Reports to the President 1994-95
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,
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
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.
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.
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.
Reports to the President 1994-95