The Tolman-Eichenbaum Machine: Unifying Space and Relational Memory through Generalization in the Hippocampal Formation.

The hippocampal-entorhinal system is important for spatial and relational memory tasks. We formally link these domains, provide a mechanistic understanding of the hippocampal role in generalization, and offer unifying principles underlying many entorhinal and hippocampal cell types. We propose medial entorhinal cells form a basis describing structural knowledge, and hippocampal cells link this basis with sensory representations. Adopting these principles, we introduce the Tolman-Eichenbaum machine (TEM). After learning, TEM entorhinal cells display diverse properties resembling apparently bespoke spatial responses, such as grid, band, border, and object-vector cells. TEM hippocampal cells include place and landmark cells that remap between environments. Crucially, TEM also aligns with empirically recorded representations in complex non-spatial tasks. TEM also generates predictions that hippocampal remapping is not random as previously believed; rather, structural knowledge is preserved across environments. We confirm this structural transfer over remapping in simultaneously recorded place and grid cells.

Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior.

The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and have been proposed to form the neural basis of a cognitive map of space that supports these mnemonic functions. However, the direct influence of place cell activity on spatial navigation behavior has not yet been demonstrated. Using an 'all-optical' combination of simultaneous two-photon calcium imaging and two-photon optogenetics, we identified and selectively activated place cells that encoded behaviorally relevant locations in a virtual reality environment. Targeted stimulation of a small number of place cells was sufficient to bias the behavior of animals during a spatial memory task, providing causal evidence that hippocampal place cells actively support spatial navigation and memory.

Remapping revisited: how the hippocampus represents different spaces.

The representation of distinct spaces by hippocampal place cells has been linked to changes in their place fields (the locations in the environment where the place cells discharge strongly), a phenomenon that has been termed 'remapping'. Remapping has been assumed to be accompanied by the reorganization of subsecond cofiring relationships among the place cells, potentially maximizing hippocampal information coding capacity. However, several observations challenge this standard view. For example, place cells exhibit mixed selectivity, encode non-positional variables, can have multiple place fields and exhibit unreliable discharge in fixed environments. Furthermore, recent evidence suggests that, when measured at subsecond timescales, the moment-to-moment cofiring of a pair of cells in one environment is remarkably similar in another environment, despite remapping. Here, I propose that remapping is a misnomer for the changes in place fields across environments and suggest instead that internally organized manifold representations of hippocampal activity are actively registered to different environments to enable navigation, promote memory and organize knowledge.

Do hippocampal pyramidal cells respond to nonspatial stimuli?

There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal information processing. On one hand, the cognitive map theory sees space as crucial and central, with other types of nonspatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored, and manipulated. One crucial difference, therefore, is the extent to which theories see hippocampal pyramidal cells as representing nonspatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to nonspatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards, and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these nonspatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this article, we argue that when tested in multiple locations, the hippocampal response to nonspatial stimuli is almost invariably dependent on the animal's location. Looked at collectively, the data provide strong support for the cognitive map theory.

Hippocampal place cells have goal-oriented vector fields during navigation.

The hippocampal cognitive map supports navigation towards, or away from, salient locations in familiar environments1. Although much is known about how the hippocampus encodes location in world-centred coordinates, how it supports flexible navigation is less well understood. We recorded CA1 place cells while rats navigated to a goal on the honeycomb maze2. The maze tests navigation via direct and indirect paths to the goal and allows the directionality of place cells to be assessed at each choice point. Place fields showed strong directional polarization characterized by vector fields that converged to sinks distributed throughout the environment. The distribution of these 'convergence sinks' (ConSinks) was centred near the goal location and the population vector field converged on the goal, providing a strong navigational signal. Changing the goal location led to movement of ConSinks and vector fields towards the new goal. The honeycomb maze allows independent assessment of spatial representation and spatial action in place cell activity and shows how the latter relates to the former. The results suggest that the hippocampus creates a vector-based model to support flexible navigation, allowing animals to select optimal paths to destinations from any location in the environment.

Local circuit amplification of spatial selectivity in the hippocampus.

Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex1. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs2 regulate the spatial receptive fields of pyramidal cells3. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing4 and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation. We found a local circuit mechanism in CA1 whereby the spatial tuning of an individual place cell can propagate to a functionally recurrent subnetwork5 to which it belongs. The emergence of place fields in individual neurons led to the development of inverse selectivity in a subset of their presynaptic interneurons, and recruited functionally coupled place cells at that location. Thus, the spatial selectivity of single CA1 neurons is amplified through local circuit plasticity to enable effective multi-neuronal representations that can flexibly scale environmental features locally without degrading the feedforward input structure.

Fos ensembles encode and shape stable spatial maps in the hippocampus.

In the hippocampus, spatial maps are formed by place cells while contextual memories are thought to be encoded as engrams1-6. Engrams are typically identified by expression of the immediate early gene Fos, but little is known about the neural activity patterns that drive, and are shaped by, Fos expression in behaving animals7-10. Thus, it is unclear whether Fos-expressing hippocampal neurons also encode spatial maps and whether Fos expression correlates with and affects specific features of the place code11. Here we measured the activity of CA1 neurons with calcium imaging while monitoring Fos induction in mice performing a hippocampus-dependent spatial learning task in virtual reality. We find that neurons with high Fos induction form ensembles of cells with highly correlated activity, exhibit reliable place fields that evenly tile the environment and have more stable tuning across days than nearby non-Fos-induced cells. Comparing neighbouring cells with and without Fos function using a sparse genetic loss-of-function approach, we find that neurons with disrupted Fos function have less reliable activity, decreased spatial selectivity and lower across-day stability. Our results demonstrate that Fos-induced cells contribute to hippocampal place codes by encoding accurate, stable and spatially uniform maps and that Fos itself has a causal role in shaping these place codes. Fos ensembles may therefore link two key aspects of hippocampal function: engrams for contextual memories and place codes that underlie cognitive maps.

The temporal and contextual stability of activity levels in hippocampal CA1 cells.

Recent long-term optical imaging studies have demonstrated that the activity levels of hippocampal neurons in a familiar environment change on a daily to weekly basis. However, it is unclear whether there is any time-invariant property in the cells' neural representations. In this study, using miniature fluorescence microscopy, we measured the neural activity of the mouse hippocampus in four different environments every 3 d. Although the activity level of hippocampal neurons fluctuated greatly in each environment across days, we found a significant correlation between the activity levels for different days, and the correlation was higher for averaged activity levels across multiple environments. When the number of environments used for averaging was increased, a higher activity correlation was observed. Furthermore, the number of environments in which a cell showed activity was preserved. Cells that showed place cell activity in many environments had greater spatial information content and more stable spatial representation, and thus carried more abundant and stable information about the current position. In contrast, cells that were active only in a small number of environments provided sparse representation for the environment. These results suggest that each cell has not only an inherent activity level but also play a characteristic role in the coding of space.

Investigating Egocentric Tuning in Hippocampal CA1 Neurons.

Navigation requires integrating sensory information with a stable schema to create a dynamic map of an animal's position using egocentric and allocentric coordinate systems. In the hippocampus, place cells encode allocentric space, but their firing rates may also exhibit directional tuning within egocentric or allocentric reference frames. We compared experimental and simulated data to assess the prevalence of tuning to egocentric bearing (EB) among hippocampal cells in rats foraging in an open field. Using established procedures, we confirmed egocentric modulation of place cell activity in recorded data; however, simulated data revealed a high false-positive rate (FPR). When we accounted for false positives by comparing with shuffled data that retain correlations between the animal's direction and position, only a very low number of hippocampal neurons appeared modulated by EB. Our study highlights biases affecting FPRs and provides insights into the challenges of identifying egocentric modulation in hippocampal neurons.

Hippocampal astrocytes represent navigation space.

Hippocampal place cells, which display location-specific activity, are known to encode spatial information. A recent study in PLOS Biology by Curreli and colleagues shows that hippocampal astrocytes are implicated in encoding complementary spatial information, suggesting the existence of glial place cells.

Recalibration of path integration in hippocampal place cells.

Hippocampal place cells are spatially tuned neurons that serve as elements of a 'cognitive map' in the mammalian brain1. To detect the animal's location, place cells are thought to rely upon two interacting mechanisms: sensing the position of the animal relative to familiar landmarks2,3 and measuring the distance and direction that the animal has travelled from previously occupied locations4-7. The latter mechanism-known as path integration-requires a finely tuned gain factor that relates the animal's self-movement to the updating of position on the internal cognitive map, as well as external landmarks to correct the positional error that accumulates8,9. Models of hippocampal place cells and entorhinal grid cells based on path integration treat the path-integration gain as a constant9-14, but behavioural evidence in humans suggests that the gain is modifiable15. Here we show, using physiological evidence from rat hippocampal place cells, that the path-integration gain is a highly plastic variable that can be altered by persistent conflict between self-motion cues and feedback from external landmarks. In an augmented-reality system, visual landmarks were moved in proportion to the movement of a rat on a circular track, creating continuous conflict with path integration. Sustained exposure to this cue conflict resulted in predictable and prolonged recalibration of the path-integration gain, as estimated from the place cells after the landmarks were turned off. We propose that this rapid plasticity keeps the positional update in register with the movement of the rat in the external world over behavioural timescales. These results also demonstrate that visual landmarks not only provide a signal to correct cumulative error in the path-integration system4,8,16-19, but also rapidly fine-tune the integration computation itself.

Distal but not local auditory information supports spatial representations by place cells.

Sound is an important navigational cue for mammals. During spatial navigation, hippocampal place cells encode spatial representations of the environment based on visual information, but to what extent audiospatial information can enable reliable place cell mapping is largely unknown. We assessed this by recording from CA1 place cells in the dark, under circumstances where reliable visual, tactile, or olfactory information was unavailable. Male rats were exposed to auditory cues of different frequencies that were delivered from local or distal spatial locations. We observed that distal, but not local cue presentation, enables and supports stable place fields, regardless of the sound frequency used. Our data suggest that a context dependency exists regarding the relevance of auditory information for place field mapping: whereas locally available auditory cues do not serve as a salient spatial basis for the anchoring of place fields, auditory cue localization supports spatial representations by place cells when available in the form of distal information. Furthermore, our results demonstrate that CA1 neurons can effectively use auditory stimuli to generate place fields, and that hippocampal pyramidal neurons are not solely dependent on visual cues for the generation of place field representations based on allocentric reference frames.

Neuronal signature of spatial decision-making during navigation by freely moving rats by using calcium imaging.

A challenge in spatial memory is understanding how place cell firing contributes to decision-making in navigation. A spatial recency task was created in which freely moving rats first became familiar with a spatial context over several days and thereafter were required to encode and then selectively recall one of three specific locations within it that was chosen to be rewarded that day. Calcium imaging was used to record from more than 1,000 cells in area CA1 of the hippocampus of five rats during the exploration, sample, and choice phases of the daily task. The key finding was that neural activity in the startbox rose steadily in the short period prior to entry to the arena and that this selective population cell firing was predictive of the daily changing goal on correct trials but not on trials in which the animals made errors. Single-cell and population activity measures converged on the idea that prospective coding of neural activity can be involved in navigational decision-making.

Enhanced Reactivation of Remapping Place Cells during Aversive Learning.

Study of the hippocampal place cell system has greatly enhanced our understanding of memory encoding for distinct places, but how episodic memories for distinct experiences occurring within familiar environments are encoded is less clear. We developed a spatial decision-making task in which male rats learned to navigate a multiarm maze to a goal location for food reward while avoiding maze arms in which aversive stimuli were delivered. Task learning induced partial remapping in CA1 place cells, allowing us to identify both remapping and stable cell populations. Remapping cells were recruited into sharp-wave ripples and associated replay events to a greater extent than stable cells, despite having similar firing rates during navigation of the maze. Our results suggest that recruitment into replay events may be a mechanism to incorporate new contextual information into a previously formed and stabilized spatial representation.SIGNIFICANCE STATEMENT Hippocampal place cells provide a map of space that animals use to navigate. This map can change to reflect changes in the physical properties of the environment in which the animal finds itself, and also in response to nonphysical contextual changes, such as changes in the valence of specific locations within that environment. We show here that cells which change their spatial tuning after a change in context are preferentially recruited into sharp-wave ripple-associated replay events compared with stable nonremapping cells. Thus, our data lend strong support to the hypothesis that replay is a mechanism for the storage of new spatial maps.

Learning to predict future locations with internally generated theta sequences.

Representing past, present and future locations is key for spatial navigation. Indeed, within each cycle of the theta oscillation, the population of hippocampal place cells appears to represent trajectories starting behind the current position of the animal and sweeping ahead of it. In particular, we reported recently that the position represented by CA1 place cells at a given theta phase corresponds to the location where animals were or will be located at a fixed time interval into the past or future assuming the animal ran at its typical, not the current, speed through that part of the environment. This coding scheme leads to longer theta trajectories, larger place fields and shallower phase precession in areas where animals typically run faster. Here we present a mechanistic computational model that accounts for these experimental observations. The model consists of a continuous attractor network with short-term synaptic facilitation and depression that internally generates theta sequences that advance at a fixed pace. Spatial locations are then mapped onto the active units via modified Hebbian plasticity. As a result, neighboring units become associated with spatial locations further apart where animals run faster, reproducing our earlier experimental results. The model also accounts for the higher density of place fields generally observed where animals slow down, such as around rewards. Furthermore, our modeling results reveal that an artifact of the decoding analysis might be partly responsible for the observation that theta trajectories start behind the animal's current position. Overall, our results shed light on how the hippocampal code might arise from the interplay between behavior, sensory input and predefined network dynamics.

Parallel emergence of stable and dynamic memory engrams in the hippocampus.

During our daily life, we depend on memories of past experiences to plan future behaviour. These memories are represented by the activity of specific neuronal groups or 'engrams'1,2. Neuronal engrams are assembled during learning by synaptic modification, and engram reactivation represents the memorized experience 1 . Engrams of conscious memories are initially stored in the hippocampus for several days and then transferred to cortical areas 2 . In the dentate gyrus of the hippocampus, granule cells transform rich inputs from the entorhinal cortex into a sparse output, which is forwarded to the highly interconnected pyramidal cell network in hippocampal area CA3 3 . This process is thought to support pattern separation 4 (but see refs. 5,6). CA3 pyramidal neurons project to CA1, the hippocampal output region. Consistent with the idea of transient memory storage in the hippocampus, engrams in CA1 and CA2 do not stabilize over time7-10. Nevertheless, reactivation of engrams in the dentate gyrus can induce recall of artificial memories even after weeks 2 . Reconciliation of this apparent paradox will require recordings from dentate gyrus granule cells throughout learning, which has so far not been performed for more than a single day6,11,12. Here, we use chronic two-photon calcium imaging in head-fixed mice performing a multiple-day spatial memory task in a virtual environment to record neuronal activity in all major hippocampal subfields. Whereas pyramidal neurons in CA1-CA3 show precise and highly context-specific, but continuously changing, representations of the learned spatial sceneries in our behavioural paradigm, granule cells in the dentate gyrus have a spatial code that is stable over many days, with low place- or context-specificity. Our results suggest that synaptic weights along the hippocampal trisynaptic loop are constantly reassigned to support the formation of dynamic representations in downstream hippocampal areas based on a stable code provided by the dentate gyrus.

Prioritized experience replays on a hippocampal predictive map for learning.

Hippocampal cells are central to spatial and predictive representations, and experience replays by place cells are crucial for learning and memory. Nonetheless, how hippocampal replay patterns dynamically change during the learning process remains to be elucidated. Here, we designed a spatial task in which rats learned a new behavioral trajectory for reward. We found that as rats updated their behavioral strategies for a novel salient location, hippocampal cell ensembles increased theta-sequences and sharp wave ripple-associated synchronous spikes that preferentially replayed salient locations and reward-related contexts in reverse order. The directionality and contents of the replays progressively varied with learning, including an optimized path that had never been exploited by the animals, suggesting prioritized replays of significant experiences on a predictive map. Online feedback blockade of sharp wave ripples during a learning process inhibited stabilizing optimized behavior. These results implicate learning-associated experience replays that act to learn and reinforce specific behavioral strategies.

[Screening of place cell and analysis of its influencing factors for pigeons].

Place cell with location tuning characteristics play an important role in brain spatial cognition and navigation, but there is relatively little research on place cell screening and its influencing factors. Taking pigeons as model animals, the screening process of pigeon place cell was given by using the spike signal in pigeon hippocampus under free activity. The effects of grid number and filter kernel size on the place field of place cells during the screening process were analyzed. The results from the real and simulation data showed that the proposed place cell screening method presented in this study could effectively screen out place cell, and the research found that the size of place field was basically inversely proportional to the number of grids divided, and was basically proportional to the size of Gaussian filter kernel in the overall trend. This result will not only help to determine the appropriate parameters in the place cell screening process, but also promote the research on the neural mechanism of spatial cognition and navigation of birds such as pigeons.

Directional Tuning of Phase Precession Properties in the Hippocampus.

Running direction in the hippocampus is encoded by rate modulations of place field activity but also by spike timing correlations known as theta sequences. Whether directional rate codes and the directionality of place field correlations are related, however, has so far not been explored, and therefore the nature of how directional information is encoded in the cornu ammonis remains unresolved. Here, using a previously published dataset that contains the spike activity of rat hippocampal place cells in the CA1, CA2, and CA3 subregions during free foraging of male Long-Evans rats in a 2D environment, we found that rate and spike timing codes are related. Opposite to a preferred firing rate direction of a place field, spikes are more likely to undergo theta phase precession and, hence, more strongly affect paired correlations. Furthermore, we identified a subset of field pairs whose theta correlations are intrinsic in that they maintain the same firing order when the running direction is reversed. Both effects are associated with differences in theta phase distributions and are more prominent in CA3 than in CA1. We thus hypothesize that intrinsic spiking is most prominent when the directionally modulated sensory-motor drive of hippocampal firing rates is minimal, suggesting that extrinsic and intrinsic sequences contribute to phase precession as two distinct mechanisms.SIGNIFICANCE STATEMENT Hippocampal theta sequences, on the one hand, are thought to reflect the running trajectory of an animal, connecting past and future locations. On the other hand, sequences have been proposed to reflect the rich, recursive hippocampal connectivity, related to memories of previous trajectories or even to experience-independent prestructure. Such intrinsic sequences are inherently one dimensional and cannot be easily reconciled with running trajectories in two dimensions as place fields can be approached on multiple one-dimensional paths. In this article, we dissect phase precession along different directions in all hippocampal subareas and find that CA3 in particular shows a high level of direction-independent correlations that are inconsistent with the notion of representing running trajectories. These intrinsic correlations are associated with later spike phases.

Aged Rats Exhibit Altered Behavior-Induced Oscillatory Activity, Place Cell Firing Rates, and Spatial Information Content in the CA1 Region of the Hippocampus.

Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in the behavioral state of an animal to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well studied. Here, we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31 d. Although mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups but were lower across speeds in old animals. Although these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not theta, was greater in older animals. Finally, aged rats had reduced within-field firing rates but greater spatial information per spike within the field. These data support a strong relationship between locomotor behavior and local-field potential activity and suggest that age significantly affects this relationship. Furthermore, observed changes in CA1 place cell firing rates and information content lend support to the hypothesis that age may result in more general and context-invariant hippocampal representations over more detailed information. These results may explain the observation that older adults tend to recall the gist of an experience rather than the details.SIGNIFICANCE STATEMENT Hippocampal oscillations and place cell activity are sensitive to sensorimotor input generated from active locomotion, yet studies of aged hippocampal function often do not account for this. By considering locomotion and spatial location, we identify novel age-associated differences in the scaling of oscillatory activity with speed, spike-field coherence, spatial information content, and within-field firing rates of CA1 place cells. These results indicate that age has an impact on the relationship between locomotion and hippocampal oscillatory activity, perhaps indicative of alterations to afferent input. These data also support the hypothesis that aged hippocampal place cells, compared with young, may more often represent more general spatial information. If true, these results may help explain why older humans tend to recall less specific and more gist-like information.