Mechanism behind storage of remote fear memory by the brain

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 progressively matures with time and becomes less dependent on the hippocampus. Much research now explains how recent fear memory is stored, but how the brain consolidates remote fear memories is not well understood.

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

The study demonstrates 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 are progressively strengthened after traumatic events and this strengthening playas critical role in how fear memories mature to stabilized forms in the cerebral cortex for permanent storage," said Jun-Hyeong Cho, an associate professor of molecular, cell and systems biology, who led the study. "Using a similar mechanism, other non-fear remote memories could also be permanently stored in the PFC."

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

"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, "Cho said. "When we selectively inhibited these memory neurons in the PFC, it prevented the mice 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 anaversive stimulus in an environment called a context. They learned to associatethe aversive stimulus with the context. When exposed to the same context amonth later, the mice froze in response, indicating they could recall remotefear memories. The researchers showed that connections (synapses) betweenmemory neurons in the PFC, termed prefrontal memory circuits, were graduallystrengthened with time after fear learning, and such strengthening helped thePFC permanently store remote fear memories.

Next, to extinguish the remote fear memory inthe mice, the researchers repeatedly exposed the mice to the samefear-predictive context but without the aversive stimulus. The result was areduced fear response to the context.

"Interestingly, the extinction of remote fearmemory weakened the prefrontal memory circuits that were previouslystrengthened to store the remote fear memory," Cho said. "Moreover, othermanipulations that blocked the strengthening of the PFC memory circuits alsoprevented the recall of remote fear memory."

Cho explained that a dysregulation of fearmemory consolidation can lead to chronic maladaptive fear in PTSD, whichaffects 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 weaken the prefrontal memory circuits and examine whether this manipulation suppresses the recall of remote fear memories.

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

Reference:

Jun-Hyeong Cho et al,Neocortical SynapticEngrams for Remote Contextual Memories,Nature Neuroscience,DOI:10.1038/s41593-022-01223-1