Fwd: Research With Drosophila Provides Clues to Enhancing Human Memory

From: Wade T. Smith (wade_smith@harvard.edu)
Date: Fri Dec 07 2001 - 03:41:38 GMT

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    Subject: Fwd: Research With Drosophila Provides Clues to Enhancing Human Memory
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    I thought I sent this on a year ago, but maybe I didn't....

    - Wade

    Vol. 284 No. 22, December 13, 2000

    Research With Drosophila Provides Clues to Enhancing Human Memory

    M. J. Friedrich

    The sea slug, Aplysia, is not the only invertebrate with a memory that
    can provide clues to understanding how human memory operates. Although
    Aplysia was the organism of choice for the investigations into learning
    and memory of neurobiologist Eric Kandel, MD, of Columbia University, who
    recently shared the Nobel Prize in physiology and medicine, studies of
    the modest cognitive abilities of the fruit fly, Drosophila, also have
    been providing insight into the biologic and genetic basis of memory for

    This teaching machine is used to isolate memory mutantsflies that cannot
    associate an odor with electric shockamong the Drosophila studied. About
    100 flies enter it at one time.

    Researchers such as Tim Tully, PhD, of Cold Spring Harbor Laboratory in
    New York, have focused their efforts on elucidating the alterations in
    neuronal synapses that provide a physical basis for memory in Drosophila.
    They have identified numerous genes associated with memory and learning
    in the organism, and lessons derived from their work are helping to
    improve understanding of human cognitive functioning and are pointing to
    new therapies that may help treat various forms of cognitive dysfunction,
    said Tully at the American Neurological Association's annual meeting here
    in October.

    Although fruit flies are simple organisms with fewer genes in their
    genome and fewer neurons in their neural network than humans, they are
    still capable of an elemental form of learning, said Tully. Because many
    of the basic mechanisms of learning and memory have been shown to be
    evolutionarily conserved, research in one animal species sheds light on

    "We can do gene discovery in simple systems like the fly with every
    expectation that it is a fast track, an economy of scale, to come up with
    candidate genes involved in the process in humans," said Tully, who
    pointed out that the difference between organisms has to do with neural
    circuitry, not the underlying neural plasticity. In other words, "flies
    are Philco radios, and we are MacIntosh computers, but both run on


    The discovery of genes for behavior started in the laboratory of Seymour
    Benzer, PhD, at the California Institute of Technology 30 years ago with
    Drosophila. In the 1980s, Tully, a student of one of Benzer's students,
    joined the search for behavioral mutants that demonstrated deficits in
    learning and memory.

    "I applied a Pavlovian notion to this fruit fly task and essentially
    developed Pavlov's flies," he said. Pavlov had simplified learning into
    an elemental form namely, that of a change in behavior produced by the
    temporal association of two stimuli. "Because it's so simple, we believe
    it's the elemental form of more complex types of learning that humans are
    capable of."

    Behavioral mutants were isolated on the basis of a failure to demonstrate
    associative learning between an odor and an electric shock. The
    experiment was carried out in a multichambered "teaching machine" in
    which flies can be exposed to odors wafting through on air currents and
    can receive shocks from an electrifiable floor. The unit even has a tiny
    elevator that transports the flies from one stage of the experiment to

    Flies were loaded into a chamber, exposed to an odor, and administered a
    shock. Next, the chamber was cleared out and the flies were exposed to a
    second odor, but this time they received no shock. Finally, flies were
    transported via the elevator to another area of the unit where they were
    exposed to both odors and allowed to choose which they preferred. Most
    flies learned to move away from the odor associated with shock, but some
    did not. Controls were included in the experiments to show that flies
    were indeed learning and not just mimicking the behavior of other flies.
    Experimental design also demonstrated that the mutant flies' inability to
    learn truly resulted from the inability to make a connection between
    stimuli, not from a defective sense of smell or inability to react to

    Once the behavioral mutants were identified, their biochemical and
    molecular composition was studied. One mutant of particular interest,
    said Tully, had a defect in the gene coding for cyclic adenosine
    monophosphate response element binding protein (CREB), which is a
    transcription factor involved in regulation of new gene expression.
    Because evidence throughout the animal kingdom suggests that long-term
    memory formation requires protein synthesis, whereas short-term memory
    formation does not, Tully's group hypothesized that CREB might occupy a
    unique position in the pathway involved in turning on long-term memory.


    Subsequent studies showed that by disrupting CREB, the investigators
    could impair long-term memory. Conversely, they showed that by
    genetically switching CREB to an "on" position, they could produce a fly
    with the equivalent of a photographic memory. Enhancing CREB did not
    produce more memory per se; rather, it reduced the amount of practice
    needed to convert short-term memory to long-term memory.

    The fly with the enhanced CREB activity, quipped Tully, "was equivalent
    to those guys we PhDs hated in college- most of them went on to be MDs
    who could read a page in the text and remember the facts with no
    additional practice, while the rest of us toiled repeatedly over the same

    This research indicates that activity in specific neuronal circuits can,
    under the right circumstances, activate the so-called CREB switch and
    change and regulate gene expression in the underlying neurons, stated
    Tully. And the change in gene expression ultimately results in synaptic
    growth that changes and fine-tunes the neural circuitry.

    More recently Tully's group has been attempting to identify drugs that
    enhance the CREB switch in cell culture in a manner analogous to the
    genetic flipping on of CREB. They have identified 10 drugs so far that
    not only increase regulation of the CREB gene but also enhance the
    regulation of endogenous CREB-dependent genes in primary neuronal
    cultures and in flies. Preliminary results indicate that a partial
    enhancement of memory can be achieved by a feeding regimen with one of
    the chemicals, said Tully. "The drug is beginning to produce long-term
    protein synthesis­dependent memory from training conditions that normally
    only produce short-term memory." These experiments are now being carried
    out in rodent models and Tully said the results look promising.

    Should these drugs be proven to work safely and effectively, they could
    be used to enhance long-term memory formation in humans. Tully pointed
    out there is a growing body of evidence among cognitive psychologists
    that shows that specific experiences, or "brain exercises," can be used
    to drive the normal process of synaptic refinement. While these brain
    exercises improve memory on their own, memory enhancement drugs could be
    used to augment these exercises by turning up the CREB switch.


    "We think it might be possible to exercise your brain on a periodic
    basis, maximize the economy of that exercise by drug augmentation, and
    keep your brain fine-tuned longer into the aging process," he predicted.
    These drug enhancers also may be useful in improving treatment for
    individuals with cognitive problems, he added. For example, they could
    lessen the time it takes a patient to recover from a stroke by reducing
    the amount of practice needed to achieve improvement in the area of

    The search for other genes and pathways involved in memory formation
    continues in Tully's laboratory. In this quest, DNA microarray technology
    is proving invaluable. Microarrayspostage stamp­sized devices dotted with
    snippets of DNA or RNA that are used to study gene expressionare helping
    researchers not only to identify more genes that are transcriptionally
    regulated during long-term memory formation, but also to compare gene
    regulation during memory formation in healthy brains with gene expression
    in the dysfunctional brains of single-gene mutant flies. The
    pharmacological effects on genomic responses in both single-gene mutants
    and normal insects given drugs can also be observed with microarrays.

    As researchers identify more memory-related candidate genes in the fly
    that point to homologues in the human genome, fly genetics and genomics
    will help unravel what has seemed until recently an intractable puzzle-
    how human memory works.

    © 2000 American Medical Association. All rights reserved.

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