How Stress Impacts Your Memory
(Posted on Wednesday, February 5, 2025)
Stress is the brain’s natural response to fear, but it often disrupts memory in the process. When preparing for a big presentation or taking a difficult exam, stress can make it more difficult to recall information when you need it the most. These moments of acute stress are accompanied by a surge of hormones like cortisol that disrupt the brain’s ability to make and store memories. Intense periods of stress can have long-lasting effects on the brain. Individuals with post-traumatic stress syndrome (PTSD) become inundated with intrusive traumatic memories that make it difficult for them to distinguish between threatening and non-threatening stimuli. Now, a study from the University of Toronto may have uncovered the underlying mechanisms that keep people in cycles of fear and stress. How our brains react to stress may be mediated by how neurons are recruited into memory traces or engrams.
The team began their study by training a cohort of mice to undergo a threat discrimination task. To generate the effects of acute stress, half the mice were restrained for 30 minutes before the training. During the threat discrimination task, each mouse was introduced to two tones, one of which was paired with a foot shock. The control mice responded as expected by freezing to the tone paired with a shock but not to the other neutral tone. However, the mice that were restrained before the training displayed equally fearful responses to the neutral tone. These mice seemingly failed to differentiate between the dangerous and safe stimuli, leading to generalization of the threat memory.
Fear generalization occurs when a learned fear response to one stimulus induces fear of other, otherwise neutral, stimuli. For example, a person that was bitten by a dog may develop a fear of all dogs, even those that appear calm and non-threatening. Individuals with PTSD and other anxiety disorders experience fears that become overgeneralized and difficult to avoid.
Each time a person undergoes stress the brain releases cortisol hormones. Cortisol binds to glucocorticoid receptors and tells the body to prepare its “fight-or-flight” response. This hormone also plays a vital role in maintaining blood pressure, blood sugar, and immunity. However, high levels of cortisol, such as during periods of extreme stress, has been found to impair the hippocampus, a region of the brain crucial for memory storage. The hippocampus normally acts as a negative feedback loop for cortisol, controlling how much is present in the body at any given time. When the body undergoes chronic stress, glucocorticoid receptors in this region become less sensitive to cortisol. This causes more and more of this hormone to be released throughout the body. The hippocampus becomes increasingly damaged, which disrupts the storage and retrieval of memories. Cortisol is believed to mediate fear generalization but until now the mechanism was not known.
Mice have a stress hormone analogous to cortisol called corticosterone. It is no surprise that when investigators measured corticosterone levels in their blood, the restrained mice had higher levels of this hormone, compared to the control mice. To determine if corticosterone mediates fear generalization, Lesuis blunted its activity by injecting glucocorticoid inhibitors into the bloodstream of each mouse. When put through the same training, the control mice experienced no change. The restrained mice, on the other hand, displayed a weaker fear response to the neutral tone, while maintaining appropriate fear of the shock-paired tone. Reducing corticosteroid levels seems to restore the ability to differentiate between threatening and non-threatening stimuli.
Next, Lesius found that injecting corticosterone into blood could induce fear generalization in the control mice. Fear generalization was greatest when the mice received a dose of 3 mL/kg of corticosterone, compared to levels higher or lower. This became the standard dose that they used for the rest of their experiments.
To understand the role of corticosterone in fear generalization, the team narrowed in the amygdala. Located next to the hippocampus, the amygdala processes emotional memories, especially those associated with fear. Each memory is represented by networks of neurons known as engrams. These neural networks are comprised of relatively few neurons. Whenever a memory is recalled, neurons in the engram light up, while others are inhibited or suppressed. Lesius findings suggest that the reduced inhibition of these neurons is what leads to fear generalization. In other words, as more neurons are recruited into the engram, fear is increasingly associated with otherwise non-threatening stimuli.
Using a triple neural tagging technique, the team applied visual markers to engram neurons active during the training, neurons activated in response to the shock-paired tone, and those activated when the second tone was presented alone. They found that a 3 mL/mg dose of corticosterone activated increased neurons during the threat discrimination task, thus increasing the size of the engram. The bigger the engram, the more salient the fear memory, making the mouse more likely to fear a non-threatening stimulus. These findings are consistent with how humans react to traumatic stimuli that trigger a high release of cortisol.
Upon further investigation, investigators were able to determine the mechanism through which corticosterone induces fear generalization. When corticosterone was injected directly into the amygdala of mice, Lesius observed a decrease in activity of inhibitory neurons during the threat conditioning experiment. Reduced inhibition of neurons not associated with a specific engram memory seems to be what leads to fear generalization.
Will what was found in mice translate to humans? Additional research is needed to determine how lifestyle factors and genetics influence stress and memory in humans. Reducing cortisol levels alone may not be the most effective way to reduce fear generalization and other chronic anxiety symptoms. Cortisol has numerous roles throughout the body that keep us alert and healthy. When accompanied with psychotherapy, it may be possible that weakening the activity of glucocorticoid receptors in select areas of the brain could alleviate symptoms among those experiencing extreme anxiety disorders, such as PTSD. With this study, we are one step closer to providing relief for the millions of people that struggle with these conditions.
