A distant fear memory is a memory of traumatic events that occurred in the distant past – a few months to decades ago. Previous research has shown that while the hippocampus is involved in the initial development of fear memory, it gradually matures and becomes less dependent 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 from the University of California, Riverside, has laid out the fundamental mechanisms by which the brain consolidates distant fear memories. The study suggests that the distant fear memories formed in the distant past are permanently stored in connections between memory neurons in the prefrontal cortex, or PFC.

Jun-Hyeong Cho, associate professor of molecular, cell and systems biology said: β€œIt is the prefrontal memory circuits that are gradually strengthened 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. Using a similar mechanism, other non-fear external memories can also be permanently stored in the PFC.”

In previous studies, scientists have mainly focused on the PFC, a part of the cerebral cortex involved in the consolidation of distance memory.

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

In the experiments, mice were exposed to an unpleasant sensation in an environment known as a context. They acquired the ability to link the context to the unpleasant stimuli. The mice responded by freezing when exposed to the same environment a month later, showing they could recall distant fear memories. The study showed that connections (synapses) between memory neurons in the PFC, known as prefrontal memory circuits, steadily strengthened after learning to fear. This amplification allowed the PFC to store distant fear memories indefinitely.

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

Cho said, “Interestingly, extinction of remote fear memory weakened prefrontal memory circuits that had previously been strengthened to store distant fear memory. In addition, other manipulations that blocked the amplification of the PFC memory circuits also prevented recall of fear memory at distance.”

“A dysregulation of fear memory consolidation can lead to chronic maladaptive anxiety in PTSD, which affects approximately 6% of the population at some point in their lives.”

“Given 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 anxiety in PTSD patients.”

Scientists plan to selectively attenuate prefrontal memory circuits and investigate whether this manipulation suppresses fear memory recall.

Cho said, “We expect the results to help develop a more effective intervention for PTSD and other anxiety-related conditions.”

Magazine reference:

  1. Lee, JH., Kim, WB, Park, EH et al. Neocortical synaptic engrams for external contextual memories. Nat Neurosci (2022). DOI: 10.1038/s41593-022-01223-1