Researchers Identify Where Emotional Fear Memory And Pain Become Permanently Etched In The Brain

U of T physiology professor Min Zhuo and his colleagues ProfessorBong-Kiun Kaang of Seoul National University in South Korea, andProfessor Bao-Ming Li of Fudan University in China have identifiedwhere emotional fear memory and pain begin by studying the biochemicalprocesses in a different part of the brain. In a paper published in theSept.15 issue of Neuron the researchers use mice to show how receptorsactivated in the pre-frontal cortex, the portion of the brain believedto be involved with higher intellectual functions, play a critical rolein the development of fear. Previous research had pointed to activationin the hippocampus, an area buried in the forebrain that regulatesemotion and memory, as the origin of fear memory.

"This is critical as it changes how and where scientiststhought fear was developed," says Zhuo, the EJLB-CIHR Michael SmithChair in Neurosciences and Mental Health. "By understanding thebiomolecular mechanisms behind fear, we could potentially createtherapeutic ways to ease emotional pain in people. Imagine reducing theability of distressing events, such as amputations, to be permanentlyimprinted in the brain."

Zhuo says that fear memory does not occur immediately after apainful event; rather, it takes time for the memory to become part ofour consciousness. The initial event activates NMDA receptors --molecules on cells that receive messages and then produce specificphysiological effect in the cell -- which are normally quiet buttriggered when the brain receives a shock. Over time, the receptorsleave their imprint on brain cells.

By delivering shocks to mice, the researchers activated theNMDA receptors and traced a subunit of the molecule -- a protein calledNR2B -- long believed to be associated with fear memory in thehippocampus and the amygdala, an almond-shaped structure in front ofthe hippocampus. To further test the protein's influence, researchersreduced the amount in mice and found they were less hesitant to avoidshocks. "We tested the animals using both spatial and auditory cues,"Zhuo says. "In one experiment, the mice received small shocks whenentering a chamber and they developed fear memory. In anotherexperiment, we used sound tones to be associated with shocks. When NR2Bwas blocked, they no longer avoided the chamber or reacted to thetone."

Zhuo and his team then studied the mice's brain slices anddiscovered traces of NR2B in the pre-frontal cortex, supporting theirtheory that fear memory develops in that region. "By identifying NR2Bin the pre-frontal cortex of the brain, we propose that fear memoryoriginates from a network of receptors, rather than one simple area,"Zhuo says. "It is more complex than previously thought."

The next step, according to Zhuo, is to determine how NR2Bdirectly affects memory formation and storage in the brain. "While weknow it exists in the hippocampus, amygdala and the pre-frontal cortex,we don't know exactly how it alters them," Zhuo says. "Once weunderstand the implications for each part, we will be able to reducelevels of NR2B accordingly and effectively reduce fear memory. In thefuture, perhaps people can take therapeutic measures beforeexperiencing a particularly discomforting situation." The University ofToronto Innovations Foundation is currently working with Zhuo to pushfor the translation of this finding into treatments.

The research was funded by the Canadian Institutes of HealthResearch, the National Institutes of Health, the EJLB-CIHR MichaelSmith Chair in Neurosciences and Mental Health, Canada Research Chairsand NeuroScience Canada. This project is also supported by the exchangeprogram between Seoul National University and the University ofToronto.