Memories of events in the brain are linked when they occur closely together


People have little difficulty remembering the chronology of events, determining how much time passed between two events, and which one occurred first.

Apparently, memories of events in the brain are linked when they occur closely together.

Using an experiment that combines virtual reality and brain scan technology, Jacob Bellmund and Christian Doeller from the Max Planck Institute for Human Cognitive and Brain Sciences describe how a temporal map of memories is created in the brain.

The entorhinal cortex, part of the medial temporal lobe, seems to play an important role.

But how, exactly, does this part of the brain, near the amygdala and hippocampus, contribute to building a memory?

To learn more, the scientists had 26 subjects learn a sequence of events by navigating a route through a virtual city.

They had to remember when certain objects appeared along the route and where they were in the city.

Participants encountered chests along the route, which they were instructed to open.

Each chest contained a different object that was displayed on a black screen when the chest was opened.

After learning, the researchers used an MRI scanner to measure how these events were displayed in the brain by showing the participants images of the objects in random order.

“Events that occurred in temporal proximity are represented by similar activation patterns in the entorhinal cortex,” explained Jacob Bellmund.

“This means that when objects were shown that were temporally close along the route, this part of the brain reacted in a similar way.

They were therefore more similar to each other than the activation patterns of events that occured at long intervals.”

Thus, the activation patterns of the entorhinal cortex reflected a kind of map of the temporal relationships of events.

The spatial relationships of the events, that is, the distance between the objects as the crow flies, could not be observed by the scientists.

The researchers used a trick to study space and time independently:

Three teleporters on the route immediately ‘beamed’ the participants to another part of the city, where participants continued navigating the route.

“This manipulation enabled us to vary the temporal and spatial distances between pairs of objects so that the spatial distance could be large, but the temporal distance very small,” explained Bellmund.

The participants’ recall of events in a later memory test was influenced by how distinct the temporal map of events in the entorhinal cortex was.

They were asked to remember all the objects encountered along the route in the order in which they came to mind.

Participants with an exact temporal map in the entorhinal cortex recalled events one after the other that occurred in temporal proximity.

They listed the objects in order, as if they were mentally walking the route again.

Taken together, these findings show that the entorhinal cortex maps the time sequence of events and that this temporal map influences how people retrieve memories.

These findings suggest that the brain stores our memories of experiences in a temporally organized way.

There is a long history of tension between the view that memories are stored independently as individual associations and the idea that new information is integrated within systematic organizational structures.

In the first half of the 20th century, the association and organization views of memory came into conflict in battles between the characterizations of stimulus-response learning (c.f. Spence 1950) and cognitive maps (Tolman 1948), and the distinction was highlighted in Bartlett’s (1932) and Piaget’s (1928) ideas on memory organization in schemas.

Critics described the organizational views proposed at that time as vague, but the pioneers of modern cognitive science proposed specific forms of systematic organization in which memories are embedded (e.g., Bower 1970Collins & Quillian 1969Mandler 1972; see also Holland 2008).

Of particular relevance to this review, Mandler (19722011) proposed three types of memory organization (Figure 1): an associative structure in which multiple events are linked by direct and indirect associations within a network, a sequential structure involving a temporal organization of serial events, and a schematic structure involving a hierarchical or similarly complex organization of items in memory (Mandler used different names for these organizations).

Mandler did not attempt to explain the brain mechanisms that underlie these structures and had no expectation that these organizations could be directly observed.

Instead, he based his theory of their existence on results from cleverly designed studies that identified types of memory organization by their consequences in memory judgments.

In this review, I argue that new approaches in neuroscience are revealing these organizational structures within neural networks and identifying distinct brain mechanisms that guide encoding and retrieval of information within these organizations.

A full understanding of how the brain organizes and controls memory requires a synthesis of findings in humans, in which we can best characterize these organizations and identify the key brain areas involved, with findings in animal models, in which we can examine how networks of neurons – the elements of information processing – support the organization and control processes.

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Figure 1
Three forms of memory organization and the role of the hippocampus in humans and animals. (Left column) Elements A, B, and C are related in ways specific to each type of organization. (Middle column) Hippocampal activation in (a) associative (Zeithamova et al. 2012), (b) sequential (Ezzyat & Davachi 2014), and (c) schematic (Zalesak & Heckers 2009) memory organizations. (Right column) Graphs depicting the results in memory performance of rats with hippocampal lesions compared to a control group without lesions. (a) Rats with hippocampal lesions succeed in learning individual elements and associations (AB and BC) but fail in linking indirectly related elements in an associative organization (reflected in the low preference for the indirectly related element association AC) (Bunsey & Eichenbaum 1996). (b) Rats with hippocampal lesions succeed in remembering items in a list but fail in remembering the order of the items in the sequential organization (Fortin et al. 2002). (c) Rats with hippocampal lesions succeed in learning trained choices of all pairings in a five-item hierarchy (A–E; B over C and C over D are shown) but fail in inferring relations between indirectly related elements (B and D) in a hierarchical schematic organization (Dusek & Eichenbaum 1997).

Beginning in the latter half of the twentieth century, neuroscientific research revealed that the hippocampus is the hub of a brain system that supports memory organization.

This article begins with an overview of the type of memory organization that is dependent on the hippocampus, then focuses on recent analyses of hippocampal neuronal activity patterns that provide insights about the nature of memory organizations supported by the hippocampus.

I then consider additional evidence that memory organization is actively controlled by the prefrontal cortex via its interactions with the hippocampus.

Parallels between the findings of behavioral and physiological studies in humans and animals and the resulting conceptual advances about the organization and control of memory by these brain areas are highlighted.


In describing the type of memory that is supported by the hippocampus, researchers have emphasized important features of memory impairment in humans with amnesia consequent to hippocampal region damage. Memory dependent on the hippocampal region has been characterized as “declarative” (Cohen & Squire 1980, p. 209) and “explicit” (Graf & Schacter 1985, p. 501), terms that highlight our capacity to remember specific events and facts through direct efforts to access memories via conscious recollection.

Characterization of the cognitive processes involved in memory dependent on the hippocampus has distinguished the ability to recognize a previously experienced stimulus via recollection of the stimulus in the context of other information associated with the experience from a sense of familiarity with the stimulus independent of the context in which it was experienced (reviewed in Eichenbaum et al. 2007Yonelinas & Parks 2007).

Furthermore, Tulving (1972) distinguished episodic memory, the ability to recall specific personal experiences that occur in a unique spatial and temporal context, from semantic memory, the accumulated knowledge about the world abstracted from many experiences and not dependent on any specific event during which the information was obtained.

Episodic memory is severely impaired following hippocampal damage, even under conditions in which semantic memory is relatively intact (Vargha-Khadem et al. 1997), although the acquisition of new semantic memories is also impaired following hippocampal damage (Bayley et al. 2008Gabrieli et al. 1988O’Kane et al. 2004).

Research has also demonstrated properties of recollection that are dependent on the hippocampus in animals. Conscious recollection, typically observed through subjective report in humans, is beyond direct access in animals.

However, there are objective measures of memory performance supported by recollection in humans that have been applied to validate animal models of recollection-based memory. One approach examines recognition memory through an analysis of receiver operating characteristics (ROCs) in which subjects study a list of items and are then tested on a larger list.

On the larger list, subjects identify old items that were on the original list and new items that were not. The proportion of correct identifications of old items (hits) is compared to the proportion of incorrect identifications of new items as old (false alarms) across a wide range of response biases (Macmillan & Creelman 2005).

The ROC function from these data is typically characterized by two prominent dimensions that distinguish recollection and familiarity (for a detailed description, see Yonelinas 2001). Applying the same basic experimental design in an animal model, research has demonstrated that the ROC function for recognition memory in rats is similar to that observed in humans (Figure 2) (Fortin et al. 2004; for a review, see Eichenbaum et al. 2010).

Furthermore, the ROCs favor recollection in rats under the same conditions that favor recollection in humans (Sauvage et al. 2008); the same is true for conditions favoring familiarity (Sauvage et al. 2010), thus validating the animal model.

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Figure 2
Receiver operating characteristic (ROC) analysis of performance on variants of recognition memory in rats. (a) Item recognition. The ROC function is characterized by both an offset in the yintercept and bowing of the ROC curve, which is strikingly similar to the ROC function for item recognition in humans (Fortin et al. 2004). (b) Associative recognition. The ROCs for item pairs are characterized by loss of the bowing of the ROC function while the offset of the y intercept is maintained, as is the case when humans are tested in recognition of word pairs (Sauvage et al. 2008). (c) Response deadline. When subjects are required to respond rapidly, the offset in the yintercept of the ROC is lost and the curvilinear shape is maintained, as is also the case in humans (Sauvage et al. 2010).

Importantly, considerable evidence indicates that the recollection component of the ROCs is differentially impaired by hippocampal damage in humans (reviewed in Eichenbaum et al. 2007Yonelinas & Parks 2007; for an alternative perspective that focuses on the different contents of memories in recollection and familiarity, see Wixted & Squire 2011).

This deficit is also observed in rats such that damage to the hippocampus in rats selectively impairs recollection-based performance, whereas lesions to another part of the medial temporal lobe (the amygdala) selectively impairs familiarity-based performance, confirming in animals the importance of the medial temporal lobe in these features of memory and providing an anatomical double-dissociation of recollection and familiarity processes (Sauvage et al. 20082010; also see Bowles et al. 2007).

These observations support the view that the fundamental cognitive processes that underlie recollection and its dependence on the hippocampus are conserved across species.

Notably, Mandler (1972) was among the first to distinguish the two processes in recognition memory that we now call recollection and familiarity.

He argued that the most important distinction between these processes is that familiarity for an individual item occurs via the integration of featural elements that compose a single percept, whereas recollection of an item occurs via elaboration of its associates within their organizational structure.

In this review, I argue that Mandler’s three organizational structures (Figure 1) provide a good characterization of the nature of hippocampus-dependent recollective memory.

Associative Organization

In ROC analyses, a demand for memory of specific associations is imposed by using a study list composed of word pairs (e.g., army–table, baseball–saddle) and then testing the ability of the subject to distinguish old pairings (army–table) from new rearranged pairings of the same words (army–saddle).

This manipulation strengthens the reliance on recollection of the specific associations for the word pairs because all of the individual words are used in the study phase and are thus equally familiar in the test phase. As a consequence, the ROC function becomes exclusively recollection based in both humans (using word pairs) and animals (using odor pairs), and performance is dramatically impaired following hippocampal damage (Sauvage et al. 2008Yonelinas & Parks 2007).

In addition to associations between specific items, Mandler (1972) also recognized associations between each item and the larger context of associations into which it fits.

Thus, for example, studies on recognition typically employ highly familiar words such that the test does not ask whether one recognizes each word per se (typically all the words are highly familiar) but rather whether one recognizes each word within the context of the studied list.

This feature of associative organization in recognition is particularly relevant in a naturalistic test of recognition of items in context that measures the preferential exploration of novel over familiar objects in context in humans and monkeys (Pascalis et al. 2004).

In this task, the subject first briefly studies a novel object within a visual context and then, after a delay, is presented with the same object and a new object to view. Humans typically spend more time looking at a novel object than a familiar one, and this simple form of recognition depends on the hippocampus (Pascalis et al. 2004).

Importantly, the same test can be applied in monkeys; these studies have shown that the novelty preference depends on the objects being presented in the same background visual context, showing that the object memory is context dependent (Bachevalier et al. 2015). Hippocampal damage also severely impairs this preferential viewing effect in monkeys (Nemanic et al. 2004Zola et al. 2000), but this deficit occurs only in context-dependent recognition (Bachevalier et al. 2015).

In a version of the test developed for rodents, subjects initially explore duplicates of a novel object in a familiar environment and then, following a delay, are presented with one of those objects and a new object replacing the duplicate.

Most studies have reported no effect from hippocampal damage when the object is presented in the same context as the original experience.

However, hippocampal lesions do impair the ability to identify an object taken out of its context, as is reflected by preferential exploration of a familiar object in a novel spatial context or even in a novel place in the familiar environment, or the ability to identify an object presented out of the initially experienced order of multiple objects, consistent with memory for temporal context being a defining feature of hippocampus-dependent memory (Eacott & Norman 2004Langston & Wood 2010; see also Cohen et al. 2013).

The associative transitivity test assesses Mandler’s (1972) characterization of associative organization structure as a set of items that are directly and indirectly linked such that cuing by a subset of items supports the ability to recall the entire set, an ability known as associative inference.

In this test, subjects are trained on associations between pairs of objects that share a common element (AB and BC) and then tested for the existence of the associative network (ABC) via assessment of knowledge about the indirectly related elements (AC). In both humans and animals, the hippocampus is not essential to training on individual associations (AB and BC) but plays a critical role in probe tests in which subjects must infer relations between indirectly related elements (AC) (Figure 1aBunsey & Eichenbaum 1996Preston et al. 2004).

Sequential Organization

As introduced by Tulving (1972), episodic memories are defined by the temporal organization of the events that compose personal experiences.

There is substantial evidence that the hippocampus is activated in association with memory for temporal order in humans (Howard et al. 2014; reviewed in Eichenbaum 2014).

Numerous studies have reported hippocampal activation associated with successful memory for sequences of faces or objects, reconstruction of the order of scenes in a movie clip, identification of items out of order in a familiar sequence, and bridging of a temporal gap between ordered stimuli (Figure 1b; reviewed in Eichenbaum 2014). Correspondingly, selective hippocampal damage in humans results in deficits in remembering the order of words in a list (Mayes et al. 2001) and the order of objects visited in a virtual environment (Spiers et al. 2001) even when recognition memory for individual words and objects was intact.

As in humans, selective hippocampal damage in animals results in impairments in memory for the order of studied object stimuli even when the same animals could recognize the individual stimuli (Fortin et al. 2002Kesner et al. 2002).

In these experiments, animals are presented in each trial with a unique series of odor stimuli, then, following a delay, they are required to judge which of a pair of stimuli arbitrarily selected from the list occurred earlier. Normal rats perform well at the task, but rats with hippocampal damage fail (Figure 1b).

Control tests showed that animals with hippocampal damage could distinguish and identify the individual odors on the list even when they could not remember the order in which they had appeared. This contrast strikingly reveals that memory for order is a defining feature of hippocampal memory function in animals, as it is in humans (see also Ergorul & Eichenbaum 2004).

Schematic Organization

Although many tests of semantic memory involve remembering individual facts, it is well known that factual knowledge is embedded within schematic organizations (e.g., Collins & Quillian 1969Piaget 1928).

Studies on human hippocampal function in semantic organization have focused on tasks that require the subject to learn multiple associations or choices between objects when different associations or choice pairings share common elements.

The studies then test for a representation that integrates learning about all of the objects by probing for knowledge about indirect relations among elements never experienced together. In some studies, subjects learn a set of overlapping choice problems (choose A over B, B over C, C over D, and D over E) and show acquisition of a hierarchical schematic organization (A over B over C over D over E) by appropriate choices on a probe test of transitive inference between newer experience pairs (e.g., B over D).

In both humans and animals, the hippocampus is not essential to learning the individual problems but plays a critical role in probe tests that reveal the establishment of a schematic organization (Figure 1cDusek & Eichenbaum 1997Zalesak & Heckers 2009). In another test, called transverse patterning, subjects are tested for the ability to learn a set of overlapping pairwise choices (choose A over B, B over C, and Cover A). Humans and animals with hippocampal damage can learn two unambiguous pairs (e.g., A over B, B over C), but not the full set, which requires a circular schematic organization (Dusek & Eichenbaum 1998Rickard et al. 2006).

More information: Jacob LS Bellmund et al, Mapping sequence structure in the human lateral entorhinal cortex, eLife (2019). DOI: 10.7554/eLife.45333

Journal information: eLife
Provided by Max Planck Society


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