May 28 – June 4, 2017
Susumu Tonegawa, Massachusetts Institute of Technology, Cambridge, USA & RIKEN Brain Science Institute, Japan
Alcino J. Silva, University of California Los Angeles. USA
Nicolas Bazan, Louisiana State University, New Orleans. USA
Richard Morris, Centre for Cognitive and Neural Systems, University of Edinburgh, UK
Susumu Tonegawa, Massachusetts Institute of Technology, Cambridge, USA & RIKEN Brain Science Institute, Japan
Alcino Silva, University of California Los Angeles, USA
Nicolas Bazan, LSU Center of Excellence in Neuroscience, New Orleans, USA
Matthew Wilson, Massachusetts Institute of Technology, Cambridge, USA
Howard Eichenbaum, Center for Memory & Brain, Boston University, USA
Kate Jeffery, University College, London, UK
Recent ground-breaking developments in neuroscience, such as optogenetics, in vivo 2-photon confocal microscopy, head mounted microscopes, powerful new developments in modeling, behavioral neuroscience approaches, and sophisticated brain imaging tools, have changed dramatically studies of memory. Most importantly, these developments have fostered interdisciplinary studies that led to integrated molecular, cellular, systems, cognitive and behavioral explanations of how memories are allocated, formed, consolidated, reconsolidated and retrieved. These studies have also led to mechanistic cross-disciplinary studies of memory disorders, which in some cases led to the development of targeted treatments that are changing how we imagine treating the considerable health burden associated with this large class of conditions.
The Course will review these advances and the background that led to them, as well as introduce students to the technologies and approaches critical to these studies. Alcino Silva (UCLA) will describe molecular, cellular, circuit mechanisms that link memories across time with an emphasis on technologies that are revolutionizing the way memory is studied. Kate Jeffrey (UCL) will introduce the hippocampal place system, and studies of neural encoding of simple and complex space. Matt Wilson (MIT) will discuss neural processes within the hippocampus and neocortex that enable memories to form and persist over long periods of time. Richard Morris (University of Edinburgh) will discuss synaptic tagging and capture as well as memory schemas. Morris will also discuss novel cognitive-based strategies to understand, prevent and treat Alzheimer’s disease. Dr. Susumu Tonegawa (RIKEN, MIT) will review efforts to artificially create, manipulate and shape the emotional valence of hippocampal memory engrams, and studies that link two major areas in memory research: studies of the engram and studies of the role of synaptic plasticity in memory. Howard Eichenbaum (Boston University) will review new findings that indicate that hippocampal neurons encode the temporal structure of events in memories. Eichenbaum will also review new insights into how the hippocampus, entorhinal cortex, and prefrontal cortex interact to develop and incorporate new memories into schemas.
May 28th: Alcino J Silva
Integrative Center for Learning and Memory, UCLA
Alcino J Silva
Integrative Center for Learning and Memory, UCLA
Molecular, cellular, and circuit mechanisms that link memories across time
Studies of the molecular, cellular and circuit mechanisms of learning and memory have focused almost exclusively on how single memories are acquired, stored and edited. By comparison, very little is known about the mechanisms that integrate and link memories across time. Recent studies from our laboratory showed that learning triggers CREB activation and a subsequent temporary increase in neuronal excitability in these circuits that for a time biases the allocation of a subsequent memory to the neuronal ensemble encoding the first memory. Recently, we have used state of the art in vivo imaging methods and other approaches to show that in the hippocampus, this mechanism can link memories across time, such that the recall of one memory increases the likelihood of recalling the other memory. Interestingly, we also showed that this mechanism is disrupted in older mice, and that artificially manipulating neuronal excitability with a chemo-genetically strategy can rescue these deficits, a result that implicates this mechanism in memory linking and in age-related cognitive decline.
Memory: from molecular and cellular mechanisms to treatments.
Mouse model studies in our laboratory have uncovered mechanisms and treatments for learning and memory disorders, including Neurofibromatosis type I, Tuberous Sclerosis, Noonan Syndrome and DISC1. We have also identified cognitive enhancers that could be used when etiology is uncertain. We will review these and other related findings that illustrate how insights into the biology of molecular and cellular processes in the brain are changing the way we understand and envision treating learning and memory disorders. Adult treatments could one day help the millions of people affected with neurodevelopmental and other learning & memory disorders.
Institute of Behavioural Neuroscience, UCL
Neural encoding of simple space
The brain has the task of organizing information coming in via the senses into representations, which help its owner behave adaptively in the world. Early “Behaviorist” ideas about representations supposed that these were simple networks of associations between stimuli, in which the nature of the stimuli did not matter. However, it gradually became apparent that not all stimuli are equal and that in fact, the brain treats different types of sensory input differently. The catalyst for this change in thinking was O’Keefe’s discovery of place cells in the rat hippocampus, in the early 1970s. Subsequent study of place cells and their sensory antecedents revealed structures in the brain specialised for processing sensory information in different ways: for example, the visual input produced by sight of a landmark might be used to identify a place, determine facing direction, help estimate speed of movement or signpost a goal, and different parts of the brain handle these different tasks. This talk will introduce the hippocampal place system and describe its major components, and explore the way in which the study of the brain’s representation of space has also shed light on more general principles of cognitive representation.
Neural encoding of complex space
Studies of the hippocampal place system have previously mostly taken place in controlled laboratory environments in which animals were confined to single enclosures having simple geometry. However, the natural world is much more complex: it has multiple compartments or no compartments at all; it has complex surface topography such as hills, valleys, crevices, cliffs etc; it can be very small (a burrow) or very large (the ocean), and many animals, including our marine ancestors, can move freely in all three dimensions. This talk will explore the computational challenges faced by encoding complex space, and describe some of the studies that have begun to explore how mammalian brains deal with this complexity.
RIKEN-MIT Center for Neural Circuit Genetics, Picower Institute, MIT
1- Engram Cell Circuits for Memory Retention
Our study (Ryan et al., Science 2015) suggested that while a rapid increase of synaptic strength is crucial for encoding of a memory, a newly formed pattern of connectivity between the upstream and downstream engram cell ensembles may serve as the primary means for long-term memory storage. Supporting this concept is the fact that a mouse suffering from retrograde amnesia can be induced to express the full level of memory by optogenetic stimulation one day after encoding, despite the fact that these engram cells are without enhanced synaptic strength, and that these amnesic engram cells (in hippocampal DG) retain preferential connectivity with downstream engram cells (in CA3 and BLA) (Ryan et al., Science 2015). We have further investigated this hypothesis from several different angles and have shown that the engram-to-engram connectivity is stable both in control and amnesic mice, lasting for at least 8 days after encoding, and that optogenetic activation of the engram in amnesic mice is stimulus strength-dependent.
These and other recent studies on memory engram cells are generating the concept of “silent engram cells” that hold memory information but are not susceptible to reactivation by natural cues for recall. These silent engram cells are found not only in retrograde amnesia but also in mouse models of early Alzheimer’s disease (Roy et al., Nature 2016). Furthermore, our recent study revealed that remote episodic memory is in a silent state during recent time points, and that hippocampal episodic memory engram cells that are active in recent time points are converted to the silent state over time. The common structural and physiological features of these silent engram cells, compared to active engram cells, are reduced spine density and reduced synaptic strength. We have also showed that a silent engram could be converted to an active engram by repeated optogenetic enhancement of synaptic strength (Roy et al., Nature 2016). Based on these observations, we propose that the primary purpose of molecular consolidation of memory is to make memory engram cells accessible to natural recall cues.
2: Maturation of Silent Engrams and Systems Consolidation of Memory
We have investigated the systems consolidation of episodic memory by applying engram and optogenetic technologies. The results indicate that the PFC engrams for remote memory are formed rapidly on day 1 of learning. However, these PFC engrams are inactive in the sense that they cannot be re-activated by natural cues for memory retrieval. The “silent” PFC engrams undergo slow maturations during the following few weeks with the aid of input from hippocampal engram cells via the deep layer of the medial entorhinal cortex. Conversely, the hippocampal engram cells formed rapidly on day 1 de-mature slowly and become silent. For contextual fear memory, an active engram is rapidly formed in BLA and remains active throughout the systems consolidation, but there is a switch in the route through which recall cues are delivered: through the hippocampal-entorhinal circuit at recent times and through PFC engram cells at remote times. This study identified the engrams and neural circuits crucial for systems consolidation of a memory.
Centre for Cognitive and Neural Systems, University of Edinburgh
1- Memory consolidation: synaptic tagging and schemas
A widely held model of memory encoding is activity-dependent synaptic plasticity, as studied in the physiological phenomena of long-term potentiation (LTP) and depression. Synaptic potentiation mediated by NMDA receptor triggered changes in AMPA receptor trafficking and expression has a number of features that make it an attractive storage mechanism, but the initial encoding of ‘traces’ at numerous synapses in a distributed associative memory system is no guarantee that they will last. This presentation will focus on two aspects of memory consolidation – cellular and systems. Cellular consolidation to help memory persistence involves a diverse set of interacting mechanisms including neuromodulatory transmitters, intracellular signal transduction pathways, gene activation etc. The synaptic tagging and capture model of protein synthesis-dependent synaptic potentiation offers a new framework for thinking about the timescale over which such cellular activity-dependent interactions may take place. In contrast, systems consolidation across diverse neural networks beyond the single cell involves additional mechanisms. Whereas this form of consolidation has sometimes been conceived as a process of ‘transferring’ information from one anatomical network to others, new research suggests that there may sometimes parallel encoding in neocortical and allocortical networks, with the activation of prior knowledge guiding the subsequent process of assimilation in a top-down manner.
2- Can what we yet know about learning and memory help in the search for new therapies for Alzheimer’s Disease?
We all know what Alzheimer’s Disease (AD) and the growing age-related burden it represents already. As an early indicator of incipient AD is the loss of recent memory, it is surely likely that what we have learned about the organization of memory systems in the brain could be helpful in tackling this area of biomedical uncertainty. However, the field remains dominated by its scientific heritage in neuropathology, in biochemistry and genetics, and does little more than pay lip-service to the possibility that ‘cognition’ could be a valuable addition to the biomarkers that are being explored in connection with understanding the disease. Of course, understanding, slowing down and eventually treating AD is an enormously difficult problem requiring an interdisciplinary approach – but I shall endeavor to illustrate some examples of work conducted with mouse models over the past 20 years that collectively represent a valuable contribution to the field. This will include some recent work from my group on the very early and preventive treatment of a mouse model of AD prior to deposition of beta-amyloid plaques. As part of this abstract, I invite everyone in the audience to write ‘yes’ or ‘no’ after the following statement: “The primary responsibility of scientists is to understand the world around us, but we should also not miss opportunities to pause to apply our understanding for the betterment of humankind”. Then let’s discuss!
Center for Memory & Brain, Boston University
1-The hippocampus in time
The hippocampus has long been implicated in spatial mapping and navigation. However, recent evidence indicates that hippocampal neurons also encode the temporal structure of events in memories, suggesting a parallel to spatial information processing in the temporal domain. These and related findings indicate that the hippocampus organizes memories in time in support of its role in our capacity for episodic memory.
2-The organization and control of hippocampal memory representations
Using a representational similarity analysis (RSA) on ensembles of simultaneously recorded neurons combined with analyses of functional connectivity, we can examine the structure of memory representations in the cortical-hippocampal system, including the hippocampus, entorhinal cortex, and prefrontal cortex, and we can determine the flow of information between connected areas. These studies are revealing an elaborate, systematic organization of memories encoded within this system, as well as new insights into how these areas interact to support the retrieval of memory representations.
Picower Center, MIT
1- Reactivation of sequential activity in neural ensembles during waking and sleep
This lecture will focus on the neural processes within the hippocampus and neocortex that enable memories to form and persist over long periods of time. This work takes advantage of a technique that allows the simultaneously recording of the activity of hundreds of individual neurons across multiple brain regions in freely behaving animals. When combined with genetic, pharmacological, and behavioral manipulations, these recordings result in a mechanistic understanding of how animals learn and remember.
The lectures will cover studies of the reactivation of sequential activity in neural ensembles during waking and sleep. Because many cells in the hippocampus represent specific locations, it is possible to use their firing patterns to reconstruct movement trajectories that are being “replayed” during periods of rest. The function of such replay is not well understood, but it may play a role in memory consolidation, or even in action planning.
2- Coordinated brain activity during memory formation
This lecture will describe studies of the interplay between the hippocampus and other brain regions, such as prefrontal cortex, cingulate cortex, thalamus, and the ventral tegmental area. Understanding how activity is coordinated between multiple areas is likely to be crucial for understanding how memories are stored and retrieved. Key to the material presented will be methodological innovations. Recent advancements include motorized microdrives for improving tetrode yield and stability, the ArtE system for real-time feedback during experiments, and new computational tools for the analysis of neural activity.
Department of Ophthalmology, Biochemistry and Molecular Biology, and Neurology
LSU’s School of Medicine
1- Molecular organization of phospholipids in dendritic spines and neuronal networks, membrane-derived lipid mediators, signal transduction and transcriptional regulation. Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived mediator, induces cell survival in uncompensated oxidative stress, neurodegenerations or ischemic stroke. The molecular principles underlying this protection remain unresolved. We will describe how NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-ĸB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-ĸB pathways. RelB expression follows a similar pattern as BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. BIRC3 silencing prevents NPD1 induction of survival against oxidative stress. Moreover, brain NPD1 biosynthesis and selective neuronal BIRC3 abundance are increased by DHA after experimental ischemic stroke followed by remarkable neurological recovery. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription events decisive for neural cell and networks integrity when confronted with potential disruptions of homeostasis.
The essential omega-3 fatty acid family member docosahexaenoic acid (DHA) is avidly retained in excitable membranes. The molecular mechanisms that control DHA uptake and retention in the central nervous system are unknown. We discovered that Adiponectin receptor 1 (AdipoR1) ablation results in dramatic reductions in DHA levels, profoundly-decreased phosphatydylcholine molecular species containing very long chain polyunsaturated fatty acids (VLC-PUFA. These biochemical and physiological changes preceded progressive neural cell degeneration in mice lacking AdipoR1. AdipoR1 overexpression in greatly enhanced DHA uptake, whereas AdipoR1 silencing had the opposite effect. These results establish that AdipoR1 regulates DHA uptake, retention and conservation. This presentation will describe the opportunities that metabolomics and particularly lipidomics offers to understand neuronal networks. The application of LC-MS/MS as well as of MALDI MS imaging will be highlighted.
2- Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are modulated by neuroprotectin D1, a docosanoid derived from excitable membranes. Limbic epileptogenesis triggers molecular and cellular events that foster the establishment of aberrant neuronal networks that, in turn, contribute to temporal lobe epilepsy (TLE). Here we have examined hippocampal neuronal network activities in the pilocarpine post-status epilepticus model of limbic epileptogenesis and asked whether or not the docosahexaenoic acid (DHA)-derived lipid mediator, neuroprotectin D1 (NPD1), modulates epileptogenesis. Status epilepticus (SE) was induced by intraperitoneal administration of pilocarpine in adult male mice. To evaluate simultaneous hippocampal neuronal networks, local field potentials were recorded from multi-microelectrode arrays (silicon probe) chronically implanted in the dorsal hippocampus. NPD1 or vehicle was administered intraperitoneally daily for five consecutive days 24 hours after termination of SE. Seizures and epileptiform activity were analyzed in freely-moving control and treated mice during epileptogenesis and epileptic periods. Then hippocampal dendritic spines were evaluated using Golgi-staining. We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis. These aberrant activities were attenuated following systemic NPD1 administration, with concomitant hippocampal dendritic spine protection. Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures. This presentation will show that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis. Insight into the molecular signaling mediated by neuroprotective bioactivity of NPD1 on neuronal network dysfunction may contribute to memory and particularly to early stages of Alzheimer’s when monomeric A-beta peptide damages synapses .