Prefrontal-hippocampal interactions in episodic memory.

The roles of the hippocampus and prefrontal cortex (PFC) in memory processing - individually or in concert - are a major topic of interest in memory research. These brain areas have distinct and complementary roles in episodic memory, and their interactions are crucial for learning and remembering events. Considerable evidence indicates that the PFC and hippocampus become coupled via oscillatory synchrony that reflects bidirectional flow of information. Furthermore, newer studies have revealed specific mechanisms whereby neural representations in the PFC and hippocampus are mediated through direct connections or through intermediary regions. These findings suggest a model of how the hippocampus and PFC, along with their intermediaries, operate as a system that uses the current context of experience to retrieve relevant memories.

Temporal binding function of dorsal CA1 is critical for declarative memory formation.

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.

Time cells in the hippocampus: a new dimension for mapping memories.

Recent studies have revealed the existence of hippocampal neurons that fire at successive moments in temporally structured experiences. Several studies have shown that such temporal coding is not attributable to external events, specific behaviours or spatial dimensions of an experience. Instead, these cells represent the flow of time in specific memories and have therefore been dubbed 'time cells'. The firing properties of time cells parallel those of hippocampal place cells; time cells thus provide an additional dimension that is integrated with spatial mapping. The robust representation of both time and space in the hippocampus suggests a fundamental mechanism for organizing the elements of experience into coherent memories.

Memory: Organization and Control.

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.

Time Cells in Hippocampal Area CA3.

UNLABELLED: Studies on time cells in the hippocampus have so far focused on area CA1 in animals performing memory tasks. Some studies have suggested that temporal processing within the hippocampus may be exclusive to CA1 and CA2, but not CA3, and may occur only under strong demands for memory. Here we examined the temporal and spatial coding properties of CA3 and CA1 neurons in rats performing a maze task that demanded working memory and a control task with no explicit working memory demand. In the memory demanding task, CA3 cells exhibited robust temporal modulation similar to the pattern of time cell activity in CA1, and the same populations of cells also exhibited typical place coding patterns in the same task. Furthermore, the temporal and spatial coding patterns of CA1 and CA3 were equivalently robust when animals performed a simplified version of the task that made no demands on working memory. However, time and place coding did differ in that the resolution of temporal coding decreased over time within the delay interval, whereas the resolution of place coding was not systematically affected by distance along the track. These findings support the view that CA1 and CA3 both participate in encoding the temporal and spatial organization of ongoing experience. SIGNIFICANCE STATEMENT: Hippocampal "time cells" that fire at specific moments in a temporally structured memory task have so far been observed only in area CA1, and some studies have suggested that temporal coding within the hippocampus is exclusive to CA1. Here we describe time cells also in CA3, and time cells in both areas are observed even without working memory demands, similar to place cells in these areas. However, unlike equivalent spatial coding along a path, temporal coding is nonlinear, with greater temporal resolution earlier than later in temporally structured experiences. These observations reveal both similarities and differences in temporal and spatial coding within the hippocampus of importance to understanding how these features of memory are represented in the hippocampus.

Complementary Functional Organization of Neuronal Activity Patterns in the Perirhinal, Lateral Entorhinal, and Medial Entorhinal Cortices.

It is commonly conceived that the cortical areas of the hippocampal region are functionally divided into the perirhinal cortex (PRC) and the lateral entorhinal cortex (LEC), which selectively process object information; and the medial entorhinal cortex (MEC), which selectively processes spatial information. Contrary to this notion, in rats performing a task that demands both object and spatial information processing, single neurons in PRC, LEC, and MEC, including those in both superficial and deep cortical areas and in grid, border, and head direction cells of MEC, have a highly similar range of selectivity to object and spatial dimensions of the task. By contrast, representational similarity analysis of population activity reveals a key distinction in the organization of information in these areas, such that PRC and LEC populations prioritize object over location information, whereas MEC populations prioritize location over object information. These findings bring to the hippocampal system a growing emphasis on population analyses as a powerful tool for characterizing neural representations supporting cognition and memory. SIGNIFICANCE STATEMENT: Contrary to the common view that brain regions in the "what" and "where" streams distinctly process object and spatial cues, respectively, we found that both streams encode both object and spatial information but distinctly organize memories for objects and space. Specifically, perirhinal cortex and lateral entorhinal cortex represent objects and, within the object-specific representations, the locations where they occur. Conversely, medial entorhinal cortex represents relevant locations and, within those spatial representations, the objects that occupy them. Furthermore, these findings reach beyond simple notions of perirhinal cortex and lateral entorhinal cortex neurons as object detectors and MEC neurons as position detectors, and point to a more complex organization of memory representations within the medial temporal lobe system.

The role of the hippocampus in navigation is memory.

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.

Orbitofrontal cortex encodes memories within value-based schemas and represents contexts that guide memory retrieval.

There are a substantial number of studies showing that the orbitofrontal cortex links events to reward values, whereas the hippocampus links events to the context in which they occur. Here we asked how the orbitofrontal cortex contributes to memory where context determines the reward values associated with events. After rats learned object-reward associations that differed depending on the spatial context in which the objects were presented, neuronal ensembles in orbitofrontal cortex represented distinct value-based schemas, each composed of a systematic organization of the representations of objects in the contexts and positions where they were associated with reward or nonreward. Orbitofrontal ensembles also represent the different spatial contexts that define the mappings of stimuli to actions that lead to reward or nonreward. These findings, combined with observations on complementary memory representation within the hippocampus, suggest mechanisms through which prefrontal cortex and the hippocampus interact in support of context-guided memory.

Memory and Space: Towards an Understanding of the Cognitive Map.

More than 50 years of research have led to the general agreement that the hippocampus contributes to memory, but there has been a major schism among theories of hippocampal function over this time. Some researchers argue that the hippocampus plays a broad role in episodic and declarative memory, whereas others argue for a specific role in the creation of spatial cognitive maps and navigation. Although both views have merit, neither provides a complete account of hippocampal function. Guided by recent reviews that attempt to bridge between these views, here we suggest that reconciliation can be accomplished by exploring hippocampal function from the perspective of Tolman's (1948) original conception of a cognitive map as organizing experience and guiding behavior across all domains of cognition. We emphasize recent studies in animals and humans showing that hippocampal networks support a broad range of domains of cognitive maps, that these networks organize specific experiences within the contextually relevant map, and that network activity patterns reflect behavior guided through cognitive maps. These results are consistent with a framework that bridges theories of hippocampal function by conceptualizing the hippocampus as organizing incoming information within the context of a multidimensional cognitive map of spatial, temporal, and associational context. SIGNIFICANCE STATEMENT: Research of hippocampal function is dominated by two major views. The spatial view argues that the hippocampus tracks routes through space, whereas the memory view suggests a broad role in declarative memory. Both views rely on considerable evidence, but neither provides a complete account of hippocampal function. Here we review evidence that, in addition to spatial context, the hippocampus encodes a wide variety of information about temporal and situational context, about the systematic organization of events in abstract space, and about routes through maps of cognition and space. We argue that these findings cross the boundaries of the memory and spatial views and offer new insights into hippocampal function as a system supporting a broad range of cognitive maps.

Transient optogenetic inactivation of the medial entorhinal cortex biases the active population of hippocampal neurons.

The mechanisms that enable the hippocampal network to express the appropriate spatial representation for a particular circumstance are not well understood. Previous studies suggest that the medial entorhinal cortex (MEC) may have a role in reproducibly selecting the hippocampal representation of an environment. To examine how ongoing MEC activity is continually integrated by the hippocampus, we performed transient unilateral optogenetic inactivations of the MEC while simultaneously recording place cell activity in CA1. Inactivation of the MEC caused a partial remapping in the CA1 population without diminishing the degree of spatial tuning across the active cell assembly. These changes remained stable irrespective of intermittent disruption of MEC input, indicating that while MEC input is integrated over long time scales to bias the active population, there are mechanisms for stabilizing the population of active neurons independent of the MEC. We find that MEC inputs to the hippocampus shape its ongoing activity by biasing the participation of the neurons in the active network, thereby influencing how the hippocampus selectively represents information.

Hippocampus at 25.

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. © 2016 Wiley Periodicals, Inc.

Representation of memories in the cortical-hippocampal system: Results from the application of population similarity analyses.

Here we consider the value of neural population analysis as an approach to understanding how information is represented in the hippocampus and cortical areas and how these areas might interact as a brain system to support memory. We argue that models based on sparse coding of different individual features by single neurons in these areas (e.g., place cells, grid cells) are inadequate to capture the complexity of experience represented within this system. By contrast, population analyses of neurons with denser coding and mixed selectivity reveal new and important insights into the organization of memories. Furthermore, comparisons of the organization of information in interconnected areas suggest a model of hippocampal-cortical interactions that mediates the fundamental features of memory.

Still searching for the engram.

For nearly a century, neurobiologists have searched for the engram-the neural representation of a memory. Early studies showed that the engram is widely distributed both within and across brain areas and is supported by interactions among large networks of neurons. Subsequent research has identified engrams that support memory within dedicated functional systems for habit learning and emotional memory, but the engram for declarative memories has been elusive. Nevertheless, recent years have brought progress from molecular biological approaches that identify neurons and networks that are necessary and sufficient to support memory, and from recording approaches and population analyses that characterize the information coded by large neural networks. These new directions offer the promise of revealing the engrams for episodic and semantic memories.

A unified mathematical framework for coding time, space, and sequences in the hippocampal region.

The medial temporal lobe (MTL) is believed to support episodic memory, vivid recollection of a specific event situated in a particular place at a particular time. There is ample neurophysiological evidence that the MTL computes location in allocentric space and more recent evidence that the MTL also codes for time. Space and time represent a similar computational challenge; both are variables that cannot be simply calculated from the immediately available sensory information. We introduce a simple mathematical framework that computes functions of both spatial location and time as special cases of a more general computation. In this framework, experience unfolding in time is encoded via a set of leaky integrators. These leaky integrators encode the Laplace transform of their input. The information contained in the transform can be recovered using an approximation to the inverse Laplace transform. In the temporal domain, the resulting representation reconstructs the temporal history. By integrating movements, the equations give rise to a representation of the path taken to arrive at the present location. By modulating the transform with information about allocentric velocity, the equations code for position of a landmark. Simulated cells show a close correspondence to neurons observed in various regions for all three cases. In the temporal domain, novel secondary analyses of hippocampal time cells verified several qualitative predictions of the model. An integrated representation of spatiotemporal context can be computed by taking conjunctions of these elemental inputs, leading to a correspondence with conjunctive neural representations observed in dorsal CA1.

Perspectives on 2014 Nobel Prize.

In celebration of the 2014 Nobel Prize in Physiology or Medicine, this issue of Hippocampus includes a collection of commentaries from a broad range of perspectives on the significance of position coding neurons in the hippocampal region. From the perspective of this student of hippocampal physiology, it is argued that place cells and grid cells reflect the outcome of experiments that strongly select the information available and correspondingly observe singular "trigger features" of these neurons. Notably, however, in more naturalistic situations where multiple dimensions of information are available, hippocampal neurons have mixed selectivity wherein population-firing patterns reflect the organization of many features of experience. Thus, while discoveries on position coding were major breakthroughs in penetrating the hippocampal code, future studies exploring more complex behaviors hold the promise of revealing the full contribution of the hippocampal region to cognition and memory.

Combined administration of levetiracetam and valproic acid attenuates age-related hyperactivity of CA3 place cells, reduces place field area, and increases spatial information content in aged rat hippocampus.

Learning and memory deficits associated with age-related mild cognitive impairment have long been attributed to impaired processing within the hippocampus. Hyperactivity within the hippocampal CA3 region that is associated with aging is mediated in part by a loss of functional inhibitory interneurons and thought to underlie impaired performance in spatial memory tasks, including the abnormal tendency in aged animals to pattern complete spatial representations. Here, we asked whether the spatial firing patterns of simultaneously recorded CA3 and CA1 neurons in young and aged rats could be manipulated pharmacologically to selectively reduce CA3 hyperactivity and thus, according to hypothesis, the associated abnormality in spatial representations. We used chronically implanted high-density tetrodes to record the spatial firing properties of CA3 and CA1 units during animal exploration for food in familiar and novel environments. Aged CA3 place cells have higher firing rates, larger place fields, less spatial information content, and respond less to a change from a familiar to a novel environment than young CA3 cells. We also find that the combination of levetiracetam (LEV) + valproic acid (VPA), previously shown to act as a cognitive enhancer in tests of spatial memory, attenuate CA3 place cell firing rates, reduce place field area, and increase spatial information content in aged but not young adult rats. This is consistent with drug enhancing the specificity of neuronal firing with respect to spatial location. Contrary to expectation, however, LEV + VPA reduces place cell discrimination between novel and familiar environments, i.e., spatial correlations increase, independent of age even though drug enhances performance in cognitive tasks. The results demonstrate that spatial information content, or the number of bits of information encoded per action potential, may be the key correlate for enhancement of spatial memory by LEV + VPA.

Distinct pathways for rule-based retrieval and spatial mapping of memory representations in hippocampal neurons.

Hippocampal neurons encode events within the context in which they occurred, a fundamental feature of episodic memory. Here we explored the sources of event and context information represented by hippocampal neurons during the retrieval of object associations in rats. Temporary inactivation of the medial prefrontal cortex differentially reduced the selectivity of rule-based object associations represented by hippocampal neuronal firing patterns but did not affect spatial firing patterns. In contrast, inactivation of the medial entorhinal cortex resulted in a pervasive reorganization of hippocampal mappings of spatial context and events. These results suggest distinct and cooperative prefrontal and medial temporal mechanisms in memory representation.

Distinct hippocampal time cell sequences represent odor memories in immobilized rats.

Previous studies have revealed the existence of hippocampal "time cells," principal neurons in CA1 that fire at specific moments in temporally organized experiences. However, in all these studies, animals were in motion; and so, temporal modulation might be due, at least in part, to concurrent or planned movement through space or self-generated movement (path integration). Here the activity of hippocampal CA1 neurons was recorded in head-fixed and immobile rats while they remembered odor stimuli across a delay period. Many neurons selectively and reliably activated at brief moments during the delay, as confirmed by several analyses of temporal modulation, during a strong ongoing θ rhythm. Furthermore, each odor memory was represented by a temporally organized ensemble of time cells composed mostly of neurons that were unique to each memory and some that fired at the same or different moments among multiple memories. These results indicate that ongoing or intended movement through space is not necessary for temporal representations in the hippocampus, and highlight the potential role of time cells as a mechanism for representing the flow of time in distinct memories.

Learning causes reorganization of neuronal firing patterns to represent related experiences within a hippocampal schema.

According to schema theory as proposed by Piaget and Bartlett, learning involves the assimilation of new memories into networks of preexisting knowledge, as well as alteration of the original networks to accommodate the new information. Recent evidence has shown that rats form a schema of goal locations and that the hippocampus plays an essential role in adding new memories to the spatial schema. Here we examined the nature of hippocampal contributions to schema updating by monitoring firing patterns of multiple CA1 neurons as rats learned new goal locations in an environment in which there already were multiple goals. Before new learning, many neurons that fired on arrival at one goal location also fired at other goals, whereas ensemble activity patterns also distinguished different goal events, thus constituting a neural representation that linked distinct goals within a spatial schema. During new learning, some neurons began to fire as animals approached the new goals. These were primarily the same neurons that fired at original goals, the activity patterns at new goals were similar to those associated with the original goals, and new learning also produced changes in the preexisting goal-related firing patterns. After learning, activity patterns associated with the new and original goals gradually diverged, such that initial generalization was followed by a prolonged period in which new memories became distinguished within the ensemble representation. These findings support the view that consolidation involves assimilation of new memories into preexisting neural networks that accommodate relationships among new and existing memories.