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.

Intrinsic dynamics of randomly clustered networks generate place fields and preplay of novel environments.

During both sleep and awake immobility, hippocampal place cells reactivate time-compressed versions of sequences representing recently experienced trajectories in a phenomenon known as replay. Intriguingly, spontaneous sequences can also correspond to forthcoming trajectories in novel environments experienced later, in a phenomenon known as preplay. Here, we present a model showing that sequences of spikes correlated with the place fields underlying spatial trajectories in both previously experienced and future novel environments can arise spontaneously in neural circuits with random, clustered connectivity rather than pre-configured spatial maps. Moreover, the realistic place fields themselves arise in the circuit from minimal, landmark-based inputs. We find that preplay quality depends on the network's balance of cluster isolation and overlap, with optimal preplay occurring in small-world regimes of high clustering yet short path lengths. We validate the results of our model by applying the same place field and preplay analyses to previously published rat hippocampal place cell data. Our results show that clustered recurrent connectivity can generate spontaneous preplay and immediate replay of novel environments. These findings support a framework whereby novel sensory experiences become associated with preexisting "pluripotent" internal neural activity patterns.

Protocol for geometric transformation of cognitive maps for generalization across hippocampal-prefrontal circuits.

Memory generalization is the ability to abstract knowledge from prior experiences and is critical for flexible behavior in novel situations. Here, we describe a protocol for simultaneous recording of hippocampal (area CA1)-prefrontal cortical neural ensembles in Long-Evans rats during task generalization across two distinct environments. We describe steps for building and assembling experimental apparatuses, animal preparation and surgery, and performing experiments. We then detail procedures for histology, data processing, and assessing population geometry using Uniform Manifold Approximation and Projection. For complete details on the use and execution of this protocol, please refer to Tang et al. (2023).1.

Geometric transformation of cognitive maps for generalization across hippocampal-prefrontal circuits.

The ability to abstract information to guide decisions during navigation across changing environments is essential for adaptation and requires the integrity of the hippocampal-prefrontal circuitry. The hippocampus encodes navigational information in a cognitive map, but it remains unclear how cognitive maps are transformed across hippocampal-prefrontal circuits to support abstraction and generalization. Here, we simultaneously record hippocampal-prefrontal ensembles as rats generalize navigational rules across distinct environments. We find that, whereas hippocampal representational maps maintain specificity of separate environments, prefrontal maps generalize across environments. Furthermore, while both maps are structured within a neural manifold of population activity, they have distinct representational geometries. Prefrontal geometry enables abstraction of rule-informative variables, a representational format that generalizes to novel conditions of existing variable classes. Hippocampal geometry lacks such abstraction. Together, these findings elucidate how cognitive maps are structured into distinct geometric representations to support abstraction and generalization while maintaining memory specificity.

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 oscillations during non-REM sleep. However, the contribution of high-frequency cortical ripples to consolidation is still unclear. We used continuous recordings in the hippocampus and prefrontal cortex (PFC) over the course of spatial learning and show that independent PFC ripples, when dissociated from SWRs, predominantly suppress hippocampal activity in non-REM sleep. PFC ripples paradoxically mediate top-down suppression of hippocampal reactivation, which is inversely related to reactivation strength during coordinated CA1-PFC ripples. Further, we show non-canonical, serial coordination of ripples with cortical slow and spindle oscillations. These results establish a role for cortical ripples in regulating consolidation.

Multiple time-scales of decision-making in the hippocampus and prefrontal cortex.

The prefrontal cortex and hippocampus are crucial for memory-guided decision-making. Neural activity in the hippocampus exhibits place-cell sequences at multiple timescales, including slow behavioral sequences (~seconds) and fast theta sequences (~100-200 ms) within theta oscillation cycles. How prefrontal ensembles interact with hippocampal sequences to support decision-making is unclear. Here, we examined simultaneous hippocampal and prefrontal ensemble activity in rats during learning of a spatial working-memory decision task. We found clear theta sequences in prefrontal cortex, nested within its behavioral sequences. In both regions, behavioral sequences maintained representations of current choices during navigation. In contrast, hippocampal theta sequences encoded alternatives for deliberation and were coordinated with prefrontal theta sequences that predicted upcoming choices. During error trials, these representations were preserved to guide ongoing behavior, whereas replay sequences during inter-trial periods were impaired prior to navigation. These results establish cooperative interaction between hippocampal and prefrontal sequences at multiple timescales for memory-guided decision-making.

Dynamics of Awake Hippocampal-Prefrontal Replay for Spatial Learning and Memory-Guided Decision Making.

Spatial learning requires remembering and choosing paths to goals. Hippocampal place cells replay spatial paths during immobility in reverse and forward order, offering a potential mechanism. However, how replay supports both goal-directed learning and memory-guided decision making is unclear. We therefore continuously tracked awake replay in the same hippocampal-prefrontal ensembles throughout learning of a spatial alternation task. We found that, during pauses between behavioral trajectories, reverse and forward hippocampal replay supports an internal cognitive search of available past and future possibilities and exhibits opposing learning gradients for prediction of past and future behavioral paths, respectively. Coordinated hippocampal-prefrontal replay distinguished correct past and future paths from alternative choices, suggesting a role in recall of past paths to guide planning of future decisions for spatial working memory. Our findings reveal a learning shift from hippocampal reverse-replay-based retrospective evaluation to forward-replay-based prospective planning, with prefrontal readout of memory-guided paths for learning and decision making.

Coherent Coding of Spatial Position Mediated by Theta Oscillations in the Hippocampus and Prefrontal Cortex.

Interactions between the hippocampus (area CA1) and prefrontal cortex (PFC) are crucial for memory-guided behavior. Theta oscillations (∼8 Hz) underlie a key physiological mechanism for mediating these coordinated interactions, and theta oscillatory coherence and phase-locked spiking in the two regions have been shown to be important for spatial memory. Hippocampal place-cell activity associated with theta oscillations encodes spatial position during behavior, and theta phase-associated spiking is known to further mediate a temporal code for space within CA1 place fields. Although prefrontal neurons are prominently phase-locked to hippocampal theta oscillations in spatial memory tasks, whether and how theta oscillations mediate processing of spatial information across these networks remains unclear. Here, we addressed these questions using simultaneous recordings of dorsal CA1-PFC ensembles and population decoding analyses in male rats performing a continuous spatial working memory task known to require hippocampal-prefrontal interactions. We found that in addition to CA1, population activity in PFC can also encode the animal's current spatial position on a theta-cycle timescale during memory-guided behavior. Coding of spatial position was coherent for CA1 and PFC ensembles, exhibiting correlated position representations within theta cycles. In addition, incorporating theta-phase information during decoding to account for theta-phase associated spiking resulted in a significant improvement in the accuracy of prefrontal spatial representations, similar to concurrent CA1 representations. These findings indicate a theta-oscillation-mediated mechanism of temporal coordination for shared processing and communication of spatial information across the two networks during spatial memory-guided behavior.SIGNIFICANCE STATEMENT Theta oscillation- (∼8 Hz) mediated interactions between the hippocampus and prefrontal cortex are known to be important for spatial memory. Hippocampal place-cell activity associated with theta oscillations underlies a rate and temporal code for spatial position, but it is not known whether these oscillations mediate simultaneous coding of spatial information in hippocampal-prefrontal networks. Here, we found that population activity in prefrontal cortex encodes animals' current position coherently with hippocampal populations on a theta-cycle timescale. Further we found that theta phase-associated spiking significantly improves prefrontal coding of spatial position, in parallel with hippocampal coding. Our findings establish that theta oscillations mediate a temporal coordination mechanism for coherent coding of spatial position in hippocampal-prefrontal networks during memory-guided behavior.

Hippocampal-Prefrontal Reactivation during Learning Is Stronger in Awake Compared with Sleep States.

Hippocampal sharp-wave ripple (SWR) events occur during both behavior (awake SWRs) and slow-wave sleep (sleep SWRs). Awake and sleep SWRs both contribute to spatial learning and memory, thought to be mediated by the coordinated reactivation of behavioral experiences in hippocampal-cortical circuits seen during SWRs. Current hypotheses suggest that reactivation contributes to memory consolidation processes, but whether awake and sleep reactivation are suited to play similar or different roles remains unclear. Here we addressed that issue by examining the structure of hippocampal (area CA1) and prefrontal (PFC) activity recorded across behavior and sleep stages in male rats learning a spatial alternation task. We found a striking state difference: prefrontal modulation during awake and sleep SWRs was surprisingly distinct, with differing patterns of excitation and inhibition. CA1-PFC synchronization was stronger during awake SWRs, and spatial reactivation, measured using both pairwise and ensemble measures, was more structured for awake SWRs compared with post-task sleep SWRs. Stronger awake reactivation was observed despite the absence of coordination between network oscillations, namely hippocampal SWRs and cortical delta and spindle oscillations, which is prevalent during sleep. Finally, awake CA1-PFC reactivation was enhanced most prominently during initial learning in a novel environment, suggesting a key role in early learning. Our results demonstrate significant differences in awake and sleep reactivation in the hippocampal-prefrontal network. These findings suggest that awake SWRs support accurate memory storage and memory-guided behavior, whereas sleep SWR reactivation is better suited to support integration of memories across experiences during consolidation.SIGNIFICANCE STATEMENT Hippocampal sharp-wave ripples (SWRs) occur both in the awake state during behavior and in the sleep state after behavior. Awake and sleep SWRs are associated with memory reactivation and are important for learning, but their specific memory functions remain unclear. Here, we found profound differences in hippocampal-cortical reactivation during awake and sleep SWRs, with key implications for their roles in memory. Awake reactivation is a higher-fidelity representation of behavioral experiences, and is enhanced during early learning, without requiring coordination of network oscillations that is seen during sleep. Our findings suggest that awake reactivation is ideally suited to support initial memory formation, retrieval and planning, whereas sleep reactivation may play a broader role in integrating memories across experiences during consolidation.

Multiple modes of hippocampal-prefrontal interactions in memory-guided behavior.

The hippocampus and prefrontal cortex are crucial for learning and memory-guided behavior, but neural mechanisms underlying their coordinated operation are currently unclear. Recent evidence indicates that different network activity patterns, each marked by local field potential signatures, play distinct roles in mediating long-range interactions between these regions to support memory processing. We propose that network patterns underlie multiple communication modes between these regions, and support different cognitive demands during ongoing behavior. Network patterns may represent a fundamental neurophysiological mechanism through which the hippocampus communicates memory-related information with other regions. Dissecting the causal roles of these network patterns in cognitive processes has the potential to delineate a coherent and dynamic functional organization across hippocampal and prefrontal networks during memory-guided behavior.