MIT Indentifies Mechanism Behind Fear - Work
Could Lead To First Drug For Post-Traumatic Stress Disorder
July 16, 2007
Researchers from MIT's Picower Institute for Learning and Memory have uncovered
a molecular mechanism that governs the formation of fears stemming from
traumatic events. The work could lead to the first drug to treat the millions of
adults who suffer each year from persistent, debilitating fears - including
hundreds of soldiers returning from conflict in Iraq and Afghanistan.
The team will report their results in the July 15 advance online publication of Nature
Neuroscience.
A study conducted by the Army in 2004 found that one in eight soldiers returning
from Iraq reported symptoms of post-traumatic stress disorder (PTSD). According
to the National Center for PTSD in the United States, around eight percent of
the population will have PTSD symptoms at some point in their lives. Some 5.2
million adults have PTSD during a given year, the center reports.
Li-Huei Tsai, Picower Professor of Neuroscience in the Department of Brain and
Cognitive Sciences, and colleagues show that inhibiting a kinase (kinases are
enzymes that change proteins) called Cdk5 facilitates the extinction of fear
learned in a particular context. Conversely, the learned fear persisted when the
kinase's activity was increased in the hippocampus, the brain's center for
storing memories.
Cdk5, paired with the protein p35, helps new brain cells, or neurons, form and
migrate to their correct positions during early brain development. In the
current work, the MIT researchers looked at how Cdk5 affects the ability to form
and eliminate fear-related memories.
"Remarkably, inhibiting Cdk5 facilitated extinction of learned fear in
mice. This data points to a promising therapeutic avenue to treat emotional
disorders and raises hope for patients suffering from post-traumatic stress
disorder or phobia," Tsai said.
Emotional disorders such as post-traumatic stress and panic attacks stem from
the inability of the brain to stop experiencing the fear associated with a
specific incident or series of incidents. For some people, upsetting memories of
traumatic events do not go away on their own, or may even get worse over time,
severely affecting their lives.
Treating these disorders involves methods geared toward making the behavior go
away, or become extinct, but the molecular mechanisms underlying the extinction
process are not well understood. However, Tsai said, studies have shown that
some of the molecular machinery that initially encodes the troubling memories
also regulates their extinction.
In the current work, genetically engineered mice received mild foot shocks in a
certain environment and were re-exposed to the same environment without the foot
shock. Mice with increased levels of Cdk5 activity had more trouble letting
go--or extinguishing--the memory of the foot shock and continued to freeze in
fear. Conversely, in mice whose Cdk5 activity was inhibited, the bad memory of
the shocks disappeared when the mice learned that they no longer needed to fear
the environment where the foot shocks had once occurred.
"In our study, we employ mice to show that extinction of learned fear
depends on counteracting components of a molecular pathway involving the protein
kinase Cdk5," said Tsai, a Howard Hughes Medical Institute investigator.
"We found that Cdk5 activity prevents extinction, at least in part by
negatively affecting the activity of another key kinase.
In addition to Tsai, authors include MIT affiliate Farahnaz Sananbenesi; Picower
Institute research affiliates Andre Fischer and Xinyu Wang; Christina Schrick
and Jelena Radulovic of Northwestern University; and Rachel Neve of McLean
Hospital in Belmont, Mass.
This work was supported by the National Institutes of Health and the National
Institute of Mental Health.
http://www.mit.edu
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