Picower Center for Learning and Memory

The Picower Center for Learning and Memory's mission is to understand the complex phenomena of learning and memory and the associated cognitive functions such as perception, attention, and consciousness. Research is focused on analysis of such functions at multiple levels of complexity: the molecular, cellular, synaptic, neuronal ensemble level, and the behavior of the whole living animal. The center's research not only advances our understanding of the brain with regards to learning and memory, but also has broader impacts in such diseases as Alzheimer's, Parkinson's, Schizophrenia, depression, and autism.

With a major gift from the Picower Foundation, the center is now poised for an expansion of faculty, added research and support staff, and more graduate and undergraduate students. Anthony Wagner of the Department of Brain and Cognitive Sciences joined the center this year as a faculty affiliate.

Faculty Research Developments

The Hayashia laboratory focused on the several projects on molecular biology of excitatory synaptic transmission. They have been working on the molecular mechanisms underlying long-term potentiation (LTP) of hippocampal CA1 synapse. They previously found that LTP induction delivers AMPA type glutamate receptor into the synapse which contribute to the enhanced transmission. Lab members are currently working to elucidate the detailed molecular mechanism of this phenomenon by combining electrophysiology, two-photon microscopy and molecular biology. They also found a motoneuron specific subunit of NMDA receptor subunit NR3B and currently testing if a dysfunction of this receptor causes motoneuron disease represented by amyotrophic lateral sclerosis.

The focus of the Littleton laboratory is to elucidate the molecular mechanisms underlying synapse formation, function and plasticity. They combine molecular biology, protein biochemistry, electrophysiology, and imaging approaches with Drosophila genetics to investigate the molecular mechanisms involved in neuronal signaling. Using DNA microarray analysis on conditional mutants in Drosophila that induce neuronal hyperexcitation, they have analyzed theDrosophila genome for activity-regulated gene expression in the fly brain. These approaches have allowed them to identify many previously unsuspected candidates for activity-dependent modulation of neuronal function. They are now determining how these genes contribute to cellular forms of behavioral plasticity by analyzing their ability to modulate neuronal function or connectivity. Together, these approaches should greatly expand the understanding of the basic mechanisms of synapse function and plasticity, as well as provide insights into expression changes that allow synaptic ensembles to store information through changes in neuronal connectivity and function.

The focus of the Guosong Liu Laboratory is to identify the principles that guide the formation of functional neural circuits. They continue to expand on their previous findings that presynaptic terminals undergo a major period of functional maturation during the initial phase of neural network formation and found several molecules (Shank, BDNF) that play an important role in controlling presynaptic maturation. Recently, his lab has discovered that the excitatory/inhibitory synapse ratio in a single dendritic tree is always conserved and the total amount of excitatory synaptic inputs per dendritic branch is scaled according to the surface area of the tree. Based on these findings, they propose a new rule that governs the organization of synaptic inputs in a dendritic tree.

The Miller Lab has made key discoveries of the neural basis of the high-level concepts, abstractions and functions that guide intelligent behavior. In trained monkeys, they have found neural representations of perceptual categories ("cat" vs. "dog"), abstract rules ("same" vs. "different"), and the numbers 1–5, and have also uncovered the neural dynamics underlying short-term memory. This work has resulted in two papers in Science, and one each in Nature, the Journal of Neurophysiology, and the European Journal of Neuroscience. They have also published a major theoretical paper in the Annual Review of Neuroscience as well as a number of book chapters and reviews.

The Nedivi lab has been working on characterizing CPG15, a gene they isolated in a forward genetic screen for activity-regulated genes that may play a role in synaptic plasticity. CPG15 encodes a small highly conserved protein, CPG15, which is attached to the extracellular membrane, and in its membrane bound form promotes growth of dendritic and axonal arbors, and synapse maturation. They recently discovered the existence of a second form of CPG15 that is secreted as a soluble extracellular molecule. This soluble form of CPG15 has a neuroprotective function, and can protect hippocampal neurons from cell death induced by serum starvation or apoptotic agents. CPG15's mode of action likely interferes with classically defined programmed cell death pathways. Thus, similarly to neurotrophic factors like BDNF and NGF, CPG15 has a dual role in the nervous system. It functions as both a survival factor that can rescue from cell death, and as a growth and differentiation factor that affects process outgrowth. In contrast to the neurotrophins where both functions are performed by the same secreted molecule, in the case of CPG15 the two forms mediate different functions. The soluble extracellular form of CPG15 mediates survival and protection from cell death, while growth and differentiation is mediated by the GPI linked, membrane-attached form.

Morgan Sheng's laboratory is interested in the molecular mechanisms by which synapses in the brain change their strength and connections in response to experience. A major way to strengthen synapses is to deliver more neurotransmitter receptors to the postsynaptic membrane. In the past year, fundamental rules governing the synaptic delivery of one class of glutamate receptor (AMPA receptor) were discovered. In addition, three specific proteins were shown to control the growth of synapses, particularly of dendritic spines (the specialized postsynaptic structures that compartmentalize synapses along the dendrite). A current effort is focused on global "proteomic" analysis of protein changes in synapses during different patterns of neural activity.

Mriganka Sur's laboratory carried out a range of experiments examining the development and plasticity of the cerebral cortex. Using the technique of gene microarrays, postdoctoral fellow Catherine Leamey discovered several genes that mark the initial development of visual and of somatosensory cortex. By recording physiologically from visual cortex in monkeys, postdoctoral fellow Valentin Dragoi discovered that networks of the visual cortex can alter their responses rapidly, on the time scale of visual fixation while scanning scenes, and that such rapid plasticity markedly influences vision.

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 few years Tonegawa's laboratory made a ground-breaking 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. This work is now published in the prestigious journal Science and drew wide attention, both in the neuroscience community as well as in the popular press.

Matt Wilson's laboratory has continued to focus on the role of the hippocampus in the formation and maintenance of memory in the mammalian nervous system. Recently published work in collaboration with Susumu Tonegawa has demonstrated for the first time, the role of the circuits within hippocampal area CA3 in the retrieval of partially cued memories which represents the manner in which memories are typically accessed in our everyday lives, identifying an explicit physiological correlate of memory retrieval through what is known as "pattern completion" (Nakazawa et al.) They have also advanced their understanding of the mechanisms of sequence memory formation and retrieval with the demonstration of sequence memory reactivation during slow-wave sleep, and identification of cellular mechanisms that could contribute to sequence memory encoding and retrieval (Mehta et al.).

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Faculty Honors and Awards

Troy Littleton received a Human Frontier Science Program junior faculty award and Alfred P. Sloan research fellowship.

Earl Miller was promoted to full professor, and serves on the following boards: Editorial Board, Journal of Neurophysiology; Editorial Board, Behavioral Neuroscience; Editorial Board for Cognitive Sciences, MIT Press; Advisory Board, Norwegian International Centre for Research on the Biology of Memory.

Morgan Sheng was elected President of the Society of Chinese Neuroscientists of America.

Mriganka Sur received the distinguished alumnus award, Indian Institute of Technology, Kanpur, was named a fellow of the Neuroscience Research Program and a fellow of the National Academy of Sciences, India.

Matt Wilson received a 2002 Picower scholars award.

Susumu Tonegawa
Picower Professor of Biology and Neuroscience

More information about the Picower Center for Learning and Memory can be found online at http://web.mit.edu/clm/.


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