quite clear caudally, while itbecomes more blurred at rostral levels.

As mentioned above, the entorhinal cortex of the babooncan be partitioned rostrocaudally into seven subfields based onthe cytoarchitectonic analysis. (Fig. 3a):

EO (Olfactory Subfield of the Entorhinal Cortex). Layer II isvery thin or absent in patches. Layer III is made up of clustersof neurons. No lamina dissecans is present and layers V and VIare fused and not easy to differentiate.

ER (Rostral Subfield of the Entorhinal Cortex). Layer II isthicker than in EO, with islands of multipolar, darkly stainedcells separated by wide cell-sparse zones. As in EO, layer III ismade up of large and irregular patches of neurons (darker andbigger in the outer part) separated by cell-sparse areas. Layer IVis absent except for the caudal most portion, where it can bedemonstrated by myelin stain while layer V presents an incom-plete sublamination.

ELr and ELc (Lateral Rostral and Lateral Caudal Subfields of

the Entorhinal Cortex). Along the rhinal sulcus and close toarea 35, EL is different from the more medial areas ER and EI atthe level of the layers V and VI, that are quite similar to thoseobserved in area 35 with big and darkly stained neurons.Furthermore, sublamination of layers V and VI in EL is less

evident than in EI, ER or EC. EL can be divided in two sub-fieldsELr and ELc because of the differences observed in layer II andIII: Layer II in ELr, near the rostral border of the entorhinalcortex, is made up of wide islands of darkly stained neurons.These islands become wider at more caudal levels, in ELc, andtend to form a continuous and homogenous band. In the sameway, layer III of ELc is notably more homogenous because ofthe presence of small cells that fill in the gaps seen in ELr, thusincreasing the cell density.

EI (Intermediate Subfield of the Entorhinal Cortex). EI is thelevel of the entorhinal cortex more representative of theentorhinal cortex. Layer II is made up of islands of multipolarcells. The inner cells of layer II merge in columns with the

Figure 2. (e)

Figure 2. (f)

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superficial layer III neurons, while the deep portion of layer IIIis more continuous in appearance, what is reminiscent of layerIII of EI in humans. Lamina dissecans is clearly present as anacellular band. Furthermore, EI presents a marked sublamina-tion in layer V with a clear sublayer Vc.

EC (Caudal Subfield of the Entorhinal Cortex). Overall, EC

has a more columnar appearance. Layer II presents wideislands of big, stellate neurons. By contrast, layer III has arather homogenous appearance with a hint of columnar organ-ization. Lamina dissecans is no longer noticeable in Nissl stain,although very rostrally in EC, myelin stain produces a band thatcorresponds to lamina dissecans. Finally, as in EI, sublayers oflayer V in EC can be easily distinguishable.

ECL (Caudal Limiting Subfield of the Entorhinal Cortex). ECL

is located at the caudal extreme of the entorhinal cortex and isfollowed caudally by a medial extension of the parasubiculumfor a short distance, to be replaced by area TH of the posteriorparahippocampal cortex. Layer II is thicker and more contin-uous (wider cell islands) than any other portion of theentorhinal cortex. Layer III is thinner and more columnar thanEC and lamina dissecans is totally absent. In contrast to EC, thesublamination in layer V is less clear, especially at the level ofsublayer Vc.

Cytoarchitectonic Organization of the Perirhinal Cortex

(Areas 36pm and 36pl, 35, 36r and 36c)

Perirhinal cortex is included as proisocortex or mesocortex, inthe sense that it is a transitional type of cortex, between alloco-

rtex (and periallocortex, i.e. entorhinal cortex) and neocortexas it does not show the full typical features of the neocortex(Braak, 1980; Gloor, 1997). In general, we have followed thedescription of Insausti et al. (1987a) for temporopolar cortexand the cytoarchitectonic features described by Suzuki andAmaral (1994) for the Macaca fascicularis monkey for theremainder of perirhinal cortex. The baboon perirhinal cortexhas in general cytoarchitectonic characteristics comparable tothe fascicularis monkey brain.

Temporal Pole. The temporal pole is included as the mostrostral and dorsal part of the perirhinal cortex (Insausti et al.,1987a). Ventrally, it is bordered by area 36r of the perirhinalcortex, laterally and dorsally by the superior temporal gyrus,while medially and dorsally it is replaced by piriform cortex(adjacent to the limen insulae) and dorsal portion of area 35 ofthe perirhinal cortex (Fig. 1).

The temporopolar cortex or area 36p in the baboon ischaracterized by a rather thin layer II, which is discontinuous

Figure 2. (g)

Figure 2. (h)

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at the ventromedial portion and forms small clusters of darklystained neurons, while it becomes quite homogeneous in thedorsolateral field. This feature is the basis to recognize a polar-medial division (area 36pm) that contains clusters in layer II,and a polar-lateral (36pl) division with a continuous layer II(Fig. 3b). Both areas, 36pm and 36pl display the same cyto-archotectonic features in the remainder of the layers. Layer IIIis thick, populated by medium to big pyramids that often

present a gradient from superficial to deep levels. Layer IV isthin but recognizable, while layer V is thick and populated bydarkly stained, large pyramids. The limit between layers V andVI is blurred especially rostrally.

Area 35. Area 35 is the agranular portion of perirhinalcortex. It parallels closely the course of the rhinal sulcus bothat its ventral portion — where it is bordered medially by the

Figure 3. Photomicrographs with high magnification of coronal thionin-stained sections of a baboon’s brain showing the cytoarchitectony of entorhinal (a), perirhinal (b) andposterior parahippocampal (c) fields. Neuronal layers are identified by the corresponding number and borders among layers are outlined by white lines.

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entorhinal cortex — and at its dorsal portion, where the rhinalsulcus takes a vertical course in the medial aspect of thetemporal pole and it is bordered by area 36pm (see previoussection).

While area 35 keeps a basic cytoarchitectonic scheme thatgives unity to the area, it is by no means uniform throughoutand although it does not seem to justify further subdivisions, ahint of the areal specification found in the human area 35(Insausti et al., 1995) can be recognized. Layer II, is prominent

and made up of clumps of darkly stained neurons. Layer III isnarrow and patchy and separated from a robust layer V by anacellular band of fibers, darkly stained in myelin stain. Layer Vis very outstanding because of the presence of large darklystained pyramids. At the vertical portion of the rhinal sulcus,layer V of area 35 is tangentially cut and takes the shape of adark ribbon under the superficial layers of the rostral subfieldsof the entorhinal cortex. Layer VI is poorly populated and littleprominent. Further confirmation of the border of area 35 with

Figure 3. (b).

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the entorhinal cortex (ELR and ELC) is provided by the histo-chemical (AchE) and immunohistochemical (parvalbumin)preparations as shown in Figure 2h.

Area 36. Area 36 is the granular portion of the perirhinalcortex. Rostrally, area 36 (area 36r, see below) borders theventral portion of area 36pm of the temporal pole, whilecaudally it runs along the lateral bank of the rhinal sulcus.Medially, it is bordered by area 35 and laterally by the infero-

temporal cortex or area TE of Bonin and Bailey (1947). Overall,area 36 has a more columnar appearance, reminiscent of thelateral neighboring area TE. The clear separation betweenlayers V and VI in TE allows the delimitation from area 36.

While area 36 shows a basic cytoarchitectonic patternunified by the presence of a clear internal granular layer (layerIV), it shows enough differences between rostral and caudalportions that warrants a subdivision into a rostral 36r and acaudal 36c areas (Fig. 3b). Area 36r is characterized by a

Figure 3. (c).

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bilaminar layer II with small clumps of darkly stained neurons.Layer III is populated with small, medium pyramids thatpresent a gradient size, more accentuated than in tempo-ropolar cortex areas 36pm and 36pl. Layer IV is present andthicker than in the temporopolar cortex, but thinner than inarea 36c. Layer V is very outstanding, with the presence oflarge, darkly stained pyramids. Layer VI contains neurons ofvarious sizes and shapes extending into the white matter.

Area 36c presents differences compared to area 36r invarious layers. Layer II is thinner and more continuous than inarea 36r. Layer III is more columnar than in area 36r and layerIV is well developed. Layer V is thick and presents big pyra-mids, darkly stained, also oriented in columns. Layer VI doesnot present differences compared to area 36r.

In contrast to the fascicularis monkey, where Suzuki andAmaral (1994) describe medial and lateral portions in bothareas 36r and 36c, this difference could not be conclusivelyobserved in the baboon.

Cytoarchitectonic Organization of the Posterior

Parahippocampal Cortex — Areas TH and TF of Bonin and

Bailey

The posterior parahippocampal cortex was described in therhesus monkey by Bonin and Bailey (1947) and divided intotwo distinct areas, TF and TH. Both together make up thecaudal portion of the parahippocampal gyrus and theycontinue caudally both the entorhinal and perirhinal cortices,behind the rhinal sulcus as far as the transition with visual asso-ciation areas (Fig. 1).

As in perirhinal cortex, the cytoarchitectonic features of theposterior parahippocampal cortex in the baboon are compa-rable, although less defined, to the fascicularis monkey asdescribed by Suzuki and Amaral (1994).

The main distinction between area TH and TF is the presenceof an inner granular layer in area TF. Area TH is the more medi-ally located of the two and it is bordered medially by thepresubiculum. Layer II is thick and continuous; layer III israther homogeneous and densely packed with small pyramids.Layer IV is absent and layer V is very outstanding by the pres-ence of large pyramids, also densely packed, in contrast withlayer VI that is more sparsely populated.

Area TF has in general a closer appearance to the adjacentneocortex. Layer II is thin and uniform. Layer III is morecolumnar that in area TH and less densely populated. Layer IV,although thin, is unmistakable. Layer V is not as conspicuous asin area TH, but still contains large and darkly stained neurons.Layer VI is fused with layer V and extends into the whitematter.

The distinction between THr (rostral) and THc (caudal) isnot as clear as in the macaque and although a gradient towarda more neocortical appearance at caudal levels is noticeable,we did not subdivide areas TH and TF into rostral and caudaldivisions as in the fascicularis monkey (Suzuki and Amaral,1994)

Inferotemporal — Area TE of Bonin and Bailey — Visual

Association Cortex

The visual association area TE (Bonin and Bailey, 1947) borderslaterally the perirhinal cortex and forms a wide band of typicalneocortex, with distinct cytoarchitectonic features, neuronsorganized into clear-cut columns (see Figs 2 and 3c). Layer IV is

much thicker than in proisocortical regions and layers V and VIare well separated.

Delimitation of the Parahippocampal Regions on MR ImagesFigure 4 shows all the subdivisions of the parahippocampalregion in case AB-3. The different subfields of the temporalpole, perirhinal, entorhinal and posterior parahipocampalcortices are approximately placed onto MRI cuts according tothe precise rostrocaudal histological level of the same case.After analyzing the cytoarchitectonics of the parahippocampalregion every 0.25 mm on thionin-stained sections of eachbrain, 15 slices, taken on average every 1.25 mm, were used forcoregistration with the 15 corresponding 1.5 mm thickness MRimages, on which we correlated the histologically definedborders with the MR image of the medial temporal lobe. Thetotal rostrocaudal extent of parahippocampal region, calcu-lated from MR images, is ∼21 mm (14 × 1.5 mm). Histologically,it extended for ∼17.5 mm (14 × 1.25 mm), the difference dueto the shrinkage occurred during histological processing andstaining, estimated at 16.6% and comparable to shrinkageobtained in other studies. Real rostro-caudal distances, i.e.calculated from MR-images, of each subfield of the parahippo-campal region as well as characteristic landmarks from the

Figure 4. Localization of the brain areas of the parahippocampal gyrus from 15 MR-images after determination on the corresponding histological slices (represented asdrawings) of the same baboon.

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beginning of the temporal pole (that can be helpful in thedelimitation of these subfields) are presented in Table 1.

Bidimensional Reconstruction of the Parahippocampal RegionFigure 5 represents an unfolded, two-dimensional map of thesurface of the whole parahippocampal gyrus, including thetemporal pole, perirhinal, entorhinal and posterior para-hippocampal cortices in the baboon. We used the fundus ofthe rhinal sulcus as a reference from which the profile of layerIV or the interval between layers III and V have been unfolded.This line has been represented in the map as the line betweenentorhinal and perirhinal cortices, artificially elongated (dottedline) rostrally as far as the dorsal portion of the rhinal sulcus(section 4 in Fig. 5) and caudally between areas TH and TF.

As revealed in the unfolded map, the temporal pole occupiesa large proportion of the parahippocampal region, especiallyarea 36pm, as compared to the macaque, although the rostro-caudal extent of the temporal pole is limited (∼5 mm for area36p). Other than that, the topography and shape of theentorhinal, perirhinal and posterior parahippocampal corticesare quite comparable to those observed in the macaque.

DiscussionIn this work we studied the anatomical and cytoarchitectoniccharacteristics of the brain areas in the parahippocampal gyrusof the baboon, i.e. the entorhinal, temporo-polar, perirhinal,

and posterior parahippocampal cortices. Overall, the generalorganization of the parahippocampal region in the baboon iscomparable to macaques (Suzuki and Amaral, 2003) andhumans (Insausti et al., 1994, 1995). However, the laminationof the different areas in this region is less defined in the babooncompared to macaques, in particular the fascicularis monkey,but more evident than in humans.

The baboon entorhinal cortex presents a characteristiccytoarchitectonic organization in seven sub-fields, EO, ER, ELR,ELC, EI, EC and ECL, as already described both in the fascicularis

monkey (Amaral et al., 1987) and in humans (Insausti et al.,1995).

In the same way, the cytoarchitectonic organization of thetemporo-polar, perirhinal and posterior parahippocampalcortices in the baboon is quite comparable in the three primatespecies. The rostral portion of the perirhinal cortex constitutesthe temporo-polar region made up of areas 36pm and 36pl,that corresponds to area TG of Bonin and Bailey (1947) and toBrodmann’s area 38. We included this region as a part of theperirhinal cortex because of the similarities of its cytoarchitec-tonic organization with the area 36 at more caudal levels, inparticular area 36r. Area 36pl, more dorsal and lateral than36pm and for which layer II is more homogenous, would beroughly equivalent to area 36d of Suzuki and Amaral (1994,2003), while the ventromedial portion 36pm would beincluded in the rostral portion of area 36r of the perirhinalcortex. Although we consider the temporo-polar cortex as a

Figure 4. Continued. Figure 4. Continued.

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rostral extension of the perirhinal cortex, its cytoarchitectoniccharacteristics are not as well defined as in 36r and 36c. Area35 of the perirhinal cortex extends along the fundus of therhinal sulcus. This agranular cortex between the entorhinalcortex and area 36r is present both in humans -where it hasbeen also called transentorhinal cortex by Braak and Braak(1985) as well as in nonhuman primates. The cytoarchitec-tonics of the lateral adjacent perirhinal area 36 resemble tothose seen in visual association area TE (Bonin and Bailey,1947), especially with its granular layer IV and its columnarappearance.

The posterior parahippocampal cortex extends from the endof the rhinal sulcus as far as the visual association area TEO.Two areas can be distinguished, i.e. the agranular area THmedially and area TF laterally, with a well defined layer IV, asdescribed by Suzuki and Amaral (1994, 2003). In this study, theauthors distinguished the rostral portion of TH (THr) from thecaudal one (THc) as well as the medial part of TF (TFm) fromthe lateral one (TFl). In the baboon, differences along the rostr-ocaudal and mediolateral axes are not very clear, and therefore,as in humans, we have not partitioned them.

MRI StudyNowadays, nonhuman primate species are commonly used infunctional studies such as PET (Perlmutter et al., 1991; Takechiet al., 1994; Eberling et al., 1995; Tsukada et al., 1997; Blaizotet al., 2000) or fMRI (Dubowitz et al., 1998; Stefanacci et al.,1998; Logothetis et al., 1999). We thus found it interesting to

delimitate the different regions that compose the parahippoc-ampal gyrus on MR images as it has been already done inhumans by Insausti et al. (1998). Indeed, although MRI isusually used for the anatomical identification of the brain areasin activation studies, after coregistration with PET images, itsresolution does not allow one to distinguish the limits betweencytoarchitectonically different areas such as, for example, thelimit between TH and TF of the posterior parahippocampalcortex.

Several neuroanatomical functional studies performed inhumans reveal the activation of the parahippocampal regionduring episodic encoding and retrieval (for reviews, see Dolanand Fletcher, 1999; Schacter and Wagner, 1999). However, theidentification of the activated brain areas is often vague,because of the lack of precise anatomical data concerning thisregion and of the nomenclature used. Furthermore, the inter-pretation of the neuronal networks revealed during activationin human studies could be strengthened by the knowledge andthe use of nonhuman primates data for which anatomicalconnections have been demonstrated (Insausti et al., 1987a,b;Suzuki, 1996; Saleem and Hashikawa, 1998; Insausti andMuñoz, 2001) because of this high similarity between humanand monkeys as also previously shown, for example, for theentorhinal cortex (Insausti, 1993).

Therefore, the overall anatomy and cytoarchitectonics of theparahippocampal region is comparable between human andnonhuman primates.

Despite of this homogeneity, we have found differences inthe general organization, especially in the rostral part of theperirhinal cortex, the temporal pole. We first observed severalmacroscopic characteristics in the baboon: the anterior anddorsal extent of the rhinal sulcus is limited as compared tomacaque in which it does extend as far as the dorsal side of the

Figure 4. Continued.

Figure 4. Continued.

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temporal pole. Additionally, in the macaque the course of therhinal sulcus and the hippocampal fissure are roughly parallel;in contrast, in the baboon they form an angle that gives a largerextension to the entorhinal cortex. In the human brain, therhinal sulcus is rather short and almost perpendicular to thehippocampal fissure (Insausti et al., 1995). But the main macro-scopic feature is the proportional extent of the temporal pole,

that is greater in baboons as compared to macaques but smallerthan in humans, as revealed by the 2D-unfolded maps of theparahippocampal region. Indeed, area 36p and especially36pm, tends to expand laterally in baboons as compared tomacaques and in a bigger extent in humans. In parallel, cyto-architectonics of this area, is more diffuse, as compared to themacaque, displaying the absence of a clear-cut lamination and

Figure 5. Unfolded two-dimensional map of the surface of the whole parahippocampal gyrus including the temporal pole, the perirhinal, entorhinal and posterior parahippocampalcortices in the baboon. The map was performed from the 15 histological cuts represented as drawings all around (see Fig. 2 for further details). The rhinal sulcus is represented asa dashed line and all fields are enclosed by solid lines. Inset, top right: Approximate orientation of the surface representation. Arrows at top left indicate the major axis of thedrawing. R, rostral; C, caudal; M, medial; L, lateral.

Table 1Distances in millimetres of various landmarks from the beginning of the temporal pole

Beginning of the entorhinal cortex

Limen insula Beginning of the amygdala

Anterior commissure Transition between amygadala and hippocampus

End of hippocampus Beginning of the posterior parahippocampal cortex

End of the posterior parahippocampal cortex

Baboon 1 4.5 5.5 7 9 10.5 25 16 21

Baboon 2 6 7.5 9 12 12 27 18 25

Mean 5.25 6.5 8 10.5 11.25 26 17 23

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a general neural organization closer to the neighboringneocortex. Patches of layer II in the entorhinal cortex are ingeneral less evident than in the macaque; the variation inneuron size as well as in staining intensity between layers (forexample, between the superficial and deep levels of layer III ofthe entorhinal cortex) is not clear in the baboon. Because ofthese characteristics, the delimitation of the parahippocampalareas in the baboon is thus harder than in the macaque andeasier than in the human species in which differences amongcytoarchitectonic features of the parahippocampal areas areless pronounced.

This cytoarchitectonic analysis seems thus to reveal agradient of complexity among primates, especially at the levelof the temporal pole which looks more developed in phyloge-netically higher species, taking into account the gyrificationdegree that is higher in baboons than in macaques (Zilles et al.,1989). Interestingly, several lesion or functional experimentalstudies have revealed the particular implication of thetemporal pole in declarative memory in primates (Murray andMishkin, 1986; Meunier et al., 1993; Blaizot et al., 2000).Furthermore, this region is strongly connected to theentorhinal cortex as well as with the field CA1 of the hippo-campus, or the orbitofrontal cortex, all known to be largelyimplicated in memory (Witter et al., 1989; Suzuki and Amaral,1990). Considering these data altogether, the followinghypothesis can be suggested: does the phylogenetic develop-ment of the temporal pole contribute to the specialization ofdeclarative memory ?

ConclusionIn this work, we have described the anatomy and cytoarchitec-ture of the parahippocampal region in the baboon. Globally, itsneuronal organization is comparable to macaques and humans.These observations allow thus to compare directly dataobtained in these three primate species in terms of neuro-anatomy to explain memory circuits and neuronal networks asrevealed by PET or fMRI. The advantage of the use ofnonhuman primates in this kind of study is the possibility toinvestigate, for example, the consequences of specific brainlesions (such as lateral entorhinal and perirhinal cortices) onbrain metabolism to explore neuronal mechanisms of reorgan-ization and/or plasticity, that will allow better understanding ofneurodegenerative disorders such as Alzheimer’s disease. Theanalysis of the parahippocampal region also revealed that itscytoarchitecture has an overall organization in baboons closerto humans than to macaques, especially in its rostral part, thetemporal pole, suggesting that this region could represent animportant site for the processing of declarative memory infor-mation, by means of its connections with the hippocampalformation and cortical association areas.

AcknowledgementsThis authors wish to thank Florence Mézenge, Carmen Ruiz and IsabelUbeda for technical help. This work was supported by the FondationFyssen, the Secretaría de Estado de Educación y Universidades and bythe Franco-Spanish project Picasso/Acciones Integradas HF 1998-0076, grant BFI-2000-0418 of the Ministry of Science and Technology,and grant GC02-022 of the Science and Technology Department, Juntade Comunidades de Castilla-la Mancha.

Address correspondence to Ricardo Insausti, Department of HealthSciences, University of Castilla–La Mancha, School of Medicine,Avenida de Almansa s/n, 02071 Albacete, Spain. Email:[email protected].

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