Received: by alpheratz.cpm.aca.mmu.ac.uk id DAA07533 (8.6.9/5.3[ref pg@gmsl.co.uk] for cpm.aca.mmu.ac.uk from fmb-majordomo@mmu.ac.uk); Fri, 7 Dec 2001 03:46:26 GMT Message-Id: <200112070341.fB73faZ06668@sherri.harvard.edu> Subject: Fwd: Research With Drosophila Provides Clues to Enhancing Human Memory Date: Thu, 6 Dec 2001 22:41:38 -0500 x-sender: wsmith1@camail2.harvard.edu x-mailer: Claris Emailer 2.0v3, Claritas Est Veritas From: "Wade T. Smith" <wade_smith@harvard.edu> To: "Memetics Discussion List" <memetics@mmu.ac.uk> Content-Type: text/plain; charset="iso-8859-1" Content-transfer-encoding: quoted-printable Sender: fmb-majordomo@mmu.ac.uk Precedence: bulk Reply-To: memetics@mmu.ac.uk
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
Boston
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
decades.
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
others.
"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
transistors."
PAVLOV'S FLIES
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
another.
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
shock.
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.
MEMORY SWITCH
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
material."
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.
BRAIN EXERCISE
"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
deficit.
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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