How Stress Alters Memory and Leads to Unwanted Fear

A recent study on mice has revealed how stress alters memory processing in the brain, potentially leading to unwarranted fear responses. Researchers also identified drugs capable of reversing these effects, offering insights into possible therapies for anxiety and PTSD.

Stress-Induced Fear Responses

Stress appears to disrupt the brain’s memory packaging process, causing mice to react fearfully to neutral events. This may explain why stressed individuals often feel threatened in safe situations. For example, someone who burns their finger on a hot pan might avoid not only pans but cooking altogether. Such generalized fear is frequently seen in people with PTSD and generalized anxiety disorder.

The study, published in Cell, highlights how stress impacts memory formation, particularly memories tied to fear. “This paper is a tour-de-force,” said Ryuichi Shigemoto, a neuroscientist at the Institute of Science and Technology Austria. “They used many different methods to unravel this complex pathway.”

The Role of Engrams

Memories are stored in neuron groups called engrams, which activate when memories form. Sheena Josselyn, a neuroscientist at the Hospital for Sick Children in Toronto, and her team investigated whether stress disrupts engram formation in the amygdala, the brain region linked to stress and emotional responses.

In the study, adult mice were subjected to stress using methods like administering the hormone corticosterone or confining them in small tubes for 30 minutes. Later, they were placed in a chamber where they experienced two distinct sounds: one neutral and one paired with a foot shock to simulate a fear-inducing event.

When the mice were placed in a new environment and exposed to the sounds again, unstressed mice froze only at the fear-associated sound. Stressed mice, however, froze at both sounds, suggesting difficulty distinguishing between neutral and fear-linked experiences.

Stress Expands Memory Engrams

Using advanced techniques to observe neural activity, researchers found that unstressed mice created small engrams specific to the fearful event, reactivating only when exposed to the associated sound. Stressed mice, on the other hand, formed larger engrams that responded to both sounds.

Under normal conditions, inhibitory neurons in the amygdala regulate engram size by releasing gamma-aminobutyric acid (GABA). This “velvet rope” effect restricts neuron activation during memory formation. Stress disrupts this process, as excitatory neurons release endocannabinoids that prevent inhibitory neurons from releasing GABA. This results in larger engrams, akin to dropping the velvet rope and allowing excessive neuron activity.

Potential Drug Interventions

The research team found that two drugs, including mifepristone (commonly used to terminate early pregnancies), could reverse stress-related changes in memory formation. These drugs block glucocorticoid receptors or prevent endocannabinoid production, enabling stressed mice to process memories like their unstressed counterparts.

However, researchers warn these medications have significant side effects and are effective only when administered during memory formation, limiting their use in humans.

Future Directions

Josselyn’s team is now exploring whether engrams can be modified after memories have already formed or if alternative methods could mitigate stress’s effects on memory. These efforts could pave the way for new treatments for PTSD and anxiety disorders.