There are two schools of thought about what role the hippocampus – a region of the brain – plays in memory. Some neuroscientists think that it is involved in retrieving all memories. Others believe that its contribution is restricted to the retrieval of recent memories, while a neighboring part of the brain called the parahippocampal region takes over to retrieve older memories.

The hippocampus contains two distinct areas called CA1 and CA3, which have recently been suggested to have, at least partially, separate roles. For example. previous studies have shown that CA3 plays an important role in processes that tend to be less efficient as time goes by. However, it remains unclear whether CA1 and CA3 contribute equally to the retrieval of recent and older memories.

Lux et al. addressed this question by observing brain activity in mice as they retrieved recent and older memories. The experiments show that both areas of the hippocampus are involved in retrieving recent memories, but that only the CA1 area is involved in the retrieval of older memories. The parahippocampal region is much more active during the retrieval of older memories than recent ones.

These findings clarify the role of the hippocampus in memory by showing that it is involved in the retrieval of both recent and older memories. The next steps will be to better understand how the CA1 and CA3 areas contribute to memory and to pin point the specific molecular mechanisms these regions rely on to do so.

While it is a consensus that the hippocampus is engaged for the retrieval of recent memory, its involvement in retrieving more remote memories is still controversial. Some studies showing temporally-graded retrograde amnesia following hippocampal damage in humans have provided evidence that memory becomes hippocampal-independent as it ages and is ultimately ‘stored’ in the cortex (Alvarez and Squire, 1994: “the system consolidation theory”). An alternative theory posits that the hippocampus is not only engaged in retrieving recent memories but that it also supports cortical areas in retrieving more remote memories (Nadel and Moscovitch, 1997: the ‘multiple trace theory’). The hippocampal subfields CA1 and CA3 are functionally segregated and quite a few studies have investigated their role in recent memory, for example in the retrieval of contextual fear conditioning (Tanaka et al., 2014; Wheeler et al., 2013; Remaud et al., 2014; Daumas et al., 2005; Rampon et al., 2000; McHugh and Tonegawa, 2009; Hunsaker et al., 2009; Goshen et al., 2011; see for reviews: Nakazawa et al., 2004; Kesner, 2007). However, it is unclear whether they contribute to a similar extent to the retrieval of more remote memories. A recent lesion study in humans indicates that CA1 participates to the retrieval of early and very remote memories (over 30 years-old) in addition to its well-established role for recent memories (Bartsch et al., 2011). In contrast, the role of CA3 in the retrieval of remote memory has not been yet studied in humans and has rarely been investigated in animals for memories older than a month, a period of time roughly equivalent to four years in humans based on life expectancy. Hence, very little is known about the extent to which CA3 contributes to the retrieval of remote and very remote memory. Nonetheless, computational studies suggest that CA3 would contribute to retrieving memories, at least recent and early remote memory, via processes involving the completion of memory representations based on partial or degraded features of these representations (the ‘pattern completion’ theory: Rolls et al., 1997). However, the memory for single features and/or details that could serve as retrieval cues degrades over time (Wiltgen and Silva, 2007; Wiltgen et al., 2010). Hence, it raises the question whether CA3 would also contribute to the retrieval of very remote memories or whether its contribution depends on the age of the memory trace.

In addition, a critical involvement of the parahippocampal region in the retrieval of recent and early remote memory is supported by a handful of animal studies and by recent reports of flat retrograde amnesia in patients with damage extending from the hippocampus to other medial temporal lobe areas. However, these studies did not investigate very remote memory traces while the contribution of cortical areas to the retrieval of memory is thought to be maximal at this stage. (Squire and Alvarez, 1995; Gusev et al., 2005; Bucci et al., 2002; Burwell et al., 2004; Izquierdo et al., 1997). Moreover, despite evidence for a functional segregation between parahippocampal areas in terms of spatial/non-spatial information processing and/or of the mediation of distinct memory processes (Mishkin et al., 1983; Eichenbaum et al., 2007; Beer et al., 2013), no study has yet dissociated the specific contribution of the perirhinal (PER) and postrhinal cortices (POR) nor that of the lateral and medial entorhinal cortices (LEC, MEC) to the retrieval of remote memory.

Here, we address these issues using a contextual fear conditioning task by testing whether CA3 contributes to a comparable extent as CA1 to the retrieval of recent (1 day and 1 week-old), early remote (1 month-old) and very remote memories (6 months or 1 year-old), the latter corresponding roughly to 20 and 40 years-old memories in humans based on life expectancy which are among the delays the most investigated in studies focusing on very remote memory (Figure 1A). In addition, we investigated the extent to which the PER, the POR, the LEC and the MEC differentially contribute to the retrieval of these memories. Because performing in-vivo electrophysiology recording simultaneously in six distant brain areas remains a major challenge and using a lesion/inactivation approach in adjacent brain areas in mice was unlikely to yield the spatial resolution necessary to tease apart the specific function of each area, a high-resolution molecular imaging technique (e.g. to the cellular level) was employed. This imaging technique is based on the detection of the expression of the immediate-early gene Arc which has been especially linked to plasticity processes and cognitive demands and has been recently used for mapping cognitive processes in the medial temporal lobe (Guzowski et al., 1999; Nakamura et al., 2013; Sauvage et al., 2013; Figure 2B–G). 

Figure 1

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Investigating memory retrieval over such an extended period of time enabled us to provide the first evidence of a time-limited contribution of CA3 to the retrieval of memory while, in striking contrast, CA1 remained involved regardless of the age of the memory trace. In addition, parahippocampal areas were substantially more involved in retrieving very remote memory traces than more recent ones and their activity patterns appeared to reflect memory demands rather than information content.

To our knowledge, no study has investigated the role of CA3 in retrieving remote memory traces in humans and only one studied early remote memory in animals (e.g. up to one month-old traces which roughly corresponds to a 4 year-old memory trace in humans based on life expectancy; Gusev et al., 2005). Thus, the contribution of CA3 to the retrieval of memory traces as old as what is considered to be a remote/very remote memory trace in humans (in the order of decades) is not known. For this reason, we studied 6 months-and one year- old memories traces in mice, which roughly correspond to 20 and 40 year-old memory traces in humans. Doing so enabled us to report for the first time the lack of engagement of CA3 in the retrieval of very remote memories. This time-limited role of CA3 was supported by a lack of recruitment during the retrieval of the most remote memory traces (6 months- and one year-old) while CA3 was strongly activated for recent and early remote memories (up to 1 month-old traces). This result was confirmed by a significant correlation between CA3 activity levels and memory performance during the retrieval of the recent and early remote memories, which did not hold for very remote traces. The approach we have adopted does not allow for the characterization of the specific process by which CA3 fails to aid in retrieving memory. However, since computational studies and studies that have limited their investigations to recent and early remote memory traces have speculated that CA3’s contribution to memory retrieval would increase as memory ages because of an increasing demand on the completion of representations using partial or degraded features of these stored representations (the ‘pattern completion theory’: Rolls et al., 1997), we speculate that the lack of engagement of CA3 in retrieving very remote memories stems from a failure to ‘pattern complete’ memory representations. Indeed, by this time, these very old memory representations might have degraded to such an extent that it is impossible to use any specific features as an efficient retrieval cue. This hypothesis would go along with reports demonstrating that details of memory representations are lost as memory ages (Wiltgen and Silva, 2007; Wiltgen et al., 2010) and will require further investigations to be tested.

In striking contrast to the limited involvement of CA3, we found an ongoing involvement of CA1 in memory retrieval. This result is in agreement with the only two studies specifically investigating the role of CA1 in remote memory retrieval. Indeed, transient inhibition of cell firing in CA1 in mice using optogenetics drastically impaired fear memory retrieval, one or twenty eight days after conditioning (Goshen et al., 2011). Likewise, a recent fMRI study in humans showed impairments in autobiographic and episodic memory for traces even older than 30 years-old following focal CA1 lesions (Bartsch et al., 2011). Our result of a selective involvement of CA1 in the retrieval of very remote memories at this time point is supported by the lack of a recruitment of this area in the memory-impaired group tested one year after conditioning as opposed to a strong activation in the memory intact group and the fact that CA3 was not recruited in either group (Figure 4B). Importantly, using a high resolution molecular imaging technique, we bring the first evidence that the persistent engagement of the hippocampus in memory retrieval does not involve CA3. This result, in turn, suggest that hippocampal patterns of activation observed in previous human fMRI studies investigating the retrieval of very remote memory, might essentially be driven by CA1, but could not be specifically identified as such because of the limited spatial resolution of standard fMRI techniques (Ryan et al., 2001; Rekkas and Constable, 2005; Bonnici et al., 2012). Moreover, the fact that only CA1 is activated for these late time points suggests a preferential involvement of the temporoammonic pathway over that of the trisynaptic loop for the retrieval of very remote memories. Robust evidence for this hypothesis is not yet available for very remote memories, but lesions of the temporoammonic pathway in rats specifically impaired early remote memory (28 days-old) in rats tested in a Morris watermaze task, while recent memory (one day-old) was spared. This result suggests that direct entorhinal cortex inputs to CA1 contribute to the retrieval of early remote memory, possibly by further consolidating memories that were not consolidated after 28 days (Remondes and Schuman, 2004). In the present study, because we investigated a much larger time-window and found that CA1 was still activated in addition to the parahippocampal cortical areas, but not CA3, we speculate that the temporoammonic pathway is not only important for the consolidation of memories but also for the retrieval of already consolidated memories.

Furthermore, parallel to the disengagement of CA3 in the retrieval of very remote memories, we found a maximal involvement of the parahippocampal areas. The hypothesis of a functional segregation of the parahippocampal region between a 'PER-LEC stream' and a 'POR-MEC stream' is essentially based on studies investigating the role of the PER during the retrieval of recent memory, while much fewer have addressed the specific role of the POR, the LEC and the MEC within this frame and during the retrieval of early remote memories. In addition, no study has yet investigated their contribution for very remote memories, despite the belief that the contribution of cortical areas to memory retrieval would be the largest for the most remote memories. Our results for recent and early remote time-points match published data according to which, for example, the PER and the POR are recruited to a similar extent for contextual fear conditioning and the LEC and MEC contribute to a similar extent to memory retrieval (Bucci et al., 2002; Burwell et al., 2004; Izquierdo et al., 1997; Goshen et al., 2011). In addition, we show for the first time that the contribution of the PER, the POR, the LEC and the MEC is indeed the largest for the retrieval of very remote memories. Patterns of activation were comparable between the LEC and the PER and between the MEC and the POR. Interestingly though, LEC and PER were more activated than the MEC and the POR during the retrieval of very remote memory traces. This result appears to rather reflect the type of memory process the areas were engaged into (fear conditioning) rather than the content of information processed (contextual information), supporting a view that has recently emerged from the literature (Eichenbaum et al., 2007; Beer et al., 2013). Indeed, the amygdala which plays a crucial role in fear conditioning, sends stronger projections to the PER/LEC than to the MEC/POR (Pitkänen et al., 2000) and higher activity levels in the POR and MEC than in the PER and LEC would have been expected if information content was primarily reflected in the pattern of activation observed. Altogether, our data show a preferential role of the parahippocampal region for the retrieval of very remote memories as opposed to that of early remote and recent memories, matching the pattern commonly reported for the prefrontal cortex (Frankland and Bontempi, 2005).

In summary, our results provide the first evidence of a disengagement of CA3 for the retrieval of very remote memories and identify CA1 as the main player at this time point. These results are consistent with the view that at least the hippocampal subfield CA1 is involved in retrieving memory independently of the age of memory trace, possibly by providing support to cortical areas that include the parahippocampal areas. Of note, averaging activity levels of the hippocampal areas on the one hand and those of the parahippocampal areas on the other hand revealed that both the hippocampus and the parahippocampal region were activated independently of the age of the memory trace (Figure 5C). Hence, the gradual “transfer” of the memory trace from the hippocampus to the cortex is unlikely to be an all-or-nothing phenomenon, but seems to go along with a shift in the relative contribution of the two regions as the memory trace ages, and possibly a shift in the contribution of the networks they belong to. More specifically, our results suggest that the trisynaptic loop could play a preponderant role in retrieving early memories as reflected by an involvement of CA3, CA1 and the parahippocampal areas at this stage, while the retrieval of very remote memories would require an heavier contribution of the temporoamonic pathway as indicated by the lack of recruitment of CA3 and a strong activation of CA1 and the parahippocampal areas.

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Author details

1. Vanessa Lux

   Functional Architecture of Memory unit, Mercator Research Group, Medical Faculty, Ruhr University Bochum, Bochum, Germany

   Contribution

   VL, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Erika Atucha

   1. Functional Architecture of Memory unit, Mercator Research Group, Medical Faculty, Ruhr University Bochum, Bochum, Germany
   2. Functional Neuroplasticity Department, Otto von Guericke University, Magdeburg, Germany
   3. Functional Architecture of Memory Dpt, Leibniz-Institute for Neurobiology, Magdeburg, Germany

   Contribution

   EA, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Takashi Kitsukawa

   Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

   Contribution

   TK, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

4. Magdalena M Sauvage

   1. Functional Architecture of Memory unit, Mercator Research Group, Medical Faculty, Ruhr University Bochum, Bochum, Germany
   2. Functional Neuroplasticity Department, Otto von Guericke University, Magdeburg, Germany
   3. Functional Architecture of Memory Dpt, Leibniz-Institute for Neurobiology, Magdeburg, Germany

   Contribution

   MMS, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   magdalena.sauvage@gmail.com

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-7586-6410

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