THE Frank

Laboratory at UCSF

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Recent Discoveries

Here we highlight some of our recent 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

Coordinated activity during learning

Although the hippocampus is known to be essential for spatial learning, little is known about the specific neural mechanisms that allow this circuit to store new information.  In Cheng and Frank (2008) we examined the firing of CA1 place cells in animals exploring an environment with both new and familiar arms.  We found that cells representing new places were strongly coactive during learning, and that this coactivity was found not within the cells' place fields but instead during brief high frequency network events that appear to be identical to the sharp-wave ripples seen most commonly during slow wave sleep and awake immobility.   These coordinated events occurred throughout the new and the familiar arms, indicating that new experiences leave a strong, lasting trace that is reactivated during and after new experiences.  Further, the structure of these coordinated events is well suited to induce plasticity in both local and downstream structures, potentially supporting the storage and consolidation of new memories.

Hippocampal responses to novelty

One important but often overlooked element of learning is the ability to distinguish between new experiences where a new memory needs to be stored and familiar experiences where a previously stored memory should be retrieved. Theorists  had speculated that hippocampus might be important for these processes, but its role in novelty detection and signalling was unclear.  In Karlsson and Frank (2008) we examined reponses to new places in hippocampal areas CA3 and CA1 as animals learned a spatial alternation task.  We found that CA1, but not upstream area CA3, doubles its total spiking output in new places.  Thus, CA1 may be specialized to signal the presence of new information with a large increase in spiking.  Furthermore, we found that this initial high rate activity and it's subsequent decay is associated with a region specific plasticity mechanism.  Plasticity in hippocampal area CA1 is governed by a simple dynamical rule where the activity of neurons with strong spatial signaling is enhanced and the activity of neurons with weak spatial signaling is suppressed.  This creates a sparse, highly informative set of CA1 cells that persist as part of a long term representation.  The long time scale of these changes suggests that they may also be involved in "registering" the hippocampal and cortical representations so that a pattern of activity in the hippocampus can generate the associated pattern in the cortex during consolidation and retrieval.

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 of 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.
 

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