Researchers at The Hospital for Sick Children (SickKids) have discovered how stress alters the brain’s encoding and retrieval of negative memories, revealing a potential method for improving memory specificity in individuals with post-traumatic stress disorder (PTSD).
If you’ve ever stumbled over your words during a presentation, you may find yourself feeling anxious the next time you present, as your brain links that upcoming event with a negative past experience. This stress response pertains to a single memory. However, stress stemming from traumatic incidents, such as violence or generalized anxiety, can trigger feelings far beyond the initial event. This phenomenon is referred to as stress-induced aversive memory generalization, where common sounds like fireworks or car backfires may evoke unrelated fearful memories and negatively impact your entire day. For individuals with PTSD, these effects can be even more severe.
In a study featured in Cell, Drs. Sheena Josselyn and Paul Frankland, Senior Scientists in the Neurosciences & Mental Health program, investigate the biological mechanisms of stress-induced aversive memory generalization and present an intervention that could help improve memory specificity for those suffering from PTSD.
“Some stress is beneficial; it’s what motivates you in the morning when your alarm goes off, but excessive stress can be overwhelming,” states Josselyn, who serves as a Canada Research Chair in the Circuit Basis of Memory. “We understand that individuals with PTSD react fearfully to safe environments, and we have developed a method to confine this fearful reaction to specific situations, potentially alleviating the adverse effects of PTSD.”
In collaboration with Dr. Matthew Hill from the University of Calgary Hotchkiss Brain Institute, the research team was able to inhibit endocannabinoid receptors on interneurons, thereby restricting stress-induced aversive memory generalization to more relevant memories.
Understanding stress-induced memory generalization
In a preclinical model, the researchers subjected participants to a brief, safe stressor preceding a negative event designed to create a non-specific fearful memory, similar to the presentation of PTSD symptoms in humans.
The team then evaluated the participants’ memory engrams—physical manifestations of memory within the brain, which were initially explored by the labs of Josselyn and Frankland at SickKids. While engrams typically consist of a small number of neurons, the stress-induced memory engrams involved a significantly larger neuronal population. This amplification resulted in generalized fearful memories that could be activated even in safe environments.
Upon closer inspection of these extensive engrams, the study revealed that stress triggered an increase in endocannabinoid release (natural cannabinoids), which disrupted the function of interneurons that help regulate the engram size.
“Endocannabinoid receptors work like a velvet rope at an exclusive venue. When stress causes an excess release of endocannabinoids, the rope comes down, leading to the formation of more generalized fearful memories,” Josselyn explains. “By inhibiting these endocannabinoid receptors specifically in these interneurons, we could effectively mitigate one of the most debilitating symptoms associated with PTSD.”
A surprising connection between stress and the developing brain
Research conducted in 2023 and published in Science found larger, more generalized memory engrams in developing brains, similar to those formed under stress. As they continue to investigate this unexpected relationship between engram size, stress, and age, the teams are also examining how everyday stressors might affect positive memories.
“The diverse biological processes that contribute to the complexity of human memory are still being explored,” notes Frankland, who is also a Canada Research Chair in Cognitive Neurobiology. “We aspire to deepen our understanding of human memory, which may inform practical therapies for those dealing with various psychiatric and neurological disorders throughout their lives.”
This research received funding from the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), the Dutch Research Council, the Niels Stensen Fellowship, ZonMw Memorabel, Alzheimer Nederland, the Toronto Cannabis and Cannabinoid Research Consortium, and the Brain Canada Foundation.
