Scientists at the Hospital for Sick Children (SickKids) have uncovered that stress changes how our brain encodes and retrieves aversive memories. The team’s research, including work in live mice, discovered a role for endocannabinoid (eCB) signaling in biological processes behind stress-induced aversive memory generalization. The scientists, headed by Sheena Josselyn, PhD, and Paul Frankland, PhD, both senior scientists in the neurosciences & mental health program, in addition, identified an intervention that might point to new treatment approaches for restoring appropriate memory specificity in people with post-traumatic stress disorder (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,” said 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.”
The researchers reported on their findings in Cell, in a paper titled, “Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice,” in which they concluded, “The present data increase our understanding of how stress, via eCBs, impacts memory at the circuit level and may provide potential avenues for therapeutic interventions in stress-related disorders.”
If you stumble during a presentation you might feel stressed the next time you have to present because your brain associates this memory with your next presentation. This type of stress is tied to one memory. Stress is also a double-edged sword when it comes to memory. While stressful or otherwise emotional events are usually more memorable, stress can also make it harder for us to retrieve memories.
Stress from traumatic events can also spread far beyond the original event. In PTSD and generalized anxiety disorder, overgeneralizing aversive memories results in an inability to discriminate between dangerous and safe stimuli. This stress-induced aversive memory generalization can spread far beyond the original event, where fireworks or car backfires can trigger seemingly unrelated fearful memories. “Inappropriately overgeneralized threat memories, in which there is a failure to discriminate dangerous from safe stimuli, are a hallmark of several psychiatric disorders, including post-traumatic stress disorder (PTSD) and generalized anxiety disorder,” the authors wrote.
However, until now, it wasn’t clear whether stress played a role in memory generalization. “Stress has been implicated in the genesis of PTSD and induces threat memory generalization,” the team continued. “Therefore, understanding how stress promotes threat memory generalization remains an important, and unanswered, question.”
To test whether stress impacts memory specificity, the researchers trained mice to associate one sound with stress, and another sound with no stress. Then, they tested the mice’s ability to react appropriately to the different sounds. Mice placed in an acutely stressful, controlled experience exhibited defensive behavior regardless of which sound was played to them, suggesting that the stressful experience interfered with their ability to form specific memories. In contrast, control mice that had not been subjected to stress exhibited defensive freezing only in response to the original sound.
The stressed mice had elevated levels of corticosterone (CORT) in their blood, and the researchers next tested whether corticosterone itself could impact memory formation. They showed that mice receiving corticosterone prior to training were also unable to form specific memories to the two sounds, and that administering metyrapone, a chemical that inhibits glucocorticoid synthesis, restored the ability of stressed mice to form specific memories.
Specific memories are encoded by groups of neurons called engrams. “Memories for events, including threatening events, are encoded by ensembles of principal neurons active during the event, termed a memory trace or engram ensemble,” the authors explained. Most engrams involve only a few neurons, but the researchers showed that the generalized engrams formed by stressed mice were larger, because inhibitory interneurons that usually keep engrams exclusive—failed to do their job. This change, in turn, was driven by endocannabinoids (eCBs) that were released in the amygdala in response to corticosterone.
The endocannabinoid system enhances memory formation and helps link lived experiences with specific behavioral outcomes. In the amygdala, the emotional processing center of the brain, certain “gatekeeper” interneurons have special receptors for endocannabinoids and help constrain the size of the engram and the specificity of the memory. But when too many endocannabinoids are released, the function of the gatekeeping interneurons is disrupted, causing an increase in the size of the engram.
“When we manipulated endocannabinoid receptors in just one particular cell type in one brain region, it restored memory specificity and the size of the engram,” said stress researcher and co-senior author Matthew Hill, PhD, a professor at the University of Calgary. “This whole phenomenon is mediated by a very discrete microcircuit in the amygdala, but you can do a systemic pharmacological manipulation and still prevent it, which is very encouraging from the perspective of whether this could one day be translated for therapeutic use in humans.”
Josselyn added, “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. By blocking these endocannabinoid receptors just on these specific interneurons, we could essentially prevent one of the most debilitating symptoms of PTSD.”
The authors stated, “… consistent with previous reports, we find that aversive learning mobilizes eCB signaling in the amygdala and extend these findings by showing that this effect is augmented by pre-exposure to systemic administration of CORT or stress … The current findings add to the rich literature on the role of eCBs in many brain regions in modulating and mediating the effects of stress on threat and anxiety, in addition to other behavioral and physiological responses to stress.”
Josselyn further commented, “We are now beginning to really understand how stress impacts aversive memories, and I think that’s good news for everybody … We were able to isolate the synaptic mechanisms that drove this and also show that this same phenomenon can be manipulated or blocked by using systemically available drugs.”
In 2023 Josselyn, Frankland, and colleagues reported on work that identified larger, more generalized memory engrams in the developing brain than in the adult brain, just like stress-induced memory engrams. As the researchers 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,” said 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.”
The authors concluded, “… this study provides insights into how acute stress induces threat memory generalization in mice at both the molecular and circuit level.” The findings, they suggested, “… offer potential avenues for therapeutic interventions aimed at ameliorating stress-induced memory alterations and may have implications for stress-related psychiatric conditions.”
In future, the researchers want to investigate whether stress also impacts the specificity of non-aversive memories. They also plan to examine whether exogenous cannabinoids—for example, cannabis—would have a similar effect on memory specificity, which could have implications for PTSD management.
“We only examined aversive threat memories, but it would be interesting to examine whether stress similarly increases the generalization of rewarding memories,” Frankland noted. Added Hill, “Given that this phenomenon involved the activation of endocannabinoid receptors, it would be very interesting to see if a stoned animal shows a similar generalization response. That’s one of the things that I’d be curious to quickly run as a follow up, because if it did, that would have some interesting implications given that the whole conversation that exists right now around cannabis and PTSD is very confusing.”
