How stress is fundamentally changing our memories
The Hospital for Sick Children
Researchers at The Hospital for Sick Children (SickKids) have uncovered that stress changes how our brain encodes and retrieves aversive memories, and discovered a promising new way to restore appropriate memory specificity in people with post-traumatic stress disorder (PTSD).
If you stumble during a presentation, you might feel stressed the next time you have to present because your brain associates your next presentation with that one poor and aversive experience. This type of stress is tied to one memory. But stress from traumatic events like violence or generalized anxiety disorder can spread far beyond the original event, known as stress-induced aversive memory generalization, where fireworks or car backfires can trigger seemingly unrelated fearful memories and derail your entire day. In the case of PTSD, it can cause much greater negative consequences.
In a study published in 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.”
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.
Journal
Cell
Article Title
Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice
Article Publication Date
15-Nov-2024
Stress makes mice’s memories less specific
Stress is a double-edged sword when it comes to memory: stressful or otherwise emotional events are usually more memorable, but stress can also make it harder for us to retrieve memories. In PTSD and generalized anxiety disorder, overgeneralizing aversive memories results in an inability to discriminate between dangerous and safe stimuli. However, until now, it wasn’t clear whether stress played a role in memory generalization.
Now, neuroscientists report November 15 in the Cell Press journal Cell that acute stress prevents mice from forming specific memories. Instead, the stressed mice formed generalized memories, which are encoded by larger numbers of neurons.
“We are now beginning to really understand how stress impacts aversive memories, and I think that's good news for everybody,” says memory researcher and co-senior author Sheena Josselyn of The Hospital for Sick Children (SickKids) and the University of Toronto. “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.”
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 which had been 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 who had not been subjected to stress exhibited defensive freezing only in response to original sound.
Because the stressed mice had elevated levels of corticosterone in their blood, the researchers next tested whether corticosterone itself could impact memory formation. They showed that mice that received 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. Most engrams involve only a few neurons, but the researchers showed that the generalized engrams formed by stressed mice were larger, because inhibitory interneurons—gatekeeping cells that usually keep engrams exclusive—failed to do their job. This change, in turn, was driven by endocannabinoids that were released in the amygdala in response to corticosterone.
“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,” says stress researcher and co-senior author Matthew Hill of 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.”
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 (e.g., 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 a rewarding memories,” says memory researcher and co-senior author Paul Frankland, also at SickKids and the University of Toronto.
“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,” says Hill. “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.”
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This research was supported by the Dutch Research Council, Niels Stensen Fellowship, ZonMw Memorabel, Canadian Institutes of Health Research, Alzheimer Nederland, Toronto Cannabis and Cannabinoid Research Consortium, and the Brain Canada Foundation.
Cell, Lesuis et al., “Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice” https://cell.com/cell/fulltext/S0092-8674(24)01216-9
Cell (@CellCellPress), the flagship journal of Cell Press, is a bimonthly journal that publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. Visit http://www.cell.com/cell. To receive Cell Press media alerts, contact press@cell.com.
Journal
Cell
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice
Article Publication Date
15-Nov-2024
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