Chronic Stress Leads to Depression

For my Harvard neuroscience class this summer, I had to read a technical publication and recap it. I found the paper to be very interesting as it discussed the long term effect of social stress leading to clinical depression. Social stress takes on a whole new meaning during these times of social distancing and isolation and highlights a major issue facing vulnerable people.

Social interaction is an integral part of our lives. We thrive off of communication and relationship with one another. However, with all of the benefits of being social come certain drawbacks. One such negative impact is social stress that arises from social interactions and relationships, and someone who is repeatedly exposed to it suffers from chronic stress. Scientists have now proven that there is a direct link between chronic social stress and clinical depression- in fact, they have found a prominent pathway linking the two. In other words, prolonged diminishing of self-worth can cause depressive behavior, and lead to Major Depressive Disorder, also known as clinical depression.

Researchers at the Mount Sinai School of Medicine discovered that social stress causes depression symptoms in mice by inducing chemical changes in the brain, specifically by compromising the Blood-Brain Barrier (BBB). The BBB is a border around the brain that regulates the blood entering the brain. Cells form tight junctions between one another so that only certain molecules and components of peripheral blood can pass into the brain.  The researchers were also able to determine the exact mechanism leading to depression from stress. The protein Cldn-5 was found to be linked to depression symptoms. Cldn-5 is one of the proteins that bring about this tight junction. The researchers were able to deduce that social stress causes the reduction of this protein, thereby allowing unwanted chemicals, molecules, and pathogens into the vicinity of the brain and neurons. 

Blood Brain Barrier

In their experiments, the researchers exposed twenty-four mice to ten larger, aggressive and vocal mice to induce social defeat, and found that there existed two distinct sets of mice: one set was stress susceptible and the other was resilient to stress (stress-resilient). By comparing these two groups of mice to each other, and also to a control group that had not been exposed to social stress, they were able to observe the effects of various proteins and different brain regions on the stress response of each set of mice.

When repeatedly exposed to stress, the stress-susceptible mice showed a forty percent decrease in the expression of the Cldn-5 protein. To test the actual effects of the protein, researchers used a virus to knock out the protein in some mice. The effects of this knockout were dependent on the mouse. The stress susceptible mice began to seclude themselves, among other tell-tale signs of depression, following exposure to social stress, thus proving the effect of the protein on depression. 

In addition to structural changes in the BBB, social stress also causes inflammation and an increase in a small cytokine protein called IL-6. With the BBB compromised, this protein is able to enter the brain. The researchers tested the permeability of the BBB to IL-6 by tagging the protein with fluorescence and imaging the mice brains to locate where the protein was able to travel in the different groups of mice. IL-6 only entered the brain when the mice were stress susceptible. Although the involvement of the cytokine IL-6 on the development of MDD has been known for some time, its actual role and the process through which it affected the brain was unknown until this work [1]. IL-6 was directly implanted into the brains of mice to prove that it directly causes the emergence of depressive behavior like social avoidance. This proved that the increased permeability of the BBB to IL-6 due to the presence of larger spaces between cells caused by the reduction of the Cldn-5 junction protein directly led to depressive behavior. It is through this pathway that social stress is able to affect mood and cause major depression. 

In their research, Scott Russo’s lab also found that the effects of social stress are brain region-dependent. One region called the nucleus accumbens is particularly susceptible to stress-induced changes following the reduction of Cldn-5. It is responsible for the reward mechanism in the brain. In stress susceptible mice, the nucleus accumbens was found to be the primary location of increased IL-6 uptake. This supports the idea that the nucleus accumbens could have an important role in clinical depression and behavior. 

Although many of the mechanisms that connect stress to depression have been identified, there are still many aspects that this research was not able to address. For example, the exact effects of the IL-6 protein on the nucleus accumbens are unknown. Researchers have only been able to study the behavior patterns that result from the changes in the brain. Additionally, the emotional expression of humans is far more complex than any other species, including mice. The research done on mice cannot be directly applied to human therapy and stress understanding until further clinical research has been done.

This study is very important in our understanding of mental illness and social anxiety. One of the primary forms of social stress faced by youth today is childhood bullying. This study highlights the long-term effects of bullying, which can lead to a lifetime of depression and other physical health issues. Understanding the long-lasting psychological effects of bullying and childhood trauma, long after the initial social stress ceases, can lead to a greater push for providing positive environments during childhood development and a stricter stance against bullying.

Clinical depression is a serious mental disorder that can cause major disability, sometimes even physically. It can impact a person’s mood and behavior along with vital functions such as appetite [2]. Additionally, it has been linked to cardiovascular disease— in fact, it is estimated that depression can increase the risk of cardiovascular issues. The causes of depression have long been studied, and in addition to genetic factors, stress has been suspected to play a role in depression. Until now, however, the exact mechanism of how stress leads to depression has been unclear. As Dr. Russo believes, shedding light on the chemical pathway leading to depression can go a long way in helping in the development of new therapies for depression and making treatment more effective. 

References:

Caroline Menard, Madeline L. Pfaul, Georgia E. Hodes1, Veronika Kana2, Victoria X. Wang, Sylvain Bouchard1, Aki Takahashi, Meghan E. Flanigan, Hossein Aleyasin, Katherine B. LeClair, William G. Janssen, Benoit Labonté, Eric M. Parise, Zachary S. Lorsch, Sam A. Golden, Mitra Heshmati, Carol Tamminga, Gustavo Turecki, Matthew Campbell, Zahi A. Fayad, Cheuk Ying Tang, Miriam Merad, Scott J. Russo. (2017). Social stress induces neurovascular pathology promoting depression. Nature Neuroscience, 20, 1752-1760.

[1] Jankord, R., Zhang, R., Flak, J. N., Solomon, M. B., Albertz, J., & Herman, J. P. (2010). Stress activation of IL-6 neurons in the hypothalamus. American journal of physiology. Regulatory, integrative and comparative physiology, 299, R343–R351.

[2] Kerr, M. (2018, October 1). Major Depressive Disorder: Symptoms, Causes, and Treatment. Retrieved from https://www.healthline.com/health/clinical-depression