Shantanu Jadhav

Multiple brain regions need to coordinate activity to support cognitive flexibility and behavioral adaptation. Neural activity in both the hippocampus (HPC) and medial prefrontal cortex (mPFC) is known to represent spatial context and is sensitive to reward and rule alterations. Midbrain dopamine (DA) activity is key in reward seeking behavior and learning. There is abundant evidence that midbrain DA modulates HPC and PFC activity. However, it remains underexplored how these networks engage dynamically and coordinate temporally when animals must adjust their behavior according to changing reward contingencies. In particular, is there any relationship between DA reward prediction change during rule switching, and rule representation changes in mPFC and CA1? We addressed these questions using simultaneous recording of neuronal population activity from the hippocampal area CA1, mPFC and ventral tegmental area (VTA) in male TH-Cre rats performing two spatial working memory tasks with frequent rule switches in blocks of trials. CA1 and mPFC ensembles showed rule-specific activity both during maze running and at reward locations, with mPFC rule coding more consistent across animals compared to CA1. Optogenetically tagged VTA DA neuron firing activity responded to and predicted reward outcome. We found that the correct prediction in DA emerged gradually over trials after rule-switching in coordination with transitions in mPFC and CA1 ensemble representations of the current rule after a rule switch, followed by behavioral adaptation to the correct rule sequence. Therefore, our study demonstrates a crucial temporal coordination between the rule representation in mPFC/CA1, the dopamine reward signal and behavioral strategy. This study examines neural activity in mammalian brain networks that support the ability to respond flexibly to changing contexts. We use a rule-switching spatial task to examine whether the key reward-responsive and predictive dopamine (DA) activity changes in coordination with changes in rule representations in key cognitive regions, the medial prefrontal cortex (mPFC) and hippocampus. We first established distinct rule representations in mPFC and hippocampus, and predictive coding of reward outcomes by DA neuronal activity. We show that the rule-specific DA reward prediction after a rule switch develops in temporal coordination with changes in rule representations in mPFC, eventually leading to behavioral changes. These results thus provide an integrated understanding of reward prediction, cognitive representations of rules and behavioral adaptation.

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.

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.

Memory-guided decision making involves long-range coordination across sensory and cognitive brain networks, with key roles for the hippocampus and prefrontal cortex (PFC). In order to investigate the mechanisms of such coordination, we monitored activity in hippocampus (CA1), PFC, and olfactory bulb (OB) in rats performing an odor-place associative memory guided decision task on a T-maze. During odor sampling, the beta (20-30 Hz) and respiratory (7-8 Hz) rhythms (RR) were prominent across the three regions, with beta and RR coherence between all pairs of regions enhanced during the odor-cued decision making period. Beta phase modulation of phase-locked CA1 and PFC neurons during this period was linked to accurate decisions, with a key role of CA1 interneurons in temporal coordination. Single neurons and ensembles in both CA1 and PFC encoded and predicted animals' upcoming choices, with different cell ensembles engaged during decision-making and decision execution on the maze. Our findings indicate that rhythmic coordination within the hippocampal-prefrontal-olfactory bulb network supports utilization of odor cues for memory-guided decision making.

When navigating through space, we must maintain a representation of our position in real time; when recalling a past episode, a memory can come back in a flash. Interestingly, the brain's spatial representation system, including the hippocampus, supports these two distinct timescale functions. How are neural representations of space used in the service of both real-world navigation and internal mnemonic processes? Recent progress has identified sequences of hippocampal place cells, evolving at multiple timescales in accordance with either navigational behaviors or internal oscillations, that underlie these functions. We review experimental findings on experience-dependent modulation of these sequential representations and consider how they link real-world navigation to time-compressed memories. We further discuss recent work suggesting the prevalence of these sequences beyond hippocampus and propose that these multiple-timescale mechanisms may represent a general algorithm for organizing cell assemblies, potentially unifying the dual roles of the spatial representation system in memory and navigation. Expected final online publication date for the
, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.
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•Continuous hippocampal-prefrontal (CA1-PFC) replay tracking during spatial learning•Reverse replay for retrospective evaluation, forward replay for prospective planning•Opposing learning gradients for CA1 reverse- and forward-replay prediction of paths•CA1-PFC replay supports past recall and future decisions for spatial working memory
Shin, Tang, and Jadhav use continuous activity tracking to show that awake CA1 reverse- and forward-replay events predict past and future choices, respectively, with opposing spatial learning gradients. CA1-PFC replay supports recall and planning for spatial working memory tasks.

Abstract An animal’s survival depends on finding food, and the memory of food and contexts are often linked. Given that the hippocampus is required for spatial and contextual memory, it is reasonable to expect related coding of space and food stimuli in hippocampal neurons. However, relatively little is known about how the hippocampus responds to tastes, the most central sensory property of food. In this study, we examined the taste-evoked responses and spatial firing properties of single units in the dorsal CA1 hippocampal region as male rats received a battery of taste stimuli differing in both chemical composition and palatability within a specific spatial context. We identified a subset of hippocampal neurons that responded to tastes, some of which were place cells. These taste and place responses had a distinct interaction: taste-responsive cells tended to have less spatially specific firing fields, and place cells only responded to tastes delivered inside their place field. Like neurons in the amygdala and lateral hypothalamus, hippocampal neurons discriminated between tastes predominantly on the basis of palatability, with taste-selectivity emerging concurrently with palatability-relatedness; these responses did not reflect movement or arousal. However, hippocampal taste responses emerged several hundred msec later than responses in other parts of the taste system, suggesting that the hippocampus does not influence real-time taste decisions, instead associating the hedonic value of tastes with a particular context. This incorporation of taste responses into existing hippocampal maps could be one way that animals use past experience to locate food sources. Significance statement Finding food is essential for animals’ survival, and taste and context memory are often linked. While hippocampal responses to space and contexts have been well characterized, little is known about how the hippocampus responds to tastes. Here, we identified a subset of hippocampal neurons that discriminated between tastes based on palatability. Cells with stronger taste responses typically had weaker spatial responses, and taste responses were confined to place cells’ firing fields. Hippocampal taste responses emerged later than in other parts of the taste system, suggesting that the hippocampus does not influence taste decisions, but rather, associates the hedonic value of tastes consumed within a particular context. This could be one way that animals use past experience to locate food sources.

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.
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.

Interactions between the hippocampus and prefrontal cortex (PFC) are critical for learning and memory. Hippocampal activity during awake sharp-wave ripple (SWR) events is important for spatial learning, and hippocampal SWR activity often represents past or potential future experiences. Whether or how this reactivation engages the PFC, and how reactivation might interact with ongoing patterns of PFC activity, remains unclear. We recorded hippocampal CA1 and PFC activity in animals learning spatial tasks and found that many PFC cells showed spiking modulation during SWRs. Unlike in CA1, SWR-related activity in PFC comprised both excitation and inhibition of distinct populations. Within individual SWRs, excitation activated PFC cells with representations related to the concurrently reactivated hippocampal representation, while inhibition suppressed PFC cells with unrelated representations. Thus, awake SWRs mark times of strong coordination between hippocampus and PFC that reflects structured reactivation of representations related to ongoing experience.
•Prefrontal cortical neurons reactivate during awake hippocampal sharp-wave ripples•Distinct prefrontal ensembles exhibit excitation or inhibition during reactivation•Reactivation is coordinated across hippocampal and prefrontal populations•Coordinated hippocampal-prefrontal reactivation may support event memory retrieval
Jadhav, Rothschild et al. show coordinated reactivation of representations related to behavioral experience in the hippocampus and prefrontal cortex during awake sharp-wave ripple events. This coordinated reactivation is well suited to support awake memory processes.