MIT Reports to the President 1999–2000
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 new faculty members were recruited last year. J. Troy Littleton joined the center in as an Assistant Professor in the Department of Biology. He arrived at MIT in January, and has already acquired an NIH R01 grant and attracted four biology graduate students and two postdoctoral fellows to his lab. Yasunori Hayashi joined the Center in July from Cold Spring Harbor Laboratories. He is an investigator in RIKEN-MIT Neuroscience Research Center and an Assistant Professor in the Department of Brain and Cognitive Sciences.
Yasunori Hayashi’s laboratory focuses on a region in the brain called the hippocampus which is burried deep in the cerebrum. To study the phenomenon called long-term potentiation or 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. We 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 we would like to know the molecular events that mediates memory in mammalian brain.
The focus of research in 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 lab studies the mechanisms that control the levels of NMDA receptor activation at single synapses. This is a critical issue for the understanding of molecular mechanisms of synaptic plasticity. They found that the levels of NMDA receptor activation during synaptic transmission are determined by the concentration of transmitters in the synaptic cleft and can be enhanced by genetic modification of the NMDA gene. These findings shed new light on the mechanisms controlling NMDA receptor activation during synaptic transmission.
Earl Miller’s lab found a neural correlate of the concepts "match" and "nonmatch" in monkeys that could apply them to any image. They also found prefrontal neurons that conveyed which of 3 complex rules a monkey was currently using. Finally, they discovered a neural correlate of perceptual learning. After 5 days practice with a set of objects, monkeys were better at recognizing them when they were degraded with noise. Practice also resulted in fewer neurons being activated in their prefrontal cortices, but these neurons communicated more information and were better at discriminating the degraded objects compared to when they were novel.
At the cellular level little is known about mechanisms underlying activity-evoked synaptic remodeling during visual system development. In Elly Nedivi’s lab, screening a pool of candidate plasticity genes (cpgs) that they previously identified revealed a subset that are expressed in the developing visual cortex and are activated by light, suggesting they may be involved in activity-dependent aspects of visual system development as well as everyday efficient function. They are now using cpgs as molecular tools to probe activity-dependent plasticity in the visual system.
William Quinn’s laboratory isolates new Drosophila mutants that affect learning and clone the altered genes to discover genuinely novel information about learning and memory. One of the mutants they have isolated flunks one long-term memory test established by vertebrate researchers, but passes the second like normal flies. These studies indicate that there are at least two separate types of long-term memory. Understanding one form of long-term memory–consolidated memory–depends on cloning the mutant’s gene. The lab has localized the gene to a 180-kilobase interval of DNA on the fly’s X-chromosome and is intensively involved in finding the relevant gene transcript within this interval.
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. They have recently generated a new strain of mouse in which the NMDA-type glutamate receptor is specifically knocked out in the CA1 pyramidal cells of the hippocampus. Analyses of these mutant mice have shown that the function of a single protein (i.e., NMDA receptor) in a single type of neuron plays a crucial role in the acquisition of memory. In another study, we have shown that using a transgenic strategy that a hormone-like protein called brain-derived neurotrophic factor regulates the postnatal development of animals’ visual functions.
Research in Matthew Wilson’s lab 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 recently found direct evidence of dreaming in rodents by identifying the reactivation during REM sleep of memory patterns established during recent awake experience.
Earl Miller received the Troland Research Award from the National Academy of Sciences and the
Society for Neuroscience Young Investigator Award. Elly Nedivi holds the Fred and Carol Middleton Career Development Chair.
More information about the Center for Learning and Memory can be found on the World Wide Web at http://web.mit.edu/clm/.
Susumu Tonegawa
MIT Reports to the President 1999–2000