Lab Discoveries

Recent Discoveries

Here we highlight some of our discoveries and our perspective on why these discoveries are important.

Findings from our laboratory have also been discussed in the press. In addition, videos of talks and interviews are available. Press coverage and Videos

Awake replay of past experiences

One prominent theory of memory formation posits that there are two stages of memory formation.  First, synaptic plasticity in the hippocampus would support memory storage during an experience. Subsequently, reactivation of hippocampal memory traces during sleep would promote synaptic plasticity in distributed hippocampal-neocortical networks, leading to more permanent storage of the memory.  The presence of hippocampal replay during sleep is well established, but given that we do not sleep after every experience and that the strength of this replay decays with time since the experience, it is not clear how this scheme could allow us to remember experience throughout the day.  In Karlsson and Frank (2009) we asked whether we could see replay of past experiences while the animals was awake.  We found that that the hippocampus continually reactivates recently experienced memories, even when the animal is located outside of the place where the memory was formed.  This reactivation was stronger during awake behavior than during sleep-like states, suggesting that waking replay could be particularly important for memory retrieval and the long-term storage of memories in distributed neocortical networks.


Reward enhances replay of recent experience

We do not remember all our experiences.  Instead, the most exciting or emotional memories stick with us while the more mundane seem to fade over time.   In addition, we are able to recall the emotional context of these memories, implying that we can somehow bind specific experiences to their outcomes. While these phenomena are well established, the mechanisms that link experiences to their outcomes and promote long term storage are not well understood.  In Singer and Frank (2009) we investigated the relationship between memory reactivation and reward.  We found that, as compared to not receiving a reward, receiving a reward after traversing a path lead to an eight-fold increase in the likelihood that cells would be reactivated.  Thus, receiving a reward lead to strong reactivation of the hippocampal representation of paths associated with the rewarded location.  By reactivating these paths after the outcome of traversing the path was known, reward-driven reactivation is ideally suited to allow the animal to learn the association between a set of actions and their consequence.  Furthermore, the greater strength of reactivation following reward may help explain why salient or emotionally relevant events are well remembered. 


Awake SWRs are important for memory-guided decision making

Animals use past experience to guide decisions, an ability that requires storing memories for the events of daily life and retrieving those memories as needed. This storage and retrieval depends on the hippocampus and associated structures in the medial temporal lobe, but the specific patterns of neural activity that support these memory functions remain poorly understood.  We know that, during exploration, individual neurons fire in specific regions of space known as place fields.  In contrast, during periods of slow movement, immobility and slow-wave sleep, groups of neurons are active during sharp-wave ripple (SWR) events.   This activity frequently represents a rapid timescale replay of a past experience.  Awake SWRs in particular can reactivate sets of place fields encoding forward and reverse paths associated with both current and past locations.  This reactivation has been hypothesized to contribute to multiple functions including learning, retrieval, consolidation and trajectory planning, but its specific role in learning remained unclear. In Jadhav et al. (2012) we selectively disrupted awake SWRs in rats learning in our W-track task.  We observed a specific learning and performance deficit that persisted throughout training.  This deficit was associated with awake SWR activity as SWR interruption left place field activity and post-experience SWR reactivation intact.  These results provide a link between awake SWRs and hippocampal memory processes, and suggest that awake replay of memory-related information during SWRs supports learning and memory-guided decision making.  More broadly, we hypothesize that the memory replay events seen during behavior propagate out to many other brain regions and engage circuits involved with outcome evaluation, planning and decision-making.  We are currently exploring how replay events contribute to those processes.

A hippocampal network for spatial location during immobility and sleep.

Previous studies of hippocampal place representations have focused largely on the spatially specific activity seen when animals are moving from place to place.  Normal behavior involves both movement as well as periods of immobility, leading us to ask the question “how does an animal know where it is when it stops moving?” In Kay et. al. (2016) We examined patterns of neural activity across multiple hippocampal subregions and identified a population of cells in area CA2 that preferentially encoded current location during periods of immobility.  Interestingly, these cells, unlike all other previously identified principle cells in the hippocampus, are inhibited during the sharp-wave ripple events where we see memory replay.  As a result, these cells come on as animals slow down and approach a stopping point.  Their activity then continues, but is transiently interrupted by SWRs, indicating that the representation of current location is suppressed during memory replay events.  We also saw this same sort of suppression in the prefrontal cortex (see below). 

We also identified a low frequency (~1-4 Hz) local field potential event that is associated with the activity of these CA2 cells, and using that event as a probe, we found a set of cells in other hippocampal subregions that also maintain a representation of current location during immobility.  Further, these representations of current location resurfaced during sleep, specifically in a sleep phase known as SIA.  These findings indicate that the hippocampal place code is maintained across states, and suggest that there are rapid alternations between representations of current experiences and replay related to past experiences.


Coordinated hippocampal-prefrontal reactivation during awake sharp-wave ripple events. 

If, as we have hypothesized, awake SWRs could support memory processes like retrieval or consolidation, they should engage a broad network of areas that are involved in representing different aspects of a memory.  In Jadhav, Rothschild et. al. (2016) we asked whether that was the case by carrying out dual site recordings from hippocampus and medial prefrontal cortex (mPFC) in animals learning spatial tasks. We found that a surprisingly large proportion of mPFC cells showed spiking modulation during SWRs (~35%). Unlike in hippocampal area CA1, however, 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. These findings demonstrate that awake SWRs mark times of strong coordination between hippocampus and PFC that reflects structured reactivation of representations related to ongoing experience.  More broadly, the patterns of excitation and inhibition in the mPFC during SWRs suggested that upon the initiation of an SWR, the representation in PFC related to the current state can be suppressed and replaced with a representation of recent active behavior consistent with the representation reactivated in the hippocampus.  In conjunction with our observation described above that a similar pattern of suppression is seen in CA2 cells, we hypothesize that this could be important maintaining the separation between current experience and retrieved memories.


A cortical-hippocampal-cortical loop of information flow during sleep sharp-wave ripple events.    

Hippocampal replay during sharp-wave ripple events (SWRs) is thought to drive memory consolidation in hippocampal and cortical circuits. This is most often discussed as a process whereby the hippocampus replays memories to drive neocortical activity patterns that would reinforce a distributed memory representation.  Here we asked whether that description is accurate.  Specifically, previous work had shown that changes in neocortical activity can precede SWR events, but whether and how these changes influence the content of replay was not clear. In Rothschild et. al. (2017) we showed that during sleep there is actually a rapid cortical–hippocampal–cortical loop of information flow around the times of SWRs. We recorded neural activity in auditory cortex (AC) and hippocampus of rats as they learned a sound-guided task and during sleep. We found that patterned activation in AC precedes and predicts the subsequent content of hippocampal activity during SWRs, while hippocampal patterns during SWRs predict subsequent AC activity. Delivering sounds during sleep biased AC activity patterns, and sound-biased AC patterns predicted subsequent hippocampal activity. These findings provide a potential mechanism to explain observations from other laboratories that stimuli presented during sleep can enhance subsequent task performance.  These results also suggest that activation of specific cortical representations during sleep influences the identity of the memories that are consolidated into long-term stores.  We hypothesize that coordinated reactivation across sensory cortical regions immediately preceding SWRs facilitates a flow of reactivated sensory information into the hippocampus. This incoming information biases hippocampal reactivation, which then broadcasts an integrated representation back to the reactivated cortical networks, linking the patterns of activity across multiple cortical areas to consolidate a coherent memory representation.




Press Coverage and Videos

Nature podcast on awake replay

New York Times article on downtime

Interview with Roger Bingham of The Science Network

Interview with Carry the One Radio

Discussion on science and religion at the San Jose Tech Museum

NIMH Press release on awake SWR interruption