How stress affects memory and causes anxiety

How stress affects memory and causes anxiety

Stress causes mice to form large bundles of neurons in their brains, disrupting memory formation and making them fearful of harmless situations 1. This could explain why stressed people often appear threatened in safe environments.

Researchers have long found that stress or trauma can cause people to fear harmless situations. After burning a finger on a hot pan, one could stressed person Avoid not just hot pans, but the entire kitchen or cooking. This type of generalized anxiety is often seen in people with post-traumatic stress disorder (PTSD) as well as generalized anxiety disorder.

A study published today in the journal Cell describes how stress can... Memory formation and in particular disrupts the memory of frightening events. The findings could influence the development of treatments for people with PTSD and anxiety disorders.

“This paper is truly a masterpiece,” says Ryuichi Shigemoto, a neuroscientist at the Institute of Science and Technology Austria in Klosterneuburg. “They used so many different methods and techniques to prove this long journey.”

Memory Packages: Memories are packaged into groups of neurons called engrams that are active when a memory is formed. Sheena Josselyn, a neuroscientist at the Hospital for Sick Children in Toronto, Canada, and her colleagues investigated whether stress affects the formation of engrams disturbs, particularly in an area of ​​the brain known as the amygdala, which is involved in responding to stress and emotions.

The study involved an elaborate three-stage experiment on mice. First, some adult mice were put into a stressed state by injecting them with the stress hormone corticosterone or forcing them into a small tube for 30 minutes, which resulted in increased corticosterone levels.

Afterwards, the mice - some stressed and some not - were placed in a chamber where a medium-pitched tone was played for 30 seconds, which was considered a neutral event. After a break, mice returned to the chamber and experienced a high-frequency whistle for 30 seconds, followed by a 2-second shock to the foot to simulate a fear-provoking event.

To test how the mice retained memories of these experiences, they were placed in a new environment and the two tones were repeated. The unstressed mice froze primarily when they heard the high-frequency whistle tone, while the stressed mice responded and froze to both tones, suggesting that they could not distinguish between the neutral and fear-provoking event.

Exclusive Club: The researchers used various techniques to visualize neural activity in the rodents. They found that during memory formation, the unstressed mice formed small engrams in response to the whistle and footshock that were only activated when exposed to the whistle. The stressed mice, on the other hand, formed larger engrams that were reactivated with both tones.

Further experiments revealed the chain reaction in the brain that led to larger engrams in stressed mice. Under normal conditions, certain neurons in the amygdala block neuronal activity by releasing chemical messengers known as gamma-aminobutyric acid (GABA). This ensures that a small engram is formed in response to a negative memory. “It's a bit like the velvet curtain in a nightclub: it only lets certain neurons into the nightclub,” says Josselyn. When stressed, excitatory neurons pump the brain full of a neurotransmitter called an endocannabinoid, which binds to glucocorticoid receptors on inhibitory neurons and prevents their GABA release, resulting in larger engrams. In other words, the velvet curtain falls and “a lot of neurons can get into this exclusive club,” explains Josselyn.

The team was able to reverse the effects of stress on memory formation using two drugs, one of which is approved for terminating early pregnancy, mifepristone. These drugs block either glucocorticoid receptors or the production of endocannabinoids, so the stressed mice were able to recall memories just as well as non-stressed mice. But researchers warn that the drugs have side effects beyond the brain and are only effective when given at the time of memory formation, so are unlikely to be of benefit to humans.

Josselyn and her colleagues are now trying to investigate whether engrams can be changed after memory formation or whether there are other ways to mitigate the effects of stress on memory.

1. Lesuis et al., Cell 188, (https://doi.org/10.1016/j.cell.2024.10.034) 2024.

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