Depression is a global problem, affecting an ever-growing number of individuals. In a bid to better understand its physiological underpinnings, a team from the Tokyo University of Science has explored how neural deterioration in areas of the brain such as the hippocampus, as well as physical and psychological stress, is tied to depression.

There are several theories regarding why and how depression emerges, both from psychological and physiological factors. In regards to the latter, the “neurogenic hypothesis of depression” has garnered a lot of scientific interest. It states that depression can stem from physical degradation in areas of the brain such as the hippocampus, degradation which can be incurred by stress.

While the link between physical stress and depression has been investigated in the past, much less is known about the effects of psychological stress. A new study aims to give us a better understanding of this topic, using mice as a model organism.

A grinding toll

“The number of individuals suffering from depression has been on the rise the world over. However, the detailed pathophysiology of depression still remains to be elucidated. So, we decided to focus on the possible mechanism of psychological stress in adult hippocampal neurogenesis, to understand its role in depressive disorders,” says Prof. Akiyoshi Saitoh from Tokyo University of Science, co-lead author of the study.

“We have found out that chronic mental stress affects the neurogenesis of the hippocampal dentate gyrus. Also, we believe that this animal model will play an important role in elucidating the pathophysiology of depression, and in the development of corresponding novel drug.”

For the study, the team exposed mice to “repeated psychological stress” in order to test how this impacts hippocampus degeneration in their brains. The experiment consisted of making the mice experience chronic social defeat stress (cSDS) via their peers — a source of psychological stress for the animals, as they are a highly social species. Chronic social defeat stress is an experimental tool through which stress is induced in a subject (such as a mouse), the ‘naive mouse’ to ‘aggressor’ mice. As part of this research, the mice were made to witness the naive mice, who were participating in the stressful situation.

After this exposure, the team analyzed their brains to measure the level of degradation it produced in key brain areas, as well as noting changes in behavior.

First off, they report that the mice exposed to this repeated source of stress started exhibiting behavioral issues such as social withdrawal, indicative of depression. In their brains, more specifically the dentate gyrus area of the hippocampus, the team recorded a decreased survival rate of new-born neurons compared to those of controls. This area is heavily involved in memory and sensory perception.

Lower new-born neuron survival rates persisted for up to four weeks after the animals were exposed to the stress-inducing scenarios. Chronic treatment with antidepressant fluoxetine was efficient in restoring neuronal survival rates for these mice. Other characteristics, such as cell growth, differentiation, and maturation rates were not impacted by stress in the experimental mice (as compared to controls), the team adds.

The authors link neural degradation in the hippocampus to the emergence of depression through the fact that avoidance behaviors in the experimental mice was “significantly enhanced” 4 weeks after the last stress-inducing exercise, compared to the first day after it. This behavior, they explain, is likely produced by degradation mounting in neurons of the hippocampus following the experience.

Although these findings have not yet been validated in humans, the authors believe that they can form an important part of understanding how depression emerges in the brain even among us. Further work is needed to validate the results and see whether they translate well to humans, however.

The paper “Chronic vicarious social defeat stress attenuates new-born neuronal cell survival in mouse hippocampus” has been published in the journal Behavioural Brain Research.