Why are fearful memories so hard to shake? The answer may lie in developmental changes in the extracellular environment in the amygdala -- the emotional center of the brain -- where such memories are formed, according to a study published this week in Science.

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"This is an extremely important observation because it suggests a mechanism for why fear memories are so indelible," neuroscientist Gregory Quirk of the University of Puerto Rico School of Medicine, who was not involved in the work, wrote in an email to The Scientist.

Memories of traumatic events can evoke excessive fear in inappropriate situations, in some cases leading to posttraumatic stress disorder (PTSD). One treatment for PTSD involves re-exposing individuals to elements of the bad event without the associated emotional trauma, in order to decrease the fear stirred up by the memory. In adults, this process, known as extinction, involves learning a new association -- between the event and safety -- as opposed to unlearning the original memory. Because the original association remains, however, the fear can resurface unexpectedly later in life.

Unlike adults, young animals have no resistance to forgetting. In rats less than three weeks old, studies show, fear does not reappear after extinction training. Neuroscientist Andreas Lüthi of the Friedrich Miescher Institute for Biomedical Research in Switzerland and his colleagues set out to figure out why. They stained the amygdala of young mice with a fluorescent dye and identified a distinct structural change during the first few weeks of development that corresponded with the animals' abilities to unlearn fearful memories.

That difference was a marked increase in the number of perineuronal nets (PNNs) in the extracellular matrix on which cells live. These nets are highly organized systems of proteoglycans that surround the neurons, and are known to play a role in neuronal plasticity in the visual system. When the researchers injected an enzyme to degrade these nets before exposing the mice to a fearful experience, adults reverted to a juvenile-like state in which they were later able to forget the fear.

"This is a beautiful proof of principle that the adult brain is not fixed but you can reverse engineer it to a [juvenile-like] state," said neuroscientist Takao Hensch of Harvard University, who did not participate in the research. This discovery may eventually be relevant to the success of therapies for anxiety disorders, he added.

Quirk pointed out that incorporating these findings into a clinical setting may not be easy, however. Forgetting the fear took more than time; the animals still needed extinction training to get rid of the fear response, and dissolving the PNNs after the fear had been learned did not boost the effectiveness of the extinction training. This suggests that the PNNs act during fear memory formation, not forgetting, and thus may limit the clinical application of manipulating these neural nets, he said.

"A treatment based on this approach could not be given as an adjunct to extinction-based therapies," Quirk said. "Instead, the treatment would have to be given prior to the trauma, perhaps to individuals with a high likelihood of experiencing traumatic events."

Furthermore, the method used in this study was highly invasive, Hensch said. "We need to know better how these extracellular factors are regulated in the first place, so we could come up with some noninvasive behavioral therapy."

The next step, Lüthi said, is nailing down the mechanism by which the PNNs affect fear memory acquisition. The nets form specifically around a certain class of inhibitory neurons, suggesting that reorganization of inhibitory pathways may be involved. "[But] we don't really understand what synaptic connections [are involved and how] neurons change during normal extinction learning in adults," he said. "This will definitely require further experiments."


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Picturing Fear
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Fear: real and imagined
[3rd April 2001]