Stress can distort memory formation, linking negative experiences to unrelated events. While mild stress can enhance focus and motivation, excessive stress can blur memory boundaries, causing harmless situations to trigger fear responses. For PTSD sufferers, this phenomenon, known as stress-induced aversive memory generalisation, can disrupt daily life and intensify symptoms.

Senior scientists Dr. Sheena Josselyn and Dr. Paul Frankland led the study, in collaboration with Dr. Matthew Hill from the University of Calgary Hotchkiss Brain Institute. The team discovered that blocking endocannabinoid receptors on specific brain cells, called interneurons, could prevent the creation of overly generalised fearful memories. This breakthrough could pave the way for targeted PTSD therapies.

Using preclinical models, researchers exposed subjects to acute stress followed by an aversive event. This process replicated PTSD-like memory patterns where unrelated safe situations triggered fear. The team analysed memory engrams, physical representations of memories in the brain. Stress-induced engrams were significantly larger than typical engrams, involving more neurons, which led to the formation of generalised fearful memories.

Further examination revealed that stress increased the release of endocannabinoids—naturally occurring compounds in the brain—which disrupted the activity of interneurons. These interneurons, located in the amygdala (the brain's emotional processing centre), normally limit the size of memory engrams and maintain memory specificity. When excessive endocannabinoids were released, this gatekeeping function was impaired, causing the engrams to grow larger and more generalised.

"Endocannabinoid receptors act like a velvet rope at an exclusive club, controlling which memories are formed," explained Josselyn, who holds a Canada Research Chair in Circuit Basis of Memory. "When stress floods the system with endocannabinoids, the velvet rope fails, allowing unrelated fearful memories to form. By selectively blocking these receptors on interneurons, we could potentially prevent one of PTSD’s most debilitating symptoms."

The study builds on earlier findings published in Science, which showed that larger, more generalised memory engrams naturally occur in the developing brain. This similarity to stress-induced memory engrams suggests a potential link between age, stress, and memory processing. Researchers are now investigating how daily stressors influence positive memories and the broader implications for mental health across the lifespan.

"The complexity of human memory continues to reveal itself," said Frankland, who holds a Canada Research Chair in Cognitive Neurobiology. "By understanding how memories are shaped, we aim to inform therapies for psychiatric and neurological disorders affecting memory and emotional regulation."

This research highlights the intricate balance between stress, memory formation, and brain function, offering a path toward better treatments for PTSD and related conditions.

HT