1 Department of Neurology; Division of Behavioral Neurology and Cognitive Neuroscience and , 2 Department of Anatomy and Cell Biology; University of Iowa, Iowa City, IA 52242, USA
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Abstract |
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Introduction |
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Another key site of integration for object identity and location is the hippocampal formation. Lesion and imaging studies, as well as electrophysiological experiments, demonstrate involvement of the hippocampus in spatial perception, cognition and action (Burgess et al., 1997), in addition to its close association with memory-related processes. At the single unit level, `view fields' have been identified, which combine information about position in space with information about objects that are in a given spatial position (Rolls, 1989
; O'Mara et al., 1994
).
The connectional basis of this integration is likely to involve in some measure corticohippocampal connections. The hippocampal formation is densely interconnected with large sectors of the cerebral cortex; and the general importance of these connections can be inferred by the devastating effects of corticohippocampal disconnection in disorders such as Alzheimer's disease.
The principal cortical input source to the hippocampal formation is the entorhinal cortex (EC). The EC receives input from many cortical areas, directly or via multisynaptic relays through the parahippocampal gyrus. These include the parietal and temporal lobes (Van Hoesen, 1982; Amaral et al., 1983
; Insausti et al., 1987
; Selemon and Goldman-Rakic, 1988
; Cavada and Goldman-Rakic, 1989
; Andersen et al., 1990
; Suzuki and Amaral, 1994
; Saleem and Tanaka, 1996
), so that the EC might well be a source of visual and spatial convergence. Layer II of the EC projects massively to the dentate gyrus, the first step in the well-established circuit that proceeds through CA3 and CA1 (Amaral and Witter, 1989
; Witter et al., 1989
). In addition, auxiliary corticohippocampal access routes link the EC directly to CA1 and CA3. The functional importance of auxiliary connections is suggested by the persistence of spatial selectivity in neurons of CA1 and CA3 after massive destruction of the granule cells of the dentate gyrus in rats (McNaughton et al., 1989
).
In the primate, several reports have described a fourth corticohippocampal route whereby some ventromedial temporal areas project directly to CA1 (Yukie and Iwai, 1988; Shi et al., 1994
; Wellman and Rockland, 1997
; Saleem and Hashikawa, 1998
). The present study confirms temporal cortical connections to CA1, further demonstrates that there are direct connections to CA1 from parietal areas 7a and 7b, and indicates that these latter partially converge with the temporal projection focus.
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Materials and Methods |
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The six monkeys in the temporal lobe series received iontophoretic injections of Phaseolus vulgaris leucoagglutinin [PHA-L, Vector Labs, Burlingame, CA: 2.5% in 10.0 mM phosphate buffer (PB), 7 s onoff positive current cycle over 20 min]. The five monkeys in the parietal series received pressure injections of biotinylated dextran amine [BDA, Molecular Probes, Eugene, Oregon: 10% in 0.0125 M phosphate-buffered saline (PBS); 0.250.75 µl per injection]. Animals were allowed to recover and survived 1421 days after injections. They were then re-anesthetized, given an overdose of Nembutal (75 mg/kg) and perfused transcardially, in sequence, with saline, 4% paraformaldehyde and chilled 0.1 M PB with 10, 20 and 30% sucrose.
Brains were processed by frozen microtomy (at 50 µm thickness) and histology. Tracers were demonstrated by DAB histochemistry. For tissue injected with BDA (Brandt and Apkarian, 1992; Veenman et al., 1992
), this followed 24 h in ABC solution at room temperature (one drop of reagents per 7 ml of 0.1 M PBS, Elite Kits, Vector Labs). For PHA-L (Gerfen and Sawchenko, 1984
), standard immunochemical steps were followed (2 days in anti-PHA-L at 15°C at dilutions of 1:2000; and repeated 7090' steps, at room temperature, through the secondary antibody and ABC solutions. All reagents used were from Vector Labs).
Analysis was by serial section scanning at magnifications of 100400x and, for bouton analysis, at 1000x under oil. Projection foci were transposed onto section outlines via a drawing tube microscope attachment. Injection sites were localized to specific cortical areas by reference to published cortical maps and by comparing the resulting projections with known connectivity patterns. In addition, selected sections were counterstained for cell bodies to allow verification of architectonic features.
In case T5, two injections were placed close together in the lateral bank of the OTS. The more posterior injection (sections 515530) measured 0.5 mm mediolateral (ML) x 0.75 mm anteroposterior (AP); and the more anterior one (sections 560590) measured 0.5 mm ML x 1.5 mm AP. In case T7, a single injection (sections 570582) measured ~0.75 mm in diameter. In both cases P5 and P7 there were three closely placed injections which merged together, covering a region that measured 1.75 mm (P5) or 3.0 mm (P7) in diameter (Fig. 1).
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Results |
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The organization of temporal and parietal connections was similar in several respects. First, both terminated mainly in a superficial location near the hippocampal fissure in the stratum lacunosum-moleculare (Figs 24). This is the same termination zone that receives connections from the EC, and may partially coincide with subcortical afferents. Postsynaptic targets in this superficial position are most probably the distal apical dendrites of underlying pyramidal cells.
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In the mediolateral axis, projection foci in the parietal cases measured 0.40.6 mm; those in the temporal cases were slightly larger (0.7 mm). At their densest extent, foci in all cases formed a band 0.15 mm wide (Fig. 4). The actual number of axons is difficult to estimate with this technique, but may have been several hundred, at least for T5, P5 and P7. This impression is based on surveying the number of axon segments in the white matter subjacent to the projection focus at spaced intervals along its anterior, posterior and middle portions.
Third, both temporal and parietal terminations targeted the posterior portion of CA1, and appeared to converge in a similar location. The temporal foci were more extensive and continued over 10.0 mm through much of the anteroposterior axis of the hippocampal main body (Fig. 5). Parietal projections remained within the posterior 2.0 mm, despite the larger size of the injections in these cases (see Materials and Methods).
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Fifth, both sets of connections had terminal fields that appeared to form elongated rather than clustered or spherical arbors. Terminal segments of 0.75 mm, aligned mediolaterally, were common in individual sections (Fig. 3); and serial reconstruction of temporal cortical axons demonstrated that these have large fields, extending 46 mm, mainly in the anteroposterior dimension (Shi et al., 1994
).
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Discussion |
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Some of the auxiliary pathways are directly reciprocal, but others are not. That is, neurons in CA1 both receive from and project to ventromedial temporal areas (Iwai and Yukie, 1988; Yukie and Iwai, 1988
; Shi et al., 1994
; Wellman and Rockland, 1997
; Blatt and Rosene, 1998
; Saleem and Hashikawa, 1998
). CA1 sends projections to orbital and medial frontal cortex (Barbas and Blatt, 1995
), but has not been reported to receive direct projections back. CA1, as shown by our findings, receives projections from areas 7a and 7b, but has not been reported to send direct projections back (also unpublished observations based on retrograde tracer injections in areas 7a or 7b).
Direct temporal cortical connections to CA1 had previously been described after retrograde tracer injections within the hippocampus, although the exact localization of the cortical label has been controversial. Yukie and Iwai (1988) identified the projections as originating from area TE, but Suzuki and Amaral (1990)
considered the field to be within the parahippocampal gyrus. Saleem and Hashikawa (1998)
report direct connections to the hippocampal formation from the ventral part of anterior TE. Our results, especially injection T5, within the lateral bank of the OTS, support the interpretation of an origination from TE, although this may well be a functionally distinct subdivision. This is the same region that has been shown to send direct connections to primary visual cortex, by retrograde (Rockland and Van Hoesen, 1994
) and anterograde techniques (Rockland and Drash, 1996
). The suggestion that ventromedial and lateral temporal areas are functionally distinct has also been made from combined anatomical and behavioral evidence (Martin-Elkins and Horel, 1992
).
Temporal-parietal convergence
Ventromedial temporal and posterior parietal areas are intricately linked through numerous corticocortical connections and, along with the dorsolateral prefrontal cortex, are considered to form a network involved in visuospatial processing and memory (Selemon and Goldman-Rakic, 1988). Functional coupling has been demonstrated between some inferior temporal and parietal regions by imaging experiments, in conditions in which perceptual learning of faces or objects might involve spatial attention, feature binding and memory recall (Dolan et al., 1997
). The convergence of temporal and parietal connections in CA1 is consistent with recently postulated roles of the hippocampus in topographic learning (Maguire, 1997
), dynamic aspects of spatial memory (`topokinetic memory': Berthoz, 1997
), or the snapshot-like memory of objects in a complex scene (Gaffan and Hornak, 1997
; Buckley and Gaffan, 1998
). The convergence of vestibular and visual inputs (potentially from areas 7b and 7a respectively) is predicted from the physiological findings that hippocampal cells, believed to be pyramidal, respond to whole-body motion, or to combinations of wholebody motion and a view of the environment (O'Mara et al., 1994
).
Axonal divergence
Our findings provide further evidence that axonal divergence is an important feature in the functional architecture of the hippocampal formation. Other examples of divergence, as demonstrated at the level of single axons, are the projections from area TF to the EC, which can extend over 611 mm (Wellman and Rockland, 1997), the network of collaterals within CA3, and the Schaeffer collateral projections from CA3 to CA1 (Amaral and Witter, 1989
; Li et al., 1994
). The total projected axon length of a CA3 neuron has been estimated as 150300 mm (Li et al., 1994
). This divergent pattern is reminiscent of the distributed connections into olfactory cortex, cerebellar parallel fibers and feedback corticocortical connections in layer I. It contrasts with the spatially topographic mappings characteristic of the primary auditory, somatosensory and visual cortical systems.
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Summary and Conclusions |
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Notes |
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Address correspondence to Kathleen S. Rockland, Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 522421053, USA. Email: rockland{at}blue.weeg.uiowa.edu.
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References |
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