Hippocampal Representations Research Articles

Self-supervised learning of scale-invariant neural representations of space and time.

Hippocampal representations of space and time seem to share a common coding scheme characterized by neurons with bell-shaped tuning curves called place and time cells. The properties of the tuning curves are consistent with Weber's law, such that, in the absence of visual inputs, width scales with the peak time for time cells and with distance for place cells. Building on earlier computational work, we examined how neurons with such properties can emerge through self-supervised learning. We found that a network based on autoencoders can, given a particular inputs and connectivity constraints, produce scale-invariant time cells. When the animal's velocity modulates the decay rate of the leaky integrators, the same network gives rise to scale-invariant place cells. Importantly, this is not the case when velocity is fed as a direct input to the leaky integrators, implying that weight modulation by velocity might be critical for developing scale-invariant spatial receptive fields. Finally, we demonstrated that after training, scale-invariant place cells emerge in environments larger than those used during training. Taken together, these findings bring us closer to understanding the emergence of neurons with bell-shaped tuning curves in the hippocampus and highlight the critical role of velocity modulation in the formation of scale-invariant place cells.

Dorsal hippocampus represents locations to avoid as well as locations to approach during approach-avoidance conflict.

Worrying about perceived threats is a hallmark of multiple psychological disorders including anxiety. This concern about future events is particularly important when an individual is faced with an approach-avoidance conflict. Potential goals to approach are known to be represented in the dorsal hippocampus during theta cycles. Similarly, important information that is distant from the animal's position is represented during hippocampal high-synchrony events (HSEs), which coincide with sharp-wave ripples (SWRs). It is likely that potential future threats may be similarly represented. We examined how threats and rewards were represented within the hippocampus during approach-avoidance conflicts in rats faced with a predator-like robot guarding a food reward. We found decoding of the pseudo-predator's location during HSEs when hesitating in the nest and during theta prior to retreating as the rats approached the pseudo-predator. After the first attack, we observed new place fields appearing at the location of the robot (not the location the rat was when attacked). The anxiolytic diazepam reduced anxiety-like behavior and altered hippocampal local field potentials (LFPs), including reducing SWRs, suggesting that one potential mechanism of diazepam's actions may be through altered representations of imagined threat. These results suggest that hippocampal representation of potential threats could be an important mechanism that underlies worry and a potential target for anxiolytics.

Closed-loop modulation of remote hippocampal representations with neurofeedback.

Humans can remember specific remote events without acting on them and influence which memories are retrieved based on internal goals. However, animal models typically present sensory cues to trigger memory retrieval and then assess retrieval based on action. Thus, it is difficult to determine whether measured neural activity patterns relate to the cue(s), the memory, or the behavior. We therefore asked whether retrieval-related neural activity could be generated in animals without cues or a behavioral report. We focused on hippocampal "place cells," which primarily represent the animal's current location (local representations) but can also represent locations away from the animal (remote representations). We developed a neurofeedback system to reward expression of remote representations and found that rats could learn to generate specific spatial representations that often jumped directly to the experimenter-defined target location. Thus, animals can deliberately engage remote representations, enabling direct study of retrieval-related activity in the brain.

Novel off-context experience constrains hippocampal representational drift.

The hippocampus forms unique neural representations for distinct experiences, supporting the formation of different memories.1,2,3,4,5,6 Hippocampal representations gradually change over time as animals repeatedly visit the same familiar environment ("representational drift").7,8,9,10,11,12 Such drift has also been observed in other brain areas, such as the parietal,13,14 visual,15,16,17 auditory,18,19 and olfactory20 cortices. While the underlying mechanisms of representational drift remain unclear, a leading hypothesis suggests that it results from ongoing learning processes.20,21,22 According to this hypothesis, because the brain uses the same neural substrates to support multiple distinct representations, learning of novel stimuli or environments leads to changes in the neuronal representation of a familiar one. If this is true, we would expect drift in a given environment to increase following new experiences in other, unrelated environments (i.e., off-context experiences). To test this hypothesis, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly visited a familiar linear track over weeks. We introduced off-context experiences by placing mice in a novel environment for 1h after each visit to the familiar track. Contrary to our expectations, these novel episodes decreased place cells' representational drift. Our findings are consistent with a model in whichrepresentations of distinct memories occupy different areas within the neuronal activity space,and the drift of each of them within that space is constrained by the area occupied by the others.

The role of REM sleep in neural differentiation of memories in the hippocampus.

When faced with a familiar situation, we can use memory to make predictions about what will happen next. If such predictions turn out to be erroneous, the brain can adapt by differentiating the representations of the cues that generated the prediction from the mispredicted item itself, reducing the likelihood of future prediction errors. Prior work by Kim et al. (2017) found that violating a sequential association in a statistical learning paradigm triggered differentiation of the neural representations of the associated items in the hippocampus. Here, we used fMRI to test the preregistered hypothesis that this hippocampal differentiation occurs only when violations are followed by rapid eye movement (REM) sleep. In the morning, participants first learned that some items predict others (e.g., A predicts B) then encountered a violation in which a predicted item (B) failed to appear when expected after its associated item (A); the predicted item later appeared on its own after an unrelated item. Participants were then randomly assigned to one of three conditions: remain awake, take a nap containing non-REM sleep only, or take a nap with both non-REM and REM sleep. While the predicted results were not observed in the preregistered left CA2/3/DG ROI, we did observe evidence for our hypothesis in closely related hippocampal ROIs, uncorrected for multiple comparisons: In right CA2/3/DG, differentiation in the group with REM sleep was greater than in the groups without REM sleep (wake and non-REM nap); this differentiation was item-specific and concentrated in right DG. Differentiation effects were also greater in bilateral DG when the predicted item was more strongly reactivated during the violation. Overall, the results presented here provide initial evidence linking REM sleep to changes in the hippocampal representations of memories in humans.

Closed-loop modulation of remote hippocampal representations with neurofeedback.

Humans can remember specific remote events without acting on them and influence which memories are retrieved based on internal goals. However, animal models typically present sensory cues to trigger memory retrieval and then assess retrieval based on action. Thus, it is difficult to determine whether measured neural activity patterns relate to the cue(s), the memory, or the behavior. We therefore asked whether retrieval-related neural activity could be generated in animals without cues or a behavioral report. We focused on hippocampal "place cells" which primarily represent the animal's current location (local representations) but can also represent locations away from the animal (remote representations). We developed a neurofeedback system to reward expression of remote representations and found that rats could learn to generate specific spatial representations that often jumped directly to the experimenter-defined target location. Thus, animals can deliberately engage remote representations, enabling direct study of retrieval-related activity in the brain.

Hippocampal representations of alternative possibilities are flexibly generated to meet cognitive demands.

The cognitive ability to go beyond the present to consider alternative possibilities, including potential futures and counterfactual pasts, can support adaptive decision making. Complex and changing real-world environments, however, have many possible alternatives. Whether and how the brain can select among them to represent alternatives that meet current cognitive needs remains unknown. We therefore examined neural representations of alternative spatial locations in the rat hippocampus during navigation in a complex patch foraging environment with changing reward probabilities. We found representations of multiple alternatives along paths ahead and behind the animal, including in distant alternative patches. Critically, these representations were modulated in distinct patterns across successive trials: alternative paths were represented proportionate to their evolving relative value and predicted subsequent decisions, whereas distant alternatives were prevalent during value updating. These results demonstrate that the brain modulates the generation of alternative possibilities in patterns that meet changing cognitive needs for adaptive behavior.

FOS mapping reveals two complementary circuits for spatial navigation in mouse

Here, we show that during continuous navigation in a dynamic external environment, mice are capable of developing a foraging strategy based exclusively on changing distal (allothetic) information and that this process may involve two alternative components of the spatial memory circuit: the hippocampus and retrosplenial cortex. To this end, we designed a novel custom apparatus and implemented a behavioral protocol based on the figure-8-maze paradigm with two goal locations associated with distinct contexts. We assessed whether mice are able to learn to retrieve a sequence of rewards guided exclusively by the changing context. We found out that training mice in the apparatus leads to change in strategy from the internal tendency to alternate into navigation based exclusively on visual information. This effect could be achieved using two different training protocols: prolonged alternation training, or a flexible protocol with unpredictable turn succession. Based on the c-FOS mapping we also provide evidence of opposing levels of engagement of hippocampus and retrosplenial cortex after training of mice in these two different regimens. This supports the hypothesis of the existence of parallel circuits guiding spatial navigation, one based on the well-described hippocampal representation, and another, RSC-dependent.

Event boundaries drive norepinephrine release and distinctive neural representations of space in the rodent hippocampus.

Episodic memories are temporally segmented around event boundaries that tend to coincide with moments of environmental change. During these times, the state of the brain should change rapidly, or reset, to ensure that the information encountered before and after an event boundary is encoded in different neuronal populations. Norepinephrine (NE) is thought to facilitate this network reorganization. However, it is unknown whether event boundaries drive NE release in the hippocampus and, if so, how NE release relates to changes in hippocampal firing patterns. The advent of the new GRABNE sensor now allows for the measurement of NE binding with sub-second resolution. Using this tool in mice, we tested whether NE is released into the dorsal hippocampus during event boundaries defined by unexpected transitions between spatial contexts and presentations of novel objections. We found that NE binding dynamics were well explained by the time elapsed after each of these environmental changes, and were not related to conditioned behaviors, exploratory bouts of movement, or reward. Familiarity with a spatial context accelerated the rate in which phasic NE binding decayed to baseline. Knowing when NE is elevated, we tested how hippocampal coding of space differs during these moments. Immediately after context transitions we observed relatively unique patterns of neural spiking which settled into a modal state at a similar rate in which NE returned to baseline. These results are consistent with a model wherein NE release drives hippocampal representations away from a steady-state attractor. We hypothesize that the distinctive neural codes observed after each event boundary may facilitate long-term memory and contribute to the neural basis for the primacy effect.

Impaired Dynamics of Positional and Contextual Neural Coding in an Alzheimer's Disease Rat Model.

The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells' spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.

Abstract representations emerge in human hippocampal neurons during inference

Humans have the remarkable cognitive capacity to rapidly adapt to changing environments. Central to this capacity is the ability to form high-level, abstract representations that take advantage of regularities in the world to support generalization1. However, little is known about how these representations are encoded in populations of neurons, how they emerge through learning and how they relate to behaviour2,3. Here we characterized the representational geometry of populations of neurons (single units) recorded in the hippocampus, amygdala, medial frontal cortex and ventral temporal cortex of neurosurgical patients performing an inferential reasoning task. We found that only the neural representations formed in the hippocampus simultaneously encode several task variables in an abstract, or disentangled, format. This representational geometry is uniquely observed after patients learn to perform inference, and consists of disentangled directly observable and discovered latent task variables. Learning to perform inference by trial and error or through verbal instructions led to the formation of hippocampal representations with similar geometric properties. The observed relation between representational format and inference behaviour suggests that abstract and disentangled representational geometries are important for complex cognition.

Prefrontal cortical ripples mediate top-down suppression of hippocampal reactivation during sleep memory consolidation

Consolidation of initially encoded hippocampal representations in the neocortex through reactivation is crucial for long-term memory formation and is facilitated by the coordination of hippocampal sharp-wave ripples (SWRs) with cortical slow and spindle oscillations during non-REM sleep. Recent evidence suggests that high-frequency cortical ripples can also coordinate with hippocampal SWRs in support of consolidation; however, the contribution of cortical ripples to reactivation remains unclear. We used high-density, continuous recordings in the hippocampus (area CA1) and prefrontal cortex (PFC) over the course of spatial learning and show that independent PFC ripples dissociated from SWRs are prevalent in NREM sleep and predominantly suppress hippocampal activity. PFC ripples paradoxically mediate top-down suppression of hippocampal reactivation rather than coordination, and this suppression is stronger for assemblies that are reactivated during coordinated CA1-PFC ripples for consolidation of recent experiences. Further, we show non-canonical, serial coordination of independent cortical ripples with slow and spindle oscillations, which are known signatures of memory consolidation. These results establish a role for prefrontal cortical ripples in top-down regulation of behaviorally relevant hippocampal representations during consolidation.

Retuning of hippocampal representations during sleep.

Hippocampal representations that underlie spatial memory undergo continuous refinement following formation1. Here, to track the spatial tuning of neurons dynamically during offline states, we used a new Bayesian learning approach based on the spike-triggered average decoded position in ensemble recordings from freely moving rats. Measuring these tunings, we found spatial representations within hippocampal sharp-wave ripples that were stable for hours during sleep and were strongly aligned with place fields initially observed during maze exploration. These representations were explained by a combination of factors that included preconfigured structure before maze exposure and representations that emerged during θ-oscillations and awake sharp-wave ripples whileon the maze, revealing the contribution of these events in forming ensembles. Strikingly, the ripple representations during sleep predicted the future place fields of neurons during re-exposure to the maze, even when those fields deviated from previous place preferences. By contrast, we observed tunings with poor alignment to maze place fields during sleep and rest before maze exposure and in the later stages of sleep. In sum, the new decoding approach allowed us to infer and characterize the stability and retuning of place fields during offline periods, revealing the rapid emergence of representations following new exploration and the role of sleep in the representational dynamics of the hippocampus.

Tuned geometries of hippocampal representations meet the computational demands of social memory

Social memory consists of two processes: the detection of familiar compared with novel conspecifics and the detailed recollection of past social episodes. We investigated the neural bases for these processes using calcium imaging of dorsal CA2 hippocampal pyramidal neurons, known to be important for social memory, during social/spatial encounters with novel conspecifics and familiar littermates. Whereas novel individuals were represented in a low-dimensional geometry that allows for generalization of social identity across different spatial locations and of location across different identities, littermates were represented in a higher-dimensional geometry that supports high-capacity memory storage. Moreover, familiarity was represented in an abstract format, independent of individual identity. The degree to which familiarity increased the dimensionality of CA2 representations for individual mice predicted their performance in a social novelty recognition memory test. Thus, by tuning the geometry of structured neural activity, CA2 is able to meet the demands of distinct social memory processes.

Environment geometry alters subiculum boundary vector cell receptive fields in adulthood and early development

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animal’s location as a vector displacement from boundaries. Here we characterise the prevalence and spatial tuning of subiculum BVCs in adult and developing male rats, and investigate the relationship between BVC spatial firing and boundary geometry. BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space.

A dynamic attractor network model of memory formation, reinforcement and forgetting.

Empirical evidence shows that memories that are frequently revisited are easy to recall, and that familiar items involve larger hippocampal representations than less familiar ones. In line with these observations, here we develop a modelling approach to provide a mechanistic understanding of how hippocampal neural assemblies evolve differently, depending on the frequency of presentation of the stimuli. For this, we added an online Hebbian learning rule, background firing activity, neural adaptation and heterosynaptic plasticity to a rate attractor network model, thus creating dynamic memory representations that can persist, increase or fade according to the frequency of presentation of the corresponding memory patterns. Specifically, we show that a dynamic interplay between Hebbian learning and background firing activity can explain the relationship between the memory assembly sizes and their frequency of stimulation. Frequently stimulated assemblies increase their size independently from each other (i.e. creating orthogonal representations that do not share neurons, thus avoiding interference). Importantly, connections between neurons of assemblies that are not further stimulated become labile so that these neurons can be recruited by other assemblies, providing a neuronal mechanism of forgetting.

Neural patterns differentiate traumatic from sad autobiographical memories in PTSD.

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of 'regular' negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type from hippocampal multivoxel patterns. Finally, individual symptom severity modulated semantic representation of the traumatic narratives in the posterior cingulate cortex. Taken together, these findings suggest that traumatic memories are an alternative cognitive entity that deviates from memory per se.

Volitional activation of remote place representations with a hippocampal brain-machine interface.

The hippocampus is critical for recollecting and imagining experiences. This is believed to involve voluntarily drawing from hippocampal memory representations of people, events, and places, including maplike representations of familiar environments. However, whether representations in such "cognitive maps" can be volitionally accessed is unknown. We developed a brain-machine interface to test whether rats can do so by controlling their hippocampal activity in a flexible, goal-directed, and model-based manner. We found that rats can efficiently navigate or direct objects to arbitrary goal locations within a virtual reality arena solely by activating and sustaining appropriate hippocampal representations of remote places. This provides insight into the mechanisms underlying episodic memory recall, mental simulation and planning, and imagination and opens up possibilities for high-level neural prosthetics that use hippocampal representations.

Goal-Dependent Hippocampal Representations Facilitate Self-Control.

Hippocampal activity linking past experiences and simulations of the future with current goals can play an important role in decision-making. The representation of information within the hippocampus may be especially critical in situations where one needs to overcome past rewarding experiences and exert self-control. Self-control success or failure may depend on how information is represented in the hippocampus and how effectively the representation process can be modified to achieve a specific goal. We test this hypothesis using representational similarity analyses of human (female/male) neuroimaging data during a dietary self-control task in which individuals must overcome taste temptations to choose healthy foods. We find that self-control is indeed associated with the way individuals represent taste information (valance) in the hippocampus and how taste representations there adapt to align with different goals/contexts. Importantly, individuals who were able to shift their hippocampal representations to a larger degree to align with the current motivation were better able to exert self-control when facing a dietary challenge. These results suggest an alternative or complementary neurobiological pathway leading to self-control success and indicate the need to update the classical view of self-control to continue to advance our understanding of its behavioral and neural underpinnings.SIGNIFICANCE STATEMENT The paper provides a new perspective on what leads to successful self-control at the behavioral and neurobiological levels. Our data suggest that self-control is enhanced when individuals adjust hippocampal processing to align with current goals.

Hippocampal representation during collective spatial behaviour in bats

Social animals live and move through spaces shaped by the presence, motion and sensory cues of multiple other individuals1–6. Neural activity in the hippocampus is known to reflect spatial behaviour7–9 yet its study is lacking in such dynamic group settings, which are ubiquitous in natural environments. Here we studied hippocampal activity in groups of bats engaged in collective spatial behaviour. We find that, under spontaneous conditions, a robust spatial structure emerges at the group level whereby behaviour is anchored to specific locations, movement patterns and individual social preferences. Using wireless electrophysiological recordings from both stationary and flying bats, we find that many hippocampal neurons are tuned to key features of group dynamics. These include the presence or absence of a conspecific, but not typically of an object, at landing sites, shared spatial locations, individual identities and sensory signals that are broadcasted in the group setting. Finally, using wireless calcium imaging, we find that social responses are anatomically distributed and robustly represented at the population level. Combined, our findings reveal that hippocampal activity contains a rich representation of naturally emerging spatial behaviours in animal groups that could in turn support the complex feat of collective behaviour.