New research shows that stress impacts how memories are formed and recalled, contributing to generalized memories typical in PTSD. By targeting endocannabinoid receptors, scientists can potentially refine memory retrieval, advancing PTSD therapy.
Researchers at The Hospital for Sick Children (SickKids) have discovered that stress significantly impacts how the brain encodes and retrieves negative memories. They also identified a promising method to restore memory specificity in individuals with post-traumatic stress disorder (PTSD).
Memory Generalization in PTSD
If you make a mistake during a presentation, for example, you might feel anxious the next time you present because your brain links that experience to your earlier failure. This kind of stress is typically tied to a single memory. However, stress from traumatic events, such as violence or persistent anxiety, can generalize beyond the initial experience. This phenomenon, called stress-induced aversive memory generalization, causes seemingly unrelated triggers—like fireworks or a car backfiring—to evoke fearful memories. While disruptive for anyone, in PTSD, this generalization can lead to far more severe consequences.
Biological Insights and Interventions
In a study published on November 15 in the journal Cell, Drs. Sheena Josselyn and Paul Frankland, Senior Scientists in the Neurosciences & Mental Health program, identify the biological processes behind stress-induced aversive memory generalization and highlight an intervention which could help restore appropriate memory specificity for people with PTSD.
“A little bit of stress is good, it’s what gets you up in the morning when your alarm goes off, but too much stress can be debilitating,” says Josselyn, who holds a Canada Research Chair in Circuit Basis of Memory. “We know that people with PTSD show fearful responses to safe situations or environments, and have found a way to limit this fearful response to specific situations and potentially reduce the harmful effects of PTSD.”
Together with their colleague Dr. Matthew Hill at the University of Calgary Hotchkiss Brain Institute, the research team was able to block endocannabinoid receptors on interneurons, and limit stress-induced aversive memory generalization to the specific, appropriate memory.
Stress-Induced Memory Generalization
In a preclinical model, the research team exposed subjects to an acute, but safe, stress before an aversive event to create a non-specific fearful memory that could be triggered by unrelated safe situations, similar to how PTSD presents in humans.
The team then examined the subject’s memory engrams, which are physical representations of a memory in the brain pioneered by the Josselyn and Frankland labs at SickKids. Usually, engrams are made up of a sparse number of neurons, but the stress-induced memory engrams involved significantly more neurons. These larger engrams produced generalized fearful memories that were retrieved even in safe situations.
When they looked closer at these large engrams, the study found that stress caused an increase in the release of endocannabinoids (endogenous cannabinoids) which disrupted the function of interneurons, whose role is it to constrain the size of the engram.
Memory and the Endocannabinoid System
“Endocannabinoid receptors function like a velvet rope at an exclusive club. When stress induces the release of too many endocannabinoids, the velvet rope falls, causing more generalized aversive fearful memories to form,” explains Josselyn. “By blocking these endocannabinoid receptors just on these specific interneurons, we could essentially prevent one of the most debilitating symptoms of PTSD.”
A Surprising Link Between Stress and the Developing Brain
In 2023, previous research in Science identified larger, more generalized memory engrams in the developing brain than in the adult brain, just like stress-induced memory engrams. As they continue to explore this unexpected link between engram size, stress, and age, the teams are also delving into how daily stressors may impact happy memories.
“The many biological functions and processes that make up the complexity of human memory are still being uncovered,” says Frankland, who holds a Canada Research Chair in Cognitive Neurobiology. “We hope that as we better understand human memory, we can inform real-world therapies for those with various psychiatric and other brain disorders throughout their lifespan.”
For more on this study, see Stress Scrambles Memories: New Insights From Neuroscience.
Reference: “Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice” by Sylvie L. Lesuis, Sungmo Park, Annelies Hoorn, Asim J. Rashid, Andrew J. Mocle, Eric W. Salter, Stefan Vislavski, Madison T. Gray, Angelica M. Torelli, Antonietta DeCristofaro, Wouter P.F. Driever, Mario van der Stelt, Larry S. Zweifel, Graham L. Collingridge, Julie L. Lefebvre, Brandon J. Walters, Paul W. Frankland, Matthew N. Hill and Sheena A. Josselyn, 15 November 2024, Cell.
DOI: 10.1016/j.cell.2024.10.034
This research was funded by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), the Dutch Research Council, Niels Stensen Fellowship, ZonMw Memorabel, Alzheimer Nederland, Toronto Cannabis and Cannabinoid Research Consortium and Brain Canada Foundation.
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