Stress plays a pivotal role in shaping how the brain encodes and retrieves aversive memories, with profound implications for individuals with post-traumatic stress disorder (PTSD). A groundbreaking study from The Hospital for Sick Children (SickKids) reveals how stress-induced memory generalization occurs and highlights a potential intervention to restore memory specificity, offering hope for mitigating PTSD’s debilitating effects.
Stress can serve as both a motivator and a disruptor. For instance, recalling a stumble during a presentation may trigger stress before your next speech due to the brain’s association with the negative experience. However, traumatic stress, such as that caused by violence or anxiety disorders, often spreads beyond the original event. This phenomenon, known as stress-induced aversive memory generalization, can transform seemingly unrelated stimuli like fireworks or car backfires into triggers for fearful memories, significantly affecting daily life and intensifying PTSD symptoms.
Published in Cell, the study led by Drs. Sheena Josselyn and Paul Frankland, in collaboration with Dr. Matthew Hill from the University of Calgary, sheds light on the biological mechanisms behind this memory generalization. The team identified the role of endocannabinoid receptors on interneurons in moderating the size and specificity of memory engrams—the brain’s physical representation of memories. Blocking these receptors limited the formation of generalized aversive memories, redirecting stress responses to specific and relevant situations.
Using a preclinical model, researchers demonstrated that acute stress prior to an aversive event created larger, generalized memory engrams. These expansive engrams, composed of significantly more neurons than typical engrams, were retrieved even in safe environments, mirroring PTSD symptoms in humans. Stress increased the release of endocannabinoids, which disrupted interneurons responsible for constraining engram size, leading to the formation of overly generalized memories.
Dr. Josselyn likens the endocannabinoid system to a “velvet rope” controlling access to an exclusive club. Under stress, excessive endocannabinoid release “removes the velvet rope,” allowing a flood of generalized aversive memories. By selectively blocking endocannabinoid receptors on interneurons, the researchers successfully constrained engram size and reduced memory generalization, potentially alleviating one of PTSD’s most disruptive symptoms.
The study’s findings also connect stress-induced memory generalization with earlier research revealing larger, more generalized memory engrams in the developing brain. This similarity underscores a link between stress, engram size, and age, prompting further exploration of how stress might also impact positive memories.
“Our understanding of memory’s complexity continues to evolve,” says Dr. Frankland, who holds a Canada Research Chair in Cognitive Neurobiology. “As we uncover more about human memory’s biological underpinnings, we can develop real-world therapies for those facing psychiatric and neurological challenges.”
This research received funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Dutch Research Council, Niels Stensen Fellowship, ZonMw Memorabel, Alzheimer Nederland, the Toronto Cannabis and Cannabinoid Research Consortium, and the Brain Canada Foundation.
