The offline brain: understanding memory consolidation and reconsolidation

09:00-09:05 Welcome by Royal Society

09:05-09:25 Same or seperate? Functions and mechanisms of memory replay during sleep and wake

Dr Susanne Diekelman, University of Tubingen, Germany

Abstract

Sleep strengthens and stabilizes newly acquired memories in an active process of system consolidation. This process is assumed to rely on covert reactivations of new memories that occur spontaneously after learning, mainly during slow-wave sleep (SWS), but can also be externally triggered by learning-associated memory cues. In a series of experiments, we show that the application of learning-associated odor cues during sleep resulted in an immediate stabilization of new memories, whereas similar odor reactivations in the wake state induced memory labilization. Functional magnetic resonance imaging revealed different activation patterns following reminder presentation during sleep and wakefulness. Moreover, different types of reminders (complete/incomplete) exerted different effects on memory during sleep and wakefulness. While in the wake state, only incomplete reminders but not complete reminders labilized the memory traces, both the incomplete reminder and the complete reminder stabilized memories during sleep. This evidence collectively suggests that reactivation has different effects on memory during wakefulness and sleep, presumably serving different functions for the dynamic long-term storage of memory.

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09:25-09:45 Sleep structure and replay across species

Professor Daniel Margoliash, University of Chicago, USA

Abstract

The majority of sleep behavioural research is conducted in humans, results which are complemented by extensive animal experiments in rodents. Here we present neural and behavioural evidence for a role of sleep in sensorimotor vocal learning in juvenile and adult songbirds, and for perceptual learning in adult songbirds (the latter mostly behavioural work). We show deep similarities of the behavioural results in songbirds and humans, highlight similarities and differences between the songbird and rodent results, and discuss the implications of these similarities and differences. We show preliminary evidence that within Aves, the complex pattern of sleep observed in songbirds extends at least to parrots. Knowing the extent to which the behavioural and neurophysiological results apply broadly, beyond mammals and perhaps far across the animal kingdom, can open opportunities for developing new advantageous model systems to gain deeper insights into the neurobiology of sleep. Our results, in complement with recent data from reptiles and other poikilotherms and invertebrates, suggest the possibility of a broad diversity of species that exhibit sleep dependent processing. This places constraints on neuronal network models to explain these behaviours.

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09:45-10:05 Sleep replay and memory consolidation in the hippocampus and amygdala

Dr Gabrielle Girardeau, NYU Langone Medical Center, USA

Abstract

The hippocampus and the amygdala are two structures required for emotional memory. The hippocampus, through place cells, is believed to encode the spatial or contextual part of the memory. During slow-wave sleep, the activity of place cells is replayed in the same order as during the preceding learning epoch. These reactivations specifically occur during local field potential (LFP) short oscillatory events associated with highly synchronous neuronal activity called “ripples”. The group have shown previously that the specific suppression of ripples during sleep impairs performance on a spatial task, underlying their crucial role in memory consolidation. On the other hand, the amygdala processes the emotional valence of an event. Disrupting activity in the basolateral amygdala (BLA) immediately after training impairs performance on emotional tasks like contextual fear conditioning. However, how the amygdala and the hippocampus interact to consolidate an emotional event is yet unknown. To study that, the group designed a new task where the rats learn the location of an aversive stimulus. Using large scale simultaneous neuronal ensemble recordings in the hippocampus and BLA, we found coordinated reactivations between the two structures during sleep following training. Moreover, these reactivations specifically involve a small subset of BLA neurons that are modulated during hippocampal ripples and this modulation increases during sleep ripples following training. Hippocampal ripples during sleep thus emerge as a crucial time windows for intra-hippocampus and cross-structure reactivations sustaining the consolidation of spatial and emotional memories.

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10:05-10:25 Mismatch, labilization and reinforcement during memory reactivation

Dr Olavo Amaral, Federal University of Rio de Janeiro, Brazil

Abstract

Due to their opposite behavioural outcomes, memory reconsolidation and extinction have usually been considered as separate entities, despite being induced by similar reactivation protocols. Based on modelling and pharmacological data, the group will argue that the two processes nevertheless seem to involve similar sets of plasticity mechanisms. One of these sets seems to be pharmacologically similar to the one involved in initial consolidation and Hebbian plasticity, while the second appears to be more involved with the labilization of existing memories and synaptic changes. Moreover, memory labilization mechanisms resemble those involved in forms of homeostatic plasticity, such as synaptic scaling. With this in mind, the group will discuss whether memory destabilization during reactivation might be a consequence of homeostatic-like plasticity induction, and why mismatch between learning and re-exposure could lead this to happen. On this basis, the group will argue that the field of memory updating might benefit from a paradigm shift in which reconsolidation and extinction, as well as online and offline reactivation, are viewed not as fully distinct processes but as different instantiations of common plasticity systems.

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10:25-10:45 Coffee Break

10:45-11:30 Discussion Session

Professor Loren Frank, HHMI and University of California, USA

11:30-12:30 Hippocampal neurogenesis and forgetting

Professor Paul Frankland, Program in Neuroscience and Mental Health, Hospital for Sick children, Toronto, Canada

Abstract

Neurogenesis persists throughout life in the hippocampus, and there is a lot of interest in how the continuous addition of new neurons impacts hippocampal memory function. Behavioural studies have shown that artificially elevating hippocampal neurogenesis often facilitates new memory formation. However, since the integration of new neurons remodels existing hippocampal circuits, it has been hypothesized that hippocampal neurogenesis may also promote the degradation (or forgetting) of memories already stored in those circuits. Consistent with this idea, we have recently discovered that elevating rates of hippocampal neurogenesis after memory formation leads to forgetting. This finding changes the way we think about how hippocampal neurogenesis contributes to memory function, suggesting that it regulates a balance between encoding new memories and clearing out old memories.

12:30-13:30 Lunch

13:30-13:50 Transition from retrieval, to reconsolidation, to extinction

Professor Merel Kindt, University of Amsterdam, The Netherlands

Abstract

For years it was believed that after fear memory has been established, the memory trace is engraved into the physical structure of the brain. But the burgeoning field of neuroscience has convincingly overturned this view by demonstrating that once (fear) memories are retrieved, they may enter a labile, protein synthesis dependent state, rendering it amenable to change. This process of memory reconsolidation may provide a window of opportunity to target emotional memory in patients suffering from anxiety disorders and other related disorders. In this talk a series of experimental studies in humans will be presented demonstrating that disrupting the process of memory reconsolidation by a noradrenergic β-blocker weakens or even eliminates the expression of fear memory. Although the process of memory reconsolidation has the potential to actually neutralize excessive fear memory, we cannot observe the molecular and cellular processes in the human brain underlying either the presence or absence of memory expression. The group can only infer the underlying neurobiological processes from the behavioural, cognitive, physiological or neural read-outs of fear memory. Because there is no one-to-one relationship between these memory expressions and the underlying neurobiological processes, erasure of memory traces cannot be proven. However, by critically testing hypotheses that follow from the reconsolidation conjecture, we may gradually unveil the conditions that govern the transition from simply retrieval, to reconsolidation, to extinction learning.

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13:50-14:10 Destabilization and restabilization of spatial memory

Dr Janine I. Rossato, Federal University of Rio Grande do Norte, Brazil

Abstract

Spatial learning requires hippocampal NMDA receptors activity. Although studies have shown that rats treated with AP5, an NMDA receptor antagonist, do not learn a spatial task, few reports described the role of these receptors on spatial memory reconsolidation. This study explored the idea that NMDAR participate on spatial memory reconsolidation when animals retrieve the trace under circumstances in which new encoding is likely to occur. Using the Morris watermaze task, the group compared the impact AP5 in two conditions: when memory retrieval occurred in a reference memory task over several days, and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intra-hippocampal AP5 was observed only in the protocol involving new memory encoding at the time of retrieval. The group’s results suggest the existence of a reconsolidation process dependent of NMDA receptors that operates to update retrieved memories.

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14:10-14:30 The impact of suppression on consolidation processes

Professor Michael C. Anderson, MRC Cognition and Brain Sciences Unit, University of Cambridge, UK

Abstract

Synaptic consolidation is a critical process in stabilising the neural representation of episodic experience in the human brain.  Synaptic consolidation is not perfectly effective, however, and not all plasticity triggered by experience results in lasting, durable memories.  Here the group examined the intriguing possibility that the probability of consolidation may depend, in part, on high-level mental processes that systemically alter the environment within which consolidation takes place.  Prior work in humans has shown that intentionally suppressing memory retrieval (retrieval stopping) reduces hippocampal activity via control mechanisms mediated by the lateral prefrontal cortex. In the current work, the group found that when people suppress retrieval given a reminder of an unwanted memory, they are considerably more likely to forget unrelated experiences from periods surrounding suppression. This amnesic shadow follows a dose-response function, becomes more pronounced after practice suppressing retrieval, exhibits characteristics indicating disturbed hippocampal function, and is predicted by reduced hippocampal activity. These findings indicate that stopping retrieval engages a suppression mechanism that broadly compromises hippocampal processes and that hippocampal stabilization processes can be interrupted strategically.  This process may operate via a top-down increase in tonic GABAergic inhibition in the hippocampus that compromises plasticity.

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14:30-14:50 Consolidation of cortical plasticity in sleep: more than meets the eye

Professor Marcos Frank, Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University

Abstract

Sleep is thought to play an important role in the consolidation of hippocampal-dependent forms of memory. Much less, however, is known about how sleep influences the consolidation of experience-dependent plasticity in the cerebral cortex. The group have shown that sleep enhances synaptic plasticity in the visual cortex in a manner consistent with consolidation, as has been described in the hippocampus. The underlying mechanisms are also shared with those known to be important in memory consolidation. These include the activation of several protein kinases and protein synthesis. Collectively, the groups findings indicate that waking experience creates temporary, labile synaptic changes in the cortex that are then made more permanent during sleep.

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14:50-15:10 Coffee Break

15:10-16:00 Discussion Session

Professor Paul Frankland, Program in Neuroscience and Mental Health, Hospital for Sick children, Toronto, Canada

16:00-17:00 Poster session: New techniques and their application

09:00-09:20 Hippocampus-prefrontal cortex interactions during sleep

Dr Francesco Battaglia, Donders Institute, Netherlands

Abstract

The recording of large groups of neurons from behaving animals has been instrumental for investigating brain network dynamics, and ultimately information encoding and the generation of behaviour.  The group applied these techniques to the study of a complex brain network, centered on the hippocampus, which supports episodic memories throughout their lifetimes. Classically, upon memory encoding during active behaviour, hippocampal activity is dominated by theta oscillations. During inactivity, hippocampal neurons burst synchronously, constituting sharp waves, which can propagate to other structures, theoretically supporting memory consolidation, the PFC as a prominent target. This ‘two-stage’ model has been updated by new data from high-density electrophysiological recordings in animals that shed light on how information is encoded and exchanged between hippocampus and hand PFC. This talk will provide an update on recent results on large scale cortical synchronization events (spanning most of the cerebral cortex) that are orchestrated by the hippocampus.

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09:20-09:40 Assembly-ing limbic-cortical information processing during non-REM sleep

Dr Matt Jones, University of Bristol, UK

Abstract

During behaviour, “cell assemblies” are transiently engaged as functional modules, cooperatively encoding information.  However, the extent to which these same assemblies are reactivated during sleep remains unclear. To characterize distributed assemblies spanning posterior parietal cortex (PPC), medial prefrontal cortex (mPFC) and dorsal CA1 of the hippocampus (dCA1), we performed triple-site local field potential (LFP) and multiple single unit recordings in rats learning a spatial decision-making task, and during rest immediately before and after each training session. During non-REM, a coherent 5–8 Hz LFP oscillation spanning mPFC-PPC emerged during 8–15 Hz spindles.  mPFC cells that phase-locked strongly to PPC 5–8 Hz oscillations were also more strongly phase-locked to the dCA1 theta rhythm during wake, and were more likely to be rate-modulated during hippocampal ripples.  Thus mPFC cells tuned to dCA1 during wake are predisposed to participate in long-range 5–8 Hz cortico-cortical coordination during non-REM. This array of covariant activity was associated with recruitment of cell assemblies spanning dCA1-mPFC and PPC, many of which showed activation/inhibition specifically around ripple or spindle times.  Assemblies recruited during task performance were more strongly modulated during post-task sleep, potentially reflecting experience-dependent plasticity and integration of memory traces across limbic-cortical circuits.

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09:40-10:00 Hippocampal-cortical interactions during sleep: behaviour matters

Dr Lisa Genzel, University of Edinburgh, UK

Abstract

Distinct forms of memory consolidation (cellular and systems) influence the persistence of spatial memory within the hippocampus (cellular) and following hippocampal-neocortical interactions (systems). Factors influencing these processes include: (1) novelty exposure that enhances the persistence of hippocampal traces via neuromodulation; and (2) sleep that aids systems consolidation and thus cortical memory. In a sequence of experiments, the group could show that sleep leads to systems consolidation via learning-dependent cortical consolidation. In contrast, novelty tags a memory to remain more hippocampal by increasing gene expression. Further, evidence will be shown that different behaviour such as novelty and normal learning influence hippocampal-cortical communication during subsequent sleep and such behaviours after learning influence the behavioural expression of memory.

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10:00-10:20 Targeted memory reactivation during slow-wave sleep, functional brain connectivity changes and their relation to memory stabilization

Ruud Berkers, Donders Institute for Brain, Cognition & Behaviour, RadboudUMC, Netherlands

Abstract

Post-learning memory replay, especially during slow-wave sleep is thought to enhance memory consolidation. However, this process has been scarcely studied in detail using fMRI data acquired during deep sleep. Data from participants that studied object-location-sound associations will be discussed in this talk. Half of these sounds were presented as cues during post-learning sleep to externally trigger memory replay. Cueing of associated memories during sleep did not produce an overall effect on memory retention. However, there were large inter-individual differences in the effect of cueing, which the group sought to explain using our imaging data. Specifically, the group looked at complex connectivity patterns during cueing with object-related and unrelated control-sounds. The presentation of object-related sounds was specifically associated with increased network participation of early visual cortex. This increased network involvement was positively related to overnight memory retention. Moreover, early visual cortex displayed enhanced connectivity during targeted reactivation with the hippocampus, parahippocampal cortex, thalamus, dorsomedial prefrontal cortex and anterior cingulate cortex and parietal cortex. Together, these results are indicative of externally cued replay that might be.

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10:20-10:40 Coffee Break

10:40-11:30 Discussion Session

Professor Loren Frank, HHMI and University of California, USA

11:30-12:30 Hippocampal - cortical interactions underlying memory processes

Professor Loren Frank, HHMI and University of California, USA

Abstract

Hippocampal memory reactivation during sharp-wave ripple (SWR) events has been linked to memory processes during both sleep and waking, but how these events engage structures outside the hippocampus remains only partially understood.  These results will be presented here first; from simultaneous recordings of hippocampal and auditory cortical (AC) activity during sleep.  The group found that there is a rapid cortical-hippocampal-cortical loop of information flow around the times of SWRs: patterned activation in AC precedes and predicts the subsequent content of hippocampal activity during SWRs, while hippocampal patterns during SWRs predict subsequent AC activity. These findings suggest that the activation of specific cortical representations during sleep influences the identity of the memories that are consolidated into long-term stores. The groups investigations into the organization of memories in both the hippocampus and cortex will then be discussed.  While event memories have identifiable beginnings and ends, ongoing experience proceeds continuously. The neural mechanisms that transform the stream of neural activity patterns representing ongoing experience into discrete episodes are unknown.  The group examined simultaneous hippocampal and prefrontal activity patterns and identified discrete neural codes and discrete patterns of reactivation for different types of experience. These discrete representations suggest a mechanism for creating boundaries between temporally adjacent experiences.

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12:30-13:30 Lunch

13:30-13:50 What is the role of deficient sleep-dependent memory consolidation in schizophrenia?

Professor Dara Manoach, Harvard Medical School, USA

Abstract

Although schizophrenia is defined by waking phenomena, abnormal sleep is a common feature. In particular, there is accumulating evidence of a sleep spindle deficit.  Sleep spindles correlate with IQ and are thought to promote long-term potentiation and enhance memory consolidation.  This talk will review evidence that reduced spindle activity in schizophrenia is an endophenotype that impairs sleep-dependent memory consolidation, cognitive function more generally, contributes to symptoms and is a novel treatment biomarker. Studies showing that spindles can be pharmacologically enhanced in schizophrenia and that increasing spindles improves memory in healthy individuals suggest that treating spindle deficits in schizophrenia may improve cognition. This talk will highlight the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of schizophrenia and implicate reduced sleep spindles as a potentially treatable mechanism. The ultimate goal of this research program is to forge empirical links in causal chains from risk genes to proteins and cellular functions, through to endophenotypes, cognitive impairments, symptoms and diagnosis, with the hope of advancing the mechanistic understanding and treatment of schizophrenia.

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13:50-14:10 Flexibility of threat-related responses and episodic memory in humans upon reactivation

Dr Marijn Kroes, Department of Psychology and Center for Neural Science, New York University, USA

Abstract

Contemporary research suggests that a reminder can reactivate and temporarily renew flexibility of a consolidated memory requiring restabilization mechanisms to be maintained, referred to as reconsolidation. Reconsolidation raises the intriguing opportunity to modify specific memories and holds great clinical potential as it may enable targeting and changing of maladaptive learned responses and memories that contribute to psychiatric disorders. A major accomplishment of memory research is the recognition that there are multiple memory systems that underlie different forms of behavioural expression, which may contribute to distinct symptoms in psychopathology. The majority of evidence for reconsolidation, however, comes from Pavlovian fear-conditioning studies that suggest that learned threat responses can again become flexible but that episodic memories remain stable. As a result it is unclear if reconsolidation also occurs in other memory systems, especially in humans. In this talk studies will be discussed investigating renewed flexibility of both threat responses and episodic memories in humans. It will be shown that episodic memories also undergo reconsolidation but that the efficacy of interventions to modify more complex forms of memory is limited. In addition, discussion will consider that if interventions targeting reconsolidation fail or affect other mnemonic mechanisms they may do more harm than good.

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14:10-14:30 Exploiting reconsolidation update mechanisms to reduce intrusive trauma memories of experimental trauma using cognitive tasks (Tetris)

Professor Emily Holmes, Karolinska Institute, Sweden

Abstract

Intrusive memories of a trauma event comprise the core clinical feature of disorders such as acute stress disorder and post-traumatic stress disorder (PTSD). Therefore, the group are particularly interested in intrusive memories - i.e. memories that intrude to mind unbidden following a traumatic event in the form of emotional mental imagery. In an experimental psychopathology approach using the trauma film paradigm, human participants view film-footage with traumatic content in the lab.  The frequency of intrusive memories is monitored in a daily-life over one week.  Experiments will be discussed showing that (i) a cognitive task designed to interfere with the consolidation of visual memory for experimental trauma, reduces the frequency of subsequent intrusive memories, for example the computer game Tetris. (ii) The frequency of intrusive memories for established (24h old) memories of experimental trauma can be reduced using a visuospatial task. Memory reactivation plus Tetris game-play (“cognitive blockade”) led to fewer intrusions compared to either memory reactivation or Tetris game-play in isolation. Findings suggest a brief “cognitive therapeutic vaccine” after trauma may offer a non-invasive method to ameliorate intrusive memories by exploiting consolidation / reconsolidation update mechanisms.

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14:30-14:50 The importance of circuit-specific bidirectional synaptic plasticity during sleep dependent memory consolidation and reconsolidation and the implications of maladaptive sleep for mental health disorders.

Professor Gina R. Poe, Department of Integrative Biology and Physiology and Department of Psychiatry, UCLA, USA

Abstract

This talk will present evidence and arguments that consolidation and reconsolidation failures induced by a variety of causes (sleep restriction, weak spindles, brain injury, anaesthesia) lead to mental and neurological health issues such as PTSD, Autism, Schizophrenia, and Alzheimer’s disease. Studies from the group’s lab and others indicate that specifics of timing of neural and local field potential patterning and the neurochemical milieu in which consolidation and reconsolidation occur both strongly impact the efficacy of consolidation ad reconsolidation, and that failures in one or some these factors will impact cognition and contribute to disease. The group argue that interventions that normalize the reconsolidation environment can set an organism back on the path from disease to health.

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14:50-15:10 Coffee Break

15:10-16:00 Discussion Session

Professor Paul Frankland, Program in Neuroscience and Mental Health, Hospital for Sick children, Toronto, Canada

16:00-16:45 Blitz session: New techniques and their application

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16:45-17:00 Summary of discussions