Long-term Molecular Changes In The Brain Explain Susceptibility Or Resilience To A Traumatic Event

March 1, 2023

PTSD is a chronic mental health disorder. However, science still does not understand why some people are susceptible to the condition. Understanding why some develop PTSD when exposed to stress and others remain resilient may help develop better treatments. In the new study in mice, researchers found that mice susceptible to PTSD seem to have more glucocorticoid receptors in the hippocampus and increased HCN1 protein. PTSD is quite a common mental health issue, causing undue fear, sleep disruption, aggression, memory issues, social avoidance, and more in prone individuals. PTSD is not just about bad memories that can be readily overcome. Researchers have long known that it results due to some more permanent changes in the brain. That is why the condition is so challenging to cure.

Additionally, it is no secret that some individuals are susceptible to the condition. However, if two individuals are exposed to a similar kind of traumatic experience, it does not mean that both would develop PTSD. Some are quite resilient to traumatic experiences, while others are quite sensitive. All this means that there must be some biochemical differences in those susceptible to PTSD and resilient. Additionally, PTSD must be causing some brain changes that are difficult to reserve, and thus the condition is challenging to cure.

In a new study, researchers could identify molecular changes in the brain that make some people more susceptible to PTSD. In a study of a group of mice exposed to stress, an upsurge in stress hormone caused short-term excitability in the memory area of some mice, this initiating fight or flee response. However, in other genetically identical mice, such a response did not occur. Instead, researchers saw reduced excitability in the key brain area, the dorsal hippocampus. These were mice who later developed PTSD-like symptoms. Researchers published the findings of their study in the journal Molecular Psychiatry1.

Early studies suggest that such kind of low excitability of the dorsal hippocampus is quite characteristic of PTSD patients. Further, studies have shown that it has something to do with glucocorticosteroid receptors, which are expressed in greater numbers in the part of the brain in PTSD-prone individuals. To mimic the real-life situation of stress in mice, researchers introduced aggressive mice to the group of mice under investigation. However, the group of mice prone to PTSD avoided aggressors, quite like humans living with PTSD avert social interaction.

Individuals with chronic migraine disorder may be more susceptible to developing PTSD. It is important to identify and treat PTSD in patients with chronic migraine disorder to improve their quality of life. Effective post traumatic stress disorder treatment may include cognitive behavioral therapy, exposure therapy, and medications such as antidepressants and antipsychotics. The researchers found that the brain of mice prone to PTSD has an overexpression of receptors for stress hormones in the CA1 region of the dorsal hippocampus of the brain. Moreover, continuous stimulation of these receptors seems to increase the expression of protein HCN1, a protein that modulates neuronal connectivity in the hippocampus.

HCN1 protein was the primary focus of the study. Interestingly, researchers found that even a single stress episode was enough to induce increased production of HCN1 protein. It also increased TRIP8b protein in the susceptible mice. Thus, the study could not only shed light on the molecular mechanism of PTSD but also confirm that in susceptible mice, a single stressful episode is enough to cause PTSD-like brain changes. Additionally, they also found that these molecular changes are quite persistent and can be seen even months after exposure to stress. The susceptible mice not only avoided social interaction, but they also had poorer spacial memory. In humans living with PTSD also, spacial memory suffers, and thus they tend to forget things like where they left their car keys.

Therefore, researchers concluded that different expression of HCN1 protein in the specific hippocampal region was the primary cause of PTSD and social avoidance. The researchers could find changes in HCN1 expression even after three months. Considering that mice generally live for 2-3 years, this is quite a long period in their life. Though it is known that the dorsal hippocampal region is associated with memory and learning, researchers say that there is still a need for more studies to understand what makes some mice more susceptible and others resilient to stress. Nonetheless, this study is a step forward, and we may see drugs targeting these molecules to manage the condition in the future.

By Gurpreet Singh Padda, MD, MBA, MHP