How does the brain stores remote fear memory?

UC Riverside mouse study could lead to novel therapies for people living with PTSD.

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A remote fear memory is a memory of traumatic events that occurred in the distant past — a few months to decades ago. Previous research has revealed that while the hippocampus is involved in the initial development of fear memory, it gradually matures with time and becomes less reliant on the hippocampus. The brain’s ability to store recent fear memories has been extensively studied, but less is known about how the brain consolidates distant fear memories.

A new study by the University of California, Riverside, has spelled out the fundamental mechanisms by which the brain consolidates remote fear memories. The study suggest that the remote fear memories formed in the distant past are permanently stored in connections between memory neurons in the prefrontal cortex, or PFC.

Jun-Hyeong Cho, an associate professor of molecular, cell, and systems biology said, “It is the prefrontal memory circuits that are progressively strengthened after traumatic events, and this strengthening plays a critical role in how fear memories mature to stabilized forms in the cerebral cortex for permanent storage. Using a similar mechanism, other non-fear remote memories could also be permanently stored in the PFC.”

In previous studies, scientists mainly focused on the PFC, a part of the cerebral cortex implicated in remote memory consolidation.

Cho said, “We found a small group of nerve cells or neurons within the PFC, termed memory neurons, were active during the initial traumatic event and were reactivated during the recall of remote fear memory. 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, mice were exposed to an unpleasant sensation in a setting known as a context. They acquired the ability to link the context with the unpleasant stimuli. The mice responded by freezing when exposed to the same setting a month later, demonstrating that they could recall distant fear memories. The study demonstrated that connections (synapses) between memory neurons in the PFC, also known as prefrontal memory circuits, steadily strengthened after learning to fear. This strengthening enabled the PFC to store distant fear memories indefinitely.

Next, to extinguish the remote 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. 

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

“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.”

Scientists are planning to selectively weaken the prefrontal memory circuits and examine whether this manipulation suppresses the recall of remote fear memories.

Cho said“We expect the results will contribute to developing a more effective intervention in PTSD and other fear-related disorders.”

Journal Reference:

  1. Lee, JH., Kim, W.B., Park, E.H. et al. Neocortical synaptic engrams for remote contextual memories. Nat Neurosci (2022). DOI: 10.1038/s41593-022-01223-1
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