Review article
Separation or binding? Role of the dentate gyrus in hippocampal mnemonic processing

https://doi.org/10.1016/j.neubiorev.2017.01.049Get rights and content

Highlights

  • Pattern separation is a leading hypothesis for the dentate gyrus.

  • Its theoretical grounds and empirical evidence are not as strong as commonly assumed.

  • Dentate gyrus has also been proposed to bind different types of information together.

  • ‘Binding’ better captures the role of the dentate gyrus than ‘pattern separation’.

Abstract

As a major component of the hippocampal trisynaptic circuit, the dentate gyrus (DG) relays inputs from the entorhinal cortex to the CA3 subregion. Although the anatomy of the DG is well characterized, its contribution to hippocampal mnemonic processing is still unclear. A currently popular theory proposes that the primary function of the DG is to orthogonalize incoming input patterns into non-overlapping patterns (pattern separation). We critically review the available data and conclude that the theoretical support and empirical evidence for this theory are not strong. We then review an alternative theory that posits a role for the DG in binding together different types of incoming sensory information. We conclude that ‘binding’ better captures the contribution of the DG to memory encoding than ‘pattern separation’.

Introduction

The dentate gyrus (DG) is an anatomically idiosyncratic structure of the cerebral cortex in several respects (Amaral, 1993, Amaral and Lavenex, 2007, Witter, 2007). First, unlike the case for other regions of the cerebral cortex, its principal cells are granule cells instead of pyramidal cells. Second, its output projections to CA2/CA3 are extremely non-divergent. In rats, each granule cell projects to an average of only 12 CA3 pyramidal cells, so that a precise topography exists in DG-CA3 projections along the septo-temporal axis of the hippocampus. Such non-divergent intracortical projections are rarely found in other areas of the cerebral cortex. Third, DG output fibers (mossy fibers) form unusually large synaptic terminals at proximal apical dendrites of CA3 pyramidal cells with multiple release sites. These features are well suited to exerting strong influences on recipient CA3 pyramidal cells, as has been confirmed by physiological studies (Henze et al., 2002, Salin et al., 1996). These output fibers are also special in that their axon terminals contain high levels of zinc (Frederickson et al., 2000, Haug, 1967). Finally, the DG is different from other cortical regions in that the generation and addition of new neurons in this structure continue into adulthood (Eriksson et al., 1998, Kaplan and Hinds, 1977, van Praag et al., 2002).

What then is the role of such an idiosyncratic hippocampal structure? Several different theories on this issue have been put forward (e.g., Treves and Rolls, 1992, Buckmaster and Schwartzkroin, 1994, Lisman et al., 2005, Aimone et al., 2006, Rangle et al., 2014, Scharfman, 2016) with ‘pattern separation’ being the dominant theory in the field (Knierim and Neunuebel, 2016, McNaughton and Nadel, 1990, Rolls and Treves, 1998, Yassa and Stark, 2011). In this article, we critically review the theoretical basis and empirical findings related to the pattern separation theory for the DG. We argue that the theoretical support and empirical evidence for pattern separation are not as strong as commonly assumed. We then consider another theory—‘binding’—as an alternative account. We argue that, although the two theories are not mutually exclusive, binding better captures the contribution of the DG to hippocampal mnemonic processing than pattern separation.

Section snippets

Pattern separation theory

The classic hippocampal trisynaptic circuit consists of the DG, CA3, and CA1 (Fig. 1). Of these, CA3 has occupied center stage in theorizing neural circuit dynamics of hippocampal mnemonic processing since Marr (1971). The CA3 region of the mammalian hippocampus is distinct from other subregions in that it contains massive and extensive recurrent collaterals that connect CA3 neurons together bilaterally (Amaral, 1993, Amaral and Lavenex, 2007, Witter, 2007). CA3 recurrent collaterals also

Critical assessment of pattern separation theory: theoretical aspects

Theoretically, assuming that the CA3 is where associative memory is stored, a pattern-separation function of the DG could enhance the memory storage capacity of CA3. Given that humans are known to have an enormous capacity for declarative memory, it is plausible that the DG contributes to the increased memory capacity of the hippocampus by performing pattern separation. It is also consistent with the physiology of the DG. DG granule cells show particularly low mean discharge rates in behaving

Critical assessment of pattern separation theory: empirical findings

Now let us consider empirical findings that have been claimed to support a pattern-separation role of the DG. The majority of studies claiming empirical evidence for pattern separation are behavioral studies. In these studies, some manipulation of the DG (lesions, inactivation, or NMDA receptor knockout) alters the animal’s performance in discriminating between two similar patterns, typically spatial locations or contexts (Eadie et al., 2012, Gilbert et al., 2001, Hunsaker et al., 2008, McHugh

An alternative account: binding

Let us now consider another theory, ‘binding’, as an alternative account for the role of the DG in hippocampal mnemonic processing. Since the discovery of grid cells in the MEC, numerous authors have proposed that spatial and non-spatial information are combined in the DG and CA3 (Gorchetchnikov and Grossberg, 2007, Hafting et al., 2005, Knierim et al., 2006, Leutgeb and Leutgeb, 2007, Manns and Eichenbaum, 2006, O’Keefe and Burgess, 2005, Witter and Moser, 2006; also see Redish and Touretzky,

Evidence for a DG role in binding

To test the binding theory, we performed a series of experiments using mice lacking Bax, which is required for the programmed cell death (PCD) of post-mitotic neuronal cells. In Bax-KO mice, newly generated granule cells progressively accumulate (Fig. 5A), disrupting neural circuitry, synaptic transmission, and synaptic plasticity specifically in the DG and its output projections to CA3 (Kim et al., 2009, Lee et al., 2009, Sun et al., 2004). We found that hippocampal spatial firing was

Conclusion

Pattern separation has been a popular theory to account for the role of the DG in hippocampal mnemonic processing. The pattern separation theory is plausible if we assume that CA3 is the place where a large number of patterns are stored with minimal interference. However, the theory is not perfectly in line with the findings that the avian hippocampus handles memory interference problems without a structure similar to the mammalian DG, that CA3 is likely to store sequence memory, and that the

Acknowledgements

We thank Woonryoung Kim and Woong Sun for their contributions to developing the binding hypothesis for the DG, and Alessandro Treves and Inah Lee for their helpful comments on the initial manuscript. This work was supported by the Research Center Program of the Institute for Basic Science (IBS-R002-G1).

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