The memory for time and space differentially engages the proximal and distal parts of the hippocampal subfields CA1 and CA3.

A well-accepted model of episodic memory involves the processing of spatial and non-spatial information by segregated pathways and their association within the hippocampus. However, these pathways project to distinct proximodistal levels of the hippocampus. Moreover, spatial and non-spatial subnetworks segregated along this axis have been recently described using memory tasks with either a spatial or a non-spatial salient dimension. Here, we tested whether the concept of segregated subnetworks and the traditional model are reconcilable by studying whether activity within CA1 and CA3 remains segregated when both dimensions are salient, as is the case for episodes. Simultaneously, we investigated whether temporal or spatial information bound to objects recruits similar subnetworks as items or locations per se, respectively. To do so, we studied the correlations between brain activity and spatial and/or temporal discrimination ratios in proximal and distal CA1 and CA3 by detecting Arc RNA in mice. We report a robust proximodistal segregation in CA1 for temporal information processing and in both CA1 and CA3 for spatial information processing. Our results suggest that the traditional model of episodic memory and the concept of segregated networks are reconcilable, to a large extent and put forward distal CA1 as a possible "home" location for time cells.

Processing of spatial and non-spatial information reveals functional homogeneity along the dorso-ventral axis of CA3, but not CA1.

The ventral hippocampus is thought to principally contribute to emotional memory, while its dorsal part would be more involved in spatial processes. However, few studies have investigated ventral hippocampal function in spatial or non-spatial memories devoid of strong emotional components, and conflicting results have emerged regarding the role of the dorsal hippocampus in non-spatial (object) recognition memory. Moreover, even fewer reports have dissociated the contribution of the hippocampal subfields CA1 and CA3 to those processes, despite growing evidence of a functional segregation between these subfields. In a recent study, we detected the immediate-early gene Arc, used as a marker of neuronal activity, during spontaneous spatial and non-spatial recognition memory tasks, and showed that dorsal CA3 was spatially tuned while dorsal CA1 processed spatial and non-spatial information to the same extent (Beer, Chwiesko, Kitsukawa, & Sauvage, 2013). Here, we analyze the pattern of Arc expression detected in ventral CA1 and CA3 to determine their role in spatial or non-spatial recognition memory, and investigate whether ventral CA1 and CA3 activation differs from that of their dorsal counterparts. We report that ventral CA1 and CA3 are recruited for both spatial and non-spatial memories, but more strongly for spatial memory (e.g. were spatially tuned), and that CA3 is functionally homogeneous along the dorso-ventral axis, but not CA1.

Spatial and stimulus-type tuning in the LEC, MEC, POR, PrC, CA1, and CA3 during spontaneous item recognition memory.

According to the "two streams" hypothesis, the lateral entorhinal (LEC) and the perirhinal (PrC) cortices process information related to items (a "what" stream), the postrhinal (POR) and the medial entorhinal cortices (MEC) process spatial information (a "where" stream), and both types of information are integrated in the hippocampus (HIP). However, within the framework of memory function, only the HIP is reliably shown to preferentially process spatial information, and the PrC items' features. In contrast, the role of the LEC and MEC in memory is virtually unexplored, and conflicting results emerge for the POR. Moreover, the specific contribution of the hippocampal subfields CA1 and CA3 to spatial and non-spatial memory is not thoroughly understood. To investigate which of these areas is specifically tuned to spatial demands or stimulus identity (odor or object), we assessed the pattern of activation of these areas during recognition memory by detecting the immediate-early gene Arc, commonly used as a marker of neuronal activation. We report that all MTL areas were recruited during the spatial and the non-spatial tasks. However, the LEC, MEC, POR, and CA1 were activated to a comparable level in spatial and non-spatial tasks, while the PrC was tuned to stimulus-type, not spatial demands, and CA3 to spatial demands but not stimulus-type. Results are discussed within the frame of a recent model suggesting that the MTL could be segregated in terms of memory processes, such as recollection and familiarity, rather than information content.

NMDA signaling in CA1 mediates selectively the spatial component of episodic memory.

Recent studies focusing on the memory for temporal order have reported that CA1 plays a critical role in the memory for the sequences of events, in addition to its well-described role in spatial navigation. In contrast, CA3 was found to principally contribute to the memory for the association of items with spatial or contextual information in tasks focusing on spatial memory. Other studies have shown that NMDA signaling in the hippocampus is critical to memory performance in studies that have investigated spatial and temporal order memory independently. However, the role of NMDA signaling separately in CA1 and CA3 in memory that combines both spatial and temporal processing demands (episodic memory) has not been examined. Here we investigated the effect of the deletion of the NR1 subunit of the NMDA receptor in CA1 or CA3 on the spatial and the temporal aspects of episodic memory, using a behavioral task that allows for these two aspects of memory to be evaluated distinctly within the same task. Under these conditions, NMDA signaling in CA1 specifically contributes to the spatial aspect of memory function and is not required to support the memory for temporal order of events.

The caudal medial entorhinal cortex: a selective role in recollection-based recognition memory.

Recent studies have suggested that the caudal medial entorhinal cortex (cMEC) is specialized for path integration and spatial navigation. However, cMEC is part of a brain system that supports episodic memory for both spatial and nonspatial events, and so may play a role in memory function that goes beyond navigation. Here, we used receiver operating characteristic analysis to investigate the role of the cMEC in familiarity and recollection processes that underlie nonspatial recognition memory in rats. The results indicate that cMEC plays a critical and selective role in recollection-based performance, supporting the view that cMEC supports memory for the spatial and temporal context in which events occur.

Recognition memory: adding a response deadline eliminates recollection but spares familiarity.

A current controversy in memory research concerns whether recognition is supported by distinct processes of familiarity and recollection, or instead by a single process wherein familiarity and recollection reflect weak and strong memories, respectively. Recent studies using receiver operating characteristic (ROC) analyses in an animal model have shown that manipulations of the memory demands can eliminate the contribution of familiarity while sparing recollection. Here it is shown that a different manipulation, specifically the addition of a response deadline in recognition testing, results in the opposite performance pattern, eliminating the contribution of recollection while sparing that of familiarity. This dissociation, combined with the earlier findings, demonstrates that familiarity and recollection are differentially sensitive to specific memory demands, strongly supporting the dual process view.

Mapping memory function in the medial temporal lobe with the immediate-early gene Arc.

For the past two decades an increasing number of studies have underlined the crucial role of the immediate - early gene Arc in plasticity processes thought to sustain memory function. Because of the high spatial and temporal resolution of this technique, the detection of Arc products appears to have become a new standard for the mapping of cognitive processes. To date, most Arc studies have focused on identifying the contribution of the hippocampal subfields CA1 and CA3 to spatial processes. In contrast, few have investigated their role in non-spatial memory, or the role of other medial temporal lobe (MTL) areas in spatial and non-spatial memory. This short review describes recent studies focusing on these issues. After a brief overview of Arc's functions, we report a set of studies that put to the test some well-accepted theories in recognition memory. First, we describe data indicating that the parahippocampal areas may not be strictly segregated into spatial and non-spatial streams, as originally described. Second, we report findings revealing a functional segregation along the dorsoventral axis in CA1, but not in CA3. Finally, we bring evidence for a segregation of CA3 along the proximodistal axis and discuss the involvement of a proximal CA3-distal CA1 network during non-spatial memory. In summary, 'Arc imaging' appears to be a powerful tool to identify neural substrates of cognitive processes, not only in the hippocampus but also in the remaining of the MTL. Moreover, because of its fundamental role in synaptic processes, it offers a rare and exciting opportunity to further bridge plasticity processes and memory function.