MIT Reports to the President 1994-95

Center for Learning and Memory

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 1994. Matthew A. Wilson joined as an Assistant Professor on July 1, 1994. William G. Quinn who has been a faculty member in Department of Brain and Cognitive Sciences since July 1, 1994 joined the Center on April 1, 1995.


Susumu Tonegawa
The Tonegawa laboratory has been exploiting gene knockout technology to produce a series of mutant mice, each with a defined genetic deficiency. The brain functions chosen for analysis were 1) contextual and motor learning, 2) activity-dependent remodeling of synaptic connections that takes place during development, and 3) roles of the dopaminergic system in motor control, emotion, and drug addiction. In addition, the laboratory is developing second generation technology for gene knockout, brain region specific knockout, and inducible knockout.

For the analysis of learning and memory, Tonegawa has so far produced and analyzed mutant mouse strains, in each of which a gene encoding a protein kinase ([[alpha]] CaMkII or PKC [[gamma]]) or a glutamate receptor (NMDA receptor or metabotropic glutamate receptor) is deleted. Electrophysiological and behavioral analysis of the [[alpha]] CaMkII, PKC [[gamma]], and mGluR1 mutant mice suggest that the hippocampal LTP contributes to but is not the sole synaptic plasticity responsible for contextual learning. Likewise, data with mGluR1 mutant mice indicate that cerebellar LTD contributes to but is not essential for associative learning of eyeblink response.

NMDAR1 mutant mice die within the second postnatal day but have been useful in the demonstration of the essential role of this glutamate receptor in the activity-dependent formation of whisker-related patterns in the brain stem.

The anatomy of the brain from dopamine 1 receptor (D1) mutant mice is largely normal except for clear deficits in dynorphin expression in the striatum. Perhaps related to this is locomotion hyperactivity. The D1 mutant mice are extremely useful for assessment of the role of this dopamine receptor in addiction with drugs of abuse such as cocaine.

William G. Quinn
Fruit flies, Drosophila, can learn an associative odor-discrimination task, and they can remember the information for several days. The Quinn lab is investigating the molecular mechanisms underlying learning and memory storage by inducing and selecting single-gene mutations that affect learning and by engineering transgenic fly strains. They have previously shown that transgene constructs which transiently disrupt the activity second-messenger enzyme of a cyclic-AMP-dependent kinase (PKA) will also transiently disrupt learning. The molecular components immediately downstream from this kinase in the metabolic cascade are CREB gene-transcription factors, which are activated by PKA. Dr. Jerry Yin cloned and characterized genes for two such CREB proteins in the laboratory, and he helped engineer transgenic flies with inducible CREB gene fragments that block normal CREB activity. Behavioral test data from these transgenic flies in the laboratory of T. Tully at Cold Spring Harbor indicates that inducing the transgenes disrupts long term memory in Drosophila. Their long-term memory storage can be correlated with specific changes in expression in a biological system where the gene regulatory network can be traced further downstream.

Quinn's laboratory pioneered the use of transgenes to disrupt learning and memory. Nevertheless, in the long term they believe that the forward-genetic approach offers the surest path to genuinely novel information about learning. This approach involves (a) random induction of single-gene mutations, (b) behavioral selection among these to find the ones that affect learning or memory, (c) further behavioral characterization of those mutant fly strains that look promising, and (d) molecular cloning of the altered gene, to deduce enzyme function from sequence. Among the mutants they have isolated, amnesiac and radish are currently the most interesting. Amnesiac has been cloned and encodes a neuropeptide gene. Radish flies show nearly normal learning ability followed by steady memory decay. Most strikingly, radish, in contrast to other memory mutants, is almost entirely lacking in consolidated (anesthesia-resistant) memory but is normal in protein-synthesis dependent long-term memory. Using classical and molecular genetics methods, we have localized the radish gene to a 140-kilobase interval of DNA on the fly's X-chromosome. The Quinn laboratory is now using molecular methods to find the relevant gene transcript within this interval.

Matthew A. Wilson
How is experience represented and stored within the brain? A fundamental tenet of modern brain theory has been that information is coded in the coordinated activity of neuronal ensembles. Research in the Wilson laboratory focuses on the study of information representation across large populations of neurons in the mammalian nervous system, as well as on the mechanisms that underlie formation and maintenance of distributed memories in freely behaving animals.

To study the basis of these processes, Wilson employs a combination of electrophysiological, pharmacological, behavioral, and computational approaches. Using techniques that allow the simultaneous activity of ensembles of hundreds of single neurons to be examined in freely behaving animals, laboratory personnel are examining how memories of places and events are encoded across networks of cells within the hippocampus - a region of the brain long implicated in the processes underlying learning and memory. This theory was demonstrated in a recent experiment showing that ongoing patterns of neuronal ensemble activity can predict an animal's moment-by-moment position as it moves about in space.

These studies of learning and memory in awake behaving animals have led to the exploration of the nature of sleep and its role in memory. Previous theories have suggested that sleep states may be involved in the process of memory consolidation, in which memories are transferred from short- to longer-term stores and possible reorganized into more efficient forms. Evidence of this was found when ensembles of neurons within the hippocampus, which had been recently activated during subsequent sleep periods, became reactivated during subsequent sleep periods, suggesting the presence of dream-like states. By reconstructing the content of these states, specific memories can be tracked during the course of the consolidation process. Pharmacological and genetic manipulations of these systems allows Wilson's lab to investigate the role of putative mechanisms of learning and memory on neuronal activity in the freely behaving animal. Laboratory work also employs computational and biophysical modeling of the hippocampus and related memory systems as a means of guiding hypothesis formation and interpreting experimental data.


At least two collaborative projects among the three laboratories were established as a result of the discussion group meetings. The Wilson and Tonegawa laboratories began extending Dr. Wilson's multielectrode approach, developed for rats, for application to mice. This collaboration will allow the analysis of memory mutants that are either already available or will be produced in the Tonegawa laboratory by Wilson's multielectrode approach. Such experiments may be helpful in linking experience-induced changes in the activities of ensembles of neurons to the activity of specific gene products. Presently Dr. Tonegawa's graduate student, Thomas McHugh, is working in Dr. Wilson's laboratory to develop the mouse multielectrode analysis system.

A second collaboration between the Quinn and Tonegawa laboratories is in the exploratory stages. Dr. Quinn's laboratory previously demonstrated that the Drosophila amnesiac mutant harbors an impairment in long-term memory and has recently shown that the gene encodes a neuropeptide. Dr. Quinn's laboratory is currently cloning the mouse homologue of this gene. If successful, the Tonegawa lab will produce a mouse and analyze the mouse mutant in which the amnesia gene is knocked out.


In December, the Center for Learning and Memory organized a bimonthly Neural Plasticity Club among 12 laboratories located within the Center, the Department of Brain and Cognitive Sciences, and the Biology Department. The laboratories that participated were those of Drs. Emilio Bizzi, Ann Graybiel, Robert Horvitz, Vernon Ingram, Rudolf Jaenisch, Arthur Lander, Tomaso Poggio, William Quinn, Hermann Steller, Mriganka Sur, Susumu Tonegawa, and Matthew Wilson. All laboratory personnel including graduate and undergraduate students attended. Meetings were usually held from 6:00 to 8:00 p.m. on the first and third Mondays of each month. At each meeting the head of a laboratory gave an overview of the research activity in his or her lab which led to lively and informal discussions. Occasionally a postdoctoral fellow or graduate student from the same lab supplemented the presentation with additional information. This event has been very useful in promoting interactions among MIT's laboratories interested in neurobiology and neuroscience, particularly the role of neural plasticity in learning and memory and neural development. In addition, the informal atmosphere elicited questions from students and postdocs and provided a educational opportunity for them.


Efforts have been made to raise additional funds from private sources. Documents for fund raising have been prepared and specific strategies are being discussed. So far, a few contacts have been made.

Susumu Tonegawa

MIT Reports to the President 1994-95