Normal explicit/declarative memory requires a system of anatomically related structures in the medial temporal lobe that includes the hippocampus and the entorhinal, perirhinal, and parahippocampal cortex. Although extensive medial temporal lobe damage in primates causes robust anterograde amnesia, defining the contribution of the hippocampus proper has proved challenging. We revisited that enduring puzzle here, directly addressing a number of factors suspected to contribute to conflicting results across earlier studies. Among them, we explored the effects of selective hippocampus lesions produced by two common excitotoxin methods, ibotenic acid and N-methyl-D-aspartic acid. Sample sizes were substantial, and all behavioral testing was conducted postoperatively. Performance was assessed on several standard procedures designed for monkeys, including multiple variants of the delayed nonmatching-to-sample test of visual object recognition, a series of rapidly acquired two-choice object discriminations, and a delayed response test of spatiotemporal memory. We used task-specific parametric manipulations (e.g., increasing retention intervals and reduced stimulus set size) to systematically vary demands on memory and test/retest analyses to enhance sensitivity for detecting impairment. Although both lesion groups sustained substantial hippocampal damage, their performance failed to differ from that of intact controls on any task, under any key test condition, regardless of data analytic strategy. The findings constrain plausible accounts of extant discrepancies in the literature and, moreover, highlight the need for fresh perspectives on the core operating characteristics of memory mediated by the primate hippocampus. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

In the version of this article initially published, author Charan Ranganath's last name was misspelled Rangananth in the author list. Also, A. David Redish (redish@umn.edu) has been added as a corresponding author. The error has been corrected, and the corresponding author added, in the HTML and PDF versions of the article.

The temporal order of an experience is a fundamental property of episodic memories, yet the mechanism for the consolidation of temporal sequences in long-term memory is still unknown. A potential mechanism for memory consolidation depends on the reactivation of neuronal sequences in the hippocampus. Despite abundant evidence of sequence reactivation in the formation of spatial memory, the reactivation of hippocampal neuronal sequences carrying non-spatial information has been much less explored. In this work, we recorded the activity of time cell sequences while rats performed multiple 15-s treadmill runnings during the intertrial intervals of a spatial alternation memory task. We observed forward and reverse reactivations of time cell sequences often occurring during sharp-wave ripple events following reward consumption. Surprisingly, the reactivation events specifically engaged cells coding temporal information. The reactivation of time cell sequences may thus reflect the organization of temporal order required for episodic memory formation.

It has long been hypothesized that a primary function of the hippocampus is to discover and exploit temporal relationships between events. Previously, it has been reported that sequences of "time cells'' in the hippocampus extend for tens of seconds. Other studies have shown that neuronal firing in the hippocampus fluctuates over hours and days. Both of these mechanisms could enable temporal encoding of events over very different timescales. However, thus far, these two classes of phenomena have never been observed simultaneously, which is necessary to ascribe broad-range temporal coding to the hippocampus. Using in vivo calcium imaging in unrestrained mice, we observed sequences of hippocampal neurons that bridged a 10 s delay. Similar sequences were observed over multiple days, but the set of neurons participating in those sequences changed gradually. Thus, the same population of neurons that encodes temporal information over seconds can also be used to distinguish periods of time over much longer timescales. These results unify two previously separate paradigms of temporal processing in the hippocampus that support episodic memory.

Since the discovery of place cells and other findings indicating strong involvement of the hippocampus in spatial information processing, there has been continued controversy about the extent to which the hippocampus also processes non-spatial aspects of experience. In recent years, many experiments studying the effects of hippocampal damage and characterizing hippocampal neural activity in animals and humans have revealed a clear and specific role of the hippocampus in the processing of non-spatial information. Here this evidence is reviewed in support of the notion that the hippocampus organizes the contents of memory in space, in time, and in networks of related memories.

To provide a substrate for remembering where in space events have occurred, place cells must reliably encode the same positions across long time-scales. However, in many cases, place cells exhibit instability by randomly reorganizing their place fields between experiences, challenging this premise. Recent evidence suggests that, in some cases, instability could also arise from coherent rotations of place fields, as well as from random reorganization. To investigate this possibility, we performed in vivo calcium imaging in dorsal hippocampal region CA1 of freely moving mice while they explored two arenas with different geometry and visual cues across 8 days. The two arenas were rotated randomly between sessions and then connected, allowing us to probe how cue rotations, the integration of new information about the environment, and the passage of time concurrently influenced the spatial coherence of place fields. We found that spatially coherent rotations of place-field maps in the same arena predominated, persisting up to 6 days later, and that they frequently rotated in a manner that did not match that of the arena rotation. Furthermore, place-field maps were flexible, as mice frequently employed a similar, coherent configuration of place fields to represent each arena despite their differing geometry and eventual connection. These results highlight the ability of the hippocampus to retain consistent relationships between cells across long timescales and suggest that, in many cases, apparent instability might result from a coherent rotation of place fields.

Modification of the ongoing influence of maladaptive cognitive, emotional, and behavioral patterns is a fundamental feature of many psychological treatments. Accordingly, a clear understanding of the nature of memory adaptation and accommodation to therapeutic learning becomes an important issue for (1) understanding the impact of clinical interventions, and (2) considering innovations in treatment strategies. In this article, we consider advances in the conceptualization of memory processes and memory modification research relative to clinical treatment. We review basic research on the formation of memories, the way in which new learning is integrated within memory structures, and strategies to influence the nature and degree to which new learning is integrated. We then discuss cognitive/behavioral and pharmacological strategies for influencing memory formation in relation to disorder prevention or treatment. Our goal is to foster awareness of current strategies for enhancing therapeutic learning and to encourage research on potential new avenues for memory enhancement in service of the treatment of mental health disorders.

In the version of this article initially published, author Charan Ranganath’s last name was misspelled Rangananth in the author list. Also, A. David Redish (redish@umn.edu) has been added as a corresponding author. The error has been corrected, and the corresponding author added, in the HTML and PDF versions of the article.

Research on how information is encoded by the brain is largely based on studies of feature detector properties of single neurons, but considerable new data shows that single neurons in many brain areas have mixed selectivity for multiple features and change their tuning properties across realistic information processing situations. Here I consider new approaches that explore cell assemblies as the units of information processing and how these approaches are revealing the structure and organization of neural representations in perception and cognition.

Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment.

The hippocampus serves a critical function in memory, navigation, and cognition. Nature Neuroscience asked John Lisman to lead a group of researchers in a dialog on shared and distinct viewpoints on the hippocampus.

The hippocampus is famous for mapping locations in spatially organized environments, and several recent studies have shown that hippocampal networks also map moments in temporally organized experiences. Here I consider how space and time are integrated in the representation of memories. The brain pathways for spatial and temporal cognition involve overlapping and interacting systems that converge on the hippocampal region. There is evidence that spatial and temporal aspects of memory are processed somewhat differently in the circuitry of hippocampal subregions but become fully integrated within CA1 neuronal networks as independent, multiplexed representations of space and time. Hippocampal networks also map memories across a broad range of abstract relations among events, suggesting that the findings on spatial and temporal organization reflect a generalized mechanism for organizing memories.

There is considerable research on the neurobiological mechanisms within the hippocampal system that support spatial navigation. In this article I review the literature on navigational strategies in humans and animals, observations on hippocampal function in navigation, and studies of hippocampal neural activity in animals and humans performing different navigational tasks and tests of memory. Whereas the hippocampus is essential to spatial navigation via a cognitive map, its role derives from the relational organization and flexibility of cognitive maps and not from a selective role in the spatial domain. Correspondingly, hippocampal networks map multiple navigational strategies, as well as other spatial and nonspatial memories and knowledge domains that share an emphasis on relational organization. These observations suggest that the hippocampal system is not dedicated to spatial cognition and navigation, but organizes experiences in memory, for which spatial mapping and navigation are both a metaphor for and a prominent application of relational memory organization.

There is considerable recent evidence that, in addition to its representation of space, the hippocampus also represents the temporal organization of memories. Time plays a central role in episodic memory, and studies have identified the hippocampus as playing an essential role in the temporal organization of memories in humans and animals. Temporal organization is supported by a gradually changing temporal context signal in the hippocampus, and this changing context signal involves 'time cells' in the hippocampus that code sequential moments in temporally organized experiences. Finally, hippocampal temporal context representations involve mechanisms in intrinsic circuitry and oscillatory patterns throughout hippocampal subfields and depend on inputs from parahippocampal cortical areas as well as a widespread temporal processing system in the neocortex.

A major goal of memory research is to understand how cognitive processes in memory are supported at the level of brain systems and network representations. Especially promising in this direction are new findings in humans and animals that converge in indicating a key role for the hippocampus in the systematic organization of memories. New findings also indicate that the prefrontal cortex may play an equally important role in the active control of memory organization during both encoding and retrieval. Observations about the dialog between the hippocampus and prefrontal cortex provide new insights into the operation of the larger brain system that serves memory.

In the version of this article initially published, author Charan Ranganath’s last name was misspelled Rangananth in the author list. Also, A. David Redish (redish@umn.edu) has been added as a corresponding author. The error has been corrected, and the corresponding author added, in the HTML and PDF versions of the article.

Memory is not a unitary process and is neither isolated to one brain area nor fully distributed across all brain areas. Rather, there are several forms of memory, each of which is processed by a distinctive anatomical system. Here I will review the history of multiple memory systems in the brain and introduce the organization of this volume as a progress report on our understanding of these memory systems and their neurobiological substrates.

Recent studies have shown that hippocampal "time cells" code for sequential moments in temporally organized experiences. However, it is currently unknown whether these temporal firing patterns critically rely on upstream cortical input. Here we employ an optogenetic approach to explore the effect of large-scale inactivation of the medial entorhinal cortex on temporal, as well as spatial and object, coding by hippocampal CA1 neurons. Medial entorhinal inactivation produced a specific deficit in temporal coding in CA1 and resulted in significant impairment in memory across a temporal delay. In striking contrast, spatial and object coding remained intact. Further, we extended the scope of hippocampal phase precession to include object information relevant to memory and behavior. Overall, our work demonstrates that medial entorhinal activity plays an especially important role for CA1 in temporal coding and memory across time.