Elsevier

Behavioural Brain Research

Volume 174, Issue 2, 11 November 2006, Pages 251-264
Behavioural Brain Research

Research report
Connections of the subiculum of the rat: Topography in relation to columnar and laminar organization

https://doi.org/10.1016/j.bbr.2006.06.022Get rights and content

Abstract

This paper summarizes published as well as yet unpublished data on the organization of the subiculum. Because of the complex three-dimensional structure of the hippocampus, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis; particular focus therefore is on data using the so-called extended preparation. On the basis of our yet fragmented insights in the intrinsic network, as well as the known organization of major efferents and afferents, we propose that the subiculum is organized as a matrix of columnar modules along the transverse axis showing partial laminar connectivity. Although many pieces of the large-scale puzzle on the subicular neuronal network as part of an input–output network for the hippocampus are still missing, it appears that subicular organization is different from that known for CA1. This indicates that major functional differences between CA1 and the subiculum are to be expected.

Introduction

Numerous studies employing a variety of different experimental approaches in various species convergently indicate that the parahippocampal–hippocampal system plays a crucial role in normal learning and memory processes. Although differences in nomenclature between different labs and in different species may lead to confusion, there appears to be consensus that this system comprises at least nine different domains: the dentate gyrus, fields CA3 and CA1, the subiculum, pre- and parasubiculum, entorhinal, perirhinal and postrhinal (in rodents) or parahippocampal (in primates) cortices [27], [77]. A critical, as yet unanswered question is whether these nine domains contribute differently to the overall performance of the system. One argument that this might be the case is that, at least to some extent, the intrinsic organization of these domains is different and/or that they differ with respect to their main afferent and efferent connections. It has further been suggested that complex topographical differences within each single domain point to functional heterogeneity, such as for example has been suggested for the dorsal versus the ventral hippocampus for example [45], [79]. Yet another, more recent example deals with the rather confusing data addressing the functional relevance of the entorhinal cortex. Here, studies have benefited significantly from taking into account the complex three-dimensional organization of cortico-entorhinal–hippocampal connections [15], [22], [25], [61]. Over the years, one of our aims has been to further the understanding of the system through systematic descriptions of its complex anatomical organization. For the present paper, the focus will be on the subiculum.

The subiculum, together with area CA1, represent main output structures of the hippocampal formation, insofar as that their projections terminate in a variety of subcortical and cortical areas including the entorhinal cortex. It is noteworthy that both subiculum and CA1 share quite a few of their major afferent and efferent connections, still they are in a different connectional position within the hippocampal network such that CA1 receives input from CA3 and provides input for the subiculum. For both CA1 and the subiculum, it holds true that reciprocating pathways to CA3 and to CA1, respectively, are rather weak. Whereas the CA1 area has been studied quite extensively with respect to its intrinsic organization, including detailed descriptions about the electrophysiological and anatomical properties of a baffling variety of interneurons [13], [59] much less is known about the subiculum. Although in recent years more studies have dealt with aspects of the subiculum, some report quite different and sometimes even contradictory findings.

The subiculum comprises a multilayered homogenously looking population of neurons. Over the years, we, and others have strongly advocated that within this homogeneously looking subiculum a marked connectional topography is present, indicative for a differentiation/subdivision along the longitudinal or dorsoventral axis. In addition, reports have stressed a rather precise columnar organization along the transverse or proximo-distal axis, which runs from the border with CA1 to that with the presubiculum [36], [46], [65], [66], [67], [80]. In contrast, Ishizuka [29], on the basis of the origin of efferent projections to a limited number of subcortical structures, proposed a laminar differentiation in the subiculum. He reported that deeply located neurons project to brain areas different from those reached by projections from intermediate and more superficially positioned subicular neurons. Irrespective of this rather striking discrepancy, there appears obvious agreement that single subicular neurons apparently project to only one or very few target areas in the brain. This makes neurons in the subiculum very different from their CA1 counterparts which tend to distribute axons that highly collateralize towards numerous brain areas [47].

Electrophysiological studies have led to comparable contrasting findings concerning a preferential laminar or columnar organization. There is general agreement that subicular principal pyramidal cells can be subdivided into intrinsically bursting cells and regular spiking cells. These two cell types show a differential distribution within the pyramidal cell layer. According to some authors, bursting neurons are more numerous deep in the pyramidal cell layer, whereas regular spiking cells are more common superficially in the cell layer [20], [44]. However, it has also been reported that bursting cells are preferentially found further away from CA1, i.e. in the distal subiculum [60]. Interestingly, these two cell types also display differences in both dendritic as well as axonal arborization such as to support both a columnar as well as a laminar organization [26].

In view of these confusing data, an attempt to re-evaluate the anatomical organization of the subiculum appears timely. This paper therefore summarizes published data and, in addition, provides a detailed description of some of our data that were only published as an abstract or included into review-type of papers. It is relevant to point out that because of the complex three-dimensional structure of the hippocampus, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis. Initially described by Gaarskjaer [16], and advocated by Ishizuka [29], and likewise by Amaral and Witter [1], this problem can be ameliorated by using the so-called extended preparation, and in a number of studies this approach has resulted in improved understanding of the connectional organization of the system [1], [29], [30]. In this paper, data using both extended preparations as well as traditionally prepared brain sections will be described, on the basis of which I will argue that although some laminar organization is apparent, the efferent and afferent organization of the subiculum strongly favours a columnar, also called radial organization along the proximo-distal axis. However, in order to understand the subiculum, we have to take these two fundamentally different types of organization into account, since the organization of a particular connection according to either one of these two organizational schemes may have implications for the role it has to play.

Section snippets

Materials and methods

In addition to describing and summarizing own data from experiments already published, previously unpublished data will be reported. In both instances data are derived from experiments for which we made use of the anterograde tracers Phaseolus vulgaris-leucoagglutin (PHA-l; Vector, Burlingame, CA, USA, 2.5% solution in 0.05 Tris-buffered saline, pH 7.4) or biotinylated dextran amine (BDA; Molecular Probes, Leiden, The Netherlands, 5% solution in 0.01 M phosphate buffer, pH 7.4) and retrograde

Organization of reciprocal rhinal–subicular connections

Strong reciprocal connections have been described between the subiculum and the entorhinal, perirhinal and postrhinal cortices. In a recent paper [35], we have described projections from the subiculum, emphasizing the marked topographical organization along both the dorsoventral and the proximo-distal axes of the subiculum. Neurons in the proximal half of the dorsal subiculum project almost exclusively to the perirhinal cortex (PER) and adjacent portions of the lateral entorhinal cortex (LEC).

Organization of efferent projections outside the parahippocampal–hippocampal system

The subiculum gives rise to projections to a number of cortical and subcortical structures, as well as to the thalamus, and the hypothalamus, including the mammillary bodies. Projections to the cortex include prominent projections to the medial and ventral orbitofrontal, and the pre- and infralimbic cortices. Subicular projections also reach medial portions of the anterior olfactory nucleus and the agranular insular cortex [8], [31], [32], [54], [75], [76], [78], [79]. Also, a substantial

Organization of afferent projections originating outside the parahippocampal–hippocampal system

In the rat, there is a paucity of detailed information regarding direct cortical inputs to the subiculum. It is of interest that many of the cortical regions that project fairly heavily to the entorhinal cortex do not appear to project to the subiculum cf. [77], indicating that the position of the subiculum within the cortico-hippocampal network is mainly that of a hippocampal output structure. Aside from moderate bilateral inputs from the presubiculum [14], [26], [38], [72], [73], weak inputs

Intrinsic organization

The principal cell layer of the subiculum is populated by large pyramidal neurons that end just beneath the distal end of CA1 and continue underneath the proximal portion of layers II/III of the presubiculum. These cells are relatively uniform in shape and size and extend their apical dendrites into the molecular layer; the basal dendrites extend into deeper portions of the pyramidal cell layer. Intermingled among the pyramidal cells are many smaller neurons, presumably representing the

Functional relevance of subicular organization

Our understanding of the intrinsic organization of the subicular neuronal network as yet is far from complete, and many pieces of the large-scale puzzle of the subicular neuronal network as part of an input–output network are still missing. Yet, it may be of use to summarize our current understanding with the aim to provide tentative functionally relevant inferences. The subiculum is organized such that both the distribution of dendrites of subicular neurons as well as the distribution of local

Acknowledgements

This paper would not have been possible without having access to data generated by a large number of undergraduate and graduate students who worked with me over the past years. In particular the work carried out by Andrea de Gier and Heidi Ammerlaan needs to be mentioned. I am further indebted to my colleagues and co-workers Floris Wouterlood, Barbara Jorritsma-Byham, and Lucienne Baks-te Bulte. Original research reported in this paper has been supported by grant 903-47-008 from the Netherlands

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