Though most people have nothing to fear but fear itself, those grappling with anxiety disorders and post-traumatic stress experience the feeling in a debilitating form.
Treatments for these conditions are currently available, but U of T physiologist Dr. Min Zhuo, working with colleagues in China and South Korea, may have stumbled across a promising new way to treat these conditions, by pinpointing the part of the brain where fear memory is stored. This they reported in a paper in the journal Neuron last month.
Previous research had hinted at the hippocampus (a sea-horse-shaped structure in the middle of the brain) and the amygdala (an almond-shaped structure located in front of the hippocampus) as potential sites for the origin of fear memories.
But Zhuo and his team discovered that the actual site is located in a part of the prefrontal cortex called the anterior cingulate cortex (ACC). Their results suggest that the pathways involved in the formation of fear memories are much more complex than initially thought.
A key player in that process, Zhuo found, is a type of molecule found on neurons, called NMDA receptors. (Receptors receive messages from other neurons in the form of molecules that bind to them, triggering a response.) NMDA receptors come in several flavours, NR1, NR2, and NR3, with another letter suffix attached.
In their experiment, the investigators injected the ACCs of mice with a compound that blocked the NR2B receptor. Then, the mice received pairings of a tone and shock, which elicited fear. The next day, the mice were placed back into the cages in which they were trained and their fear responses were measured.
Mice injected with the blocker of NR2B exhibited little fear compared to animals that received a neutral injection. They did not avoid the chamber in which they were previously trained, and exhibited little fear when exposed to the tone used in training. This showed that blocking these receptors blocks early memory for fear.
When the investigators examined brain slices of these mice, they found NR2B receptors in the prefrontal cortex. These findings lend support to their theory that NR2B receptors in the ACC receive signals that help form fear memories,
Although previous studies showed that selectively damaging areas of the prefrontal cortex does not affect fear memory, Zhuo and his colleagues argued that such a procedure can have more widespread effects in the brain than is intended.
“We believe that the current study, which combines genetic and pharmacological approaches, avoids many side effects when compared with brain-lesioning techniques.”
According to Zhuo, “NMDA receptors are important for inducing long-term plastic changes that code fear memory. NMDA NR2B receptors are a major subunit of NMDA receptors for this memory function.”
Zhuo said that “there are three main findings in this study. First, NMDA NR2B are the key protein for producing long-term plastic changes in the ACC. Second, ACC plays a key role in the formation of fear memory. Finally, pharmacological inhibition or genetic reduction of NR2B expression in the ACC reduced fear memory; providing the potential clinic treatment methods for [fear-related disorders].”
How can these findings be used to implement treatments in humans with fear-related disorders?
“We do not know right now. However, with new mechanisms for fear memory, we may introduce early treatment in patients,” said Zhuo.
Although such drugs may affect other forms of memory as well, Zhuo said that established memory should remain intact. It may take five to 15 years of research before this discovery makes it to medicine, but, said Zhuo, “I am sure that it is possible.”
