Artist's rendering of nerve cells.
The study, published in the June 1 advanced online
issue of the journal Nature, is the first to show the ability to selectively
remove a memory and predictably reactivate it by stimulating nerves in the brain
at frequencies that are known to weaken and strengthen the connections between
nerve cells, called synapses.
"We can form a memory, erase that memory and we can
reactivate it, at will, by applying a stimulus that selectively strengthens or
weakens synaptic connections," said Roberto Malinow, MD, PhD, professor of
neurosciences and senior author of the study.
Scientists optically stimulated a group of nerves in
a rat's brain that had been genetically modified to make them sensitive to
light, and simultaneously delivered an electrical shock to the animal's foot.
The rats soon learned to associate the optical nerve stimulation with pain and
displayed fear behaviors when these nerves were stimulated.
Analyses showed chemical changes within the
optically stimulated nerve synapses, indicative of synaptic strengthening.
In the next stage of the experiment, the research
team demonstrated the ability to weaken this circuitry by stimulating the same
nerves with a memory-erasing, low-frequency train of optical
pulses. These rats subsequently no longer responded to the original nerve
stimulation with fear, suggesting the pain-association memory had been erased.
In what may be the study's most startlingly
discovery, scientists found they could re-activate the lost memory by
re-stimulating the same nerves with a memory-forming, high-frequency train of
optical pulses. These re-conditioned rats once again responded to the original
stimulation with fear, even though they had not had their feet re-shocked.
"We can cause an animal to have fear and then not
have fear and then to have fear again by stimulating the nerves at frequencies
that strengthen or weaken the synapses," said Sadegh Nabavi, a postdoctoral
researcher in the Malinow lab and the study's lead author.
In terms of potential clinical applications, Malinow,
who holds the Shiley Endowed Chair in Alzheimer's Disease Research in Honor of
Dr. Leon Thal, noted that the beta amyloid peptide that accumulates in the
brains of people with Alzheimer's disease weakens synaptic connections in much
the same way that low-frequency stimulation erased memories in the rats. "Since
our work shows we can reverse the processes that weaken synapses, we could
potentially counteract some of the beta amyloid's effects in Alzheimer's
patients," he said.
Co-authors include Rocky Fox and Christophe Proulx,
UCSD Department of Neurosciences; and John Lin and Roger Tsien, UCSD Department
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