Human neuroimaging studies on the hippocampal CA3 region - integrating evidence for pattern separation and completion

Abstract

Human functional magnetic resonance imaging (fMRI) studies have long investigated the hippocampus without differentiating between its subfields, even though theoretical models and rodent studies suggest that subfields support different and potentially even opposite functions. The CA3 region of the hippocampus has been ascribed a pivotal role both in initially forming associations during encoding and in reconstructing a memory representation based on partial cues during retrieval. These functions have been related to pattern separation and pattern completion, respectively. In recent years, studies using high-resolution fMRI in humans have begun to separate different hippocampal subregions and identify the role of the CA3 subregion relative to the other subregions. However, some of these findings have been inconsistent with theoretical models and findings from electrophysiology. In this review, we describe selected recent studies and highlight how their results might help to define different processes and functions that are presumably carried out by the CA3 region, in particular regarding the seemingly opposing functions of pattern separation and pattern completion. We also describe how these subfield-specific processes are related to behavioral, functional and structural alterations in patients with mild cognitive impairment and Alzheimer's disease. We conclude with discussing limitations of functional imaging and briefly outline possible future developments of the field.

Keywords: CA3; high-resolution fMRI; hippocampus; pattern completion; pattern separation.

FIGURE 1

(A) Simplified schematic depiction of entorhinal cortex and hippocampal subfields circuitry (modified from Axmacher et al., 2006). In the trisynaptic loop, the dentate gyrus receives input from entorhinal cortex via the perforant path and relays this to CA3 via the mossy fibers. CA3 transfers information to CA1 via Schaffer collaterals, which in turn projects to the subiculum, which routes back to entorhinal cortex. (B) Segmented high-resolution fMRI scan showing the different subfields (reproduced with permission from Bonnici et al., 2012).

FIGURE 2

(A) Design (A1) and results (A2) from a functional MRI study in humans (Duncan et al., 2012) in which participants were confronted with different numbers of relevant or irrelevant changes to highly familiar virtual room layouts. Whereas a more linear signal decrease with increasing number of changes was observed in CA1, there was a more sudden, step-like decrease of activity in DG/CA3. Reproduced with permission from Duncan et al. (2012), Copyright © 2011 Wiley Periodicals Inc. (B) Design (B1) and results (B2) from a study in rats (Vazdarjanova and Guzowski, 2004) that investigated the degree of overlap between neuronal ensembles that were active during a training environment (A) and a later test environment that was either identical (A/A), increasingly dissimilar (A/Aobj, A/Aconf and A/Ab), or completely different (A/B). Again, CA1 ensembles show linearly decreasing overlap (as captured by a similarity score) with increasing dissimilarity between training and test environment, whereas CA3 ensemble overlap remains fairly high and only drops rapidly in the most dissimilar condition. Reproduced with permission from Vazdarjanova and Guzowski (2004). (C) Schematic depiction of the results of three studies in rodents (Guzowski et al., 2004) in which a similar behavior as found in the Duncan et al. (2012) study is described: CA1 output changes linearly with increasing changes in input patterns, while CA3 changes its output more in a sigmoidal fashion (i.e., when a specific threshold is crossed), indicating a transition between pattern completion and pattern separation. Reproduced with permission from Guzowski et al. (2004).