Distinguishing examples while building concepts in hippocampal and artificial networks.

The hippocampal subfield CA3 is thought to function as an auto-associative network that stores experiences as memories. Information from these experiences arrives directly from the entorhinal cortex as well as indirectly through the dentate gyrus, which performs sparsification and decorrelation. The computational purpose for these dual input pathways has not been firmly established. We model CA3 as a Hopfield-like network that stores both dense, correlated encodings and sparse, decorrelated encodings. As more memories are stored, the former merge along shared features while the latter remain distinct. We verify our model's prediction in rat CA3 place cells, which exhibit more distinct tuning during theta phases with sparser activity. Finally, we find that neural networks trained in multitask learning benefit from a loss term that promotes both correlated and decorrelated representations. Thus, the complementary encodings we have found in CA3 can provide broad computational advantages for solving complex tasks.

A realistic computational model for the formation of a Place Cell.

Hippocampal Place Cells (PCs) are pyramidal neurons showing spatially localized firing when an animal gets into a specific area within an environment. Because of their obvious and clear relation with specific cognitive functions, Place Cells operations and modulations are intensely studied experimentally. However, although a lot of data have been gathered since their discovery, the cellular processes that interplay to turn a hippocampal pyramidal neuron into a Place Cell are still not completely understood. Here, we used a morphologically and biophysically detailed computational model of a CA1 pyramidal neuron to show how, and under which conditions, it can turn into a neuron coding for a specific cue location, through the self-organization of its synaptic inputs in response to external signals targeting different dendritic layers. Our results show that the model is consistent with experimental findings demonstrating PCs stability within the same spatial context over different trajectories, environment rotations, and place field remapping to adapt to changes in the environment. To date, this is the only biophysically and morphologically accurate cellular model of PCs formation, which can be directly used in physiologically accurate microcircuits and large-scale model networks to study cognitive functions and dysfunctions at cellular level.

The Precision of Place Fields Governs Their Fate across Epochs of Experience.

Spatial memories are represented by hippocampal place cells during navigation. This spatial code is dynamic, undergoing changes across time, known as representational drift, and across changes in internal state, even while navigating the same spatial environment with consistent behavior. A dynamic code may provide the hippocampus a means to track distinct epochs of experience that occur at different times or during different internal states and update spatial memories. Changes to the spatial code include place fields (PFs) that remap to new locations and place fields that vanish, while others are stable. However, what determines place field fate across epochs remains unclear. We measured the lap-by-lap properties of place cells in mice during navigation for a block of trials in a rewarded virtual environment. We then determined the position of the place fields in another block of trials in the same spatial environment either separated by a day (a distinct temporal epoch) or during the same session but with reward removed to change reward expectation (a distinct internal state epoch). We found that place cells with remapped place fields across epochs tended to have lower spatial precision during navigation in the initial epoch. Place cells with stable or vanished place fields tended to have higher spatial precision. We conclude that place cells with less precise place fields have greater spatial flexibility, allowing them to respond to, and track, distinct epochs of experience in the same spatial environment, while place cells with precise place fields generally preserve spatial information when their fields reappear.

Cortical reactivation of spatial and non-spatial features coordinates with hippocampus to form a memory dialogue.

Episodic memories comprise diverse attributes of experience distributed across neocortical areas. The hippocampus is integral to rapidly binding these diffuse representations, as they occur, to be later reinstated. However, the nature of the information exchanged during this hippocampal-cortical dialogue remains poorly understood. A recent study has shown that the secondary motor cortex carries two types of representations: place cell-like activity, which were impaired by hippocampal lesions, and responses tied to visuo-tactile cues, which became more pronounced following hippocampal lesions. Using two-photon Ca2+ imaging to record neuronal activities in the secondary motor cortex of male Thy1-GCaMP6s mice, we assessed the cortical retrieval of spatial and non-spatial attributes from previous explorations in a virtual environment. We show that, following navigation, spontaneous resting state reactivations convey varying degrees of spatial (trajectory sequences) and non-spatial (visuo-tactile attributes) information, while reactivations of non-spatial attributes tend to precede reactivations of spatial representations surrounding hippocampal sharp-wave ripples.

Integrated Three-Electrode Dual-Mode Detection Chip for Place Cell Analysis: Dopamine Facilitates the Role of Place Cells in Encoding Spatial Locations of Novel Environments and Rewards.

The functioning of place cells requires the involvement of multiple neurotransmitters, with dopamine playing a critical role in hippocampal place cell activity. However, the exact mechanisms through which dopamine influences place cell activity remain largely unknown. Herein, we present the development of the integrated three-electrode dual-mode detection chip (ITDDC), which enables simultaneous recording of the place cell activity and dopamine concentration fluctuation. The working electrode, reference electrode, and counter electrode are all integrated within the ITDDC in electrochemical detection, enabling the real-time in situ monitoring of dopamine concentrations in animals in motion. The reference, working, and counter electrodes are surface-modified using PtNPs and polypyrrole, PtNPs and PEDOT:PSS, and PtNPs, respectively. This modification allows for the detection of dopamine concentrations as low as 20 nM. We conducted dual-mode testing on mice in a novel environment and an environment with food rewards. We found distinct dopamine concentration variations along different paths within a novel environment, implying that different dopamine levels may contribute to spatial memory. Moreover, environmental food rewards elevate dopamine significantly, followed by the intense firing of reward place cells, suggesting a crucial role of dopamine in facilitating the encoding of reward-associated locations in animals. The real-time and in situ recording capabilities of ITDDC offer new opportunities to investigate the interplay between electrophysiology and dopamine during animal exploration and reward-based memory and provide a novel glimpse into the correlation between dopamine levels and place cell activity.

A theory of hippocampal theta correlations accounting for extrinsic and intrinsic sequences.

Hippocampal place cell sequences have been hypothesized to serve as diverse purposes as the induction of synaptic plasticity, formation and consolidation of long-term memories, or navigation and planning. During spatial behaviors of rodents, sequential firing of place cells at the theta timescale (known as theta sequences) encodes running trajectories, which can be considered as one-dimensional behavioral sequences of traversed locations. In a two-dimensional space, however, each single location can be visited along arbitrary one-dimensional running trajectories. Thus, a place cell will generally take part in multiple different theta sequences, raising questions about how this two-dimensional topology can be reconciled with the idea of hippocampal sequences underlying memory of (one-dimensional) episodes. Here, we propose a computational model of cornu ammonis 3 (CA3) and dentate gyrus (DG), where sensorimotor input drives the direction-dependent (extrinsic) theta sequences within CA3 reflecting the two-dimensional spatial topology, whereas the intrahippocampal CA3-DG projections concurrently produce intrinsic sequences that are independent of the specific running trajectory. Consistent with experimental data, intrinsic theta sequences are less prominent, but can nevertheless be detected during theta activity, thereby serving as running-direction independent landmark cues. We hypothesize that the intrinsic sequences largely reflect replay and preplay activity during non-theta states.

A manifold neural population code for space in hippocampal coactivity dynamics independent of place fields.

Hippocampus place cell discharge is temporally unreliable across seconds and days, and place fields are multimodal, suggesting an "ensemble cofiring" spatial coding hypothesis with manifold dynamics that does not require reliable spatial tuning, in contrast to hypotheses based on place field (spatial tuning) stability. We imaged mouse CA1 (cornu ammonis 1) ensembles in two environments across three weeks to evaluate these coding hypotheses. While place fields "remap," being more distinct between than within environments, coactivity relationships generally change less. Decoding location and environment from 1-s ensemble location-specific activity is effective and improves with experience. Decoding environment from cell-pair coactivity relationships is also effective and improves with experience, even after removing place tuning. Discriminating environments from 1-s ensemble coactivity relies crucially on the cells with the most anti-coactive cell-pair relationships because activity is internally organized on a low-dimensional manifold of non-linear coactivity relationships that intermittently reregisters to environments according to the anti-cofiring subpopulation activity.

Simultaneous representation of multiple time horizons by entorhinal grid cells and CA1 place cells.

Grid cells and place cells represent the spatiotemporal continuum of an animal's past, present, and future locations. However, their spatiotemporal relationship is unclear. Here, we co-record grid and place cells in freely foraging rats. We show that average time shifts in grid cells tend to be prospective and are proportional to their spatial scale, providing a nearly instantaneous readout of a spectrum of progressively increasing time horizons ranging hundreds of milliseconds. Average time shifts of place cells are generally larger compared to grid cells and also increase with place field sizes. Moreover, time horizons display nonlinear modulation by the animal's trajectories in relation to the local boundaries and locomotion cues. Finally, long and short time horizons occur at different parts of the theta cycle, which may facilitate their readout. Together, these findings suggest that population activity of grid and place cells may represent local trajectories essential for goal-directed navigation and planning.

Awake hippocampal synchronous events are incorporated into offline neuronal reactivation.

Learning novel experiences reorganizes hippocampal neuronal circuits, represented as coordinated reactivation patterns in post-experience offline states for memory consolidation. This study examines how awake synchronous events during a novel run are related to post-run reactivation patterns. The disruption of awake sharp-wave ripples inhibited experience-induced increases in the contributions of neurons to post-experience synchronous events. Hippocampal place cells that participate more in awake synchronous events are more strongly reactivated during post-experience synchronous events. Awake synchronous neuronal patterns, in cooperation with place-selective firing patterns, determine cell ensembles that undergo pronounced increases and decreases in their correlated spikes. Taken together, awake synchronous events are fundamental for identifying hippocampal neuronal ensembles to be incorporated into synchronous reactivation during subsequent offline states, thereby facilitating memory consolidation.

Hippocampal place cell remapping occurs with memory storage of aversive experiences.

Aversive stimuli can cause hippocampal place cells to remap their firing fields, but it is not known whether remapping plays a role in storing memories of aversive experiences. Here, we addressed this question by performing in vivo calcium imaging of CA1 place cells in freely behaving rats (n = 14). Rats were first trained to prefer a short path over a long path for obtaining food reward, then trained to avoid the short path by delivering a mild footshock. Remapping was assessed by comparing place cell population vector similarity before acquisition versus after extinction of avoidance. Some rats received shock after systemic injections of the amnestic drug scopolamine at a dose (1 mg/kg) that impaired avoidance learning but spared spatial tuning and shock-evoked responses of CA1 neurons. Place cells remapped significantly more following remembered than forgotten shocks (drug-free versus scopolamine conditions); shock-induced remapping did not cause place fields to migrate toward or away from the shocked location and was similarly prevalent in cells that were responsive versus non-responsive to shocks. When rats were exposed to a neutral barrier rather than aversive shock, place cells remapped significantly less in response to the barrier. We conclude that place cell remapping occurs in response to events that are remembered rather than merely perceived and forgotten, suggesting that reorganization of hippocampal population codes may play a role in storing memories for aversive events.

The human brain is able to remember experiences that occurred at specific places and times, such as a birthday party held at a particular restaurant. A part of the brain known as the hippocampus helps to store these episodic memories, but how exactly is not fully understood. Within the hippocampus are specialized neurons known as place cells which 'label' locations with unique patterns of brain activity. When we revisit a place, such as the restaurant, place cells recall the stored pattern of brain activity allowing us to recognize the familiar location. It has been shown that a new negative experience at a familiar place ­ for example, if we went back to the restaurant and had a terrible meal ­ triggers place cells to update the brain activity label associated with the location. However, it remains uncertain whether this re-labelling assists in storing the memory of the unpleasant experience. To investigate, Blair et al. used a technique known as calcium imaging to monitor place cells in the hippocampus of freely moving rats. The rats were given a new experience ­ a mild foot shock ­ at a previously explored location. Tiny cameras attached to their heads were then used to record the activity of hundreds of place cells before and after the shock. Initially, the rats remembered the aversive experience and avoided the location where they had been shocked. Over time, the rats began to return to the location; however, their place cells displayed different patterns of activity compared to their previous visits before the shock. To test whether this change in place cell activity corresponded with new memories, another group of rats were administered a mild amnesia-inducing drug before the shock, causing them to forget the experience. These rats did not avoid the shock site or show any changes in place cell activity when they revisited it. These findings imply that new events cause place cells to alter their 'label' for a location only if the event is remembered, not if it is forgotten. This indicates that alterations in place cell activity patterns may play a role in storing memories of unpleasant experiences. Having a better understanding of how episodic memories are stored could lead to better treatments for diseases that impair memory, such as Alzheimer's disease and age-related dementia.

Active experience, not time, determines within-day representational drift in dorsal CA1.

Memories of past events can be recalled long after the event, indicating stability. But new experiences are also integrated into existing memories, indicating plasticity. In the hippocampus, spatial representations are known to remain stable but have also been shown to drift over long periods of time. We hypothesized that experience, more than the passage of time, is the driving force behind representational drift. We compared the within-day stability of place cells' representations in dorsal CA1 of the hippocampus of mice traversing two similar, familiar tracks for different durations. We found that the more time the animals spent actively traversing the environment, the greater the representational drift, regardless of the total elapsed time between visits. Our results suggest that spatial representation is a dynamic process, related to the ongoing experiences within a specific context, and is related to memory update rather than to passive forgetting.

Disrupted hippocampal synchrony following maternal immune activation in a rat model.

Maternal immune activation (MIA) is a risk factor for schizophrenia and other neurodevelopmental disorders. MIA in rats models a number of the brain and behavioral changes that are observed in schizophrenia, including impaired memory. Recent studies in the MIA model have shown that the firing of the hippocampal place cells that are involved in memory processes appear relatively normal, but with abnormalities in the temporal ordering of firing. In this study, we re-analyzed data from prior hippocampal electrophysiological recordings of MIA and control animals to determine whether temporal dysfunction was evident. We find that there is a decreased ratio of slow to fast gamma power, resulting from an increase in fast gamma power and a tendency toward reduced slow gamma power in MIA rats. Moreover, we observe a robust reduction in spectral coherence between hippocampal theta and both fast and slow gamma rhythms, as well as changes in the phase of theta at which fast gamma occurs. We also find the phasic organization of place cell phase precession on the theta wave to be abnormal in MIA rats. Lastly, we observe that the local field potential of MIA rats contains more frequent sharp-wave ripple events, and that place cells were more likely to fire spikes during ripples in these animals than control. These findings provide further evidence of desynchrony in MIA animals and may point to circuit-level changes that underlie failures to integrate and encode information in schizophrenia.

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.

Global remapping in granule cells and mossy cells of the mouse dentate gyrus.

Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts.

Hippocampal spatial view cells, place cells, and concept cells: View representations.

A commentary is provided on issues raised in the Special Issue of Hippocampus (2023) on hippocampal system view representations. First, the evidence for hippocampal and parahippocampal spatial view cells in primates including humans shows that the allocentric representations provided by at least some of these cells are very useful for human memory in that where objects and rewards are seen in the world "out there" is a key component of episodic memory and navigation. Spatial view cell representations provide for memory and navigation to be independent of the place where the individual is currently located and of the egocentric coordinates of the viewed location and the facing direction of the individual. Second, memory and navigation in humans are normally related to the visual cues encoded by spatial view cells that define a location "out there" such as a building, hill, and so forth, not to an unmarked place without local cues and identified only by distant environmental/room cues. Third, "mixed" representations, for example of particular combinations of spatial view and place, can arise if the training has been for only some combinations of place and view, for that is what can then be learned by the hippocampus. Fourth, rodents, with their much less good visual acuity (~1 cycle/° in rats, compared with ~60 cycles/° for the human fovea), and rodents' very wide viewing angle for the world (~270°) might be expected, when using the same computational mechanisms as in primates, to use widely spaced environmental cues to define a place where the rodent is located, supported by inputs about place using local olfactory and tactile cues. Fifth, it is shown how view-point dependent allocentric representations could form a view-point independent allocentric representation for memory and navigation. Sixth, concept cells in humans and primates with connectivity to the hippocampus are compared.

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.

Exercise accelerates place cell representational drift.

Stable neural ensembles are often thought to underlie stable learned behaviors and memory. Recent longitudinal experiments, however, that tracked the activity of the same neurons over days to weeks have shown that neuronal activity patterns can change over extended timescales even if behaviors remain the same - a phenomenon termed representational drift1. We have tested whether neural circuit remodeling, defined as any change in structural connectivity, contributes to representational drift. To do this, we tracked how hippocampal CA1 spatial representations of a familiar environment change with time in conventionally housed mice relative to mice housed with a running wheel. Voluntary exercise is an environmental stimulus that promotes hippocampal circuit remodeling, primarily via promoting adult neurogenesis in the dentate gyrus. Adult neurogenesis alters structural connectivity patterns, as the integration of adult-generated granule cells (abGCs) is a competitive process where new input-output synaptic connections may co-exist and/or even replace existing synaptic connections2. Comparing the spatial activity of downstream hippocampal CA1 place cells in the same familiar environment over two weeks, we found that the activity of place cells in exercise mice exhibited accelerated representational drift compared to control mice, suggesting that hippocampal circuit remodeling may indeed drive representational drift.

Organization of hippocampal CA3 into correlated cell assemblies supports a stable spatial code.

Hippocampal subfield CA3 is thought to stably store memories in assemblies of recurrently connected cells functioning as a collective. However, the collective hippocampal coding properties that are unique to CA3 and how such properties facilitate the stability or precision of the neural code remain unclear. Here, we performed large-scale Ca2+ imaging in hippocampal CA1 and CA3 of freely behaving mice that repeatedly explored the same, initially novel environments over weeks. CA3 place cells have more precise and more stable tuning and show a higher statistical dependence with their peers compared with CA1 place cells, uncovering a cell assembly organization in CA3. Surprisingly, although tuning precision and long-term stability are correlated, cells with stronger peer dependence exhibit higher stability but not higher precision. Overall, our results expose the three-way relationship between tuning precision, long-term stability, and peer dependence, suggesting that a cell assembly organization underlies long-term storage of information in the hippocampus.

The medial entorhinal cortex is necessary for the stimulus control over hippocampal place fields by distal, but not proximal, landmarks.

A fundamental property of place cells in the hippocampus is the anchoring of their firing fields to salient landmarks within the environment. However, it is unclear how such information reaches the hippocampus. In the current experiment, we tested the hypothesis that the stimulus control exerted by distal visual landmarks requires input from the medial entorhinal cortex (MEC). Place cells were recorded from mice with ibotenic acid lesions of the MEC (n = 7) and from sham-lesioned mice (n = 6) following 90° rotations of either distal landmarks or proximal cues in a cue- controlled environment. We found that lesions of the MEC impaired the anchoring of place fields to distal landmarks, but not proximal cues. We also observed that, relative to sham-lesioned mice, place cells in animals with MEC lesions exhibited significantly reduced spatial information and increased sparsity. These results support the view that distal landmark information reaches the hippocampus via the MEC, but that proximal cue information can do so via an alternative neural pathway.

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.