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Evidence That Neurons Prune Only “Twigs” to Rewire Themselves

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Duke Health News 919-660-1306

DURHAM, N.C. -- By using a laser microscope to spy on
individual nerve cells in living mice, researchers have
discovered that neurons' wiring remain largely stable,
providing a solid scaffold to accommodate the challenges in
their environment. Specifically, the scientists found that the
neuronal branches called "dendrites" remain largely unchanged
in the highly active olfactory processing region of the mouse
brain. Such evidence suggest that dendrites in the adult brain
form a stable background even in the face of ongoing changes
that form part of everyday experience.

Besides providing a better basic understanding of the
dynamic processes of brain rewiring, the researchers believe
their findings might yield insights into such disorders as
epilepsy and Alzheimer's disease, which are marked by aberrant
neural circuitry.

Dendrites are the branches of neurons that support the
multitude of interconnections by which one neuron triggers a
nerve impulse in its neighbors in the intricate neural pathways
of the brain.

The research was reported in the November 2003 issue of the
journal Nature
Neuroscience
by Howard
Hughes Medical Institute
investigator Lawrence Katz,
Ph.D., and colleague Adi Mizrahi, both at the Duke
University Medical Center.

"The brain faces two challenges in maintaining its
functionality in a changing environment," said Katz. "One is to
remain stable enough so that the basic things we need to do to
interpret the world remain consistent. And the other is to
continually adapt to the changing environment, which places a
high premium on the ability to alter neural circuitry."

The brain is known to undergo large-scale wiring during
embryonic development after such drastic events as a stroke or
loss of a limb. However, said Katz, a central question in
neurobiology is whether such dendritic alterations take place
during the formation of long-term memories.

To explore the nature of such rewiring, Mizrahi and Katz
studied neurons in the neural structure called the olfactory
bulb -- the collection of neurons that represent the initial
processing stage for information from odor sensing receptors in
the nose.

"The olfactory bulb is one of only two areas of the brain
where new neurons are being generated throughout life," said
Katz. "Neurons in the olfactory bulb are constantly losing
synapses linked to sensory cells that are dying and gaining new
ones connected to new sensory cells." Thus, he said, detailed
observation of those neurons should yield a clear look at
neurons in the process of rewiring during ordinary
experience.

The scientists used a laser microscopy technique that
enabled them to watch changes in specific neurons genetically
tagged with a fluorescent protein, as the mice were presented
with changes in their environment. The transgenic mice were
developed by Duke neurobiologist Guoping Feng, Ph.D., and his
colleagues.

"Importantly, this technique enabled us to look in real time
at the changes in a single neuron in the same animal; not at
populations of neurons and not at different animals," said
Katz. "We could follow over time how dendrites responded to
ongoing change." In initial studies, the researchers found only
subtle changes in the neurons.

"The changes bordered on the imperceptible -- like a tree
that lost or gained only a few twigs over time," said Katz. "It
wasn't what we initially thought, that the neurons would be
like rose bushes in spring, in which a tremendous amount of
dendritic structure would be gained." Even when the scientists
placed the mice in an enriched "Disneyland" of structures and
smells to explore, they saw few changes in dendritic structure.
This, despite the fact that other researchers had found that
manipulating the odor environment drastically increased
turnover of neurons in the olfactory bulb. Nor did the
scientists see significant changes when they taught the animals
to seek out a particular odor to gain a reward.

The only way they could induce major changes, they found was
to use the molecular "sledgehammer" of a drug known to make
neurons hyperactive, "so we knew they had the capacity to
undergo change," said Katz.

"We've concluded from these findings that the overall theme
of this area of the brain is stability, and that these
dendrites are not undergoing large-scale changes under natural
conditions, even in response to changes in their environment,"
said Katz. "My own view is that there is a large backbone of
stability in these areas and relatively low levels of
plasticity, despite the fact that new neurons are being
constantly generated," said Katz.

According to Katz ongoing studies are using the combination
of laser microscopy and cell tagging to study plasticity in
other regions of the brain, particularly the central site of
learning, the hippocampus.

Such studies could yield significant insights into disorders
that involve brain rewiring, he said. "Dendritic degeneration
is a hallmark of Alzheimer's disease, and dendritic changes are
known to occur in epilepsy," said Katz. "So, understanding what
is normal and what is pathological -- and the mechanisms that
produce such changes -- could offer insights into these
diseases." For example, he said, by crossing mouse strains that
show epilepsy with the fluorescently tagged strain, it would be
possible to study in detail alterations in dendritic wiring
that might contribute to the disorder.

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