MIT Reports to the President 1998-99
The Center for Learning and Memory was established in May 1994 as an interdepartmental research center between the Department of Brain and Cognitive Sciences and Department of Biology. The Center's primary research interest is to study the mechanisms underlying learning and memory using multifaceted approaches. Susumu Tonegawa was appointed as the first Director of the Center in May 1992. Matthew A. Wilson joined as an Assistant Professor on 1 July 1994. William G. Quinn, who has been a faculty member in the Department of Brain and Cognitive Sciences since 1 July 1994, joined the Center on 1 April 1995. Guosong Liu and Earl K. Miller joined as Assistant Professors on 1 September 1996. Elly Nedivi joined the Center on 1 July 1998.
Financial support for research in the Center comes from many sources. The core of this support currently comes from the RIKEN Brain Science Institute in Japan, which has committed over $3.5M to April, 2000 and with anticipated renewals continuing through 2003.
Susumu Tonegawa's laboratory continued to study molecular, cellular, and neuronal ensemble mechanisms underlying learning and memory by creating a host of mutant mouse strains using genetic engineering techniques. These mice either lack or overexpress a specific gene in a restricted area of the brain and therefore the function of that gene in specific physiological processes is blocked or perturbed. Analysis of these mutant mouse strains in comparison with standard unengineered animals by a variety of methods revealed the functions of several genes in memory acquisition. In particular, they discovered that a specific neurotransmitter receptor called NMDA receptor in the hippocampus of the brain plays a crucial role in the acquisition of episodic memory consisting of spatial and temporal features. Mnemonic impairments are a hallmark of aging and major neurological diseases such as schizophrenia, Alzheimer's disease and Parkinson's disease. Thus, the elucidation of learning and memory mechanisms is highly relevant to mental health and mental illness.
Dr. Tonegawa's laboratory also studies the mechanism that underlies the influence of visual stimuli on the refinement of the neuronal connections in the visual system of very young animals. They discovered that a neurotrophic protein factor called BDNF plays a crucial role in the experience-dependent refinement of the visual system by its regulatory function during the maturation of a certain set (i.e. inhibitory) of neurons. This finding is relevant to the issue of nature vs. nurture in the development of a child's brain.
Matthew A.Wilson's laboratory has been studying brain activity during sleep in search of its relationship with learning and memory. They have recently identified the first evidence of structured dreams in rodents during periods of paradoxical sleep, also known as REM sleep. In humans, periods of REM sleep are associated with vivid dreams. By monitoring the activity of cells in a region of the brain associated with episodic memory in humans and spatial memory in rodents, researchers in the Wilson lab have been able to match patterns produced as an animal performed a simple behavioral task with patterns produced during REM sleep. This study represents the first demonstration of the neural correlate of a memory trace that carries the broad content and temporal structure that corresponds to an identified behavioral episode or series of related episodes. It also provides direct evidence for dreaming in animals and offers a tool for examining the role of sleep and dreaming in memory formation and consolidation.
In the past year, Earl K. Miller's laboratory has made several important discoveries regarding the role of the prefrontal (PF) cortex in cognition. One line of work examines the brain mechanisms that mediate voluntary shifts in attention. Attention is important for normal cognition; we can only analyze a small portion of the world at any given moment. Dr. Miller has found that PF neurons convey information about stimuli that the animal intends to pay attention to and reflect shifts of attention before many other brain regions. This suggests that the PF cortex is a "control center" for attention and may lead to drug therapies that alleviate diseases such as Attention Deficit Disorder. In another line of work, Dr. Miller has shown that PF neurons play a role in recalling long-term memories, a process often disrupted during the course of normal aging. Finally, Dr. Miller has been exploring the very essence of cognition; the mechanisms that acquire and represent the "rules" used guide our thoughts and behaviors. He has found that as monkeys learn that a given sensory stimulus instructs a certain action, information about them gradually merges together in PF activity, producing neurons "tuned" for these acquired task rules. In sum, Dr. Miller's work has provided important insights into the neural mechanisms that regulate which information gains access to cognitive functions as well as the mechanisms that control them.
William G. Quinn obtained most exciting results with the amnesiac gene. The amnesiac mutant in Drosophila was isolated on the basis of its short memory span. The gene was transpositionally cloned, sequenced, and found to encode a peptide neurotransmitter that had significant homology to mammalian PACAP (pituitary-adenylyl-cyclase-activating-peptide. More recently, another lab has selected for ethanol-sensitive mutants, and on the basis of this screen has isolated new alleles of amnesiac. The gene therefore, is evidently important both for intermediate-term memory storage and for resistance to alcohol intoxication. The crucial questions are: how and where does the amnesiac gene product (a neurotransmitter) act in the fly brain, and are there close mammalian homologues, which might have potential relevance to human memory storage and psychoactive drug metabolism. To this end we have created rabbit antibodies to the inferred amnesiac gene product, we have affinity-purified these antibodies, and we have demonstrated their specificity and functional localization in Drosophila. This sets the stage for an informed screen for mammalian homologues using expression libraries.
Guosong Liu has made significant progress in several projects within the last year. He determined the origin of quantal variation and demonstrated that release of transmitter from a single package of transmitter is insufficient to activate all AMPA receptor and the trail-to-trail variation of synaptic events is due to variation of glutamate concentration in synaptic cleft. This result is published recently in Neuron. His lab extended this study and demonstrate that the concentration of glutamate in synaptic cleft is also insufficient to saturate NMDA receptor (manuscript to be submitted). These findings have important implications for understanding glutamatergic synaptic transmission and synaptic plasticity.
Also Dr. Liu has attempted to characterize postsynaptic differentiation during glutamatergic synapse formation. Understanding this process is critical for understanding synapse formation during development and plasticity. His lab has developed a novel biophysical approach that overcomes the limitations of previous immunocytochemical and electrophysiological approaches used to study this issue. They determined the distribution and density of functional glutamate receptors before and after synaptogenesis, the time course of synaptic AMPA and NMDA receptor cluster formation, and the role of activity and glutamate receptor activation in the clustering of functional AMPA receptors during synapse formation. (submitted).
In collaborating with Dr. Tsien's lab at Princeton University, Dr. Liu's lab also studied the effects of over-expression of NMDA receptor subunit 2B on the gating properties of NMDA receptor in a single synapse. We found that enhanced coincidence-detection by the NMDA receptor can result in better learning and memory in the adult animals, and has also pointed to a specific role of NMDA receptor 2B in gating synaptic plasticity and memory formation in the mammalian brain. (Nature in press).
Elly Nedivi's lab has been studying how learning and memory are specific cases of the brain's ability to modify connections in response to altered input. The property of the brain that allows it to constantly adapt to change is termed plasticity and is a prominent feature not only of learning and memory in the adult, but also of brain development. Connections between neurons (synapses) that are frequently used become stronger, while those that are unstimulated gradually dwindle away. How does activity modify a synapse to make it strong'? In the case of both developmental and adult plasticity, there is evidence that correlated neuronal activity induces expression of specific plasticity genes whose protein products then bring about molecular changes in the neurons, strengthening their response to a given stimulus. Their approach to understanding the cellular mechanisms of activity-dependent synaptic plasticity is to identify and characterize participating genes and their protein functions.
Dr. Nedivi has developed a highly sensitive subtractive cloning and differential screening method that has allowed us to identify and isolate a large pool of genes involved in neuronal plasticity (link, 93 nature). These 362 candidate plasticity-related genes (CPGs), approximately 240 of them novel, constitute the basis of our studies. The large number of CPGs isolated necessitates their priority ranking for further analysis. To asses how interesting each CPG is, how closely related it may be to plasticity and whether there are hints as to it function that could aid in its characterization, he is applying various selection criteria such as: sequence homologies and motifs, temporal and spatial expression patterns and regulation by physiological activity in the context of plasticity paradigms.
One of the first CPGs selected for full-scale characterization is CPG15, a small signaling molecule that is attached to the extracellular surface of neurons through a GPI link. In the adult rat, cpg15 is induced in the brain by kainate and in visual cortex by light. During development, cpg15 expression is correlated with times of afferent ingrowth,
dendritic elaboration and synaptogenesis. When overexpressed in the Xenopus retinotectal system in vivo, CPG15 promotes exuberant dendritic arbor growth in developing tectal neurons through an intercellular signaling mechanism that requires its GPI link. Our model for CPG15 action, based on immunocytochemistry and in situ hybridizations, proposes that CPG15 supplied by presynaptic neurons promotes dendritic arbor growth in their postsynaptic partners. This model predicts the existence of a CPG15 receptor (CPG15R) on cells responding to CPG15's growth promoting activity. Currently in the lab, CPG15 is being used as bait to try and fish out the CPG15R.
Dr. Nedivi's main approach to testing CPG participation in cellular events related to plasticity involves manipulating their expression in mammalian cell or slice preparations or in vivo using virally mediated gene transfer. The effect of cellular manipulation is then monitored by confocal microscopy for changes in neuronal morphology, or by electrophysiologically for changes is synaptic properties. Ultimately, the most interesting CPGs will be used for gene knock out' experiments where their in vivo effect on development of brain anatomy and physiology, as well as adult cortical plasticity, will be determined. The first CPG that he is attempting to knock out in a tissue specific manner is cpg15.
MIT Reports to the President 1998-99