Memory reactivation: replaying events past, present and future

During both active navigation and rest, temporally precise sequences of activity are produced across the hippocampal circuit. Recent findings suggest that pre-existing network dynamics strongly bias such sequences in all behavioral states. However, considerable evidence also demonstrates a critical role for experience in shaping the specific content of hippocampal sequences. For example, blocking synaptic plasticity during exploration of a novel environment virtually abolishes coherent re-expression of those behavioral sequences in subsequent rest. In addition, prior to goal-directed navigation, both ripple- and theta-based sequences display spatial trajectories which are heavily biased to proceed from the animal’s current location to a recently learned goal. Importantly, the encoding of the goal location in hippocampal sequences appears to emerge as a consequence of experience-dependent learning, with no goal-directed bias early in the behavioral task.  While these findings do not rule out the possibility that preconfigured circuit connectivity can impact ‘offline’ sequences or influence how the hippocampus encodes experience, they highlight the importance of experience in further shaping the network to produce specific neuronal sequences that facilitate flexible behavior.

Dr Brad Pfeiffer, UT Southwestern Medical Center, USA

Dr Brad Pfeiffer, UT Southwestern Medical Center, USA

Brad Pfeiffer performed his graduate studies under the mentorship of Kimberly M Huber, PhD, where he studied the synaptic mechanisms underlying Fragile X Syndrome. Dr Pfeiffer completed his post-doctoral training with Dr David J Foster, where he performed in vivo recordings and examined rodent hippocampal function and ‘replay’ during navigational tasks. Brad joined the faculty at UT Southwestern Medical Center in 2015, where he is an Assistant Professor in the Department of Neuroscience and an Endowed Scholar in Biomedical Research.

Cortical neuronal ensembles form rapid internal representations about the external world through the interplay between internally-generated spontaneous neuronal dynamics and externally-driven activity about the specific sensory dynamics of the world. A stronger network reliance on the recruitment of internally-generated neuronal activity would greatly enhance the speed and efficiency of encoding at the cost of limiting its capacity to the combinatorial size of the fixed repertoire of internal neuronal motifs. On the other hand, a reduced dependency on an internal network model of the world would increase the flexibility and capacity for encoding independent representations that would instead require multiple exposures and additional time to create stable novel representations. Here, the authors reveal the existence of a generative predictive model for the statistical regularities of the contextual space in the hippocampus and define the principles underlying its use in navigation and its update by inferred intrinsic-unlikely neuronal functional connectivity and selective plasticity. These generative predictive codes rely on functional connectivity within and between high-repeat, short motifs of sequential neurons called ‘tuplets’. They propose that network organization into neuronal tuplets segments the extended temporal sequences into shorter modules, analogous to segmentation of words into syllables. This novel neuronal organizational principle could vastly expand the generative capacity of the network by rapidly combining neuronal tuplets into multiple independent extended temporal sequences. This would enable the hippocampal network to achieve high-speed and high-capacity encoding at the same time, as required by the cognitive functions it supports.

Dr George Dragoi, Yale University, USA

Dr George Dragoi, Yale University, USA

Dr George Dragoi is Assistant Professor in the Department of Psychiatry at Yale University School of Medicine in New Haven, CT. He holds an MD from the Gr T Popa University of Medicine and Pharmacy of Iasi, Romania, and a PhD in Behavioral and Neural Science from Rutgers University where he worked in the laboratory of Dr Gyorgy Buzsaki. He completed his postdoctoral studies at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology in the laboratory of Dr Susumu Tonegawa. Dr Dragoi studies the neurophysiological basis of the organisation of hippocampal neurons into cellular assemblies and their dynamic grouping during novel spatial exploration and in response to long-term synaptic plasticity. Recently, he revealed the existence of preconfigured cellular assemblies that pre-play in time the spatial sequences occurring during a future novel spatial experience.

Experience-related sequences of spiking activity in the hippocampus can be segregated into two groups. The first are those occurring during theta oscillations, which appear during locomotion and active exploration as well as in REM sleep. The second are those occurring during sharp-wave ripples, during pauses in exploratory activity and during slow-wave sleep. Whereas these groups provide consistent and meaningful divisions in brain-behaviour coupling in rats and mice, in anthropoid species like macaques and humans, the distinctions are less clear. We will describe our observations of sharp-wave ripples during active visual search in macaques, as well as in offline periods including sleep. The appearance of sharp-wave ripples in place of and superimposed within theta epochs suggests a possible expanded role for ripple-driven relative to theta-driven sequences during recall and decision making in primates.

Dr Kari Hoffman, Vanderbilt University, USA

Dr Kari Hoffman, Vanderbilt University, USA

Dr Kari Hoffman was recently appointed as an Associate Professor at Vanderbilt University, after spending 10 years leading a research group in the Psychology Department at York University. Her laboratory is focused on discovering the dynamics and mechanisms of plasticity in neural ensembles during perception and memory formation in primates. Dr Hoffman received her PhD in Neuroscience in the lab of Dr Carol Barnes and Professor Bruce McNaughton at the University of Arizona, with a project that pioneered multi-electrode array (MEA) technology using high-density recordings of neural populations, before moving to Germany for a post-doctoral fellowship with Dr Nikos Logothetis at the Max Planck Institute in Tuebingen. Dr Hoffman is a National Academy of Sciences Kavli Fellow and received new investigator awards from the Ontario Ministry of Research and Innovation, the Alzheimer’s Association, and the Alfred P Sloan Foundation. She has just finished leading a Brain Canada Multi-Investigator Research Initiative to modify neural dynamics in memory-related brain structures.

Sharp-wave ripples are complex neurophysiological events recorded along the trisynaptic hippocampal circuit during slow-wave sleep and awake immobility. During these events, cognitively relevant sequences are triggered retrospectively or prospectively, and in the forward or reverse order as defined by experience. They could reflect either pre-configured sequences, learned sequences or an option space to inform subsequent decisions. How can different sequences emerge from directional connectivity is unknown. Emerging data now suggest the entorhinal-hippocampal circuit is organized in parallel loops along CA1 sublayers. It is discussed whether by incorporating cell-type specific physiological and computational mechanisms converging on deep and superficial CA1 sublayers could help to unveil the organization of sequences during sharp-wave ripples.

Dr Karunesh Ganguly, University of California, San Francisco, USA

Dr Karunesh Ganguly, University of California, San Francisco, USA

Karunesh Ganguly is a neurologist and a research scientist at the University of California, San Francisco. He graduated from Stanford University and then completed his MD/PhD degrees through the Medical Scientist Training Program at the University of California, San Diego. He is also the Director of the Laboratory of Plasticity and Neural Engineering. The laboratory’s research program focuses on understanding the role of sleep-dependent plasticity on consolidation after motor learning and recovery from injury. He was awarded the Presidential Early Career Award for Scientists and Engineers (PECASE Award) by President Obama in 2014 and was selected for the 2015 New Innovator Award by the NIH Office of the Director.

For more than 20 years, research in my laboratory has focused on investigating the behavioural determinants, neuronal substrates and neurophysiological correlates of motor skill learning and consolidation. During this presentation, I will review some of our work focusing on motor sequence learning (MSL) and will discuss our studies showing that the consolidation of this form of memory trace depends upon greater functional integration of the cortico-striatal system and non-rapid eye movement (N-REM) sleep spindle activity measured during the night following the initial training session. More specifically, I will describe the results of our simultaneous fMRI/EEG recording experiment, which show that: a) the cortico-striatal network recruited during MSL is reactivated during sleep, time-locked to spindles, b) such a reactivation of the memory trace is followed by reorganization of the neural representation toward a subcortically-dominant consolidated trace during the post-training night, and c) sleep spindles promote skill consolidation by locally reactivating and functionally binding task-relevant cortical and subcortical regions including the striatum.

Dr Julien Doyon, McGill University, Canada

Dr Julien Doyon, McGill University, Canada

After completing his PhD in 1988 at the Montreal Neurological Institute (MNI) under the supervision of Dr Brenda Milner, Dr Doyon was an assistant professor in the Department of Psychology at Laval University until 2000. He then moved to University of Montreal where he became the founding Scientific Director of the Functional Neuroimaging Unit until October 2017. Currently, Dr Doyon is Director of the McConnell Brain Imaging Center at the MNI, professor in the Department of Neurology and Neurosurgery at McGill University and the founding Director of the Quebec Bio-Imaging Network (QBIN). Research in his laboratory investigates, through a combination of imaging techniques and modalities, the brain and spinal cord plasticity associated with motor learning, as well as the role of sleep in the consolidation and reconsolidation of this form of memory. More recently, Dr Doyon has also developed a clinical research program intended to identify functional and structural biomarkers useful for the early diagnosis of Parkinson’s disease. Finally, for his scientific contribution, Dr Doyon obtained the 2011 Canadian Society for Brain Behavior & Cognitive Sciences (CSBBCS) – Richard C Tess Award and was named Fellow of this Canadian society in 2017, in recognition of his outstanding contribution to the advancement of knowledge and leadership in the field of cognitive neuroscience and neuroimaging. He was awarded the 2012 ACFAS - Léo Pariseau prize highlighting the excellence and international impact of his work and was elected Fellow of the Royal Society of Canada in September 2017 as well as a member of the Canadian Academy of Health Science in 2018.

Synapses are the structures in the brain that form and store memories through the processes of synaptic plasticity. Sleep is an essential process that supports learning and memory by acting on synapses through poorly understood molecular mechanisms. Moreover, sleep disruption is commonly associated with neurodevelopmental and neurodegenerative diseases, and likely contributes to cognitive impairment in these conditions. Using biochemistry, proteomics and imaging in mice we show that during sleep, synapses undergo widespread alterations in composition and signaling. Consistent with the sleep homeostasis hypothesis which posits that part of the restorative benefits of sleep is mediated by broad weakening of synaptic connections we observe that sleep is associated with removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate early gene Homer1a, and signaling from group I metabotropic glutamate receptors mGluR1/5. The changes that occur at synapses during sleep and the molecular requirement for Homer1a are highly reminiscent of homeostatic scaling-down in cultured neurons, further supporting the sleep homeostasis hypothesis. Our ongoing studies attempt to further dissect the molecular mechanisms that act on synapses during sleep, with a focus on synaptic signaling molecules related to mGluR1/5. We are applying this work to understanding how sleep disruption may contribute to cognitive impairments in autism spectrum disorder, and Alzheimer’s disease. Therapeutic strategies designed to enhance the restorative benefits of sleep will be discussed.

Dr Graham Hugh Diering, University of North Carolina at Chapel Hill, USA

Dr Graham Hugh Diering, University of North Carolina at Chapel Hill, USA

Dr Diering received his bachelor and doctorate degrees from the University of British Columbia, Canada, in biochemistry and molecular biology. He then worked as a post-doctoral fellow with Dr Richard Huganir in the Department of Neuroscience at Johns Hopkins University. During his post-doc Dr Diering worked to understand the molecular mechanisms of a type of synaptic plasticity called homeostatic scaling, and then went on to show that homeostatic scaling-down is engaged in the brain during sleep. Currently, Dr Diering is an assistant professor in the Department of Cell Biology and Physiology and the Neuroscience Center at the University of North Carolina. The Diering lab is focused on understanding how sleep supports the development of the brain and how sleep disruptions contribute to cognitive and behavioral problems in neurodevelopmental disorders.

The synaptic homeostasis hypothesis (SHY) proposes that sleep is an essential process needed by the brain to maintain the total amount of synaptic strength under control. SHY predicts that by the end of a waking day the synaptic connections of many neural circuits undergo a net increase in synaptic strength due to ongoing learning, which is mainly mediated by synaptic potentiation. Stronger synapses require more energy and supplies and are prone to saturation, creating the need for synaptic renormalization. Such renormalization should mainly occur during sleep when the brain is disconnected from the environment and neural circuits can be broadly reactivated off-line to undergo a systematic and yet specific synaptic down-selection. In short, according to SHY, sleep is the price to pay for waking plasticity to avoid runaway potentiation, decreased signal-to-noise ratio, and impaired learning due to saturation. The talk will cover the rationale underlying this hypothesis and summarize electrophysiological, molecular and ultrastructural studies in flies, rodents and humans that confirmed SHY’s main predictions, including the recent observation, obtained using serial block face scanning electron microscopy, that most synapses in mouse primary motor and sensory cortices grow after wake and shrink after sleep. Unpublished ultrastructural data obtained in the CA1 region of the hippocampus and in the cortex of mouse pups will also be presented.

Dr Chiara Cirelli, University of Wisconsin, USA

Dr Chiara Cirelli, University of Wisconsin, USA

Chiara Cirelli received her medical degree and PhD in Neuroscience from the University of Pisa, Italy, where she investigated the role of the noradrenergic system in sleep regulation. She continued this work as Fellow in experimental neuroscience at the Neuroscience Institute in San Diego, California, and since 2001 at the University of Wisconsin – Madison, where she is currently Professor at the Department of Psychiatry. Her laboratory aims at understanding the function of sleep and clarifying the functional consequences of sleep loss. Her team identified neuronal and glial genes whose expression changes due to sleep and sleep loss, suggesting specific cellular processes that are favored by sleep and impaired by sleep deprivation. Using large-scale mutagenesis screening in Drosophila, they also identified the first extreme short sleeper mutant. With Dr Giulio Tononi, Dr Cirelli has developed the synaptic homeostasis hypothesis, according to which sleep is needed for synaptic renormalization, to counterbalance the net increase of synaptic strength due to wake plasticity. Over the years Dr Cirelli has been testing this hypothesis with an array of methodologies, including serial block face electron microscopy. She recently used this technique to show how cortical synapses grow during waking and shrink during sleep. Dr Cirelli has published over 130 papers on sleep and is Associate Editor of SLEEP.

Sleep states are thought to have a strong homeostatic role in neocortical circuits. Previous work has shown that neocortical firing rates are modulated over sleep-wake cycles in a manner consistent with homeostasis: firing rates on average rise during waking periods and drop during sleep periods. In this work, prefrontal cortical neuronal populations in rats were recorded with silicon probe arrays to obtain large numbers of recorded neurons simultaneously to allow us to examine network-wide effects of natural sleep and wake cycles. Results from these high-channel count recordings revealed that neurons of differing overall firing rates are regulated differentially during sleep sessions with only the highest-firing rate cells showing consistent drops in firing rate with sleep, while low firing-rate neurons either did not show a net change in activity or even showed increased firing rates by some metrics. The overall variance of the network activity dropped over sleep as a result of this differential effect, pointing to a prominent homogenization effect of sleep and homeostasis. In addition these recordings revealed that high firing rate neurons tended to fire earlier than low firing rate neurons during repetitive (1 hertz) network UP state activations. This latter finding leads to the hypothesis that spike timing dependent plasticity (STDP) rules may combine with repeated sequences of high-rate then low-rate cells to create the differential effect on total drive to high versus low firing rate cells. We therefore suggest that sequences of network activity during sleep may serve not just a mnemonic function by may drive network homeostasis.

Dr Brendon Watson, University of Michigan, USA

Dr Brendon Watson, University of Michigan, USA

Brendon Watson specialises in neuroscience and psychiatry with an emphasis on the use of high throughput tools and tool development for neurobiologic studies. During his PhD he used two-photon microscopy to study the behaviour of neurons in local cortical microcircuits. He pursued a residency in psychiatry at Weill Cornell Medical College as well postdoctoral work at New York University where used high channel-count silicon probe electrodes to report novel properties of the prefrontal cortex. He received the National Institute for Mental Health’s Outstanding Resident Award, the American Psychiatric Association’s Lilly Research Fellowship and the Leon Levy Neuroscience Fellowship. He is now combining new approaches to electrical recordings with optogenetic and behavioural tools to deepen our understanding of brain circuits over varying brain states.

Experience-dependent synaptic plasticity is critical for encoding and storing information. How experience-induced synaptic plasticity is distributed and maintained in neuronal networks remains unclear. Dendritic spines are the postsynaptic sites of most excitatory synapses in the mammalian brain. Using in vivo two-photon microscopy, we examined the effects of motor learning and chronic pain on dendritic spine remodeling in the mouse cortex. We show that new spines are formed on different sets of dendritic branches of layer 5 pyramidal neurons in the motor cortex in response to different motor learning tasks. This branch-specific formation of dendritic spines facilitates the maintenance of new spines when multiple tasks are learned. In addition, chronic pain induces dendritic spine formation and elimination on a subset of dendritic branches of layer 5 pyramidal neurons in the primary somatosensory cortex. Notably, cortical neurons that are active during motor training or responsive to nociceptive stimuli exhibit a substantial increase in calcium activity during subsequent non-rapid eye movement sleep. Blockade of neuronal activity during sleep reduces experience-dependent dendritic spine plasticity and alleviates chronic pain. Together, these findings suggest that experience and subsequent sleep lead to dendritic branch-specific synaptic remodeling, thereby contributing to memory storage in neuronal circuits.

Dr Guang Yang, Columbia University, USA

Dr Guang Yang, Columbia University, USA

Dr Guang Yang is an Associate Professor in the Department of Anesthesiology at Columbia University, New York, USA. Her research focuses on understanding how sleep, anesthetics and immune cells affect changes of neural circuits underlying sensory processing and memory formation. Using in vivo two-photon microscopy to monitor fluorescently-labelled neurons in the living mouse cortex, her recent studies indicate that sleep has multifaceted functions in learning and memory consolidation: non-rapid eye movement sleep promotes new synapse formation after motor learning by reactivating task-related neurons, while rapid eye movement sleep selectively eliminates and maintains newly formed synapses via dendritic calcium spike-dependent mechanisms.