Review
Multiple anatomical systems embedded within the primate medial temporal lobe: Implications for hippocampal function

https://doi.org/10.1016/j.neubiorev.2011.09.005Get rights and content

Abstract

A review of medial temporal lobe connections reveals three distinct groupings of hippocampal efferents. These efferent systems and their putative memory functions are: (1) The ‘extended-hippocampal system’ for episodic memory, which involves the anterior thalamic nuclei, mammillary bodies and retrosplenial cortex, originates in the subicular cortices, and has a largely laminar organisation; (2) The ‘rostral hippocampal system’ for affective and social learning, which involves prefrontal cortex, amygdala and nucleus accumbens, has a columnar organisation, and originates from rostral CA1 and subiculum; (3) The ‘reciprocal hippocampal–parahippocampal system’ for sensory processing and integration, which originates from the length of CA1 and the subiculum, and is characterised by columnar, connections with reciprocal topographies. A fourth system, the ‘parahippocampal–prefrontal system’ that supports familiarity signalling and retrieval processing, has more widespread prefrontal connections than those of the hippocampus, along with different thalamic inputs. Despite many interactions between these four systems, they may retain different roles in memory which when combined explain the importance of the medial temporal lobe for the formation of declarative memories.

Highlights

► Examines topographic connections within the primate medial temporal lobe. ► Provides new insights into the segregation of medial temporal lobe pathways. ► Rostral–caudal distinctions within the primate hippocampus are highlighted. ► Four distinct medial temporal lobe systems are identified. ► These four systems suggest independent functions within the medial temporal lobe.

Introduction

Models of declarative memory formation focus on changes in activity between interconnected structures in the medial temporal lobe. Descriptions of the connectivity between medial temporal lobe structures (the hippocampus, entorhinal cortex, perirhinal cortex, and parahippocampal cortex) repeatedly emphasise the multiple ways in which these regions can influence each other. Within this group of structures, the hippocampus is usually placed at the top of a hierarchy of interconnections (Fig. 1) as it receives convergent information from all of the other medial temporal lobe areas (e.g. Wixted and Squire, 2011). This pattern of interconnectivity has been used to reinforce the notion that the hippocampus heads a ‘medial temporal lobe memory system’ (Squire and Zola-Morgan, 1991). This same hierarchical interconnectivity is given as a reason why the hippocampus is important for all forms of declarative memory, including episodic information and recognition memory (Wixted and Squire, 2011).

A contrasting approach is to emphasise functional differences within this same set of medial temporal structures. These differences often relate to perceived divisions within declarative memory. It has, for example, been argued that the hippocampus is vital for episodic memory and recollective-based recognition but not for familiarity-based recognition. Consequently, hippocampal damage should have a disproportionately greater impact on recall than recognition. (This prediction does not require that the hippocampus is selectively involved in retrieval, rather that impaired memory formation underlies subsequent poor recall.) These multi-functional models usually then assume that the parahippocampal region (especially the perirhinal cortex) is vital for familiarity-based recognition (Brown and Aggleton, 2001, Diana et al., 2007, Eichenbaum et al., 2007), and that this function is independent of the hippocampus. A potential problem with this alternate view is that it runs contrary to the notion of a highly inter-related, interdependent network of medial temporal lobe connections that ultimately lead to the hippocampus (Fig. 1).

The present review examines the connectivity of medial temporal lobe structures in the primate brain with respect to these specific functional issues. The focus is on whether there is a closely integrated, hierarchical system of medial temporal interconnections with the hippocampus at the top, or whether closer inspection reveals a number of discrete subsystems within the putative medial temporal-lobe memory system. This analysis will, therefore, concentrate on two issues. First, to what extent can the connections of the hippocampus be separated into separate streams with distinct properties? Second, to what extent does the putative medial temporal lobe memory system have outputs that are, in fact, independent of the hippocampus? For these reasons, the review will primarily examine the extrinsic projections of medial temporal lobe structures and not consider the complex intrinsic connections of the various hippocampal subfields or the ways in which different layers of the entorhinal cortex (e.g. layers II and III) preferentially project to different hippocampal subfields (van Strien et al., 2009; Fig. 1). Furthermore, while there have been major advances in imaging white matter connectivity in the human brain (Jones, 2008), this approach currently lacks sufficient resolution to address the questions being analysed. As a consequence, relevant findings are primarily taken from studies of monkeys. Rodent neuroanatomy is only considered when there are key gaps in our knowledge of primate connectivity.

The review first considers whether hippocampal projections might be segregated according to whether they arise from within the CA fields or from the subicular cortices. The rationale arises from evidence that the organisation of the subiculum is quite different to that of CA1 (Witter, 2006). The next focus is on whether there are systematic changes in connectivity along the rostral–caudal, i.e. the long, axis of the hippocampus. [Note, that in the rat hippocampus the term ‘temporal’ corresponds to ‘rostral’ for the primate hippocampus, while ‘septal’ in the rat corresponds to ‘caudal’ for the primate hippocampus.] There already exists much evidence that the long axis of the rat hippocampus has functional differences, with a greater involvement of the septal (caudal) hippocampus in the fine-grain processing of spatial information compared to a greater involvement of the temporal (rostral) hippocampus with the hypothalamic–pituitary–adrenal axis, allied to the latter's involvement in emotional and motivational functions (Bannerman et al., 1999, Bast, 2007, Fanselow and Dong, 2010, Moser et al., 1995, O’Mara, 2005, Vann et al., 2000b). If the primate hippocampus is also functionally heterogeneous along this plane then it should be reflected in its connectivity.

In addition to the rostral–caudal axis of the hippocampus, two other planes of connectivity will be considered. The first concerns the lateral plane, i.e. the proximal/distal placement of any efferents from within a given hippocampal subfield. Here, the terms ‘proximal’ and ‘distal’ refer to a region's position with respect to the dentate gyrus, assuming the hippocampus is unwound and, hence, flattened in the transverse plane. Proximal areas are closer to the dentate gyrus while distal areas are further from the dentate gyrus. The last plane to be considered concerns the depth of the cells of origin. The subiculum, along with the presubiculum and parasubiculum, are laminar structures, raising the possibility that different cell layers have different efferent connections.

After examining the topography of hippocampal efferents, this review will consider whether other parts of the medial temporal lobe memory system have projections that are potentially independent of the hippocampus. Finally, the synthesis of this information will be used to test the assumptions of hierarchical hippocampal models (Wixted and Squire, 2011) and the assumptions of those models that separate functions within the same set of medial temporal lobe structures (e.g. Aggleton and Brown, 1999, Diana et al., 2007, Eichenbaum et al., 2007), despite the high levels of interconnectivity within the temporal lobe.

Section snippets

Hippocampal connectivity

For the purposes of this review, the hippocampus is regarded as comprising the dentate gyrus, CA fields 1–4, and the subicular cortices (Fig. 1). The descriptions of the various hippocampal subfields are based on those of Lorente de Nó (1934). The term ‘hippocampus proper’ is used to refer to just the dentate gyrus and the CA fields. As there is much debate on how best to subdivide the subicular cortices (O’Mara et al., 2001), the subiculum, presubiculum, and parasubiculum will be

Identifying parahippocampal connections that appear independent from the hippocampus

The goal is to identify whether any parahippocampal connections suggest a qualitative change in function between hippocampal and parahippocampal areas. At the same time, both the subiculum and the hippocampal CA1 field project directly to the perirhinal cortex and parahippocampal cortex, and there are extremely dense hippocampal projections to the entorhinal cortex (Fig. 1). Consequently, any discussion of those connections within the medial temporal lobe memory system that appear independent

Functional implications

The connections of the medial temporal lobe have been implicated in a wide array of functions. The next sections will, however, just focus on those functions most relevant to the issue of memory formation. Other aspects of memory and cognition will be discussed in less detail.

Final observations

This review began with the question of whether it is better to characterise the medial temporal lobe as a hierarchical system with the hippocampus at the top, so precluding the emergence of independent mnemonic functions in parahippocampal areas, or whether there are two or more medial temporal systems that could potentially operate independently. While connectivity alone cannot provide a definitive answer, it emerges that many of the anatomical features of the medial temporal lobe appear to

Acknowledgements

This work was supported by the Wellcome Trust (WT092480), and by funding from the Wolfson Trust and Royal Society. The author thanks Richard C. Saunders for his advice on this manuscript.

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