Cellular and Systems Mechanisms of Learning and Memory

 

July 20 - 28, 2013

 

Coordinators: Susumu Tonegawa

Massachusetts Institute of Technology, Boston, USA

 

Alcino J. Silva

University of California Los Angeles, USA

 

Faculties:

Nicolas Bazan, LSU Center of Excellence in Neuroscience, New Orleans, USA

Yadin Dudai, Weizmann Institute of Science, Rehovot, Israel

Howard Eichenbaum, Boston University, USA

Michael Hasselmo, Boston University, USA

Richard Morris, University of Edinburgh, UK

 

Recent ground-breaking developments in neuroscience, such as optogenetics, in vivo 2-photon confocal microscopy, 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 formed, consolidated, altered 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. The following is a summary of lectures in the course:

Adult rescue of cognitive deficits associated with neurodevelopmental disorders

Alcino J. Silva

Recent findings suggest that it is possible to reverse in adults cognitive phenotypes associated with neurodevelopmental disorders. For example, our studies have shown that molecular, electrophysiological and behavioral deficits in animal models of Neurofibromatosis type I, Tuberous sclerosis and schizophrenia can be reversed in adults with pharmacological manipulations that reverse key molecular deficits. These and other recent related findings in Down Syndrome, Rett Syndrome, Fragile X, etc. are changing the way we study and imagine treating cognitive disorders.

Molecular and cellular mechanisms of memory allocation in neuronal networks

Alcino J. Silva

Until recently the mechanisms that determine how specific cells and synapses (and not their neighbors) are recruited during learning have received little attention. Recent findings using a wide range of optogenetic, in vivo 2-photon imaging techniques, transgenic and viral vector technologies demonstrated that memory allocation is not random, but rather specific mechanisms regulate where exactly information is stored within a neural circuit. These studies also indicate that some of the mechanisms involved in the consolidation of one memory affect the allocation of the next memory.

Lipid Signaling in Synaptic Circuitry

Nicolas G. Bazan

We will discuss the molecular organization of dendrites and synapses from the viewpoint of lipids. The significance of the selective enrichment and avid retention of omega-3 essential fatty acids (docosahexaenoyl (DHA) chains of synaptic membranes and dendritic membrane phospholipids) has remained, until recently, incompletely understood. We contributed to the discovery of the docosanoid synthesized from DHA by 15-lipoxygenase-1, which we dubbed neuroprotectin D1 (NPD1). This mediator is a docosanoid because it is derived from a 22C precursor (DHA), unlike eicosanoids, which are derived from the 20 C arachidonic acid family of essential fatty acids not enriched in the nervous system. We found that NPD1 is promptly made in response to conditions that might disrupt homeostasis. Thus we envision NPD1 as a protective sentinel of synaptic circuitry.

Using epileptogenesis as a model to explore key mechanisms that sustain neuronal network integrity, we found that NPD1 increases during seizures in the hippocampus, and when we administered this docosanoid during epileptogenesis it elicted a remarkable attenuation of pathological brain oscillations. This effect reflects attenuation of aberrant neuronal network activities that lead to spontaneous recurrent seizure. We used multi-microelectrode arrays in freely moving mice. Thus, docosanoid-mediated signaling rescues neuronal network disruptions.

Neuroinflammation, Protein Misfolding and Alzheimer's Disease

Nicolas G. Bazan

Since protein misfolding and proteotoxic stress are involved in early stages of neurodegenerations, we explored these events in cellular models, including primary neuronal mix cultures. We found NPD1 decreased phospho-Ser-776 in Ataxin-1 by counteracting PP2A inhibition, allowing the 82Q form to be de-phosphorylated and cleared or relocated into the spliceosome. Neuronal circuitry impairments likely involve overexpression of the normal part of the misfolded protein. Thus in addition to expansions in the poly-glutamine tract, AXH has an important role in Ataxin-1 functionality. AXH, a self-folding domain present in Ataxin-1, is responsible for protein-protein interactions between Ataxin-1 and transcription factors, such as capicua homolog CIC protein. Sequestration of the complex partners formed by Ataxin-1 by its inactive counterpart may be involved in the loss of function.

We found NPD1 is drastically reduced in CA1 areas of Alzheimer's patients. Therefore we explored the significance of NPD1 in cellular models that recapitulate part of the Alzheimer's pathology. Human neurons and astrocytes challenged by amyloid-β or by overexpressing APPsw show NPD1 downregulates amyloidogenic processing of amyloid-β precursor protein, switches off pro-inflammatory gene expression, and promotes neural cell survival. Moreover, anti-amyloidogenic processing by NPD1 targets α- and β-secretases and PPARγ receptor activation. The cell survival cascade and events that sustain neuronal network homeostatic integrity involve multiple checkpoints and signaling networks.

Hippocampal Mechanisms for Pattern Separation and Pattern Completion

Susumu Tonegawa

Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion.

Studies on Memory Engrams by Optogenetics

Susumu Tonegawa

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioral output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior. We labeled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labeled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labeled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

I shall also discuss the results of additional unpublished experiments on memory engrams.

Tinkering with the molecular machinery that registers and maintains memory in the neocortex.

Yadin Dudai

A combination of behavioral, pharmacological and molecular analyses in the behaving rat has culminated in the identification of key components of the molecular machinery that encodes, consolidates, maintains and modifies the memory of one-shot events in the mammalian cortex. The dissection of the molecular building blocks that subserve taste memory in the insular cortex provides an example. Some of the findings have already influenced the exploration of novel approaches to the amelioration of post-traumatic memories and phobia.

The consolidation of episodic memory: How it starts, does it ever end.

Yadin Dudai

The conversion of short- into long-term event memory, termed 'systems consolidation', is an intricate process that may take weeks and months to mature. Recent studies combining real-life behavioral paradigms and functional human brain imaging, have unveiled phases in which memory is registered and then transformed from one type of lasting representation to another, and the corresponding brain signatures. The processes and mechanisms uncovered can account not only for changes in the quality of event recollection over time, but also for the emergence of selective and false recollection.

Memory systems and the role of prior knowledge

Richard Morris

Contemporary neuroscience recognises the existence of a variety of semi-independent memory 'systems' that process different types of information and represent experience in distinct ways. This overview will offer an update on current thinking about memory systems, and specifically the issue of the long-term storage of traces after systems memory consolidation. Whereas this form of consolidation has sometimes been conceived as a process of 'transferring' information from one anatomical system or network to others, new research suggests that there may sometimes parallel memory encoding in neocortical and allocortical networks, with the activation of prior knowledge guiding the subsequent process of assimilation in a top-down manner. This new framework is a challenge to current textbook models of systems consolidation.

Synaptic tagging and capture

Richard Morris

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. Cellular consolidation to realise persistence can involve a diverse set of interacting mechanisms including neuromodulatory transmitters, diverse intracellular signal transduction pathways, gene activation etc. The synaptic tagging and capture model of protein synthesis-dependent synaptic potentiation offers a framework for thinking about cellular consolidation and the timescale over which cellular activity-dependent interactions may take place.

The Neurobiology of Recollection

Howard Eichenbaum

In humans, recollection is the capacity to bring to mind previous experiences and to use this information to solve new problems in life; and recollection requires hippocampal function. It would be quite useful to understand the circuitry in the hippocampus that supports recollection but, how do we study recollection in animals and what are the elements of recollection that are supported by hippocampal circuitry? Here I will present evidence that animals have a capacity for recollection that mirrors human performance, and that recollection is composed as memory for: (1) events as items in context, (2) episodes as sequences of events, and (3) networks of event and episode representations that can guide behavior in novel situations.

The hippocampus in space and time

Howard Eichenbaum

In humans, hippocampal function is generally recognized as supporting episodic memory, which is characterized by the organization of experience over time, whereas in rats, many believe that the hippocampus creates maps of the environment and supports spatial navigation. How do we reconcile the episodic memory and spatial mapping views of hippocampal function? Here I will discuss evidence that, during learning of what happens where, hippocampal place cells map the locations of events in their spatial context. In addition, I will describe recent findings that, during learning of what happens when map specific events within their temporal context. These findings support an emerging view that the hippocampus supports episodic memory by creating a "scaffolding" for the organization of events within their spatial and temporal context.

Neuromodulation and cortical memory function

Michael Hasselmo

Blockade of the modulator acetylcholine causes impairments in encoding of new memories. A range of different techniques have addressed the mechanism by which acetylcholine may enhance encoding of memory, ranging from cellular effects on the intrinsic properties of neurons to changes in the circuit dynamics of cortical networks.

Role of oscillations in memory function

Michael Hasselmo

Studies in a range of different species have found that cortical circuits involved in memory function show oscillations in a range of different frequencies. Recent data exhibits the potential functional role of these oscillations in the representation of space and time and preventing interference between encoding, retrieval and consolidation processes.

ground-breaking developments in neuroscience, such as optogenetics, in vivo 2-photon confocal microscopy, 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 formed, consolidated, altered 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 participants to the technologies and approaches critical to these studies.