Department of Morphology, School of Medicine, Autónoma University, Madrid, 28029 Spain
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Abstract |
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Introduction |
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A loosely defined orbito-insular region situated in the anterior sylvian and orbital gyri and adjacent sulci of cats has long been regarded a major association cortex in this species (Imbert et al., 1966; Avanzini et al., 1969
; Loe and Benevento, 1969
; Benevento and Loe, 1975
; Fallon and Benevento, 1977
, 1978; Reinoso-Suárez, 1984
; Guldin and Markowitsch, 1984
; Guldin et al., 1986
; Hicks et al., 1989b). Although some studies have examined the cortical connections in limited parts of the region (Avanzini et al., 1969
; Cranford et al., 1976
; Guldin and Markowitsch, 1984
; Guldin et al., 1986
; Yasui et al., 1987
, Norita et al., 1991
), large portions of the orbito-insular region remain unexplored with modern tracing methods. Moreover, these previous studies have not, in general, mapped their findings with cytoarchitectonic or stereotaxic references, making it difficult to compare their data. In addition, since their lesions or tracer injections often extend to the claustrum, and this nucleus itself has widespread cortical connections (Clascá et al., 1992
), the significance of the reported findings is unclear. Although additional data is available in different studies focused on other cortical zones (Reale and Imig, 1980
; Craig et al., 1982
; Burton and Kopf, 1984
; Reinoso-Suárez, 1984
; Cavada and Reinoso-Suárez, 1985
; Reinoso-Suárez and Roda, 1985
; Room et al., 1985
; Witter and Groenewegen, 1986
; Room and Groenewegen, 1986
; Bowman and Olson, 1988; Avendaño et al., 1988
; Clarey and Irvine, 1990
; Bowman and Olson 1988; Ghosh, 1997a
,c
), it is not possible to infer from the published data data either the precise extent of the cortical territories connected to the insular region, or the relative anatomical weight of the various connections. Overall, data on the laminar origin of cortical input to the insular region, or on the comissural connections of this region, are almost nonexistent.
We set out to analyze systematically the cortical connections of the orbito-insular region with the following specific goals: (i) to elucidate the areas connected to the various areas of this region; (ii) to determine the relative anatomical weight of the various connections, their laminar origin and their paths across cerebral comissures; (iii) to gain insight into the functional realm of each field through a comparison of its cortical connections to data from previously published physiological studies; and (iv) to explore the possibility that some of these pathways resemble cortical connections described in the insular areas of Old World primates. For this study, we took advantage of data from a parallel study of thalamic connections in the cat's orbito-insular region (Clascá et al., 1997). Results show that the cortical connections of the various areas in the orbito-insular region are far more widespread and more specific to each area than previously realized, and suggest that each area may be involved in disparate aspects of cortical integration. Preliminary results have been reported previously in abstract form (Clascá et al., 1996
)
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Materials and Methods |
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Surgery
Animals were anesthetized with sodium pentobarbital (30 mg/kg), and additional doses (10 mg/kg) were administered as required throughout the surgical procedure to keep the animal arreflectic while preserving spontaneous ventilation. We exposed the target zone through a small craniotomy. To address the possibility that some cortical connections are not homogeneously distributed within the areas investigated, we performed either small injections involving limited parts of an area, or larger ones, covering most or all of the area. Under direct visual guidance, we made unilateral microinjections in the cortex of a mixture of 30% horseradish peroxidase (HRP) + 2% wheat germ agglutinin conjugated to HRP (WGAHRP). In two animals (nos 201 and 363), we injected a 50% solution of HRP in distilled water. In most cases, we made a single injection of 4060 nl. In four experiments, we made two or three contiguous deposits (60 nl each) to impregnate a more extensive zone. We adjusted the depth and angle of injection to impregnate all cortical layers as evenly as possible. In most cases, we used a 1 µl Hamilton syringe with a beveled and gauged tip; however, in experiments aimed at the deep sulcal cortex, we air-pressure injected the tracer through a glass micropipette (1525 µm external diameter at the tip) using a Picospritzer II (General Valve, Fairfield, NJ). After injection was completed, we covered the exposed cortex with a film of hemostatic gelfoam, sealed the bone with dental cement, and sutured muscle and skin. Amoxycillin (3 mg/kg/day) was administered preoperatively and throughout the postoperative period.
Histology
Between 46 and 54 h after the injection, the animals were overdosed with sodium pentobarbital (80 mg/kg), and transcardially perfused with saline (5 min), 1% paraformaldehyde + 1.25% glutaraldehyde in phosphate buffer (pH 7.4, 4°C, 45 min), and 10% sucrose in the same buffer for 20 min. We then split the brains along a coronal plane, and subsequently cryoprotected the tissue by soaking in phosphate-buffered 30% sucrose for 48 h at 4°C. Using a freezing microtome, we cut the whole brain into 50 µm thick serial coronal sections, collecting six parallel series of sections. Two series of sections were used for histochemically revealing HRP using tetramethylbenzidine (TMB) (Mesulam, 1978). These sections were then mounted, air dried, lightly counterstained with thionin and coverslipped. Other series of sections underwent either staining with cresyl violet, acetylcholinesterase histochemistry (Geneser-Gensen and Blackstadt, 1971) or cytochrome oxidase histochemistry (Wong-Riley, 1979
). The remaining series were discarded.
Microscope Examination of the Sections
For each brain, we analyzed and drew an entire series of TMB-reacted sections throughout the rostrocaudal extent of both cerebral hemispheres (one section every 250 µm). Using either a camera lucida mounted on a stereomicroscope, or an inverted projector, we traced section contours, heavier labeling and tissue landmarks (vessels, the inner borders of cortical layers I and VI, and the outer limit of layer V) as revealed by the thionin counterstain at 6x. Subcortical fibers, anterogradely labeled axon terminals and faintly labeled cell somata were subsequently recorded, re-examining the sections under brightfield and/or darkfield optics and polarized light at 50300x in a Zeiss microscope. This was done by hand on the camera lucida drawings, using the previously drawn labeling and tissue landmarks as references for accurately positioning the labeling.
Delineation of Cortical Areas
Correct identification of the areas labeled by the axonal transport required comprehensive delineation of the cat's cerebral areas adjusted to stereotaxic coronal planes. To this end, we revised and updated the Reinoso-Suárez map (Reinoso-Suárez, 1984) with data collated from a large number of studies from this and other laboratories. For clarity, the studies relevant for the delineation of each area are referenced with the abbreviations given in Table 1
. Figure 1
summarizes the resulting cortical map over flat medial and lateral views of the cat's cerebral hemisphere. In this type of diagram, the anteroposterior extent of the areas is accuratedly matched to stereotaxic coronal planes, but the relative extent of sulcal cortex becomes substantially underrepresented. The map is not based on the analysis of any single brain but, rather, it represents an idealized average shape and extent of cortical areas. As a working diagram, this map may need revision as new experimental data become available.
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We first analyzed and reconstructed the injection sites. We considered valid for subsequent analysis only the injection experiments which had impregnated all cortical layers in a roughly proportionate manner, and had no significant spread of tracer to the subcortical white matter or the claustrum. A total of 13 injection experiments that did not meet these criteria were discarded. The results reported here, therefore, are based on the analysis of a total of 18 valid cases (Figure 2).
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Analysis of the Cortical Labeling
In our material, the cytoarchitecture revealed by the thionin counterstain of the TMB-reacted sections made it possible to delineate most of the cortical fields. When thionin staining was inconclusive, adjacent cresyl violet or acetylcholinesterase stained sections were used to elucidate the border of a cortical field. However, a number of fields, such as the extrastriate visual areas in the suprasylvian sulcus (Tusa et al., 1978; Tusa and Palmer, 1980
; Updyke, 1986
; Grant and Shipp, 1991
), or the auditory fields in the anterior ectosylvian and posterior ectosylvian gyri (Reale and Imig 1980
; Clarey and Irvine, 1990
; Winer, 1992
), are largely defined by physiological mappings, and in these regions we relied on gyral patterns and stereotaxic references reported in the original studies.
The spread of labeling across the cerebral hemispheres and the large number of sections tended to obscure the relative weight of the various projections. We therefore decided to complement the examination of single sections with a numerical analysis of labeled cells, area by area, across an entire series of sections. It must be emphasized that these counts were never intended as a quantitative estimate of the actual total population of labeled cells, but rather as an aid in perceiving the overall amount of the various sets of labeled neurons. Cell counts were made by hand on the section drawings. The resulting numbers fluctuated widely between the various experimental cases (range 5775969 cells; mean ± SD 2344 ± 1341). To normalize for comparison between experiments, cell numbers were converted to percentages against the sum of all the labeled cortical cells counted in the same experiment.
To visualize the spatial distribution of the labeled connections across the cortical mantle, we generated reconstructions of the labeling onto lateral and medial views of the individual cerebral hemispheres. In these reconstructions, the individual labeled cells in each serial section were represented as dots along parallel lines matched to the anteroposterior level of the section.
In addition to labeling in the cortical gray matter, examination of TMB-stained material under dark-field and polarized light revealed the entire course of the axons through the white matter, including the interhemispheric comissures. We recorded these fibers on the drawings of the serial coronal sections. To facilitate comparison between cases, we reconstructed, section by section, the position of the labeled interhemispheric axons on a standard midsagittal section of the cat's cerebral commissures.
To determine the cortical layers of origin for the labeled projections more precisely than by an inspection of single sections, we decided to count, for each area in both cerebral hemispheres, the neuronal somata labeled either in the superficial (IVII) or deep (VVI) cortical layers. We then calculated the ratio between both groups of layers, and subsequently compared the ratios of the various areas.
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Results |
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Area GI encompasses the posterodorsal orbital gyrus and ventral lip of the orbital sulcus between anteroposterior planes (AP) +20 and +17 (Clascá et al., 1997). Four experimental cases (nos 983, 935, 818 and 847) have injections restricted to, or primarily located in, area GI (Fig. 2
).
The representative GI case is no. 983, illustrated in Figures 4 and 5AD. Labeled cells are spread over a broad zone of the injected hemisphere. Heavy labeling is located in (i) the dorsal bank of the anterior ectosylvian sulcus (fourth somatosensory area, S-IV), as well as nearby zones of the anterior ectosylvian gyrus (second somatosensory area, S-II); (ii) sectors of the lateral bank and bottom of the presylvian sulcus that include area 6a
(Avendaño et al., 1992
), and the dorsal border of the dorsolateral prefrontal sector (DlP) (Cavada and Reinoso-Suárez, 1985
); (iii) areas 3a, 3b and 4 in the dorsal lip of the coronal sulcus and adjacent portions of the sygmoid gyri; (iv) a ventral zone of area 2 in the dorsal bank of the orbital sulcus; and (v) the fifth somatosensory area (S-V) (Mori et al., 1991
) in the dorsal bank of the suprasylvian sulcus. There is additional labeling in both lips of the cruciate sulcus (areas 6a
and 6aß, and medial sectors of areas 3a and 4), in the dysgranular insular area, as well as in caudal and ventral portions of the anterior ectosylvian sulcal cortex1 (fields PAE and VAE). In the medial aspect of the hemisphere, numerous cells are labeled in area 7m (Avendaño and Verdú, 1992
) and adjacent zones of the posterior cingulate area (CgP). A further collection of cells is labeled in the medial bank of the posterior rhinal sulcus (area 35 and the dorsolateral entorhinal area, DlE). In the contralateral hemisphere, areas GI, DI, S-IV, S-II and 3a contain the largest numbers of labeled neurons; however, in contrast to the injected hemisphere, no cells are labeled in 7m and S-V (Figs 4 and 5B
).
In most areas, the distribution of anterogradely labeled fibers closely matches that of the labeled somata (Fig. 5A,B), although there appear to be some differences in the overall amount of anterograde labeling in the various areas. The heaviest anterograde labeling is present in areas S-IV, 3a and 6a
, where it is arranged in a columnar fashion that largely matches the distribution of the retrogradely labeled somata. On the other hand, areas 3b, S-II and the motor fields of the cruciate sulcus show faint anterograde labeling (Fig. 5C,D
). In most areas, layers I, III and VI contain the densest aggregates of anterogradely labeled fibers and terminals.
The remaining three GI injection experiments (Fig. 6) largely concur with the findings in case no. 983. On the other hand, each case shows some particular features that, at least in part, may reflect the specific location of the tracer deposits within GI. For example, the injection in no. 935 partially overlaps that in no. 983, but it also spreads to a more rostral and dorsal portion of GI (Fig. 2
). Compared to case no. 983, labeling in no. 935 is almost absent in areas 5, 7m and Cg; even scarcer in 3b; but fairly heavier in S-II and PAE (Figs 3 and 6
). Likewise, in case no. 818, which involved a caudodorsal portion of GI as well as a small border zone of the ventral anterior ectosylvian field (VAE), labeling of the somatosensory cortex is less extensive, and mainly restricted to S-IV, 3a, S-II and S-V. Moreover, areas weakly labeled in case no. 983, such as area 36 and the anterolateral lateral suprasylvian area (AlLS), contain significant labeling in no. 818. Case no. 847 received a large tracer deposit that encompasses most of GI and two small bordering zones of areas DI and AId. Despite the fact that the zone impregnated nearly doubles in extent that of no. 983 (Fig. 2
), this injection basically yielded the same labeling pattern, with some additional cells and fibers labeled in area 36 of the perirhinal cortex, as well as in the infralimbic (IL), prelimbic (PL) and anterior cingulate (CgA) areas.
Injections in the Dysgranular Insular Area (DI)
Area DI extends over the anteroventral aspect of the orbital gyrus and the lateral lip of the presylvian sulcus between AP +22 and +18 (Clascá et al., 1997). Two valid experimental cases (nos 851 and 907) have injections centered in DI (Fig. 2
).
Case no. 851 is described as the representative, and illustrated in Figures 7 and 8A,C. The tracer deposit in this case covers a large extent of DI, along with a small border zone of AId (Fig. 2
). Despite the relatively large size of the injection, however, labeling spreads over a smaller zone than after similar, or even smaller, injections in adjacent area GI. Labeling is heavy in 6a
, DlP and 2 in the dorsal lip of the orbital sulcus, as well as in area AS. However, unlike in any of the GI-injected cases, the remaining somatosensory and motor fields are not labeled. Moreover, also unlike injections limited to GI (case nos 983, 935 and 818), there are labeled neurons in IL, and in a rostral zone of the posterior rhinal sulcus that is transitional between 35 and DlE. In addition, labeling in the gustatory area (G) is heavier than following injections in GI. In the opposite hemisphere, the densest labeling involves DI and GI. The tangential distribution of anterograde labeling basically matches that of the labeled somata. The densest anterograde labeling is present in the presylvian sulcus and area 35, where it mainly involves layers VI and I (Fig. 8A,C
).
Being limited to a rostral and dorsal portion of DI and a border zone of GI (Fig. 2), the tracer deposit in no. 907 is substantially smaller than that in no. 851. As would be expected from the smaller size of the deposit, fewer neurons are labeled in the cortex; nevertheless, their distribution is a virtual replica of case no. 851 except for the absence of labeling in the rostral perirhinal cortex and S-IV, and a few labeled cells in 3a and S-V (Figs 3 and 6I
).
The minute tracer deposit in case no. 363 is placed in a region that, according to our map, corresponds to a junction zone between areas DI, GI, AId and AS (Fig. 2). Accordingly, labeling in this case (Fig. 3
) involves some of the areas labeled by injections in DI or GI (areas 4, 6, 5 and S-IV); others labeled by injections in AId (PL and AL); as well as some further areas typically labeled by injections in AS (posterior suprasylvian area, PS; temporal auditory field, Te see below).
Injections in the Agranular Insular Areas (Areas AId and AIv)
The agranular insular cortex comprises the dorsal bank and fundus of the anterior rhinal sulcus between AP +19 and +13 (Fig. 2). An isocortical agranular dorsal field (AId) extends along the dorsal bank. The ventral agranular subfield (AIv) is cytoarchitectonically transitional with the olfactory allocortex, and makes up the bottom and deep part of the ventral bank of the sulcus. Since AId and AIv are folded within the anterior rhinal sulcus, it is not easy to reach them as selectively as would be desirable, and none of our three valid injections in the anterior rhinal sulcus involved a single area independently. Moreover, the claustrum is wrapped around AId and AIv, and narrowly separated from them by a thin extreme capsule. Thus, it was technically difficult to avoid some tracer spill over the claustrum, and it was decided to include two injections with some tracer spread to the claustrum (nos 788 and 711) among the valid cases. Overall, even if none of the three valid injections in AId and AIv is per se an ideal experiment, one can draw a consistent picture of the cortical connections from the comparison of the labeling patterns in the three experiments.
The injection in no. 788 involves a sector of AId and an adjacent zone of AIv at about AP +16.5. The tracer spilled over a small ventral portion of the dorsal claustrum (Fig. 2). Cortical labeling (Figs 9 and 5E
) is confined to ventral isocortical areas and allocortical olfactory fields. The largest set of HRP-positive cells is situated in the ventral and medial frontal region [ventral prefrontal sector (VPf), IL and PL]. Area DI and portions of AS adjacent to the injection also contain numerous labeled cells. The perirhinal cortex, particularly area 35, is labeled across an extensive anteroposterior range. In the allocortex, the densest labeling involves the prepyriform cortex (PpC), while some few neurons are labeled in taenia tecta (TT). In the contralateral hemisphere, AId, VPf and 35 show the heaviest retrograde labeling. Interestingly, there are virtually no HRP-positive cells in contralateral AIv, and allocortical fields are not labeled.
Anterograde labeling is heavy in all the sectors of the prefrontal cortex, but particularly in VPf (Fig. 5E). Additional anterograde labeling is present in the medial part of 35, as well as in DlE, where it is situated deep to the lamina dissecans.
The tracer deposit in case no. 811 involves AId, AIv and AS between AP +14.5 and +16 (Fig. 2), and completely spares the claustrum. Retrograde labeling in this case (Fig. 3
) shows features similar to no. 788, plus others typical of AS injections, such as labeling of auditory fields A-2 and Te, visual fields of the suprasylvian sulcus and CgP (see below). Anterogradely labeled fibers in DI and VPf show a density and laminar distribution similar to case no. 788; however, unlike no. 788, anterograde labeling in the prefrontal cortex is mainly restricted to VPf.
The tracer deposit in case no. 711 involves AIv and the adjacent PpC. Labeling is restricted to allocortical and ventral frontal isocortical regions (Fig. 9). While labeling in the isocortical and transitional areas is circumscribed to VPf, IL, and the agranular orbital area2 (AO), labeling in allocortical fields such as TT and Pp is heavier and more widespread than the previous two cases.
Injections in the Parainsular Area (Pi)
Area Pi covers the ventral bank and bottom of the pseudosylvian sulcus, except for its caudal end. Our series includes two valid Pi injection experiments (nos 709 and 778), which are partially overlapping (Fig. 2).
Case no. 709 (Fig. 10) received an injection in the rostral tip of the ventral bank of the pseudosylvian sulcus, a zone that corresponds to the rostral third of Pi. In the injected hemisphere, the largest collections of HRP-positive cells are situated in VPf and Te. Other labeled areas include IL or PL, Te, 35 and 36. In the opposite hemisphere, aside from homotopic labeling in Pi, the heaviest labeling is situated in neighboring area Te, with some additional cells labeled in VPf, IL and PL. Anterogradely labeled fibers overlap the regions containing retrogradely labeled somata. Most abundant in VPf, Te and 36, they are mainly distributed in layers I, III and VI.
The deposit in case no. 778 is situated roughly at the center of area Pi (Fig. 2). As in the previous case, numerous neurons are labeled in VPf, Te, 35 and 36 (Fig. 10
). Additional cells are labeled in AO, in caudal portions of AS and in PL. On the other hand, unlike no. 709, large collections of cells and terminals are labeled in EP and A-2. In the opposite hemisphere, the heaviest anterograde and retrograde labeling involves areas Pi, Te, AS and 36.
Injections in the Anterior Sylvian Area (AS)
Area AS covers the rostral two-thirds of the anterior sylvian gyrus and dorsal lip of the pseudosylvian sulcus (Clascá et al., 1997), and there were six valid injection cases in this area (Fig. 2
). The representative case is no. 677 and consisted of two contiguous injections that impregnated a relatively large zone in the crown of the anterior sylvian gyrus (Fig. 2
). Several major arrays of labeled cells and terminals are present in the injected hemisphere (Figs 8B,D, 11 and 12
). One array is spread along the lateral bank and lip of the suprasylvian sulcus and adjacent portions of the posterior ectosylvian and fusiform gyri. Most of the labeling is situated in retinotopic areas PlLS, DLS, PS and an adjacent zone3 referred to as EPp (Fig. 12B,C
), while other labeling probably belongs to areas VLS, 21b and AlLS. A second array of labeled cells and terminals involves a zone of DlP (Fig. 11, 8B
), with some additional cells scattered in DmP. A third array is spread on the anterior and posterior sylvian gyri (A-2, Te; Fig. 12A
), and the ventral bank of the anterior ectosylvian sulcus (field VAE). There is a smaller labeling focus in the ventral lip of the splenial sulcus, a zone that would correspond to a border between Cg and the cingulate visual area4 (CVA; Fig. 12D
). Further collections of labeling are situated in area 36 and lateral parts of area 35 (Fig. 8D
). In the contralateral cortex, the heaviest retrograde labeling is located in AS, A-2 and VAE, and there is additional labeling scattered in PlLS, DLS, EPp and PS. However, in stark contrast to the injected hemisphere, the prefrontal and perirhinal cortices of the contralateral hemisphere are not labeled.
In general, anterogradely labeled terminals largely overlap the locations of labeled somata. Anterograde labeling is heaviest in DlP (Fig. 8B) and the suprasylvian visual areas (Fig. 12B,C
), but area 36 contains few labeled terminals (Fig. 8D
). In most areas, the densest anterograde labeling is seen in layers I, III and VI.
The remaining five valid experiments with an injection in AS involved some sectors of this field not affected by the injection in no. 677. Despite small differences, the resulting labeling patterns (Figs 3 and 13) are basically like the one just described for no. 677. The deposit in case no. 201 is limited to a rostral zone of AS that was not involved by the injection in no. 677 (Fig. 2
). In comparison to no. 677, labeling in no. 201 (Fig. 13A
) is scarcer in caudal portions of the suprasylvian sulcus, as well as in areas Te and 36. On the other hand, no. 201 has HRP-positive cells in areas not noticeably labeled in no. 677, specifically S-IV, PAE and 6aß. In a further experiment (no. 705), the injection spread over an anteroventral sector of AS within the lip of the anterior rhinal sulcus (Fig. 2
). The scarcity of labeling in the posterior sylvian gyrus and suprasylvian sulcus, and the relatively large numbers of neurons labeled in the orbital gyrus (DI, GI, AId), are salient features of this case (Fig. 13C
). The injection in no. 570 involved the crown of the anterior sylvian gyrus between AP +15 and +13 (Fig. 2
). Scant labeling of PS and of the perirhinal cortex are the only significant departures from the pattern seen in no. 677 (Fig. 13B
). A further case (no. 399) injected in a caudal and ventral portion of AS, largely spared by the injection in no. 677 (Fig. 2
), yielded fairly heavier labeling in Te, EP and VAE than in no. 677, and scant labeling of AlLS, PlLS, VLS and Cg (Fig. 13D
). The injection in case no. 760 impregnated a cortical territory that, as far as can be said from our reconstruction of the injection sites, is almost totally contained within the zone injected in no. 677 (Fig. 2
), and the labeling resembles that of case no. 677. However, the labeled cells in auditory area A-2 and the ventral auditory field (V) in no. 760 are fairly more numerous and more dorsally located than those in no. 677 (compare Figs 11H and 13E
).
Patchy Tangential Distribution of Labeled Neurons and Terminals
On the individual coronal sections, HRP-positive neurons and fibers are most often found gathered together, forming small clusters or column-like arrays of variable size, separated by zones of non-labeled or poorly labeled tissue. When serial reconstructions were made (Figs 4, 6, 7, 911 and 13), it became apparent that, in many areas, these aggregates of labeling corresponded to domains of variable size and shape that involve only limited portions of the labeled areas. In some areas, these domains are fairly small (~300800 µm in diameter; Fig. 5CE
). In other areas, the labeling spreads over wider zones; however, even here, there was a tendency to waxing and waning of the labeled cells and terminals (Figs 5A, 8A,B, 12C,E
) that suggests a preferential labeling of smaller cortical domains. Although the distance between the sections sampled precludes a more fine-grained assessment, present observations show that the cortical connections of the insular fields do not involve the whole extent of the labeled areas, but rather a patchwork of restricted cortical domains within these areas. These domains are irregularly shaped, are ~300800 µm in diameter, and are separated by zones of either non-labeled or poorly labeled cortex. Together with similar findings on the connections of the somatic, auditory and visual cortices (Avendaño et al., 1988
; Rouiller et al., 1991
; Schwark et al., 1992
, Morley et al., 1997
), our observations in a variety of sensory, association and limbic areas strongly suggest that this pattern may reflect a general underlying organization of the cortico-cortical connections.
Interhemispheric Pathways Across the Cerebral Comissures
In addition to labeling in the cortical gray matter, our experiments revealed the entire course of the axons through the white matter, including the interhemispheric comissures. Figure 14 summarizes these observations. Injections in each of the areas investigated labeled two sets of interhemispheric axons. One set followed a ventral route through the external capsule, before crossing the midline in the posterior limb of the anterior commissure, while the other set follows a dorsal route, crossing the midline in the corpus callosum.5 It is noteworthy, however, that the injection limited to AIv and PpC (case no. 711) labeled only ventrally directed commissural axons.
While the paths of ventrally directed axons labeled after injections in all areas seem to be largely overlapping, paths taken by dorsally directed axons diverge markedly with each area injected (Fig. 14). Injections in AId and AIv labeled axons in the rostroventral edge of the corpus callosum. After the DI injections, labeled fibers turn dorsally and then extend across the ventral portions of the genu of the callosum. In the brains that received injections in GI, the majority of dorsally routed commissural axons surround the tapetum, and then cross the corpus callosum between AP +18.5 and +16, with some few additional axons scattered up to AP +14.5. Following injections in AS, either in the crown of the anterior sylvian gyrus or in the dorsal bank of the pseudosylvian sulcus, the main bundle of labeled axons extends first dorsocaudally and then crosses the body of the corpus callosum between AP +12 and +10, although additional labeled axons are scattered over a broader zone (AP +13 to +7.5). Finally, following injections in Area Pi, labeled fibers form a conspicuous bundle that extends first caudally in the lateroventral wall of the temporal horn of the lateral ventricle up to about AP 1, and then turns medially, around the occipital edge of the ventricle, to join the inferior branch of the forceps minor. This bundle crosses the midline through the dorsal hippocampal commissure and ventral splenium (AP +6.5 and +3.5).
Laminar Origin of Afferent Cortical Projections
The layers with the most abundant retrogradely labeled somata were, in decreasing order, layers III, II, V and VI. This pattern can be observed in Figures 4 and 5 and 712. To substantiate our impressions based on the observation of single sections, we counted, in each experiment, the somata labeled in the infragranular (VIV) or supragranular (IVII) layers of the cortex in each cortical area in both cerebral hemispheres on all the drawn sections. The ratio of supragranular to infragranular cells was calculated for each area, and then averaged among the cases injected in the same area.
The charts in Figure 15 summarize the results of this analysis. Note that, in most cortical areas, 7595% of the projections to the insular and adjacent areas originate in layers IIIII. In fact, some projections like those of field G to DI and to GI are 9799% supragranular (Fig. 8A
). There is an interesting exception, however: ~80% of the projections from the perirhinal cortex (areas 35 and 36) to areas GI, DI, AI and AS arise from neurons in layers VVI (Fig, 15C,D).
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Discussion |
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Methodological Considerations
Injections placed in the same area produced largely similar patterns of cortical labeling in different animals. However, our quantitative and topographical analysis of the labeling consistently reveals fluctuations between cases in the relative amount and spatial distribution of the connections labeled in particular areas. Differences in the efficiency of the axonal transport labeling method are an unlikely explanation for these fluctuations, since they would affect the global amount of labeling, rather than the amount in any particular area. In our view, these fluctuations probably reflect the combination of two factors. On one hand, the distribution of cortico-cortical connections within the injected areas may not be homogeneous, but patchy. Previous data showing that injections in distant areas selectively label small, patch-like domains of the orbital or anterior sylvian gyrus (Vicario et al., 1983; Burton and Kopf, 1984
; Yasui et al., 1987
; Bowman and Olson, 1988; Musil and Olson, 1992) support this interpretation. Conceivably, our small injections could have randomly involved or spared small domains with specific cortical connections, and thus led to significant shifts in the labeling pattern. On the other hand, since each experiment was carried out in a different animal, the fluctuation may also, in part, reflect genuine interindividual differences in the relative size or topographical arrangement of the various sets of cortical connections. Individual differences have been shown to be relatively substantial in cortical connections (McNeil et al., 1997
). Some of the inconsistencies in the labeling produced by injections that, as far as can be seen from our reconstructions, were overlapping, strongly suggest such individual variation. This is the case, for example, for the extensive connections labeled in areas A-2 and V in case no. 760, which were not labeled by overlapping injections in nos 677 and 570 (Figs 2, 12 and 14
); or the lack of labeling in area 36 after the injection in no. 570, as compared to nos 760, 705 or 677.
The demonstrated existence of direct connections to cortical areas whose functional significance is fairly well understood strongly suggests particular functional affiliations for each of the areas under study. In addition, the relative anatomical weight of the various projections reaching a given area might be interpreted as indicative of their relative functional impact. Thus, many connections would suggest a strong functional impact, whereas less abundant connections might be interpreted as being functionally weaker. Nevertheless, it should be remembered that there is evidence that the anatomical weight of cortico-cortical connections does not always correspond to their functional strength (Vanduffel et al., 1997), suggesting that the functional impact of the various connections can dynamically change with the different behavioral conditions under which cortico-cortical systems are activated.
Highly Convergent Inputs from Face, Neck and Upper Limb-related Sensorimotor Regions Characterize the Granular Insular Area
The cortical connections of the dorsolateral portion of the orbital gyrus now identified as area GI had not previously been investigated with modern methods. Results show that this area is strongly associated with a wide array of somatic and motor districts in both cerebral hemispheres, with additional connections to dorsolateral prefrontal and perirhinal cortices (Fig. 16).
|
Connections with area S-IV are heavy and involve the whole extent of this field in both hemispheres. Area S-II connections are heavier in the anteroventral zones of the area, which have been shown to respond to cutaneous stimulation of the face and digits (Burton et al., 1982). Following injections in S-II and S-IV, Burton and Kopf reported labeling in the orbital gyrus, and noted the poor topographic arrangement of these connections (Burton and Kopf, 1984
). Our findings confirm these observations; in addition, they show that connections of S-II and S-IV are restricted to GI and have a markedly bilateral character. Together with previous reports (Burton and Kopf, 1984
; Barbaresi et al., 1989
), our data suggest a dense meshwork of reciprocal pathways linking areas GI, S-II and S-IV, in both hemispheres.
Although less strongly than S-IV, other zones of the anterior ectosylvian sulcus (PAE, VAE) are also linked to GI. Neurons in PAE have been shown to respond to auditory and/or somesthetic stimuli (Meredith and Clemo, 1989; Clarey and Irvine, 1990
; Wallace et al., 1992
). Field VAE, despite its marked visual character (Mucke et al., 1982
; Roda and Reinoso Suárez, 1983
; Reinoso-Suárez and Roda, 1985
; Olson and Graybiel, 1987
; Clarey and Irvine, 1990
; Wallace et al., 1992
), also contains cells that respond to somatic stimuli (Clarey and Irvine, 1990
; Wallace et al., 1992
). Thus, the connections of GI with PAE and VAE may either represent a substrate for multisensory convergence, or a further link to a set of somatosensory-processing neurons, or both.
The rostral part of the medial lip of the suprasylvian sulcus is densely linked to GI. Our experiments consistently show that this pathway is only ipsilateral. A discrete sensorimotor representation of the face and body has been described in this zone [S-V (Mori et al., 1991, 1993
)]. This labeling continues caudally in the medial bank of the suprasylvian sulcus in a lateral zone of 5a. Together with the finding by Avendaño et al. of some few cells labeled in the orbital gyrus after injections in this zone of 5a (Avendaño et al., 1988
), these observations indicate that a small reciprocal pathway links GI with area 5a. Our experiments also reveal that area 7m is linked with GI. There are indications that 7m may be closely associated to area 5, and similarly involved in somatosensory integration (Avendaño and Verdú, 1992
).
Connections with the bottom of the presylvian sulcus, a transitional zone between DlP and 6a (Cavada and Reinoso-Suárez, 1985
; Ghosh, 1997a
) are heavy and reciprocal. Neuron discharges associated with voluntary eye and neck movements have been recorded in this zone (Guitton and Mandl, 1978b
). Stimulation of this region elicits saccadic eye movements (Guitton and Mandl, 1978a
; Nakai et al., 1987
). The lateral lip of the presylvian sulcus (area 6a
) is also richly and bilaterally interconnected with GI. In our experiments, the heaviest labeling is coextensive with the zone of 6a
shown to send direct projections to the reticular formation surrounding the trigeminal motor (Yasui et al., 1985a
) and facial (Schmitt and Gacek, 1986
) nuclei. This zone has been shown to elicit complex face, jaw and tongue movements when microstimulated (Morimoto and Kawamura, 1973
; Iwata et al., 1990; Guandalini et al., 1990
; Ghosh, 1997a
). More weakly, rostral portions of 6a
also project to GI. These zones of 6a
project to the cervical spinal cord, and, upon stimulation, can evoke shoulder, neck and facial movements (Nieullon and Rispal-Padel, 1976
; Ghosh, 1997a
). Weaker GI connections involve area 4 and medial area 6. The zones containing the most labeled cells are a sector of 6a
related to the control of forelimb and trunk muscles, and portions of 4
controlling distal forelimb muscles (Nieuillon and Rispal-Padel, 1976; Yumiya and Ghez, 1984
; Ghosh, 1997a
).
Besides a main body of connections to frontal and parietal cortex, GI is reciprocally connected to a zone transitional between area 35 and the dorsolateral entorhinal cortex, an observation in accordance with reports of labeling in the dorsal part of the orbital gyrus after tracer injections in the rostral part of the posterior rhinal sulcus (Witter and Groenewegen, 1986; Yasui et al., 1987
). This region of the perirhinal cortex is connected to other somatic fields such as S-II, S-IV and area 5, and it has been suggested that this zone may be a gateway for interactions between the hippocampal formation and neocortical somatosensory areas (Friedman et al., 1986
; Witter and Groenewegen, 1986
).
Thus, it may be concluded that, as a unifying theme, GI connections mainly involve cortical regions related to the sensorimotor control of the face, eyes, neck, upper limbs and trunk. The limited physiological data available on this cortex (Korn et al., 1969; Landgren and Olsson 1980) concur with this conclusion. Moreover, thalamic input to Area GI mainly arises from spinothalamic-recipient and motor nuclei (Fig. 17
) (Clascá et al., 1997
). The available evidence is compatible with the notion that GI may be part of a complex network of cortical fields and thalamic nuclei that participate in the sensorimotor control of face, eyes, neck and upper limb. Nociceptive input may play a particularly important role in GI. Furthermore, widely converging projections from a variety of sensorimotor areas in both hemispheres suggest that GI neurons are likely to have large receptive fields, which may extend across the body midline.
|
Previous data on the cortical connections of the anteroventral portion of the orbital gyrus are scant. Our data show that, in comparison with adjacent area GI, the cortical connections of DI appear to be much more limited. The main connections involve cortical zones that are also connected to GI, such as the cortex of the presylvian sulcus, lateral area 2 and area 35 (Fig. 17). The relationship of these fields to orofacial sensorimotor control has been discussed above.
Other connections, such as those with G and IL, appear to be specific to DI. The primary gustatory cortex has not been clearly delineated in cats, although anatomical and physiological data from different laboratories (Burton and Earls, 1969; Nomura et al., 1980
; Niimi et al., 1989
) consistently indicate that a distinct portion of granular cortex extending from AP +22 to +26 and situated between DI, 3b and 6a
has thalamic connections and physiological responses equivalent to those of the primary gustatory cortex in other mammals. Like other studies (Craig et al., 1982
; Avendaño and Verdú, 1992
) we refer to this zone as area G. Our observation of reciprocal connections between DI and IL confirms earlier findings by other researchers (Room et al., 1985
; Yasui et al., 1987
).
In addition to these cortical connections, thalamic connections (Fig. 17) (Clascá et al., 1997
) indicate that DI may receive ascending input from the oral mucose and upper digestive tract. Stimulation of the vagus and splanchnic nerves was reported to evoke activity in the anteroventral orbital gyrus of carnivores (Kaada 1960
; Korn, 1966). In addition, DI may have a direct effector character, since it projects directly to the nucleus of the solitary tract and adjacent reticular formation (Yasui et al., 1990
), as well as parabrachial complex (Yasui et al., 1985b
). Cortical stimulation of the anteroventral part of the orbital gyrus was reported to elicit complex lip and tongue movements, salivation and changes in gastric motility (Hess et al. 1952
; Kaada, 1960
). Area DI of cats has yet to be explored with the modern functional techniques, but the existing evidence suggests that it may integrate non-lemniscal somatic, gustatory and visceral information from the oral mucose and upper digestive tract, and participate in the cortical modulation of the motor/secretory activity of these structures.
The Dorsal Agranular Insular Area is Linked to Limbic Neocortical Fields, While the Ventral Agranular Insular is Linked to Olfactory Areas
It is clear from the comparison of the labeling in cases no. 788, 711 and 811 (Figs 2 and 3) that the cortical connections of AId and AIv differ. Area AId is richly connected with ventral isocortical regions PfV, PL, IL, DI, 36 and 35. The finding of strong connections linking AId with VPf, IL and PL fits well with reports of labeling in the cortex of the anterior rhinal sulcus following injections in ventral portions of the gyrus proreus (Cavada and Reinoso Suárez, 1985
; Room et al. 1985
; Yasui et al., 1987
). The large extent of medial frontal cortex labeled by relatively small tracer injections in AId suggests that these reciprocal pathways are both highly convergent and highly divergent. The AIv connections, on the other hand, are basically limited to allocortical fields like Pp, TT and the olfactory tubercle. In addition, AIv has some connections with VPf, AO and IL. It is interesting to note that AId is richly connected with thalamic nuclei associated with the prefrontal cortex (mediodorsal, midline, and parafascicular nuclei; Fig. 17
), while AIv has only scant thalamic connections, and these mainly with midline nuclei (Clascá et al., 1997
).
The specific functional significance of most of the fields to which to AId and AIv are connected is poorly understood at present. In broad terms, however, the anatomical data support the notion that AId is linked to frontal and parahippocampal areas involved in the control of complex motivational and visceral behavior (Cavada and Reinoso-Suárez, 1985; Room et al., 1985
; Witter and Groenewegen, 1986
), whereas AIv may process highly elaborated olfactory information (Krettek and Price, 1977a
; Cavada, 1984
; Room et al., 1984
).
The Parainsular Area is Involved in Auditory Processing, and Closely Associated with Medial Prefrontal Cortex
There is no previous direct study of the cortical connections of the ventral bank and bottom of the pseudosylvian sulcus. Results show Pi is prominently linked with the medial prefrontal and anterior limbic cortices on the one hand, and with the perirhinal and ventral auditory cortices on the other (Fig. 17).
In the frontal cortex, the heaviest Pi connections involve VPf, and adjacent parts of IL and PL. Although our series only includes two valid Pi injections, the labeling data suggest that frontal connections are heaviest near the rostral edge of the sulcus, a result that concurs with reports of labeling in the pseudosylvian sulcus after tracer injections in VPf (Cavada and Reinoso-Suárez, 1985; Room et al., 1985
; Musil and Olson, 1991
). The finding of Pi connections with the perirhinal cortex, particularly with area 36, as well as with adjacent portions of fields Te and EP accords with descriptions of labeling in the pseudosylvian sulcus following injections or lesions in these areas (Paula-Barbosa et al., 1975
; Witter and Groenewegen, 1986
; Bowman and Olson, 1988). Areas Pi, Te and rostral area 36 are reciprocally connected, and have similar connections with the medial geniculate thalamic complex (Fig. 16
), and the lateral amygdaloid nucleus (Krettek and Price, 1977a
; Room and Groenewegen 1986
; Winer, 1992
; Shinonaga et al., 1994
; Clascá et al., 1997
). It has been proposed that these ventral auditory areas are mainly involved in the cortical modulation of emotional responses to auditory stimuli (Romanski and Ledoux, 1993).
The Anterior Sylvian Area is a Complex AuditoryVisual Field, Closely Associated with the Dorsolateral Prefrontal Cortex
As a whole, the cortical connections of AS shown in this study are in basic agreement with previous anterograde degeneration (Heath and Jones, 1971; Paula-Barbosa et al., 1975
; Cranford et al., 1976
) or axonal transport studies (Imig and Reale, 1980
; Squatritto et al., 1981
; Guldin and Markowitsch, 1984
; Reinoso-Suárez, 1984
; Reinoso-Suárez and Roda, 1985
; Cavada and Reinoso-Suárez, 1985
; Guldin et al., 1986
; Witter and Groenewegen, 1986
; Bowman and Olson, 1988b
; Norita et al., 1991
; Olson and Musil, 1992
). In addition, our findings reveal the relative anatomical weight of the various inputs, and the extent of the cortical territories that originate and receive these connections. Area AS connections mainly involve several anatomically and functionally separate regions of the cerebral cortex: (i) an array of parieto-temporal fields; (ii) the dorsolateral prefrontal cortex; (iii) perirhinal area 36; and (iv) a portion of the posterior cingulate cortex (Fig. 17
).
Parieto-temporal areas connected to AS tend to fall into three broad categories: (i) monomodal retinotopically organized suprasylvian visual fields; (ii) monomodal auditory fields; and (iii) multisensory cortices. The lateral bank of the suprasylvian sulcus contains several topographic retinal representations (Palmer et al., 1978; Tusa et al., 1979
; Updyke, 1986
; Grant and Shipp, 1991
). According to Rosenquist's parceling (Rosenquist, 1985
), AS connections involve fields PlLS and DLS, while weaker connections reach fields AlLS and VLS. While the specific role of the individual suprasylvian visual fields remains to be determined, there is evidence suggesting that PLLS and DLS are prominently involved in visually guided orientation behaviors (Hardy and Stein, 1988
; Payne et al., 1996
). Among the monomodal auditory fields, the connections involve fields A-2, Te, V and Ep (Reale and Imig, 1980
). As a whole, these ventral auditory areas have been related to motivational or emotional aspects of auditory discrimination (Shinonaga et al., 1994
; Campeau and Davis, 1995
). Multisensory parieto-temporal fields connected to AS would include PS, EPp and VAE. Fields EPp and PS are situated along the border between the visual and auditory cortical districts (Rosenquist, 1985
; Updyke, 1986
; Bowman and Olson, 1988a
,b
; Payne, 1993
). Both fields share similar cortical and thalamic connections and contain cells responding to visual stimulation with no clear retinotopic arrangement, intermingled with others responding to auditory stimuli (Palmer et al., 1978
; Updyke, 1986
). Field VAE has similarities to EPp and PS, both in terms of cortical and thalamic connections and of response properties (Mucke et al., 1982
; Roda and Reinoso-Suárez, 1983
; Symmonds and Rosenquist, 1984
; Reinoso-Suárez and Roda, 1985
; Olson and Graybiel, 1987
). However, field VAE also contains some cells responding to somatic stimulation (Clarey and Irvine, 1990
; Wallace et al., 1992
; Kimura and Tamai, 1992
; Jiang et al., 1994
).
Area AS is prominently linked to DlP. This pathway is heavy, reciprocal and basically ipsilateral. The DlP zone connected to AS is adjacent to the lateral frontal eye field of Guitton and Mandl (Guitton and Mandl, 1978a), and its connections suggest it could be similarly involved in visuomotor processing (Cavada and Reinoso-Suárez, 1985
). Congruent with previous data (Room and Groenewegen, 1986
; Witter and Groenewegen, 1986
; Yasui et al., 1987
), the present results show that AS has heavy links to 36, but few connections to 35 (Fig. 8D
). A smaller reciprocal connection links AS with a zone of CgP that has a markedly visuomotor character (Olson and Musil, 1992
; Vanduffel et al., 1995
).
The present data also correlate well with available functional studies of this cortex. For example, most cells in dorsal parts of the anterior sylvian gyrus are responsive to visual stimuli (Bignall et al., 1966; Benevento and Loe, 1975
; Hicks et al., 1988a
,b
), and this zone is richly connected with monomodal visual areas. In addition, AS has been reported to contain substantial numbers of neurons responsive to auditory stimuli, and a few of these cells are responsive to both auditory and visual stimuli (Hicks et al., 1988b
). Such neurons are reportedly more frequent in the caudal and ventral aspects of AS, a fact that may correlate with our observation that these portions of AS have scant links to monomodal visual areas and abundant connections to monomodal auditory and multisensory fields (compare the labeling in nos 201 and 570 with that of nos 705 or 399; Fig. 13
). Hicks and colleagues reported some neurons that were responsive to somatic stimuli in the anterior sylvian gyrus but they did not specify their location (Hicks et al., 1988b
). An interpretation consistent with our findings is that these somatic-responsive cells would be near the rostral border of AS, a zone that receives some projections from S-IV and GI (case nos 201 and 705; Fig. 13
).
It has been proposed that the cortex of the anterior sylvian gyrus is functionally organized as a mosaic of small neuronal clusters, each one related to the processing of a specific sensory modality (Hicks et al., 1988b). The associative character of this cortex might thus occur mainly at the population level, while at the single-cell level, most cells would remain responsive to a single sensory modality. However, studies in the adjacent VAE field suggest that multimodal convergence can take subtle forms, e.g. through the spatial congruency of the receptive fields of cells that are responsive to different modalities (Wallace et al., 1992
). Whatever the case, the available anatomical and functional data seem consistent with the notion that AS may integrate highly elaborated visual and auditory information with ongoing activity in the dorsolateral prefrontal cortex, as a part of a network of cortical areas engaged in the cortical modulation of orientation responses.
Connections within the Orbitosylvian Region
Connections between some of the areas under study are substantial, while connections between other areas are weak or absent. The connections mainly involve adjacent sectors of neighboring areas. For example DI has substantial connections with GI, but these connections appear to be restricted to the zone of GI that is adjacent to DI (note that dorsocaudal injections in GI in nos 818 and 935 produced almost no labeling in DI; Figs 3 and 5). Area GI is weakly connected to AId, and has no direct connections to AIv. On the other hand, areas DI and AId are richly interconnected. The connections of GI and DI with AS and Pi are sparse, suggesting they are more or less functionally isolated.
Divergent Pathways Across the Cerebral Comissures Reveal a Basic Heterogeneity Between the Various Fields of the Insular Region
Our data show that interhemispheric connections of the insular and adjacent areas follow both a ventral route, which crosses the midline in the anterior commissure, and a dorsal route, which crosses the midline through the corpus callosum/dorsal hippocampal commissure. This finding is in consonance with earlier observations after massive tracer injections and commissure sectionings (Jouandet, 1982; Jouandet et al., 1986
). In addition, our experiments reveal a rather unexpected spatial arrangement of these connections: despite the close apposition of the areas investigated, the paths followed by dorsally routed axons diverge widely (Fig. 14
). This divergence is suggestive of basic differences in the pathfinding cues and/or timing followed by commissural axons from the various areas during development. In addition, it should be remembered that the anlagen of the anterior commissure, the corpus callosum and the dorsal hippocampal commissure are adjacent in the early embryo, but are then widely separated by the massive enlargement of the callosum that occurs during subsequent development (Sidman and Rakic, 1982
). It is tempting to speculate that neighboring axons that selectively cross the midline through one or another commissure at relatively early developmental stages may occupy widely separated locations in the adult.
It is also striking that callosal axons from the investigated areas tend to converge at the midline with callosal axons from the cortical districts with which each area is preferentially associated. For example, connections of GI and DI extend across the genu of the callosum at the same levels occupied by motor and somatosensory callosal axons (Lomber et al., 1994; Matsunami et al., 1994). Likewise, callosal axons to and from area AS cross the midline in a central portion of the body of the callosum that is reported to contain the callosal connections of auditory, visual and cingulate cortices (Payne and Siwek, 1991
; Lomber et al., 1994
; Clarke et al., 1995
). Area AId connections cross the rostrum, a region that contains interhemispheric fibers from the prefrontal cortex (Jouandet, 1985). Very much like the adjacent olfactory cortices (Jouandet et al., 1982, 1986
; Payne, 1994), area AIv commissural connections are only established via the anterior commissure. In addition to a substantial pathway through the anterior commissure, large numbers of interhemispheric area Pi connections cross at the dorsal hippocampal commissure and rostral part of the ventral splenium, a zone that is known to contain fibers from the entorhinal cortex (Jouandet et al., 1985
, 1986
).
Laminar Distribution of the Cortical Connections
Quantification of the laminar distribution of afferent projections substantiated our initial impression that, in most cortical areas, the somata of most of the cells projecting to the orbito-insular region were situated in layers IIIII (Fig. 15). Areas 35 and 36 are the consistent exception, since they show preferential labeling of their deep layers in all cases, except in those injected in Pi. This result is in consonance with reports that areas 35 and 36 project predominantly from deep cortical layers to a variety of frontal, parietal and temporal fields (Witter and Groenewegen, 1986
; Bowman and Olson, 1988b
).
Laminar distribution of labeled cortico-cortical somata and terminals has received much attention in recent years as a morphological criterion for inferring the flow of information across the cortex (Maunsell and Van Essen 1983; Rouiller et al., 1991
; Scannell et al., 1995). Criteria for establishing such hierarchical relationships include the laminar patterns of both afferent and efferent projections. Laminar distribution of the anterogradely labeled terminals could not be reliably resolved in our material because of the possibility of dendritic and local collateral staining with WGAHRP. However, since the areas of the orbito-insular region mainly receive supragranular projections from most other areas, it is tempting to speculate that they may occupy high hierarchical levels within their transcortical networks of sensory-motor integration. Furthermore, the mainly infragranular projection from the perirhinal cortex could be taken as evidence of a feedback-type connection with the insular areas. It is to be noted, however, that the general validity of these anatomical criteria regarding hierarchy is still unclear in carnivores (Reinoso-Suárez, 1984
; Schwark et al., 1992
; Turman et al., 1992
; Kitzes and Hollrigel, 1996
).
Comparisons with Cortical Areas in the Insular Lobe of Old World Primates
Cytoarchitectonic, connective and electrophysiological studies over the past two decades have characterized a number of areas in the insular lobe of macaques. Comparison with these primate areas is relevant because the insular areas of carnivores were originally named in explicit reference to the insular lobe of Old World monkeys and anthropoids (Brodmann, 1909; Gurewitsch and Chatschaturian, 1928; Ariens Kappers et al., 1936
), and this label has persisted to the present day. However, these early comparative studies were based on criteria that would be regarded as thin, at best, by modern standards (Clascá et al., 1997
). Thus, the question as to which cortical areas in carnivores, if any, bear resemblance to contemporary definitions of areas in the insula of Old World monkeys is still open.
It is widely acknowledged that carnivores and primates have evolved along separate lines from a primitive common ancestor for ~65 million years (Northcutt and Kaas, 1995). Therefore, while it is still possible to recognize a number of area homologs based on similarities in relative position, connectivity, biochemical markers and functional properties (Payne, 1993
; Krubitzer, 1995
; Payne et al., 1996
), other cortical areas may have less obvious equivalents, and may be species specific (Preuss, 1995
). Based on thalamic connectivity and cytoarchitecture, and a review of the literature, we have recently suggested a number of equivalencies between GI, DI, AId, AIv and Pi in cats and areas characterized in the macaque insula (Clascá et al., 1997
). Interestingly, however, we could not identify a field resembling the cat area AS in the macaque insula. Findings in the present study add further support to these comparative interpretations.
Cortical connections described here for the cat GI are remarkably similar to connections described in the granular insular area of macaques. As in cats, the macaque granular insular cortex is largely, if not exclusively, a somatosensory field, with particular relation to nociception (Sudakov et al., 1971; Robinson and Burton, 1980
; Friedman et al., 1986
; Schneider et al., 1993
). The granular insular cortex of macaques is richly connected to a number of somatic and motor fields, including areas 4, S-II, and lateral zones of areas 6 and S-I (Künzle, 1977
; Mesulam and Mufson, 1985
; Friedman et al., 1986
; Barbas and Pandya, 1987
; Burton et al., 1995
). As in the cat's GI, the granular insular cortex of macaques is connected with the rostral part of the perirhinal cortex (Suzuki and Amaral, 1994
). Likewise, the granular insula of macaques is heavily linked to area 7b and the retroinsular areas (Mesulam and Mufson, 1985
; Friedman et al., 1986
; Cavada and Goldman Rakic, 1989
); S-V and S-IV of cats, both richly connected to GI, have been compared, respectively, to 7b (Avendaño et al., 1988
) and the retroinsular area (Burton and Kopf, 1984
). The granular insula of macaques is heavily connected to area 12 of the prefrontal cortex (Preuss and Goldman-Rakic, 1989
; Carmichael and Price, 1995
), and the cat GI has connections to a zone in the caudolateral part of DlP; nevertheless, it is difficult to say whether the connections bear a direct relationship, given the highly specific development of the primate prefrontal cortex (Preuss, 1995
).
In macaques, there is a dysgranular insular area that is adjacent to the primary gustatory cortex and involved in gustatory and visceral functions (Mesulam and Mufson, 1985; Pritchard et al., 1987; Ogawa, 1994; Zhang et al., 1998
). Cortical connections of this area include lateral premotor cortices, the most lateral parts of areas 6 and S-I (including the precentral and gustatory opercular cortex), area 13 of the orbitofrontal cortex, and rostral portions of areas 35 and 36 (Mesulam and Mufson, 1985
; Matelli et al., 1986
; Barbas, 1988
; Suzuki and Amaral, 1994
; Carmichael and Price, 1995
). Overall, the connections shown here for cat area DI seem to have a rather direct parallel in the above macaque connections. Likewise, a connection to area 13 of the orbitofrontal cortex in macaques (Carmichael and Price, 1995
) might have a counterpart in the connections of DI to caudal DlP.
In macaques, an agranular insular cortex with an architecture that is transitional between that of the neocortex and the prepyriform cortex (Mesulam and Mufson, 1985) has been described and subdivided into a number of subareas (Carmichael and Price, 1994
). As a whole, this macaque insula cortex is richly connected to the orbital and medial prefrontal cortex, the entorhinal and perirhinal cortex, the dysgranular insular area, and the parainsular cortex (Mesulam and Mufson, 1985
; Insausti et al., 1987
; Suzuki and Amaral, 1994
; Carmichael and Price, 1995
), a pattern that resembles that shown here for area AId. Moreover, in macaques, the most medial (ventral) agranular subareas, but not the lateral ones, receive anatomically and electrophysiologically demonstrable olfactory input from the prepyriform cortex (Carmichael et al., 1994
).
Topological relationships as well as cortical and thalamic connections (Clascá et al., 1997) (see also present results) suggest a parallel between the cat area Pi, and the agranular and dysgranular isocortex of the macaque temporal operculum (Morán et al., 1987
). In a way reminiscent of Pi, the connections of the temporal operculum involve medial frontal (areas 14, 25 and 24), perirhinal, and association auditory areas (Insausti et al., 1987
; Morán et al., 1987
; Suzuki and Amaral, 1994
). A further parallel is the scarcity of connections with the insular cortex, which, as in cats, are restricted to the agranular insular area (Mesulam and Mufson, 1985
; Morán et al., 1987
).
In the literature, the cortex of the anterior sylvian gyrus has epitomized the cat's insular cortex. However, based on the analysis of its thalamic connections, we have proposed avoiding the term insular and, instead, named it AS, according to its gross anatomical location (Clascá et al., 1997). The cortical connections reported here add further support to this view. Unlike the areas in the insular lobe of macaques, the main cortical connections of AS involve extrastriate visual, secondary auditory or multimodal (auditoryvisual) cortical fields. As pointed out above, the connections of the macaque's insular lobe are mainly with somatic, visceral, motor and limbic cortical fields. It is thus possible that area AS is specific to felines (Clascá et al., 1997
). An alternative possibility, given the highly specific expansion and gyral pattern of the cerebral cortex in Old World primates, is that fields similar to AS may be located outside the insular lobe in macaques. In this regard, the parallel connectivity and functional affiliations between the cat AS and the multimodal cortex in the caudal dorsal bank of the macaque superior temporal sulcus (Jacobson and Trojanowski, 1977; Barbas and Mesulam, 1981
; Barbas, 1988
; Yeterian and Pandya, 1989
; Huerta and Kaas, 1990) is intriguing.
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Concluding Remarks |
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Notes |
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Acknowledgments |
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Address correspondence to Dr Francisco Clascá, Department of Morphology, School of Medicine, Autónoma University, Ave. Arzobispo Morcillo 4, Madrid, Spain 28029. Email: francisco.clasca{at}uam.es.
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References |
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