Mouse study may lead to new therapies for people living with PTSD — ScienceDaily

A distant fear memory is a memory of traumatic events that occurred in the distant past – a few months to decades ago. A mouse study from the University of California, Riverside published in Nature Neuroscience have now mapped out the basic mechanisms by which the brain consolidates remote fear memories.

The study shows that remote fear memories formed in the distant past are permanently stored in connections between memory neurons in the prefrontal cortex, or PFC.

“It is the prefrontal memory circuits that gradually strengthen after traumatic events, and this strengthening plays a critical role in how fear memories mature into stabilized forms in the cerebral cortex for permanent storage,” said Jun-Hyeong Cho, an associate professor of molecular, cellular and systems biology, who led the study. “Using a similar mechanism, other non-fearful remote memories can also be permanently stored in the PFC.”

The brain uses distinct mechanisms to store recent versus remote fear memories. Previous studies have suggested that while the initial formation of fear memory involves the hippocampus, it gradually matures over time and becomes less dependent on the hippocampus. Much research now explains how recent fear memory is stored, but how the brain consolidates external fear memories is not well understood.

The researchers focused on the PFC, a part of the cerebral cortex that has been implicated in external memory consolidation in previous studies.

“We found a small group of nerve cells or neurons in the PFC, called memory neurons, were active during the initial traumatic event and were reactivated during the recall of the external fear memory,” Cho said. “When we selectively inhibited these memory neurons in the PFC, it prevented the mice from recalling remote but not recent fear memory, suggesting the critical role of PFC memory neurons in the recall of remote fear memories.”

In the experiments, the mice received an aversive stimulus in an environment called a context. They learned to associate the aversive stimulus with the context. When exposed to the same context a month later, the mice froze in response, indicating that they could recall external fear memories. The researchers showed that connections (synapses) between memory neurons in the PFC, called prefrontal memory circuits, gradually strengthened over time after fear learning, and such strengthening helped the PFC to permanently store external fear memories.

Then, to extinguish the external fear memory in the mice, the researchers repeatedly exposed the mice to the same fear-predictive context, but without the aversive stimulus. The result was a reduced fear response to the context.

“Interestingly, the extinction of the external fear memory weakened the prefrontal memory circuits that were previously strengthened to store the external fear memory,” Cho said. “Unfortunately, other manipulations that blocked the strengthening of the PFC memory circuits also prevented the recall of external fear memory.”

Cho explained that a dysregulation of fear memory consolidation can lead to chronic maladaptive fear in PTSD, which affects about 6% of the population at some point in their lives.

“Considering that PTSD patients suffer from fear memories formed in the distant past, our study provides an important insight into developing therapeutic strategies to suppress chronic fear in PTSD patients,” he said.

Next, Cho’s team plans to selectively impair the prefrontal memory circuits and examine whether this manipulation suppresses the recall of external fear memories.

“We expect that the results will help develop a more effective intervention in PTSD and other fear-related disorders,” Cho said.

The study was supported by a grant from the National Institutes of Mental Health.

Cho was joined in the study by Ji-Hye Lee, Woong Bin Kim and Eui Ho Park.

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Materials provided by University of California – Riverside. Originally written by Iqbal Pittalwala. Note: Content may be edited for style and length.

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