Replay Events Research Articles

Song-like activation of syringeal and respiratory muscles during sleep in canaries.

Sleep replay activity involves the reactivation of brain structures with patterns similar to those observed during waking behavior. In this study, we demonstrate that adult male canaries exhibit spontaneous, song-like peripheral reactivation during night sleep. Our findings include: (1) the presence of activity in respiratory muscles, leading to song-like air sac pressure patterns of low amplitude, (2) the simultaneous occurrence of respiratory replay events and reactivation of syringeal muscles, and (3) the reactivation of syringeal muscles without concurrent respiratory system activity. This song-like reactivation of peripheral motor systems enables the identification of specific motor patterns, with replay events preserving individual morphological and temporal properties. The activation of peripheral motor systems in songbirds and the differences in activation patterns between species give unique insights into the fictive behavioral output of activation of a complex learned motor behavior during sleep, shedding light on the neural control mechanisms and potential functions.

Replay-triggered brain-wide activation in humans

The consolidation of discrete experiences into a coherent narrative shapes the cognitive map, providing structured mental representations of our experiences. In this process, past memories are reactivated and replayed in sequence, fostering hippocampal-cortical dialogue. However, brain-wide engagement coinciding with sequential reactivation (or replay) of memories remains largely unexplored. In this study, employing simultaneous EEG-fMRI, we capture both the spatial and temporal dynamics of memory replay. We find that during mental simulation, past memories are replayed in fast sequences as detected via EEG. These transient replay events are associated with heightened fMRI activity in the hippocampus and medial prefrontal cortex. Replay occurrence strengthens functional connectivity between the hippocampus and the default mode network, a set of brain regions key to representing the cognitive map. On the other hand, when subjects are at rest following learning, memory reactivation of task-related items is stronger than that of pre-learning rest, and is also associated with heightened hippocampal activation and augmented hippocampal connectivity to the entorhinal cortex. Together, our findings highlight a distributed, brain-wide engagement associated with transient memory reactivation and its sequential replay.

Extended Poisson Gaussian-Process Latent Variable Model for Unsupervised Neural Decoding.

Dimension reduction on neural activity paves a way for unsupervised neural decoding by dissociating the measurement of internal neural pattern reactivation from the measurement of external variable tuning. With assumptions only on the smoothness of latent dynamics and of internal tuning curves, the Poisson gaussian-process latent variable model (P-GPLVM; Wu etal., 2017) is a powerful tool to discover the low-dimensional latent structure for high-dimensional spike trains. However, when given novel neural data, the original model lacks a method to infer their latent trajectories in the learned latent space, limiting its ability for estimating the neural reactivation. Here, we extend the P-GPLVM to enable the latent variable inference of new data constrained by previously learned smoothness and mapping information. We also describe a principled approach for the constrained latent variable inference for temporally compressed patterns of activity, such as those found in population burst events during hippocampal sharp-wave ripples, as well as metrics for assessing the validity of neural pattern reactivation and inferring the encoded experience. Applying these approaches to hippocampal ensemble recordings during active maze exploration, we replicate the result that P-GPLVM learns a latent space encoding the animal's position. We further demonstrate that this latent space can differentiate one maze context from another. By inferring the latent variables of new neural data during running, certain neural patterns are observed to reactivate, in accordance with the similarity of experiences encoded by its nearby neural trajectories in the training data manifold. Finally, reactivation of neural patterns can be estimated for neural activity during population burst events as well, allowing the identification for replay events of versatile behaviors and more general experiences. Thus, our extension of the P-GPLVM framework for unsupervised analysis of neural activity can be used to answer critical questions related to scientific discovery.

Disruption of awake sharp-wave ripples does not affect memorization of locations in repeated-acquisition spatial memory tasks.

Storing and accessing memories is required to successfully perform day-to-day tasks, for example for engaging in a meaningful conversation. Previous studies in both rodents and primates have correlated hippocampal cellular activity with behavioral expression of memory. A key role has been attributed to awake hippocampal replay - a sequential reactivation of neurons representing a trajectory through space. However, it is unclear if awake replay impacts immediate future behavior, gradually creates and stabilizes long-term memories over a long period of time (hours and longer), or enables the temporary memorization of relevant events at an intermediate time scale (seconds to minutes). In this study, we aimed to address the uncertainty around the timeframe of impact of awake replay by collecting causal evidence from behaving rats. We detected and disrupted sharp wave ripples (SWRs) - signatures of putative replay events - using electrical stimulation of the ventral hippocampal commissure in rats that were trained on three different spatial memory tasks. In each task, rats were required to memorize a new set of locations in each trial or each daily session. Interestingly, the rats performed equally well with or without SWR disruptions. These data suggest that awake SWRs - and potentially replay - does not affect the immediate behavior nor the temporary memorization of relevant events at a short timescale that are required to successfully perform the spatial tasks. Based on these results, we hypothesize that the impact of awake replay on memory and behavior is long-term and cumulative over time.

Neural and behavioural state switching during hippocampal dentate spikes

Distinct brain and behavioural states are associated with organized neural population dynamics that are thought to serve specific cognitive functions1–3. Memory replay events, for example, occur during synchronous population events called sharp-wave ripples in the hippocampus while mice are in an ‘offline’ behavioural state, enabling cognitive mechanisms such as memory consolidation and planning4–11. But how does the brain re-engage with the external world during this behavioural state and permit access to current sensory information or promote new memory formation? Here we found that the hippocampal dentate spike, an understudied population event that frequently occurs between sharp-wave ripples12, may underlie such a mechanism. We show that dentate spikes are associated with distinctly elevated brain-wide firing rates, primarily observed in higher order networks, and couple to brief periods of arousal. Hippocampal place coding during dentate spikes aligns to the mouse’s current spatial location, unlike the memory replay accompanying sharp-wave ripples. Furthermore, inhibiting neural activity during dentate spikes disrupts associative memory formation. Thus, dentate spikes represent a distinct brain state and support memory during non-locomotor behaviour, extending the repertoire of cognitive processes beyond the classical offline functions.

Hippocampal replay sequence governed by spontaneous brain-wide dynamics.

Neurons in the hippocampus exhibit spontaneous spiking activity during rest that appears to recapitulate previously experienced events. While this replay activity is frequently linked to memory consolidation and learning, the underlying mechanisms are not well understood. Recent large-scale neural recordings in mice have demonstrated that resting-state spontaneous activity is expressed as quasi-periodic cascades of spiking activity that pervade the forebrain, with each cascade engaging a high proportion of recorded neurons. Hippocampal ripples are known to be coordinated with cortical dynamics; however, less is known about the occurrence of replay activity relative to other brain-wide spontaneous events. Here we analyzed responses across the mouse brain to multiple viewings of natural movies, as well as subsequent patterns of neural activity during rest. We found that hippocampal neurons showed time-selectivity, with individual neurons responding consistently during particular moments of the movie. During rest, the population of time-selective hippocampal neurons showed both forward and time-reversed replay activity that matched the sequence observed in the movie. Importantly, these replay events were strongly time-locked to brain-wide spiking cascades, with forward and time-reversed replay activity associated with distinct cascade types. Thus, intrinsic hippocampal replay activity is temporally structured according to large-scale spontaneous physiology affecting areas throughout the forebrain. These findings shed light on the coordination between hippocampal and cortical circuits thought to be critical for memory consolidation.

The role of experience in prioritizing hippocampal replay

During sleep, recent memories are replayed by the hippocampus, leading to their consolidation, with a higher priority given to salient experiences. To examine the role of replay in the selective strengthening of memories, we recorded large ensembles of hippocampal place cells while male rats ran repeated spatial trajectories on two linear tracks, differing in either their familiarity or number of laps run. We observed that during sleep, the rate of replay events for a given track increased proportionally with the number of spatial trajectories run by the animal. In contrast, the rate of sleep replay events decreased if the animal was more familiar with the track. Furthermore, we find that the cumulative number of awake replay events occurring during behavior, influenced by both the novelty and duration of an experience, predicts which memories are prioritized for sleep replay, providing a more parsimonious neural correlate for the selective strengthening of memories.

Memory consolidation: Building influence over the entorhinal cortex

Memory consolidation involves interactions between the hippocampus and other cortical areas. A new study identifies neurons in the medial entorhinal cortex that over learning increase their coordination with hippocampal replay events, suggesting a route for consolidation of spatial memories.

Reduced coupling between offline neural replay events and default mode network activation in schizophrenia.

Schizophrenia is characterized by an abnormal resting state and default mode network brain activity. However, despite intense study, the mechanisms linking default mode network dynamics to neural computation remain elusive. During rest, sequential hippocampal reactivations, known as 'replay', are played out within default mode network activation windows, highlighting a potential role of replay-default mode network coupling in memory consolidation and model-based mental simulation. Here, we test a hypothesis of reduced replay-default mode network coupling in schizophrenia, using magnetoencephalography and a non-spatial sequence learning task designed to elicit off-task (i.e. resting state) neural replay. Participants with a diagnosis of schizophrenia (n = 28, mean age 28.2 years, range 20-40, 6 females, 13 not taking antipsychotic medication) and non-clinical control participants (n = 29, mean age 28.1 years, range 18-45, 6 females, matched at group level for age, intelligence quotient, gender, years in education and working memory) underwent a magnetoencephalography scan both during task completion and during a post-task resting state session. We used neural decoding to infer the time course of default mode network activation (time-delay embedding hidden Markov model) and spontaneous neural replay (temporally delayed linear modelling) in resting state magnetoencephalography data. Using multiple regression, we then quantified the extent to which default mode network activation was uniquely predicted by replay events that recapitulated the learned task sequences (i.e. 'task-relevant' replay-default mode network coupling). In control participants, replay-default mode network coupling was augmented following sequence learning, an augmentation that was specific for replay of task-relevant (i.e. learned) state transitions. This task-relevant replay-default mode network coupling effect was significantly reduced in schizophrenia (t(52) = 3.93, P = 0.018). Task-relevant replay-default mode network coupling predicted memory maintenance of learned sequences (ρ(52) = 0.31, P = 0.02). Importantly, reduced task-relevant replay-default mode network coupling in schizophrenia was not explained by differential replay or altered default mode network dynamics between groups nor by reference to antipsychotic exposure. Finally, task-relevant replay-default mode network coupling during rest correlated with stimulus-evoked default mode network modulation as measured in a separate task session. In the context of a proposed functional role of replay-default mode network coupling, our findings shed light on the functional significance of default mode network abnormalities in schizophrenia and provide for a consilience between task-based and resting state default mode network findings in this disorder.

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.

Automated Video Debriefing Using Computer Vision Techniques.

Within any training event, debriefing is a vital component that highlights areas of proficiency and deficiency, enables reflection, and ultimately provides opportunity for remediation. Video-based debriefing is desirable to capture performance and replay events, but the reality is rife with challenges, principally lengthy video and occlusions that block line of sight from camera equipment to participants. To address this issue, researchers automated the editing of a video debrief, using a system of person-worn cameras and computer vision techniques. The cameras record a simulation event, and the video is processed using computer vision. Researchers investigated a variety of computer vision techniques, ultimately focusing on the scale invariant feature transform detection method and a convolutional neural network. The system was trained to detect and tag medically relevant segments of video and assess a single exemplar medical intervention, in this case the application of a tourniquet. The system tagged medically relevant video segments with 92% recall and 66% precision, resulting in an F1 (harmonic mean of precision and recall) of 72% (N = 23). The exemplar medical intervention was successfully assessed in 39.5% of videos (N = 39). The system showed suitable accuracy tagging medically relevant video segments, but requires additional research to improve medical intervention assessment accuracy. Computer vision has the potential to automate video debrief creation to augment existing debriefing strategies.

Experience-driven rate modulation is reinstated during hippocampal replay.

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter - based on the fidelity of sequential activity across neighboring place fields. Here, we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.

Offline memory replay in recurrent neuronal networks emerges from constraints on online dynamics.

During spatial exploration, neural circuits in the hippocampus store memories of sequences of sensory events encountered in the environment. When sensory information is absent during 'offline' resting periods, brief neuronal population bursts can 'replay' sequences of activity that resemble bouts of sensory experience. These sequences can occur in either forward or reverse order, and can even include spatial trajectories that have not been experienced, but are consistent with the topology of the environment. The neural circuit mechanisms underlying this variable and flexible sequence generation are unknown. Here we demonstrate in a recurrent spiking network model of hippocampal area CA3 that experimental constraints on network dynamics such as population sparsity, stimulus selectivity, rhythmicity and spike rate adaptation, as well as associative synaptic connectivity, enable additional emergent properties, including variable offline memory replay. In an online stimulus-driven state, we observed the emergence of neuronal sequences that swept from representations of past to future stimuli on the timescale of the theta rhythm. In an offline state driven only by noise, the network generated both forward and reverse neuronal sequences, and recapitulated the experimental observation that offline memory replay events tend to include salient locations like the site of a reward. These results demonstrate that biological constraints on the dynamics of recurrent neural circuits are sufficient to enable memories of sensory events stored in the strengths of synaptic connections to be flexibly read out during rest and sleep, which is thought to be important for memory consolidation and planning of future behaviour. KEY POINTS: A recurrent spiking network model of hippocampal area CA3 was optimized to recapitulate experimentally observed network dynamics during simulated spatial exploration. During simulated offline rest, the network exhibited the emergent property of generating flexible forward, reverse and mixed direction memory replay events. Network perturbations and analysis of model diversity and degeneracy identified associative synaptic connectivity and key features of network dynamics as important for offline sequence generation. Network simulations demonstrate that population over-representation of salient positions like the site of reward results in biased memory replay.

Adaptive stimulus selection for consolidation in the hippocampus.

Associative memories guide behavioural adaptation by binding together outcome-predictive sensory stimuli1,2. However, in a feature-rich environment, only a subset of stimuli may predict a desired outcome3,4. How neural circuits enable behavioural adaptation by selectively and durably representing subsets of sensory stimuli that arepertinent to a specific outcome is not known. We investigated this feature selection process in the hippocampus during memory acquisition and subsequent consolidation. Two-photon calcium imaging of CA3 axonal projections to CA1 combined with simultaneous local field potential recordings revealed that CA3 projections that encode behaviourally informative sensory stimuli were selectively recruited during the memory replay events that underlie hippocampal memory consolidation5. These axonal projections formed sequential assemblies thatconjunctively link sensory features to spatial location and thus reward proximity. By contrast, axons encoding uninformative, peripatetic sensory cues were notably suppressed during memory replay. Thus, while the hippocampus comprehensively encodes the real-time sensory environment, it implements a flexible filtering mechanism to maximize the utility of memories destined for long-term storage. We propose thatutility-dependent recruitment of sensory experience during memory consolidation is a general coding principle for associative learning.

Ripple band phase precession of place cell firing during replay

SummaryNeuronal “replay,” in which place cell firing during rest recapitulates recently experienced trajectories, is thought to mediate the transmission of information from hippocampus to neocortex, but the mechanism for this transmission is unknown. Here, we show that replay uses a phase code to represent spatial trajectories by the phase of firing relative to the 150- to 250-Hz “ripple” oscillations that accompany replay events. This phase code is analogous to the theta phase precession of place cell firing during navigation, in which place cells fire at progressively earlier phases of the 6- to 12-Hz theta oscillation as their place field is traversed, providing information about self-location that is additional to the rate code and a necessary precursor of replay. Thus, during replay, each ripple cycle contains a “forward sweep” of decoded locations along the recapitulated trajectory. Our results indicate a novel encoding of trajectory information during replay and implicates phase coding as a general mechanism by which the hippocampus transmits experienced and replayed sequential information to downstream targets.

Hippocampal replay of experience at real-world speeds.

Representations related to past experiences play a critical role in memory and decision-making processes. The rat hippocampus expresses these types of representations during sharp-wave ripple (SWR) events, and previous work identified a minority of SWRs that contain 'replay' of spatial trajectories at ∼20x the movement speed of the animal. Efforts to understand replay typically make multiple assumptions about which events to examine and what sorts of representations constitute replay. We therefore lack a clear understanding of both the prevalence and the range of representational dynamics associated with replay. Here, we develop a state space model that uses a combination of movement dynamics of different speeds to capture the spatial content and time evolution of replay during SWRs. Using this model, we find that the large majority of replay events contain spatially coherent, interpretable content. Furthermore, many events progress at real-world, rather than accelerated, movement speeds, consistent with actual experiences.

The what and when of olfactory working memory in humans

Encoding and retaining novel sequences of sensory stimuli in working memory is crucial for adaptive behavior. A fundamental challenge for the central nervous system is to maintain each sequence item in an active and discriminable state, while also preserving their temporal context. Nested neural oscillations have been postulated to disambiguate the "what" and "when" of sequences, but the mechanisms by which these multiple streams of information are coordinated in the human brain remain unclear. Drawing from foundational animal studies, we recorded local field potentials from the human piriform cortex and hippocampus during a working memory task in which subjects experienced sequences of three distinct odors. Our data revealed a unique organization of odor memories across multiple timescales of the theta rhythm. During encoding, odors elicited greater gamma at distinct theta phases in both regions, time stamping their positions in the sequence, whereby the robustness of this effect was predictive of temporal order memory. During maintenance, stimulus-driven patterns of theta-coupled gamma were spontaneously reinstated in piriform cortex, recapitulating the order of the initial sequence. Replay events were time compressed across contiguous theta cycles, coinciding with periods of enhanced piriform-hippocampal theta-phase synchrony, and their prevalence forecasted subsequent recall accuracy on a trial-by-trial basis. Our data provide a novel link between endogenous replay orchestrated by the theta rhythm and short-term retention of sequential memories in the human brain.

System-Wide Replay in the Sensory Cortical-Hippocampal Hierarchy is Associated with Reward Anticipation

Replay of hippocampal place cell information has been associated with memory storage, retrieval and planning, but it remains unclear how it aligns with activity in the sensory and parahippocampal cortices. During a visuospatial discrimination task, neurons in the somatosensory and perirhinal cortex were significantly coordinated with awake hippocampal replay. Perirhinal coordination was particularly strong during CA1 replay events that were forward, local, and occurred near reward sites. Perirhinal activity was roughly aligned with the timing of hippocampal representations. Triple coordination of CA1, perirhinal and somatosensory cortex defined a system-wide replay, which was prominent during goal site approach and reiterated recent, local paths. The increased likelihood of system-wide replay during reward anticipation contrasted with CA1 replay events in general, which occurred throughout different phases of behavioral trials and were highly heterogeneous. Thus, recent sequences of sensory-spatial representations in anticipation of trial outcome are recapitulated by temporally aligned replay in the sensory cortical-to-hippocampal hierarchy.

Modeling awake hippocampal reactivations with model-based bidirectional search.

Hippocampal offline reactivations during reward-based learning, usually categorized as replay events, have been found to be important for performance improvement over time and for memory consolidation. Recent computational work has linked these phenomena to the need to transform reward information into state-action values for decision making and to propagate it to all relevant states of the environment. Nevertheless, it is still unclear whether an integrated reinforcement learning mechanism could account for the variety of awake hippocampal reactivations, including variety in order (forward and reverse reactivated trajectories) and variety in the location where they occur (reward site or decision-point). Here, we present a model-based bidirectional search model which accounts for a variety of hippocampal reactivations. The model combines forward trajectory sampling from current position and backward sampling through prioritized sweeping from states associated with large reward prediction errors until the two trajectories connect. This is repeated until stabilization of state-action values (convergence), which could explain why hippocampal reactivations drastically diminish when the animal's performance stabilizes. Simulations in a multiple T-maze task show that forward reactivations are prominently found at decision-points while backward reactivations are exclusively generated at reward sites. Finally, the model can generate imaginary trajectories that are not allowed to the agent during task performance. We raise some experimental predictions and implications for future studies of the role of the hippocampo-prefronto-striatal network in learning.

Posterior Hippocampal Spindle Ripples Co-occur with Neocortical Theta Bursts and Downstates-Upstates, and Phase-Lock with Parietal Spindles during NREM Sleep in Humans.

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave ripples (SWRs) similar to those which in rodents mark memory replay. We show that while pHC generates SWRs, it also generates approximately as many spindle ripples (SSR: ripples phase-locked to local spindles). In contrast, SSRs are rare in aHC. Like SWRs, SSRs often co-occur with neocortical theta bursts (TBs), downstates (DSs), sleep spindles (SSs), and upstates (USs), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWRs co-occur with these waves in widespread cortical areas, especially frontocentral. These waves typically occur in the sequence TB-DS-SS-US, with SWRs usually occurring before SS-US. In contrast, SSRs occur ∼350 ms later, with a strong preference for co-occurrence with posterior-parietal SSs. pHC-SSs were strongly phase-locked with parietal-SSs, and pHC-SSRs were phase-coupled with pHC-SSs and parietal-SSs. Human SWRs (and associated replay events, if any) are separated by ∼5 s on average, whereas ripples on successive SSR peaks are separated by only ∼80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex.SIGNIFICANCE STATEMENT Rodent hippocampal neurons replay waking events during sharpwave ripples (SWRs) in NREM sleep, facilitating memory transfer to a permanent cortical store. We show that human anterior hippocampus also produces SWRs, but spindle ripples predominate in posterior. Whereas SWRs typically occur as cortex emerges from inactivity, spindle ripples typically occur at peak cortical activity. Furthermore, posterior hippocampal spindle ripples are tightly coupled to posterior parietal locations activated by conscious recollection. Finally, multiple spindle ripples can recur within a second, whereas SWRs are separated by ∼5 s. The human posterior hippocampus is considered homologous to rodent dorsal hippocampus, which is thought to be specialized for consolidation of specific memory details. We speculate that these distinct physiological characteristics of posterior hippocampal spindle ripples may support a related function in humans.