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Mechanism Fuelling Fear Discovered

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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.


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. (Credit: iStockphoto/Viorika Prikhodko)


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.

Nat Neurosci. 2007 Jul 15; [Epub ahead of print]

A hippocampal Cdk5 pathway regulates extinction of contextual fear.

Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, Tsai LH.

[1] Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. [2] European Neuroscience Institute (ENI), Grisebach Str. 5, Medical School University Goettingen, Max Planck Society, Göttingen, 37077, Germany.

Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1-dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1-dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.

PMID: 17632506 [PubMed – as supplied by publisher]

Written by huehueteotl

July 23, 2007 at 8:50 am

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