Center for Learning and Memory
The mission of the Center for Learning and Memory is to decipher molecular, cellular, neuronal ensemble, and brain systems mechanisms underlying learning and memory and associated cognitive functions such as perception, attention and consciousness.
In order to fully understand complex cognitive phenomena such as learning and memory, it is necessary to analyze them at multiple levels of complexity: at the molecular level, at the synaptic level, at the cellular level, at the neuronal ensemble level, and at the level of behavior of a whole living animal.
At the center we accomplish these challenging objectives by applying, in combination, an assortment of cutting edge experimental technologies that include behavioral mutants of fly, molecular and cell biology, genomics, electrophysiology of cultured neurons and brain slices, two photon laser microscopy, combined behavioral and single-unit recording and analysis of monkeys, large scale recording of the activity of neuronal ensembles of freely behaving rodents, and a wide array of behavioral paradigms
Two faculty joined the center this year: Professor Mriganka Sur, Head of the Department of Brain and Cognitive Sciences, and Professor Morgan H. Sheng. Dr. Sheng is Professor in the Departments of Brain and Cognitive Sciences and Biology and the inaugural holder of the Menicon Chair in the Neurosciences in the MIT School of Science. He is also Associate Investigator with the Howard Hughes Medical Institute and Investigator at the RIKEN-MIT Neuroscience Research Center.
The center established a faculty affiliates program for the purpose of promoting and sustaining stronger communication and interaction among the different neuroscience units at MIT. In recognition of the excellence of their research and its particular relevance to CLM, four faculty affiliates were announced in 2001: Professor Martha Constantine-Paton, Department of Biology; Professor Ann M. Graybiel, Department of Brain and Cognitive Sciences; Professor William G. Quinn, Jr., Department of Brain and Cognitive Sciences; and Professor H. Sebastian Seung, Department of Brain and Cognitive Sciences.
Professor Earl K. Miller was appointed as Associate Director of the Center for Learning and Memory, and Donna Maria Ticchi was appointed as Assistant Director for Administration.
In June 2001, the Picower Foundation pledged a major gift for the Center for Learning and Memory. Funds will be used toward the construction of the new neurosciences building complex at MIT, four professorships for CLM faculty, and an endowment for CLM research operations. The neurosciences complex is currently in the planning stages, and CLM anticipates moving into its own new building in a few years.
Yasunori Hayashi's laboratory focuses on a region in the brain called the hippocampus, which is buried deep in the cerebrum. To study the phenomenon called long-term potentiation (LTP), the lab combines different technologies. They construct various recombinant neuronal proteins and express them in neurons using molecular biological techniques. Then they analyze the expressing cells using electrophysiological and two-photon microscope techniques. They also study another peculiar phenomenon in the hippocampus: neuronal regeneration. They use a genetically altered animal to specifically ablate this process and study the effect of loss of neuronal regeneration on learning and memory. Through these analyses, they would like to know the molecular events that mediates memory in the mammalian brain.
The focus of research in J. Troy Littleton's laboratory is the elucidation of the molecular mechanisms underlying synapse formation, function and plasticity. They combine molecular biology, protein biochemistry, electrophysiology, electron microscopy and imaging approaches with Drosophila genetics to investigate molecular mechanisms involved in neuronal signaling. Current genetic approaches in the lab include the identification and characterization of novel temperature-sensitive paralytic mutants in Drosophila as a tool to identify and study new components of neuronal signaling pathways. Many of these temperature-sensitive paralytic mutants alter synaptic sprouting, membrane excitability or synaptic transmission, thus allowing the researchers to pursue novel gene products involved in epilepsy, synaptic plasticity and synapse stability.
Guosong Liu's laboratory studied the functional maturation of glutamatergic synapses, a critical process during the formation of functional neural networks. They found that synaptic transmission at newly formed synapses is functionally "silent." In contrast to the prevailing hypothesis that silent synapses lack functional AMPA receptors, they found that these synapses contain functional AMPA receptors, but cannot release transmitters from presynaptic terminals properly. These results suggest that one aspect of synaptic maturation is an enhancement in the flux of transmitter delivery into the synaptic cleft and point out new directions for identifying the locus of synaptic plasticity.
The ability to group stimuli into meaningful categories is a fundamental cognitive process, but its neural basis has been a mystery. To explore this, Earl K. Miller's laboratory trained monkeys to categorize computer-generated stimuli as "cats" and "dogs." A morphing system was used to systematically vary stimulus shape and precisely define the category boundary. They found neural correlates of these categories in the lateral prefrontal cortex, a brain region associated with the highest levels of cognitive function. Also in the lab, they discovered that the ability to abstract principles or rules from experience allows behavior to extend beyond specific circumstances that have been directly experienced. For example, we learn the "rules" for restaurant dining from specific experiences and can then apply them to new restaurants. They explored its neural basis by recording from single neutrons in the prefrontal cortex (PFC) of monkeys trained to use two abstract rules. They were required to indicate whether two successively presented pictures were the same ("match") or different ("nonmatch"), depending on which rule was currently in effect. The most prevalent neuronal activity observed in the PFC reflected the coding of the "match" and "nonmatch" rules.
Elly Nedivi's laboratory has developed a highly sensitive subtractive cloning and differential screening method that has allowed them to identify and isolate a large pool of genes involved in neuronal plasticity. These 377 candidate plasticity-related genes (CPGs), approximately 210 of them novel, constitute the basis of study. One of the CPGs currently under full-scale investigation in the lab is CPG2. They found that CPG2 is a structural protein that is localized to dendritic spines and interacts with the actin cytoskeleton. Because of its similarity to members of the spectrin/dystrophin protein family, it is possible that CPG2 also functions to regulate attachment or localization of synaptic components to the membrane and/or cytoskeleton. Since CPG2 was cloned on the basis of its activity-dependent expression, it is intriguing to consider that it may also play a role in linking levels of neuronal activity and anchorage or distribution of synaptic components.
Morgan H. Sheng moved his laboratory from Massachusetts General Hospital/Harvard Medical School to CLM in July, 2001. The Sheng laboratory is interested in the cell biology of neurons and the molecular architecture of synapses (the communication junctions between neurons). Changes in the molecular structure of synapses and the connections between neurons underlie the ability of the brain to remember and adapt to experience (brain plasticity). By studying synapses at the molecular level, using biochemical, genetic and imaging approaches, they aim to discover the most fundamental mechanisms of brain plasticity. Current research is focused on the cell biology of glutamate receptors (the proteins that bind to the neurotransmitter glutamate and that mediate postsynaptic excitation) and on the regulation of dendritic spines (the specialized morphological compartment on which excitatory synapses are formed).
Mriganka Sur's laboratory, which joined CLM in October, 2000, demonstrated several basic mechanisms of plasticity in the developing and adult brain. In developing animals, his laboratory showed that mice lacking genes for ephrins A2 and A5 exhibit pronounced plasticity of retinal projections directed to the auditory thalamus. The ephrins act as barriers that normally prevent such plasticity. In adult animals, his lab showed that visual cortex neurons exhibit much greater plasticity of orientation tuning at pinwheel centers rather than at orientation domains. The basis for this difference is that neurons at pinwheel centers integrate inputs from diverse orientations, while neurons in orientation domains receive input from a narrow range of orientations. His laboratory showed that visual cortex in alert monkeys also exhibited orientation plasticity based on previously viewed stimuli, and such plasticity would serve to enhance the discrimination of orientations during the viewing of natural scenes.
Research in Susumu Tonegawa's laboratory focuses on the molecular, cellular, and neuronal ensemble mechanisms underlying learning and memory and associated cognitive functions of rodents. Their primary approach is to produce genetically engineered mice and analyze them with multifaceted approaches including molecular and cellular biology, histochemistry, electrophysiology of neuronal culture or brain slices, fluorescence-based microscopy, multielectrode physiology of awake animals and behavioral tasks. During the past year Tonegawa's laboratory made a groundbreaking discovery on the biological mechanisms of memory recall. It is our real life experience that the rich content of a memory can be recalled with very limited cues. This phenomena, referred to as "pattern completion," has fascinated many brain researchers but no underlying biological mechanism has been identified. By creating and analyzing a new strain of mouse in which a specific gene encoding a type of glutamate receptors (called NMDA receptors) is "knocked out" from a tiny brain area called area CA3 of the hippocampus, Tonegawa's laboratory identified a protein and an area of the brain that play a crucial role in memory recall.
Research in Matthew A. Wilson's laboratory addresses the question of how memories are formed and maintained within the mammalian nervous system. Of particular interest is the possible role of sleep in the long-term establishment of memory. By studying the interactions between brain areas using simultaneous neural recording techniques, they are pursuing the flow of mnemonic information during awake and sleep states between brain areas involved in memory formation and areas involved in higher-level cognition and decision making. They have found evidence of the formation of memory representations that generalize across experience based on similarity of temporally sequenced events. They have also recently found direct evidence of dreaming in rodents by identifying the reactivation during REM sleep of memory patterns established during recent awake experience.
Yasunori Hayashi received the Ellison Medical Foundation New Scholar in Aging Award.
J. Troy Littleton received the Searle Scholar Award and the James and Patricia Poitras Scholar Award in Neuroscience.
Guosong Liu was promoted to Associate Professor in the Department of Brain and Cognitive Sciences.
Morgan H. Sheng was named the Menicon Professor in the Neurosciences.
Matthew A. Wilson was awarded tenure in the Department of Brain and Cognitive Sciences.
More information about the Center for Learning and Memory can be found online at http://web.mit.edu/clm/.