Remapping of memory encoding and retrieval networks: Insights from neuroimaging in primates

Behavioural Brain Research 275 (2014) 53–61

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Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr

Review

Remapping of memory encoding and retrieval networks: Insights from neuroimaging in primates Kentaro Miyamoto ∗ , Takahiro Osada 1 , Yusuke Adachi 1 Department of Physiology, The University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

h i g h l i g h t s • Macaque whole brain network for recognition memory was identified via functional MRI. • Inter-species common memory processes for primates were proposed in the PPC and MTL. • Memory networks localized in monkeys will be a basis of cell-level characterization.

a r t i c l e

i n f o

Article history: Received 1 August 2014 Received in revised form 21 August 2014 Accepted 23 August 2014 Available online 1 September 2014 Keywords: Recognition memory Macaque monkey Functional magnetic resonance imaging Serial position effect Posterior parietal cortex Medial temporal lobe

a b s t r a c t Advancements in neuroimaging techniques have allowed for the investigation of the neural correlates of memory functions in the whole human brain. Thus, the involvement of various cortical regions, including the medial temporal lobe (MTL) and posterior parietal cortex (PPC), has been repeatedly reported in the human memory processes of encoding and retrieval. However, the functional roles of these sites could be more fully characterized utilizing nonhuman primate models, which afford the potential for well-controlled, finer-scale experimental procedures that are inapplicable to humans, including electrophysiology, histology, genetics, and lesion approaches. Yet, the presence and localization of the functional counterparts of these human memory-related sites in the macaque monkey MTL or PPC were previously unknown. Therefore, to bridge the inter-species gap, experiments were required in monkeys using functional magnetic resonance imaging (fMRI), the same methodology adopted in human studies. Here, we briefly review the history of experimentation on memory systems using a nonhuman primate model and our recent fMRI studies examining memory processing in monkeys performing recognition memory tasks. We will discuss the memory systems common to monkeys and humans and future directions of finer cell-level characterization of memory-related processes using electrophysiological recording and genetic manipulation approaches. © 2014 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recognition memory processes in primates: perspectives from anatomy, lesions, and electrophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroimaging of memory encoding networks in monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Memory traces that predict subsequent recognition performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Differential roles of memory traces within primate medial temporal lobe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroimaging of memory retrieval networks in monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Neural correlates of the retrieval success effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Functional differentiation among memory retrieval networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +81 358413459; fax: +81 358413325. E-mail address: [email protected] (K. Miyamoto). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.bbr.2014.08.046 0166-4328/© 2014 Elsevier B.V. All rights reserved.

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Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Implications from monkey fMRI experiments for understanding human memory functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Memory encoding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Memory retrieval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Future directions for investigating memory systems in primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Recognition memory is the fundamental ability to remember past events. A long history of studies in patients with amnesia and in animals with lesions modeling memory dysfunctions has revealed that the medial temporal lobe (MTL) plays an essential role in the recognition of previously encountered events [1]. Recent developments in non-invasive neuroimaging techniques represented by functional magnetic resonance imaging (fMRI) have enabled the investigation of whole brain functions in healthy human subjects and have demonstrated that subregions included in the MTL play different roles during memory encoding [2–4]. In addition, these methods recently shed new light on the posterior parietal cortex (PPC), which is active during memory retrieval [5,6], as well as the prefrontal cortex, which supports the cognitive control of memory [7]. Neuroimaging is the most useful method for mapping memory-related functions at the level of the whole brain. On the other hand, utilization of nonhuman primate models is desirable to more precisely characterize the functional roles of these sites because well-controlled experimental procedures on a finer scale are available, including electrophysiology, histology, genetics, and lesion approaches, which are inapplicable to humans [8,9]. However, the functional counterparts of the recognition memoryrelated regions localized by neuroimaging studies in humans had not been observed in macaque monkeys. Therefore, bridging the inter-species gap by applying the same neuroimaging techniques used in humans to behaving monkeys would be beneficial [10–21]. Here, we briefly review the history of experimentation on memory systems using a nonhuman primate model and the recent attempts to investigate recognition memory processes in macaque monkeys using fMRI. Through inter-species comparisons of memory processes using the same methodology, we propose commonly shared neural processes for recognition memory in humans and monkeys. In addition, we apply the historically accumulated knowledge from nonhuman primate models to the understanding of human cognitive functions and show the future directions that promise to enrich our understanding of how recognition memory is mediated in whole brain networks. 2. Recognition memory processes in primates: perspectives from anatomy, lesions, and electrophysiology Neuropsychological studies assessing amnesia after lesions of the MTL in humans, as typified by a breakthrough study involving the patient H.M. by Scoville and Milner [22], encouraged MTL lesion experiments in nonhuman primates to examine impairments in encoding and retrieval of recognition memory [23,24]. A series of controlled lesion studies in monkeys revealed that lesions of various regions within the MTL induced diverse memory deficits [25–27]. The results are consistent with those of patient H.M., who presented with anterograde amnesia but intact short-term memory following the resection of portions of the MTL, including the hippocampus and surrounding parahippocampal gyrus, to treat epilepsy (see [28] for postmortem examinations on the lesioned areas of patient H.M.).

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Experimentation using nonhuman primate models enables the examination of the behavioral impact after deprivation of focal areas, revealing that lesions specific for the perirhinal cortex produce severe impairment for object recognition, even when the hippocampus proper is intact [29–31]. Some researchers suggest that the perirhinal cortex supports visual learning because perirhinal lesions induce severe impairments in learning a large but not a small number of discrimination problems concurrently [32,33]. However, supported by the results of lesion studies, the majority of scientists affirm that the perirhinal cortex plays critical roles in the formation and retrieval of stimulus–stimulus associations or in semantic processes based on object association [34]. Electrophysiological recordings of neuronal activity repeatedly show that cells in the perirhinal cortex contain a memory engram that represents visual long-term memory based on object–object associations [35–38] and that these neurons are differentially activated for recognition of familiar stimuli or the identification of novel stimuli [39,40]. The perirhinal cortex, which is located on both the ventral visual cortical processing stream and medial temporal memory system [41], is considered to play integral roles in both perception and memory [1,42,43]. In contrast to the general agreement for the perirhinal cortex, the extent of the memory impairment after lesions specific for the hippocampus is under dispute. Some researchers report impairments in object recognition after hippocampal lesions in monkeys [44,45], whereas others find impairments specifically for the assessment of source memory rather than object recognition itself [46,47]. Electrophysiological studies determined that the monkey hippocampus is activated during the encoding of visual stimuli associated with spatial [48] or temporal contexts [49]. Yet, depth electrode recordings in epileptic patients revealed that hippocampal cells encode visual stimuli free from any context [50,51]. For all the debate about the functional roles of the hippocampus, the results of lesion and electrophysiological studies using nonhuman primate animal models, with some assistance from human patient studies, have revealed that information processing in the MTL is critical for encoding and consolidation of recognition memory. This knowledge from monkey studies has been applied to interpret the memory-related activity of humans captured by neuroimaging techniques. However, due to inter-species differences, direct comparisons are impossible. The anatomical frame of reference for the MTL, which is based on a plethora of cytoarchitectural, histochemical, and anatomical projection studies, has been established in the macaque monkey. Information about anatomical circuits, which shapes the foundation of neurotransmission, supports the examination of memory processing in the MTL. For instance, monkey perirhinal cortex is cytoarchitecturally divided into area 36 and area 35 depending on the presence or absence of layer IV [52–54], and electrophysiological recording studies with microelectrodes indicate that memory engrams representing object–object associations are differentially encoded in these two subregions [55,56]. To fully utilize the available anatomical information and knowledge gained from electrophysiological recording in monkeys to understand recognition memory processes in the

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Fig. 1. A serial probe recognition task and the serial position effect in monkeys. (A) Trial structure for the serial probe recognition task. Monkeys were required to select the “seen” (or “unseen”) symbol when the test item was (or was not) included in the studied list of items. CR: Correct rejection, FA: false alarm. Modified from Miyamoto et al. [60]. (B) In both monkeys, the Hit rate showed a U-shaped curve as a function of the position in which the tested item was presented in the studied list. Hit rates for each item position significantly exceed the FA rate (dashed line) (all p < 0.05). *p < 0.05 (Ryan’s correction). Adopted from Miyamoto et al. [67].

MTL, mapping the distribution of the neural correlates of recognition memory onto the monkey MTL will be required. 3. Neuroimaging of memory encoding networks in monkeys 3.1. Memory traces that predict subsequent recognition performance To localize the neural substrates for encoding of recognition memory in humans using functional MRI, researchers repeatedly compared activity during the encoding of subsequently recognized stimuli (a later Hit) with that during the encoding of subsequently forgotten stimuli (a later Miss) [5,57,58]. This differential memory encoding activity predictive of later performance is termed “subsequent memory effect” and is reportedly localized within the MTL. Electrophysiological recordings from monkeys have shown that the activity of hippocampal cells predicts the performance of a subsequent memory task [59]. However, the subsequent memory effect as determined electrophysiologically in monkeys is limited to narrow areas within the hippocampus. To exhaustively map the memory traces within the macaque MTL predictive of subsequent recognition performance, Miyamoto et al. [60] conducted fMRI experiments in behaving monkeys similar to recognition memory studies previously conducted in humans.

In that study, monkeys performed a serial probe recognition memory task (Fig. 1A) in which they were required to view a list of serially presented items and to judge whether the test item had been presented in any position on the list (old/new judgment). The list of items the monkeys were to encode changed on every trial. We compared the fMRI activity during memory encoding when the encoded items were remembered and when they were forgotten in the subsequent test, and mapped the distribution of the clusters that contained the information predictive of the subsequent recognition performance (i.e., a later Hit or Miss) using a multivariate decoding technique. The memory traces that contained the information most predictive of subsequent recognition performance were identified in both the hippocampus and the perirhinal cortex consistently across monkeys (Fig. 2A). These results are in agreement with the knowledge gained from electrophysiological and lesion studies in monkeys. Our precise mapping of the memory traces predictive of the subsequent recognition performance using high-resolution functional imaging revealed that area 36 within the perirhinal cortex especially contributed to the encoding of recognition memory. Perirhinal neurons had been reported to respond differentially to repeated familiar stimuli and to novel stimuli [40], but the distribution of these cells had not been examined in detail. Our results suggest that the perirhinal cells responsible for the formation of recognition memory are not uniformly distributed but localized in focal areas within the perirhinal cortex, especially in

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Fig. 2. Anatomical connections within macaque medial temporal lobe (MTL) where memory traces reside. (A) The distribution of regions within the MTL (blue represents PRC; yellow, cERC; green, PHC) in the ventral view of the monkey brain, modified from Mayford et al. [130]. Memory traces predictive of subsequent recognition performance were identified within the perirhinal and caudal entorhinal cortex, as well as the hippocampus by Miyamoto et al. [60]. (B) Differential patterns of cortical inputs and outputs within the monkey entorhinal cortex, modified from Suzuki [131]. The entorhinal cortex intermediates the hippocampus and perirhinal cortex (PRC) as well as the hippocampus and parahippocampal cortex (PHC). RSP: retrosplenial cortex, cERC: caudal entorhinal cortex (area EC , ECL ) PIR: piriform cortex, STG: superior temporal gyrus, STSd: dorsal bank of the superior temporal sulcus, TE: visual area TE, 36d: dorsal division of area 36.

area 36. The memory engram formed within the monkey perirhinal cortex after repeated exposure to pair-associated stimuli [35] is supported by aggregates of pair-coding neurons located in a focal patch referred to as a “hotspot” [36,37]. These observations suggest an organization in the perirhinal cortex in which neurons with the same cognitive function accumulate as a “patchy” cluster. Miyamoto et al. [60] also newly identified memory traces predicting subsequent recognition performance within the macaque caudal entorhinal cortex (Fig. 2A), whereas the results from human neuroimaging studies proposed the parahippocampal cortex as the locus for memory formation. In monkeys, anatomical projections among subregions within the MTL have been investigated in detail [31,52–54,61–64]. The caudal region of entorhinal cortex, where we localized a memory trace, strongly projects to the hippocampus and receives major cortical inputs from parahippocampal and retrosplenial cortices (Fig. 2B) [65]. The major afferent pathway to the hippocampus coming from the parahippocampal cortex is intermediated by the caudal entorhinal cortex. For the first time, we demonstrated that a focal region within the entorhinal cortex, a cortical area anatomically closer to the hippocampus and hierarchically higher than the parahippocampal cortex [66], contributes to the formation of memory traces predictive of subsequent recognition performance.

the activity in the hippocampus and the caudal entorhinal cortex, which are directly connected, is predictive of the subsequent recognition of initial rather than the middle items, whereas the activity in perirhinal cortex predicts subsequent recognition performance for middle rather than initial items. This functional differentiation, shown for the first time, suggests the existence of two qualitatively different memory processing systems in the monkey MTL. In psychological models of the serial position effect, the primacy effect of better recognition for the initial items with a decline in the recognition memory performance for the middle items is thought to result from an association of each item with some representation of the start-of-list context, with the strength of the association decreasing with increasing list position [69,70]. According to these theories, contextual processing has a greater effect on the encoding of the initial list items than the middle items, and the differential activities in response to the initial items (hippocampus and caudal entorhinal cortex) or middle items (perirhinal cortex) are suggested to reflect differential contributions of this contextual process.

3.2. Differential roles of memory traces within primate medial temporal lobe

The results from human neuroimaging techniques have recently proposed the involvement of the posterior parietal cortex (PPC) [71] as well as the MTL and prefrontal cortex (PFC) [1,7,72] in memory retrieval. Multiple areas within the PPC show greater retrieval-related activity when human individuals correctly recognize previously seen items compared with the weaker activity associated with correctly identifying previously unseen new items (“retrieval success effect”; “old/new effect”) [6,73,74], and play functionally different roles [5]. However, little is known about the causal relationship between PPC activity and the retrieval of recognition memory because of a limited number of available subjects with damage in PPC subregions [75]. Nonhuman primate models can be used to directly test cognitive impairments after focal lesions as well as to more finely characterize the activity. The inferior parietal lobule in the PPC, where retrieval-related activity has been repeatedly identified in humans, is a highly developed cortical area

In the serial probe recognition task, recognition accuracy differs across the temporal position of the items that the subjects are required to retrieve for both humans and monkeys. In our studies [60,67], recognition accuracy showed a typical U-shaped curve [68] accompanied by primacy and recency effects consistently across monkeys (Fig. 1B). The existence of the primacy effect, that is, higher accuracy for recognition of the initial list items (Hit 1) than for items presented in the middle of the list (Hit 2, 3), suggests that recognition memory processes function differentially for initial and middle items. We examined whether the three memory traces identified within the macaque MTL (in the hippocampus, perirhinal cortex, and caudal entorhinal cortex) were predictive of subsequent recognition performance for initial or middle items. We found that

4. Neuroimaging of memory retrieval networks in monkeys 4.1. Neural correlates of the retrieval success effect

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Fig. 3. Inter-species comparison of retrieval success regions. (A and B) Retrieval success regions (Hit vs. CR) in monkey PPC adopted from Miyamoto et al. [67] (A) and those in humans based on a meta-analysis by Cabeza et al. [114] (B) are compared. IPL: inferior parietal lobule, IPS: intraparietal sulcus. (C and D) Primacy effect (C, left) and recency effect (C, right) related sub-networks (modules) of retrieval-related regions including the PPC sites for monkeys adopted from Miyamoto et al. [67] are compared with distributions of activations related to successful recollection (D, left) and those related to perceived oldness (D, right) for humans adopted from Wagner et al. [5].

in humans, but the existence of a cytoarchitectural counterpart has not been established in monkeys [76]. To identify the neural correlates of retrieval success in monkeys, Miyamoto et al. [67] examined the retrieval-related fMRI activity in monkeys performing a recognition memory task. Despite marked differences in the cytoarchitectural structure of the PPC between humans and monkeys, we identified two retrieval-related areas in the macaque PPC: one located in the inferior parietal lobule (IPL; area PG/PGOp) and the other located on the medial bank of the intraparietal sulcus (IPS; area PEa/DIP) (Fig. 3A). In addition, we identified several regions active for retrieval of recognition memory within the PFC (including area 9/46 V, area 45B, and area 8B) and the MTL (especially in the hippocampus). 4.2. Functional differentiation among memory retrieval networks We next examined whether the retrieval-related activity in the two PPC regions of the macaque changed depending on the position of the cue items within a list during the serial probe recognition task (Fig. 1). Then area PG/PGOp in the IPL, along with the hippocampus, is the most responsive to retrieval of the initial list items (Hit 1), while area PEa/DIP in the IPS is the most responsive to retrieval of the last items (Hit 4). In human neuropsychological cases of amnesic patients with long-term memory deficits, damage in bilateral hippocampi specifically impairs the primacy effect but not the recency effect [77]. Recent behavioral studies also suggest that long-term memory processes elicit the primacy effect in monkeys as well as in humans [78]. The modulation of hippocampal activity in monkeys during retrieval is consistent with that in humans, which most accurately predicts subsequent recognition performance for the initial items in a list, and is suggested to be related to long-term memory processing. We demonstrated that the retrieval-related region identified in the hippocampus increases the effective connectivity targeted to area PG/PGOp in the IPL during retrieval of the initial list items compared with that of the last items. Area PG/PGOp in the IPL receives disynaptic input from the CA1 region of the hippocampus via the parahippocampal gyrus [79]. A series of anterograde and retrograde tracer injection studies has established dense reciprocal connections between area PG in the IPL and area TF (with area TH) on the posterior part of the parahippocampal gyrus [80–83].

A study examining the functional connectivity of the resting-state activity for monkeys showed that spontaneous activity in the lateral posterior parietal area, including a part in area PG, is highly correlated with that in the posterior parahippocampal gyrus [84]. Our fMRI study using behaving monkeys provided the first evidence that parieto-hippocampal connections supported by axonal projections function in the retrieval of long-term recognition memory. We also recorded the spontaneous activity in the 47 identified retrieval-related areas, including the hippocampus and PPC subregions described above, from the same monkeys and calculated the functional connectivity among these areas. To objectively segregate these areas, we applied network theory to the functional connectivity [85,86] and conducted community detection analysis using modularity optimization [87]. The analysis separated the 47 retrieval-related regions into six distinct sub-networks, or modules, with area PG/PGOp in the IPL and area PEa/DIP in the IPS participating in different modules. In addition, the population activity of the module consisting of PG/PGOp in the IPL and six other regions was most responsive to retrieval of the initial items in the precedent cue list, as was the case for the activity of area PG/PGOp alone (Fig. 3C). A majority of the other areas included in the module (area 23, PECg, IPa, and Tpt) have anatomical connections with area PG/PGOp [88]. These observations converge to reveal that retrievalrelated regions anatomically connected with area PG/PGOp in the IPL form a sub-network, functionally connecting one another and cooperatively working to achieve long-term memory retrieval in the macaque. By contrast, the second retrieval-related region in the PPC, area PEa/DIP in the IPS, was most activated during the retrieval of the last item from the precedent cue list. The recency effect, facility in retrieving the last list item, has been attributed to active maintenance of encoded items in working memory rather than to retrieval from long-term memory [89,90]. Electrophysiological studies of macaque DIP neurons reported neural activity involved memorizing sequences of events (numbers) [91]. Such a neuronal substrate would be based on recognition of recently seen items. In addition, the population activity of the modules consisting of area PEa/DIP and six other regions mostly located in the frontal cortex (including prefrontal area 9/46 V and area 45) was also responsive to retrieval of the last items (Fig. 3C). Interplay between area PEa/DIP in the

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IPS and prefrontal areas has been suggested to support working memory processes in monkeys [7].

5. Outlook 5.1. Implications from monkey fMRI experiments for understanding human memory functions 5.1.1. Memory encoding Mapping memory traces in the monkey MTL using fMRI [67] revealed that activity in the hippocampus, perirhinal cortex, and caudal entorhinal cortex is predictive of subsequent recognition performance. In humans, fMRI activity in the hippocampus and perirhinal cortex, rather than the entorhinal cortex, predicts subsequent recognition performance [3,92–95]. These human studies consistently report differential patterns of activity between the hippocampus and perirhinal cortex, depending on the condition of memory encoding. Hippocampal activity is more predictive of subsequent recollection or recognition of deeply encoded memory than of subsequent familiarity-based retrieval or recognition of shallowly encoded memory. By contrast, although human perirhinal activity clearly predicts subsequent recognition performance, there are no consistent differences in predictability between these two types of memory [58]. Some researchers propose that the hippocampus subserves recollection-based encoding, whereas the perirhinal cortex subserves familiarity-based encoding [96,97]. However, others argue that no qualitative difference exists in the roles of the hippocampus and perirhinal cortex other than responsiveness to strongly or weakly encoded memory [98]. Recent investigations on human hippocampal functions with fMRI activity pattern analyses suggest that the hippocampus represents objects within specific temporal contexts, and the hippocampal activity pattern similarity across trials predicts later recognition performance when the context changes [99,100]. Specific subregions in the hippocampus (the dentate gyrus and CA3) were suggested to contribute to “pattern separation”, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, while other regions in the hippocampus and adjacent MTL cortices including perirhinal cortex treat these similar items as if they were repetitions of the previously seen item (referred to as “pattern completion”) [101]. Another recent report that combined fMRI for healthy subjects and intracranial electroencephalography for patients showed perirhinal–hippocampal coupling during source recognition: a rapid familiarity-based item recognition signal in perirhinal cortex triggered a recollection-based source retrieval process in the hippocampus, which in turn recruited perirhinal representations [102]. The perirhinal–hippocampal interaction is also proposed to contribute to consolidation processes of object-based associative memory [103]. In this way, investigations on signal transduction among MTL subregions that exhibit differential activity profiles during memory encoding are required to clarify the recognition memory formation processes within the MTL. To precisely examine the temporal dynamics of the perirhinal–hippocampal interactions, electrophysiological investigations using nonhuman primate models are necessary. The distribution of the memory traces we identified within the hippocampus and the perirhinal cortex will substantially inform these future electrophysiological studies in macaque monkeys. Unlike the hippocampus and the perirhinal cortex, involvement of the caudal entorhinal cortex in memory encoding has rarely been reported in humans [58], likely because the precise demarcation between the entorhinal cortex located on the parahippocampal gyrus and other cortex is difficult due to the scarcity of MRI-based delineations in the gyrus [104]. However, the caudal

entorhinal cortex, which has major reciprocal connections with the hippocampus, is likely to be an appropriate site to contain memory traces that work cooperatively with the hippocampus during memory encoding. Recent human fMRI studies show that the middle parahippocampal gyrus is responsible for contextual or scene processing, along with the hippocampus, whereas the anterior hippocampal gyrus, which corresponds to the human perirhinal cortex, is not [102,105]. Precise mapping of memory traces in the macaque MTL suggests that the middle part of the parahippocampal gyrus in humans, which is generally referred to as the parahippocampal cortex, corresponds to the macaque caudal entorhinal cortex. In our monkey fMRI experiments, memory traces predictive of subsequent recognition performance consistently across monkeys were not localized within the parahippocampal cortex. Perspectives from the monkey fMRI results discussed above suggest the existence of two differentially characterized memory traces in the caudal entorhinal and parahippocampal cortices in primates, and will encourage more detailed mapping of memory traces within the human parahippocampal gyrus. 5.1.2. Memory retrieval Human neuroimaging studies have revealed the association of successful recollection with the engagement of the angular gyrus (Brodmann area 39) in the ventral region of the human IPL [5]. However, there is no direct evidence from animal models that the functional counterpart of this area supports episodic memory function. The functional homologue of human Brodmann area 39 had been supposed to exist in the macaque PPC mainly based on similar axonal projections (albeit estimated via diffusion MRI in humans) and resting-state connectivity patterns between humans and monkeys [84,106,107]. However, no evidence indicated that any PPC area played roles in cognitive processing similar to those in the human IPL subregion. Miyamoto et al. [67], using task-based fMRI experiments in behaving monkeys, were the first to demonstrate that the monkey PPC contributes to the retrieval of recognition memory. A retrieval-related region localized on the IPL (area PG/PGOp), with which the hippocampus increases task-evoked connectivity when retrieval from long-term memory is required, is suggested to be a functional counterpart of human Brodmann area 39, which is known to functionally connect with the hippocampus in humans [84,108]. Inter-species comparisons based on functional neuroimaging, electrophysiological, and neuroanatomical tractography studies have shown that clear homologous subregions within the PPC do not exist between humans and monkeys [109,110]. The human posterior IPL, angular gyrus and temporoparietal junction (Brodmann areas 39 and 40), have especially expanded and developed greatly in humans compared with those regions in monkeys [76,106,110]. Whether this expansion is due to the evolution of new areas or simply duplication or enlargement of old regions is an unanswered question, and the functional correspondence of the subregions within the IPL between humans and monkeys is in dispute to this day [76,111–113]. However, a candidate for a functional counterpart of the human retrieval-related region in Brodmann area 39 has now been located within the macaque IPL of behaving monkeys. This observation supports the proposition that the function of the human angular gyrus originated from the macaque posterior IPL. Future electrophysiological investigations will provide important clues for understanding the functions of the angular gyrus, a highly developed area particularly in humans. Recently, it was proposed that the human PPC could be segmented into several subdivisions associated with different roles during memory processes [6,114–116]. Among these subdivisions, the dorsal PPC is thought to be involved in “top-down” attentional control [115,117], which reorients attention to memory [114], whereas the ventral PPC is thought to contribute to redirecting the “bottom-up” attentional signals of recollected memory from the

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hippocampus for execution of cognitive control based on recognition memory [6,114,118]. In addition, the dorsal and ventral PPC are considered to assume differential retrieval processes: dorsal PPC (lateral bank of the intraparietal sulcus; Brodmann area 7) is related to familiarity-based processes, and the ventral PPC (angular gyrus; Brodmann area 39) is related to recollection-based processes [5,6] (Fig. 3B and D). In Miyamoto et al. [67], task-based connectivity analysis during the retrieval of recognition memory revealed contrasting profiles for two macaque PPC areas: the IPL (area PG/PGOp), which is the target of bottom-up attention from hippocampus, and the IPS (area PEa/DIP), which is the source of top-down attention to visual cortex (visual area 4). Moreover, these PPC regions are functionally differentiated during recognition memory tasks. These results in monkeys are consistent with perspectives from human neuroimaging studies. Future simultaneous recordings within the two pairs of retrieval-related regions where task-evoked connectivity is observed will reveal the neuronal substrates of top-down and bottom-up attention supporting memory retrieval. 5.2. Future directions for investigating memory systems in primates In our monkey fMRI investigation on memory encoding processes [60], memory traces with similar characteristics were localized at two adjacent hierarchical levels (caudal entorhinal cortex and hippocampus). However, it is unknown how different recognition memory processes interact between the two areas. Recently, simultaneous electrophysiological recordings of neuronal activity within a single cortical region (area TE or area 36) revealed how memory representations of associated objects are consolidated and retrieved in neuronal microcircuits where neurons with differential response profiles interact each other [119,120]. A series of these electrophysiological investigations suggested that functional convergence toward associative object representation occurs as a small number of prototypes in a single area (area TE) and becomes prevalent in the subsequent, hierarchically higher area (area 36). Future application of such electrophysiological methods targeted to the memory traces predictive of subsequent recognition performance localized by fMRI experiments will clarify the neural representations of memory traces coded in hierarchically distributed microcircuits. The recent advancement of genetic methods applicable to neuroscience allows for the intervention of activity in targeted populations of neurons that are defined either structurally or functionally [121,122]. The application of optogenetic approaches in transgenic mice successfully reactivated hippocampal neuronal firing during fear conditioning sufficiently to induce freezing behavior [123,124]. Such methodologies provided direct evidence that the memory engram is consolidated during memory encoding and permitted manipulation of the engram. The optogenetic intervention of memory traces identified within the macaque MTL using fMRI will greatly assist revealing the direct causality between the activity of these memory traces and recognition-based behavior. For roles of the MTL during memory formation and retrieval, a new framework based on congruency-dependent MTL–medial prefrontal cortex (mPFC) interactions was recently proposed [125,126]. In this hypothesis, memory encoding and retrieval of information that is congruent with existing knowledge (a schema) is supported by the mPFC, whereas those incongruent with any schema are supported by the MTL. Evidence supporting this hypothesis was gathered using hippocampal and mPFC lesions in rodents and neuroimaging in humans [125,127–129], and this hypothesis would explain the severe anterograde amnesia observed after MTL damage with relatively intact remote memory before the damage as typified in patient H.M. The temporally graded retrograde amnesia observed in these cases suggests that

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memories already consolidated within the neocortex as a schema before the damage can be retrieved through interplay with the mPFC. This hypothesis has the potential to resolve the decades-long debate regarding the functions of the hippocampus in recognition memory processing. To validate the hypothesis, utilization of nonhuman primate models will be beneficial. However, the region(s) wherein the distribution of the cell populations responsible for this schema formation resides are unknown. In the future, multi-modal approaches combining fMRI, electrophysiology, and genetics in behaving monkeys will help clarify the hippocampal role in schema formation and settle the dispute regarding hippocampal functions. 6. Conclusion Application of the same neuroimaging techniques used in humans to fMRI investigations in monkeys performing recognition memory tasks enabled the direct comparison of the activity in the whole brain during memory processing for the first time. The interspecies comparison of memory traces predictive of subsequent recognition performance suggested that the caudal entorhinal cortex, as well as the hippocampus and perirhinal cortex, is responsible for memory formation. On the other hand, despite marked interspecies differences in anatomical structure, the monkey PPC was found to be responsible for memory retrieval, similar to the role of the human PPC in memory processing. In particular, the retrievalrelated region within the monkey IPL was suggested to functionally correspond with that in the human angular gyrus, a cortical area unique to humans. These findings from monkey fMRI advance the understanding of memory systems common to monkeys and humans and form the foundation for future studies using electrophysiological and genetic methods to more finely characterize memory-related processes. Acknowledgments The authors gratefully acknowledge Dr. Yasushi Miyashita for providing helpful comments on the manuscript, and Tomomi Watanabe, Hiroko M. Kimura, and Takamitsu Watanabe for collaborations. This work was supported in part by a MEXT/JSPS KAKENHI Grant number 25750399 to Y.A., and Japan Society for the Promotion of Science Research Fellowships for Young Scientists to K.M. (234682 and 265926). References [1] Squire LR, Stark CE, Clark RE. The medial temporal lobe. Annu Rev Neurosci 2004;27:279–306. [2] Strange B, Otten L, Josephs O, Rugg M, Dolan R. Dissociable human perirhinal, hippocampal, and parahippocampal roles during verbal encoding. J Neurosci 2002;22:523–8. [3] Ranganath C, Yonelinas AP, Cohen MX, Dy CJ, Tom SM, D’Esposito M. Dissociable correlates of recollection and familiarity within the medial temporal lobes. Neuropsychologia 2004;42:2–13. [4] Davachi L. Item, context and relational episodic encoding in humans. Curr Opin Neurobiol 2006;16:693–700. [5] Wagner AD, Shannon BJ, Kahn I, Buckner RL. Parietal lobe contributions to episodic memory retrieval. Trends Cogn Sci 2005;9:445–53. [6] Vilberg KL, Rugg MD. Memory retrieval and the parietal cortex: a review of evidence from a dual-process perspective. Neuropsychologia 2008;46:1787–99. [7] Curtis CE, D’Esposito M. Persistent activity in the prefrontal cortex during working memory. Trends Cogn Sci 2003;7:415–23. [8] Osada T, Adachi Y, Kimura HM, Miyashita Y. Towards understanding of the cortical network underlying associative memory. Philos Trans R Soc B: Biol Sci 2008;363:2187–99. [9] Vanduffel W, Zhu Q, Orban GA. Monkey cortex through fMRI glasses. Neuron 2014;83:533–50. [10] Logothetis NK, Guggenberger H, Peled S, Pauls J. Functional imaging of the monkey brain. Nat Neurosci 1999;2:555–62. [11] Vanduffel W, Fize D, Mandeville JB, Nelissen K, Van Hecke P, Rosen BR, et al. Visual motion processing investigated using contrast agent-enhanced fMRI in awake behaving monkeys. Neuron 2001;32:565–77.

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