A theory of hippocampal function in memory

First, what is computed by the hippocampus is considered. Based on the effects of damage to the hippocampus and neuronal activity recorded in the primate hippocampus, it is suggested that it is involved in associating together information usually originating from different cortical regions, for example, about objects and their place in a spatial environment. The rapid formation of such context-dependent memories is prototypical of memories of particular events or episodes. Second, a computational theory of how it performs this function, based on neuroanatomical and neurophysiological information about the different neuronal systems contained within the hippocampus, is described. Key hypotheses are that the CA3 pyramidal cells operate as a single autoassociation network to store new episodic information as it arrives via a number of specialized preprocessing stages from many different association areas of the cerebral cortex, and that the dentate granule cell/mossy fiber system is important particularly during learning to help to produce a new pattern of firing in the CA3 cells for each episode. The computational analysis shows how many memories could be stored in the hippocampus, and how quickly the CA3 autoassociation system would operate during recall. The analysis is then extended to show how the CA3 system could be used to recall the whole of an episodic memory when only a fragment of it is presented. It is shown how this retrieval within the hippocampus could lead to recall of neuronal activity in association areas of the cerebral neocortex similar to that present during the original episode, via modified synapses in backprojection pathways from the hippocampus to the cerebral neocortex. The recalled information in the cerebral neocortex could then by used by the neocortex in the formation of long-term memories and/or in the selection of appropriate actions. © 1997 Wiley-Liss, Inc.     

Computational analysis of the role of the hippocampus in memory

The authors draw together the results of a series of detailed computational studies and show how they are contributing to the development of a theory of hippocampal function. A new part of the theory introduced here is a quantitative analysis of how backprojections from the hippocampus to the neocortex could lead to the recall of recent memories. The theory is then compared with other theories of hippocampal function. First, what is computed by the hippocampus is considered. The hypothesis the authors advocate, on the basis of the effects of damage to the hippocampus and neuronal activity recorded in it, is that it is involved in the formation of new memories by acting as an intermediate-term buffer store for information about episodes, particularly for spatial, but probably also for some nonspatial, information. The authors analyze how the hippocampus could perform this function, by producing a computational theory of how it operates, based on neuroanatomical and neurophysiological information about the different neuronal systems contained within the hippocampus. Key hypotheses are that the CA3 pyramidal cells operate as a single autoassociation network to store new episodic information as it arrives via a number of specialized preprocessing stages from many association areas of the cerebral cortex, and that the dentate granule cell/mossy fiber system is important, particularly during learning, to help to produce a new pattern of firing in the CA3 cells for each episode. The computational analysis shows how many memories could be stored in the hippocampus and how quickly the CA3 autoassociation system would operate during recall. The analysis is then extended to show how the CA3 system could be used to recall a whole episodic memory when only a fragment of it is presented. It is shown how this recall could operate using modified synapses in backprojection pathways from the hippocampus to the cerebral neocortex, resulting in reinstatement of neuronal activity in association areas of the cerebral neocortex similar to that present during the original episode. The recalled information in the cerebral neocortex could then be used by the neocortex in the formation of long-term memories. © 1994 Wiley-Liss, Inc.     

Medial temporal lobe function and recognition memory: a novel approach to separating the contribution of recollection and familiarity

Human neuroimaging studies of recognition memory have often been interpreted to mean that the hippocampus supports recollection but not familiarity. This interpretation is complicated by the fact that recollection-based decisions are typically associated with stronger memories than familiarity-based decisions. Some studies of source memory controlled for this difference in memory strength and found that hippocampal activity during learning predicted subsequent item memory strength while recollection-based memory (performance on source memory questions) was held at chance. This result suggests that the hippocampus is important for familiarity. However, a difficulty with this approach is that when source memory is assessed by asking specific, task-relevant source memory questions, participants who fail to answer the prescribed questions might nevertheless have available other (task-irrelevant) source information. Accordingly, successful item memory could still be associated with recollection. The present study used a novel method to assess item memory and source memory. Instead of responding to specific source questions, participants rated their source memory strength based on any information about the learning episode that was available to them. When subsequent source memory strength was held constant at the lowest possible level, we identified regions bilaterally in hippocampus, as well as in perirhinal cortex, where activity during learning increased as subsequent item memory increased in strength. In addition, activity in cortical regions (including prefrontal cortex) was related to source memory success independently of item memory strength. These findings suggest that activity in the hippocampus is related to the encoding of familiarity-based item memory, independent of subsequent recollection-based success.     

The role of hippocampus in memory: A hypothesis

The role of the hippocampus in memory storage in the mammalian brain is examined. The intrinsic anatomical organization of the hippocampus is such that a multidimensional mapping of other brain regions is represented. Emerging knowledge of the cortico-limbic-subcortical anatomy suggests that the hippocampal representations preserve the topological features of the targets and possess reciprocal connectivity. Long-Term Potentiation (LTP) is a prominent physiological characteristic of hippocampal synapses and is a promising candidate mnemonic device. The hypothesis is advanced that the pattern, or index, of specific neocortical (and other) areas activated by an experiential event is represented, or indexed, in the hippocampus by means of LTP. This hypothesis, termed the Memory Indexing Theory, suggests that experiential events are initially stored in an index of neocortical locations maintained in hippocampus. Subsequently, other regions, notably neocortex itself, permanently encode these experiential events and the interrelationships between them.     

Characterizing the role of the hippocampus during episodic simulation and encoding

The hippocampus has been consistently associated with episodic simulation (i.e., the mental construction of a possible future episode). In a recent study, we identified an anterior‐posterior temporal dissociation within the hippocampus during simulation. Specifically, transient simulation‐related activity occurred in relatively posterior portions of the hippocampus and sustained activity occurred in anterior portions. In line with previous theoretical proposals of hippocampal function during simulation, the posterior hippocampal activity was interpreted as reflecting a transient retrieval process for the episodic details necessary to construct an episode. In contrast, the sustained anterior hippocampal activity was interpreted as reflecting the continual recruitment of encoding and/or relational processing associated with a simulation. In the present study, we provide a direct test of these interpretations by conducting a subsequent memory analysis of our previously published data to assess whether successful encoding during episodic simulation is associated with the anterior hippocampus. Analyses revealed a subsequent memory effect (i.e., later remembered > later forgotten simulations) in the anterior hippocampus. The subsequent memory effect was transient and not sustained. Taken together, the current findings provide further support for a component process model of hippocampal function during simulation. That is, unique regions of the hippocampus support dissociable processes during simulation, which include the transient retrieval of episodic information, the sustained binding of such information into a coherent episode, and the transient encoding of that episode for later retrieval.     

Activity in the hippocampus and neocortical working memory regions predicts successful associative memory for temporally discontiguous events

Models of mnemonic function suggest that the hippocampus binds temporally discontiguous events in memory (Wallenstein, Eichenbaum, & Hasselmo, 1998), which has been supported by recent studies in humans. Less is known, however, about the involvement of working memory in bridging the temporal gap between to-be-associated events. In this study, subsequent memory for associations between temporally discontiguous stimuli was examined using functional magnetic resonance imaging. In the scanner, subjects were instructed to remember sequentially presented images. Occasionally, a plus-sign was presented during the interstimulus interval between two images, instructing subjects to associate the two images as a pair. Following the scan, subjects identified remembered images and their pairs. Images following the plus-sign were separated into trials in which items were later recognized and the pair remembered, recognized and the pair forgotten, or not recognized. Blood-oxygen-level-dependent responses were measured to identify regions where response amplitude predicted subsequent associative- or item memory. Distinct neocortical regions were involved in each memory condition, where activity in bilateral frontal and parietal regions predicted memory for associative information and bilateral occipital and medial frontal regions for item information. While activity in posterior regions of the medial temporal lobe showed an intermediate response predicting memory for both conditions, bilateral hippocampal activity only predicted associative memory.     

The role of the ventromedial prefrontal cortex in memory consolidation

"System-level memory consolidation theory" posits that the hippocampus an initially links the neocortical representations, followed by a shift to a hippocampus-independent neocortical network. With consolidation, an increase in activity in the human subgenual ventromedial prefrontal cortex (vmPFC) has repeatedly been shown. Previously we and others have proposed that this area might link the neocortical representational areas in remote memory, similarly as has been proposed for the rodent anterior cingulate cortex (ACC). Here, we review literature involving the human vmPFC to investigate if the results in other cognitive domains are in line with this proposal. We have taken into account reports on patients with lesions in this area, findings in reward and valuation, fear extinction, and confabulation studies, and integrated these with findings in consolidation studies. We conclude: Firstly, it is unlikely that the rodent ACC is homolog to the human subgenual vmPFC. It is more likely that the rodent infralimbic cortex is, as proposed in the fear extinction literature. Secondly, we propose that the function of the subgenual vmPFC is to integrate information which is represented in separate parts of the limbic system (the hippocampus, the amygdala, and the ventral striatum) and that the integrated representation in the subgenual vmPFC might subsequently be used to suppress irrelevant representations in the limbic system. With the progression of time, the importance of the integrated representation in the subgenual vmPFC increases, because it may replace some direct connectivity across the limbic areas which decays with time.     

A bird-brain view of episodic memory

In humans, the hippocampus plays a critical role in the formation of episodic memories. Although non-human animals are unable to report whether they also re-experience past events, at least some birds and mammals exhibit ‘episodic-like’ memory characterized by an ability to recall what happened where and when. In mammals, the hippocampus interacts closely with virtually the entire neocortex to form episodic-like memories. The hippocampus receives highly processed information from high-order association areas, and thereby the rest of the neocortex. Distinct neurophysiological hippocampal rhythms (theta and sharp-wave ripples) coordinate activity between the hippocampus and high-order association areas during the encoding and retrieval of information contributing to episodic-like memories. Although recent studies have demonstrated that food hoarding birds are able to remember what food they hid where and when, neuroanatomical and neurophysiological studies suggest that there may be a fundamental difference between episodic-like memory in birds and mammals. In contrast to the mammalian hippocampus, the avian hippocampus only receives visual and olfactory input; most high-order association areas in the avian brain involved in performing functions similar to those performed by neocortical association areas do not project to the hippocampus or structures providing it with direct input. Consistent with this neuroanatomical difference, mammalian-like rhythms involved in communicating between the hippocampus and neocortical high-order association areas have not been found in birds. Collectively, this suggests that information contributing to episodic-like memory is more limited and processed in a different manner in birds when compared to mammals.     

Sleep-dependent directional coupling between human neocortex and hippocampus

Complex interactions between neocortex and hippocampus are the neural basis of memory formation. Two-step theories of memory formation suggest that initial encoding of novel information depends on the induction of rapid plasticity within the hippocampus, and is followed by a second sleep-dependent step of memory consolidation. These theories predict information flow from the neocortex into the hippocampus during waking state and in the reverse direction during sleep. However, experimental evidence that interactions between hippocampus and neocortex have a predominant direction which reverses during sleep rely on cross-correlation analysis of data from animal experiments and yielded inconsistent results. Here, we investigated directional coupling in intracranial EEG data from human subjects using a phase-modeling approach which is well suited to reveal functional interdependencies in oscillatory data. In general, we observed that the anterior hippocampus predominantly drives nearby and remote brain regions. Surprisingly, however, the influence of neocortical regions on the hippocampus significantly increased during sleep as compared to waking state. These results question the standard model of hippocampal-neocortical interactions and suggest that sleep-dependent consolidation is accomplished by an active retrieval of hippocampal information by the neocortex.     

Effortful retrieval reduces hippocampal activity and impairs incidental encoding

Functional imaging studies frequently report that the hippocampus is engaged by successful episodic memory retrieval. However, considering that concurrent encoding of the background environment occurs during retrieval and influences medial temporal lobe activity, it is plausible that hippocampal encoding functions are reduced with increased attentional engagement during effortful retrieval. Expanding upon evidence that retrieval efforts suppress activity in hippocampal regions implicated in encoding, this study examines the influence of retrieval effort on encoding performance and the interactive effects of encoding and retrieval on hippocampal and neocortical activity. Functional magnetic resonance imaging was conducted while subjects performed a word recognition task with incidental picture encoding. Both lower memory strength and increased search duration were associated with encoding failure and reduced hippocampal and default network activity. Activity in the anterior hippocampus tracked encoding, which was more strongly deactivated when incidental encoding was unsuccessful. These findings highlight potential contributions from background encoding processes to hippocampal activations during neuroimaging studies of episodic memory retrieval. © 2013 Wiley Periodicals, Inc.     

Hippocampal network connections account for differences in memory performance in the middle‐aged rhesus monkey

Recent neurophysiological and functional neuroimaging studies suggest that the memory decline found with normal aging is not solely due to regional disruptions in the hippocampus, but also is brought about by alterations in the functional coupling between the hippocampus and long‐distance neocortical regions. However, the anatomical basis for this functional “dyscoupling” has not been fully revealed. In this study, we applied a multimodal magnetic resonance imaging technique to noninvasively examine the large‐scale anatomical and functional hippocampal network of a group of middle aged rhesus monkeys. Using diffusion spectrum imaging, we have found that monkeys with lower memory performance had weaker structural white matter connections between the hippocampus and neocortical association areas. Resting state functional imaging revealed somewhat of an opposite result. Monkeys with low memory performance displayed elevated coupling strengths in the network between the hippocampus and the neocortical areas. Taken together with recent findings, this contradictory pattern may be the result of either underlying physiological burden or abnormal neuronal decoupling due to the structural alterations, which induce a neuronal compensation mechanism for the structural loss or interference on task related neuronal activation, respectively. © 2013 Wiley Periodicals, Inc.     

Spatial navigation and causal analysis in a brain-based device modeling cortical-hippocampal interactions

We describe Darwin X, a physical device that interacts with a real environment, whose behavior is guided by a simulated nervous system incorporating aspects of the detailed anatomy and physiology of the hippocampus and its surrounding regions. This brain-based device integrates cues from its environment and solves a spatial memory task. The responses of simulated neuronal units in the hippocampal areas during its exploratory behavior are comparable to place cells in the rodent hippocampus and emerged by associating sensory cues during exploration. To identify different functional hippocampal pathways and their influence on behavior, we employed a time series analysis that distinguishes causal interactions within and between simulated hippocampal and neocortical regions while the device is engaged in a spatial memory task. Our analysis identified different functional pathways within the neural simulation and prompts novel predictions about the influence of the perforant path, the trisynaptic loop and hippocampal-cortical interactions on place cell activity and behavior during navigation. Moreover, this causal time series analysis may be useful in analyzing networks in general.     

Repetition reveals ups and downs of hippocampal,thalamic, and neocortical engagement during mnemonic decisions

The extent to which current information is consistent with past experiences and our capacity to recognize or discriminate accordingly are key factors in flexible memory‐guided behavior. Despite a wealth of evidence linking hippocampal and neocortical computations to these phenomena, many important factors remain poorly understood. One such factor is repeated encoding of learned information. In this experiment, participants completed a task in which study stimuli were incidentally encoded either once or three separate times during high‐resolution fMRI scanning. We asked how repetition influenced recognition and discrimination memory judgments, and how this affects engagement of hippocampal and neocortical regions. Repetition revealed shifts in engagement in an anterior (ventral) CA1‐thalamic‐medial prefrontal network related to true and false recognition. Conversely, repetition revealed shifts in a posterior (dorsal) dentate/CA3‐parahippocampal‐restrosplenial network related to accurate discrimination. These differences in engagement were accompanied by task‐related correlations in respective anterior and posterior networks. In particular, the anterior thalamic region observed during recognition judgments is functionally and anatomically consistent with nucleus reuniens in humans, and was found to mediate correlations between the anterior CA1 and medial prefrontal cortex. These findings offer new insights into how repeated experience affects memory and its neural substrates in hippocampal‐neocortical networks. © 2016 Wiley Periodicals, Inc.     

Divergent neuronal activity patterns in the avian hippocampus and nidopallium

Sleep‐related brain activity occurring during non‐rapid eye‐movement (NREM) sleep is proposed to play a role in processing information acquired during wakefulness. During mammalian NREM sleep, the transfer of information from the hippocampus to the neocortex is thought to be mediated by neocortical slow‐waves and their interaction with thalamocortical spindles and hippocampal sharp‐wave ripples (SWRs). In birds, brain regions composed of pallial neurons homologous to neocortical (pallial) neurons also generate slow‐waves during NREM sleep, but little is known about sleep‐related activity in the hippocampus and its possible relationship to activity in other pallial regions. We recorded local field potentials (LFP) and analogue multiunit activity (AMUA) using a 64‐channel silicon multi‐electrode probe simultaneously inserted into the hippocampus and medial part of the nidopallium (i.e., caudal medial nidopallium; NCM) or separately into the caudolateral nidopallium (NCL) of adult female zebra finches (Taeniopygia guttata) anesthetized with isoflurane, an anesthetic known to induce NREM sleep‐like slow‐waves. We show that slow‐waves in NCM and NCL propagate as waves of neuronal activity. In contrast, the hippocampus does not show slow‐waves, nor sharp‐wave ripples, but instead displays localized gamma activity. In conclusion, neuronal activity in the avian hippocampus differs from that described in mammals during NREM sleep, suggesting that hippocampal memories are processed differently during sleep in birds and mammals.     

Dissociating the past from the present in the activity of place cells

It has been proposed that declarative memories can be dependent on both an episodic and a semantic memory system. While the semantic system deals with factual information devoid of reference to its acquisition, the episodic system, characterized by mental time travel, deals with the unique past experience in which an event took place. Episodic memory is characteristically hippocampus-dependent. Place cells are recorded from the hippocampus of rodents and their firing reflects many of the key characteristics of episodic memory. For example, they encode information about "what" happens "where," as well as temporal information. However, when these features are expressed during an animal's behavior, the neuronal activity could merely be categorizing the present situation and could therefore reflect semantic memory rather than episodic memory. We propose that mental time travel is the key feature of episodic memory and that it should take a form, in the awake animal, similar to the replay of behavioral patterns of activity that has been observed in hippocampus during sleep. Using tasks designed to evoke episodic memory, one should be able to see memory reactivation of behaviorally relevant sequences of activity in the awake animal while recording from hippocampus and other cortical structures.     

The role of theta-range oscillations in synchronising and integrating activity in distributed mnemonic networks

It is well established that the occurrence of theta rhythm in the hippocampus is important in a variety of mnemonic tasks. However, in this review it will be argued that theta-rhythmic activity occurs across distributed networks within the diencephalon and neocortex as well as the hippocampus, and functions to temporally coordinate activity in distributed systems within these regions during mnemonic processes. Recent evidence strongly suggests that theta-range cellular activity occurs in the supramammillary nucleus (SuM) of the hypothalamus, and that this activity is independent of that occurring in the hippocampus. We have previously proposed in fact, that the frequency of theta activity in the hippocampus is determined in the SuM, rather than in the medial septum as previously assumed. The frequency-coded information from the SuM is then fed into at least two recurrent networks proposed by Aggleton and Brown (1999). Theta activity in these networks (the hippocampo-anterior thalamic system and the perirhinal-mediodorsal thalamic system) could potentially occur independently, but when simultaneously occurring in both may function to coordinate the integration of information in the two systems. Finally, we suggest that as the two systems include temporal and frontal neocortical areas that contribute to surface EEG, scalp recording of theta EEG activity from these regions may provide a “window” through which to assess the relative involvement of different cortico-limbic circuits in different mnemonic processes. The potential utility of this technique will be increased greatly by the use of high-density EEG and algorithms to more precisely map the topography of cortical sources of EEG activity.     

One month of human memory consolidation enhances retrieval-related hippocampal activity

We studied the role of the hippocampus in memory retrieval at 1 day and 1 month following associative learning of word pairs. Retrieval-related brain activity was recorded using functional magnetic resonance imaging in 20 healthy students, of which 12 were good learners and eight were poor learners. At the day lag, the poor learners exhibited enhanced neural recruitment in the hippocampus and neocortex to reach a retrieval performance comparable to that of the good learners. Over the 20 subjects, there was a positive correlation between retrieval-related hippocampal activity at the day lag and forgetting over the month retention interval (the greater the activity, the more forgetting). Although the poor learners' retrieval performance declined dramatically from the day to the month lag, the good learners maintained a high retrieval performance, which distinguishes them as good memory consolidators. Their retrieval-related hippocampal and neocortical activity increased from the day to the month lag. This increase was observed both when retrieval performance was matched between the day and the month lag and when the learning procedure for information retrieved at the day and the month lag was matched. This activity increase in the task-specialized neural network from the day lag to the month lag may reflect an increase in task demands or the proliferation of hippocampal-neocortical memory traces during memory consolidation as suggested by the multiple trace theory.     

Hippocampal‐cortical contributions to strategic exploration during perceptual discrimination

The hippocampus is crucial for long‐term memory; its involvement in short‐term or immediate expressions of memory is more controversial. Rodent hippocampus has been implicated in an expression of memory that occurs on‐line during exploration termed “vicarious trial‐and‐error” (VTE) behavior. VTE occurs when rodents iteratively explore options during perceptual discrimination or at choice points. It is strategic in that it accelerates learning and improves later memory. VTE has been associated with activity of rodent hippocampal neurons, and lesions of hippocampus disrupt VTE and associated learning and memory advantages. Analogous findings of VTE in humans would support the role of hippocampus in active use of short‐term memory to guide strategic behavior. We therefore measured VTE using eye‐movement tracking during perceptual discrimination and identified relevant neural correlates with functional magnetic resonance imaging. A difficult perceptual‐discrimination task was used that required visual information to be maintained during a several second trial, but with no long‐term memory component. VTE accelerated discrimination. Neural correlates of VTE included robust activity of hippocampus and activity of a network of medial prefrontal and lateral parietal regions involved in memory‐guided behavior. This VTE‐related activity was distinct from activity associated with simply viewing visual stimuli and making eye movements during the discrimination task, which occurred in regions frequently associated with visual processing and eye‐movement control. Subjects were mostly unaware of performing VTE, thus further distancing VTE from explicit long‐term memory processing. These findings bridge the rodent and human literatures on neural substrates of memory‐guided behavior, and provide further support for the role of hippocampus and a hippocampal‐centered network of cortical regions in the immediate use of memory in on‐line processing and the guidance of behavior.     

Overlap between the neural correlates of cued recall and source memory: evidence for a generic recollection network?

Recall of a studied item and retrieval of its encoding context (source memory) both depend on recollection of qualitative information about the study episode. This study investigated whether recall and source memory engage overlapping neural regions. Participants (n = 18) studied a series of words, which were presented either to the left or right of fixation. fMRI data were collected during a subsequent test phase in which three-letter word-stems were presented, two thirds of which could be completed by a study item. Instructions were to use each stem as a cue to recall a studied word and, when recall was successful, to indicate the word's study location. When recall failed, the stem was to be completed with the first word to come to mind. Relative to stems for which recall failed, word-stems eliciting successful recall were associated with enhanced activity in a variety of cortical regions, including bilateral parietal, posterior midline, and parahippocampal cortex. Activity in these regions was enhanced when recall was accompanied by successful rather than unsuccessful source retrieval. It is proposed that the regions form part of a "recollection network" in which activity is graded according to the amount of information retrieved about a study episode.