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.

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.

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.

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.

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.

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.

[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.

Mapping of a non-spatial dimension by the hippocampal-entorhinal circuit.

During spatial navigation, neural activity in the hippocampus and the medial entorhinal cortex (MEC) is correlated to navigational variables such as location, head direction, speed, and proximity to boundaries. These activity patterns are thought to provide a map-like representation of physical space. However, the hippocampal-entorhinal circuit is involved not only in spatial navigation, but also in a variety of memory-guided behaviours. The relationship between this general function and the specialized spatial activity patterns is unclear. A conceptual framework reconciling these views is that spatial representation is just one example of a more general mechanism for encoding continuous, task-relevant variables. Here we tested this idea by recording from hippocampal and entorhinal neurons during a task that required rats to use a joystick to manipulate sound along a continuous frequency axis. We found neural representation of the entire behavioural task, including activity that formed discrete firing fields at particular sound frequencies. Neurons involved in this representation overlapped with the known spatial cell types in the circuit, such as place cells and grid cells. These results suggest that common circuit mechanisms in the hippocampal-entorhinal system are used to represent diverse behavioural tasks, possibly supporting cognitive processes beyond spatial navigation.

Distinct effects of reward and navigation history on hippocampal forward and reverse replays.

To better understand the functional roles of hippocampal forward and reverse replays, we trained rats in a spatial sequence memory task and examined how these replays are modulated by reward and navigation history. We found that reward enhances both forward and reverse replays during the awake state, but in different ways. Reward enhances the rate of reverse replays, but it increases the fidelity of forward replays for recently traveled as well as other alternative trajectories heading toward a rewarding location. This suggests roles for forward and reverse replays in reinforcing representations for all potential rewarding trajectories. We also found more faithful reactivation of upcoming than already rewarded trajectories in forward replays. This suggests a role for forward replays in preferentially reinforcing representations for high-value trajectories. We propose that hippocampal forward and reverse replays might contribute to constructing a map of potential navigation trajectories and their associated values (a "value map") via distinct mechanisms.

An integrated deep learning-based model of spatial cells that combines self-motion with sensory information.

A special class of neurons in the hippocampal formation broadly known as the spatial cells, whose subcategories include place cells, grid cells, and head direction cells, are considered to be the building blocks of the brain's map of the spatial world. We present a general, deep learning-based modeling framework that describes the emergence of the spatial-cell responses and can also explain responses that involve a combination of path integration and vision. The first layer of the model consists of head direction (HD) cells that code for the preferred direction of the agent. The second layer is the path integration (PI) layer with oscillatory neurons: displacement of the agent in a given direction modulates the frequency of these oscillators. Principal component analysis (PCA) of the PI-cell responses showed the emergence of cells with grid-like spatial periodicity. We show that the Bessel functions could describe the response of these cells. The output of the PI layer is used to train a stack of autoencoders. Neurons of both the layers exhibit responses resembling grid cells and place cells. The paper concludes by suggesting the wider applicability of the proposed modeling framework beyond the two simulated studies.

Choice of method of place cell classification determines the population of cells identified.

Place cells, spatially responsive hippocampal cells, provide the neural substrate supporting navigation and spatial memory. Historically most studies of these neurons have used electrophysiological recordings from implanted electrodes but optical methods, measuring intracellular calcium, are becoming increasingly common. Several methods have been proposed as a means to identify place cells based on their calcium activity but there is no common standard and it is unclear how reliable different approaches are. Here we tested four methods that have previously been applied to two-photon hippocampal imaging or electrophysiological data, using both model datasets and real imaging data. These methods use different parameters to identify place cells, including the peak activity in the place field, compared to other locations (the Peak method); the stability of cells' activity over repeated traversals of an environment (Stability method); a combination of these parameters with the size of the place field (Combination method); and the spatial information held by the cells (Information method). The methods performed differently from each other on both model and real data. In real datasets, vastly different numbers of place cells were identified using the four methods, with little overlap between the populations identified as place cells. Therefore, choice of place cell detection method dramatically affects the number and properties of identified cells. Ultimately, we recommend the Peak method be used in future studies to identify place cell populations, as this method is robust to moderate variations in place field within a session, and makes no inherent assumptions about the spatial information in place fields, unless there is an explicit theoretical reason for detecting cells with more narrowly defined properties.

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer's Disease.

Alzheimer's Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.

Altered neural odometry in the vertical dimension.

Entorhinal grid cells integrate sensory and self-motion inputs to provide a spatial metric of a characteristic scale. One function of this metric may be to help localize the firing fields of hippocampal place cells during formation and use of the hippocampal spatial representation ("cognitive map"). Of theoretical importance is the question of how this metric, and the resulting map, is configured in 3D space. We find here that when the body plane is vertical as rats climb a wall, grid cells produce stable, almost-circular grid-cell firing fields. This contrasts with previous findings when the body was aligned horizontally during vertical exploration, suggesting a role for the body plane in orienting the plane of the grid cell map. However, in the present experiment, the fields on the wall were fewer and larger, suggesting an altered or absent odometric (distance-measuring) process. Several physiological indices of running speed in the entorhinal cortex showed reduced gain, which may explain the enlarged grid pattern. Hippocampal place fields were found to be sparser but unchanged in size/shape. Together, these observations suggest that the orientation and scale of the grid cell map, at least on a surface, are determined by an interaction between egocentric information (the body plane) and allocentric information (the gravity axis). This may be mediated by the different sensory or locomotor information available on a vertical surface and means that the resulting map has different properties on a vertical plane than a horizontal plane (i.e., is anisotropic).

Calcium Imaging Reveals Fast Tuning Dynamics of Hippocampal Place Cells and CA1 Population Activity during Free Exploration Task in Mice.

Hippocampal place cells are a well-known object in neuroscience, but their place field formation in the first moments of navigating in a novel environment remains an ill-defined process. To address these dynamics, we performed in vivo imaging of neuronal activity in the CA1 field of the mouse hippocampus using genetically encoded green calcium indicators, including the novel NCaMP7 and FGCaMP7, designed specifically for in vivo calcium imaging. Mice were injected with a viral vector encoding calcium sensor, head-mounted with an NVista HD miniscope, and allowed to explore a completely novel environment (circular track surrounded by visual cues) without any reinforcement stimuli, in order to avoid potential interference from reward-related behavior. First, we calculated the average time required for each CA1 cell to acquire its place field. We found that 25% of CA1 place fields were formed at the first arrival in the corresponding place, while the average tuning latency for all place fields in a novel environment equaled 247 s. After 24 h, when the environment was familiar to the animals, place fields formed faster, independent of retention of cognitive maps during this session. No cumulation of selectivity score was observed between these two sessions. Using dimensionality reduction, we demonstrated that the population activity of rapidly tuned CA1 place cells allowed the reconstruction of the geometry of the navigated circular maze; the distribution of reconstruction error between the mice was consistent with the distribution of the average place field selectivity score in them. Our data thus show that neuronal activity recorded with genetically encoded calcium sensors revealed fast behavior-dependent plasticity in the mouse hippocampus, resulting in the rapid formation of place fields and population activity that allowed the reconstruction of the geometry of the navigated maze.