A new mouse study by scientists at UC Riverside (UCR) demonstrates that remote fear memories formed in the distant past are permanently stored in connections between memory neurons in the prefrontal cortex or PFC. Their findings provide insights and may lead to new treatments for people living with post-traumatic stress disorder (PTSD).

Their study, “Neocortical Synaptic Engrams for Remote Contextual Memories,” is published in Nature Neuroscience.

“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,” said Jun-Hyeong Cho, MD, PhD, an associate professor of molecular, cell and systems biology at UCR, who led the study. “Using a similar mechanism, other non-fear remote memories could also be permanently stored in the PFC.”

“While initial encoding of contextual memories involves the strengthening of hippocampal circuits, these memories progressively mature to stabilized forms in neocortex and become less hippocampus dependent,” wrote the researchers. “Although it has been proposed that long-term storage of contextual memories may involve enduring synaptic changes in neocortical circuits, synaptic substrates of remote contextual memories have been elusive. Here we demonstrate that the consolidation of remote contextual fear memories in mice correlated with progressive strengthening of excitatory connections between PFC engram neurons active during learning and reactivated during remote memory recall, whereas the extinction of remote memories weakened those synapses.”

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

The researchers showed that connections (synapses) between memory neurons in the PFC, termed prefrontal memory circuits, were gradually strengthened with time after fear learning, and such strengthening helped the PFC permanently store remote fear memories.

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

Looking toward the future, the researchers plan 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.

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