A new study published in Cell looked at how stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice.
“We examined how acute stress impacted fearful memories,” study author Sheena Josselyn, Senior Scientist at Hospital for Sick Children told us. “We found that acute stress before a fearful event generalized the memory of this fearful event. That is, the subjects reacted fearfully both to the cues that predicted the fearful event and also safe cues.”
Although the researchers did not examine post-traumatic stress disorder (PTSD), it seems like a similar brain mechanism may be involved.
“We were hoping to understand better how acute stress changes the ways a fearful memory is encoded,” Josselyn told us. “We believe that better understanding this mechanism may lead to better, more effective and targeted treatments for disorders such as PTSD.”
The research lab examines how memories are typically formed, stored and used in the brain. The work, as well as the work of other scientists from around the world, shows that memories are encoded in a sparse subset of brain cells (neurons) called engram ensembles.
“We hypothesized that stress might affect the architecture these engram ensembles,” Josselyn told us. “We observed that indeed, stress made the engram ensemble supporting the fear memory less sparse, and in so doing, allowed inappropriate cues (safe cues) to reactivate this engram and produce fearful memory retrieval.”
The lab is very interested in understanding basic, fundamental brain processes in order to shed light on possible avenues for the development of future treatments for a number of human disorders. Previous research has shown that stress is an important determinant in PTSD and other anxiety disorders in humans, and the research team wanted to determine how stress impacted the fundamental process of storing a fearful memory.
“We tested our theory using a suite of cutting-edge tools in our model system. We used imaging techniques and found that the size (and hence, sparsity) of an engram ensemble was impacted by stress and then determined the mechanism underlying this effect,” Josselyn told us.
The team found that when their model organism was stressed, there was a release of endocannabinoids in one brain region that is critical in encoding and storing a fearful memory, the lateral nucleus of the amygdala.
“We found that these endocannabinoids act on a particular type of neuron (an inhibitory inteneuron) and this releases the ‘brakes’ on the size of the engram ensemble,” Josselyn told us. “In this way, stress increased endocannabinoid release which increased the size of the engram ensemble supporting a fearful memory and lead to fear memory generalization.”
The researchers were surprised by the effects.
“We were most surprised that the we restore memory specificity and the size of the engram ensemble by simply knocking out endocannabinoid receptors on inhibitory interneurons in the lateral amygdala,” Josselyn told us.
These results provide key insights into how stress impacts fear memory formation and may prove critical for the development of future treatments for disorders such as PTSD.
“We firmly believe that the development of effective, targeted therapeutics for a variety of brain disorders will only be possible if we have sufficient understanding of how the brain usually works,” Josselyn told us. “Just as it is nearly impossible to fix a car without basic understanding of how a car typically works, it will continue to be challenging to develop new treatments for a myriad of brain disorders if we do not have sufficient understanding.”