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New MIT tool probes brain circuits
January 24, 2008
Method applied to learning/memory pathway
Deborah Halber, News Office Correspondent
January 24, 2008
Researchers at the Picower Institute for Learning and Memory at MIT report in
the Jan. 24 online edition of Science that they have created a way to see, for
the first time, the effect of blocking and unblocking a single neural circuit in
a living animal.
This revolutionary method allowed Susumu Tonegawa, Picower Professor of Biology
and Neuroscience, and colleagues to see how bypassing a major memory-forming
circuit in the brain affected learning and memory in mice.
"Our data strongly suggest that the hippocampal neural pathway called the
tri-synaptic pathway, or TSP, plays a crucial role in quickly forming memories
when encountering new events and episodes in day-to-day life," Tonegawa said.
Image / Toshi Nakashiba, MIT
The green-stained section of this mouse hippocampus represents where the new
DICE-K technique blocked the neural-signal transmission in one of the
hippocampal circuits of the brain.
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"Our results indicate that the decline of these abilities, such as that which
accompanies neurodegenerative diseases and normal aging in humans, is likely to
be due, at least in part, to the malfunctioning of this circuit."
Combining several cutting-edge genetic engineering techniques, Tonegawa's
laboratory invented a method called doxycycline-inhibited circuit exocytosis-knockdown,
or DICE-K--an acronym that also reflects Tonegawa's admiration of ace Boston Red
Sox pitcher Daisuke Matsuzaka. DICE-K allows researchers for the first time to
induce and reverse a blockade of synaptic transmission in specific neural
circuits in the hippocampus.
"The brain is the most complex machine ever assembled on this planet," Tonegawa
said. "Our cognitive abilities and behaviors are based on tens of thousands of
molecules that compose several billion neurons, as well as how those neurons are
connected.
"One effective way to understand how this immensely complex cellular network
works in a major form of cognition like memory is to intervene in the specific
neural circuit suspected to be involved," he said.
Computing memories
The hippocampus, a seahorse-shaped brain region, plays a part in memory and
spatial navigation. In Alzheimer's disease, the hippocampus is one of the first
regions to suffer damage; memory problems and disorientation are among the
disease's first symptoms.
The hippocampus is made up of several regions--CA1, CA3 and the dentate gyrus--that
are wired up with distinct pathways.
The MIT study sought to determine how the interactions between neural pathways
and the hippocampal regions affect learning and memory tasks.
Imagine that the three hippocampal regions are computers, and neural pathways
are the conduits through which the computers get data from all over the brain.
The computers perform different tasks, so the types of data processing will
depend on which conduits the data travels through.
The hippocampus has two major, parallel information-carrying routes: the
tri-synaptic pathway (TSP) and the shorter monosynaptic pathway (MSP). The TSP
includes data processing from all three hippocampal regions, whereas the MSP
skips through most of them.
Using DICE-K, the researchers were surprised to find that mice in which the
major TSP pathway was shut down could still learn to navigate a maze. The
shorter MSP pathway was sufficient for the job.
However, the maze is a task that is slowly learned over many repeated trials.
When the mice were tested with a different task in a new environment that
required rapid learning and memory formation, the researchers found that the
mice with TSP shut down could not perform the task. Thus, the TSP pathway is
required for animals to quickly acquire memories in a new environment. "This
kind of learning results in the most sophisticated form of memory that makes
animals more intelligent and is known to decline with age," Tonegawa said.
In addition to Tonegawa, a Howard Hughes Medical Institute investigator, authors
include Picower Institute research scientist Toshiaki Nakashiba; postdoctoral
associate Jennie Z. Young; research scientist Thomas J. McHugh; and HHMI staff
affiliate Derek L. Buhl.
This work is supported by the National Institutes of Health and the RIKEN Brain
Science Institute.
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