Witnessing Fear: How Bystander PTSD Changes the Brain

The study investigates how fear can be learned vicariously, that is, simply by observing another person or animal going through a traumatic experience. The researchers found that although the behavioral reactions of those who learn fear vicariously are similar to automatic reflexes, the processes in the brain are different and involve unique molecular signatures. These findings may help improve treatments for PTSD, considering differences between direct and indirect trauma, as well as possible variations between men and women.

Post-traumatic stress disorder (PTSD) is a serious anxiety disorder that can develop after a person experiences or witnesses a traumatic event.

Interestingly, it is not only those who directly suffer the trauma who can develop PTSD; approximately 30% of people who witness the suffering of another person can also experience the same symptoms.

This phenomenon is called bystander post-traumatic stress disorder and has been studied because it presents physiological and behavioral characteristics similar to PTSD in those who directly experienced the traumatic experience.

However, little is known about the differences in brain circuitry and molecular signatures between these two types of PTSD, as both are diagnosed and treated in the same way. Understanding these differences better could help develop more effective and personalized treatments.

Since the 1980s, scientists have used animal models to study the mechanisms of post-traumatic stress disorder, especially in relation to fear. One of the most common methods is fear conditioning, in which researchers teach an animal to associate a specific sound with an unpleasant event, such as a mild foot shock.

This allows researchers to observe how fear memories are formed in the brain and what biological processes are involved. Previous studies have shown that the amygdala, a region essential for processing emotions, plays a key role in creating these memories.

Research has also revealed that protein degradation, a process by which old or damaged proteins are removed from cells, is essential for the consolidation of fear memories. In addition, it has been identified that males and females may have different ways of processing and storing these memories due to variations in the way proteins are broken down in the amygdala.

Despite advances in the study of fear memory, most research has focused on individuals who directly experience a traumatic event. This means that we still know very little about how fear memories acquired indirectly, that is, simply by observing another person in danger, are formed and processed in the brain.

To investigate this question, scientists have developed a model of indirect fear learning (IFL). This model, also called social fear learning, has been studied in several species, including rodents and primates.

In rats, for example, one animal (the observer) watches another rat (the demonstrator) receive a footshock whenever a sound is emitted. After a few repetitions, the observer rat begins to show signs of fear when it hears the same sound, even though it has never received a shock itself. This indicates that it has learned the association simply by observing it.

Previous research has shown that some brain regions involved in direct fear, such as the amygdala and anterior cingulate cortex (ACC), are also activated when an animal experiences indirect fear. These regions also play a key role in empathy, the ability to perceive and respond to the distress of others.

Studies in humans and rodents have shown that neural activity in these areas increases both when a person or animal experiences pain and when they observe another person in pain.

In addition, communication between the anterior cingulate cortex and the amygdala has been found to be essential for the transmission of social fear, but it is not yet known whether the molecular pathways involved in vicarious fear learning are the same as those involved in direct fear learning.

In the current study, the scientists investigated the behavioral and molecular mechanisms that underpin vicarious fear memories. A particular focus was placed on protein degradation mediated by K48 polyubiquitination, a process that regulates memory formation in the brain.

The experiments involved 120 male and 104 female Sprague-Dawley rats, all aged between 8 and 9 weeks. The rats were housed in pairs and had free access to food and water, and were exposed to the experiment only during the light phase of the 12-hour light/12-hour dark cycle.

To ensure that the data was collected accurately and without human interference, the researchers used automated software to record the rats' behavioral responses during the tests.

The results of the study revealed that both male and female rats were able to learn fear indirectly, regardless of sex or familiarity with the demonstrator.

Behaviorally, the animals that acquired fear indirectly had reactions similar to those of pseudoconditioning, a phenomenon in which animals appear to react to the stimulus, but without actual learning.

However, when the researchers analyzed the molecular profile of the rats’ brains, they discovered something surprising: the molecular signatures of fear memories acquired indirectly were distinct from those of memories acquired directly and through pseudoconditioning.

This suggests that, even though the apparent behavior is similar, the biological processes involved are different. In addition, the expression of genes such as Egr2 and c-fos, which are associated with memory formation, was analyzed in a region of the brain called the retrosplenial cortex.

Interestingly, the observer rats showed gene expression patterns similar to those of the demonstrators, but very different from those of the pseudoconditioned rats. This reinforces the idea that vicariously acquired fear memories involve specific mechanisms and cannot be simply explained by reflexive behavior.

These findings have important implications for the study of bystander post-traumatic stress disorder. They suggest that vicariously acquired fear memories may have different biological mechanisms than memories acquired through direct experiences.

This means that treatments for PTSD may need to be tailored depending on how the fear was learned.

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Indirectly acquired fear memories have distinct, sex-specific molecular signatures from directly acquired fear memories

Shaghayegh Navabpour, Morgan B. Patrick, Nour A. Omar, Shannon E. Kincaid, Yeeun Bae, Jennifer Abraham, Jacobi McGrew, Madeline Musaus,

W. Keith Ray, Richard F. Helm, Timothy J. Jarome 

PLoS ONE 19(12): e0315564.

https://doi.org/10.1371/journal.pone.0315564

Abstract: 

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects women more than men. About 30% of patients suffering from PTSD develop the disorder by witnessing a traumatic event happen to someone else. However, as the focus has remained on those directly experiencing the traumatic event, whether indirectly acquired fear memories that underlie PTSD have the same molecular signature as those that are directly acquired remains unknown. Here, using a rodent indirect fear learning paradigm where one rat (observer) watches another rat (demonstrator) associate an auditory cue with foot shock, we found that fear can be indirectly acquired by both males and females regardless of the sex or novelty (familiarity) of the demonstrator animal. However, behaviorally, indirectly acquired fear responses resemble those of pseudoconditioning, a behavioral response that is thought to not represent learning. Despite this, using unbiased proteomics, we found that indirectly acquired fear memories have distinct protein degradation profiles in the amygdala and anterior cingulate cortex (ACC) relative to directly acquired fear memories and pseudoconditioning, which further differed significantly by sex. Additionally, Egr2 and c-fos expression in the retrosplenial cortex of observer animals resembled that of demonstrator rats but was significantly different than that of pseudoconditioned rats. Together, these findings reveal that indirectly acquired fear memories have sex-specific molecular signatures that differ from those of directly acquired fear memories or pseudoconditioning. These data have important implications for understanding the neurobiology of indirectly acquired fear memories that may underlie bystander PTSD.