Mouse models are very widely used in science. In fact, not only they help developing drugs, but they also are a tool to take a better look into diseases and conditions that typically only humans are concerned about. For example, now scientists at the RIKEN Brain Science Institute have used mouse model to show that there is connection between depression and the paraventricular thalamus – a region of the brain not previously tied to depression. This is the first mouse model of spontaneous depression-like episodes.
The research showed that a mouse strain with a mutation that leads to dysfunction of mitochondria—the “powerhouses” that provide energy to cells—spontaneously undergo periodic episodes of depression-like behaviour that resemble those in human. This is rather significant achievement as ultimately in the near future it could help to create new more effective therapies for depression.
Scientists note that depression takes a major health toll on society. It is also important because linking depression and the paraventricular thalamus shows that depression or at least some types of it may actually be a brain disease with a structural cause rather than a psychiatric illness. But motivation for the research may be found a little bit elsewhere.
Tadafumi Kato, leader of the research team, said that the work was motivated by the lack of animal models that accurately reproduce depressive episodes, which is crucially important in order to successfully study depression and to find treatments for it.
He noted: “it had been noted previously that mitochondrial diseases were linked to depression, and moreover, that patients with depressive symptoms harboured problems with mitochondrial DNA. We decided to investigate where this was happening, and started experiments with a mouse strain with a mutation in Polg1, which is involved in the replication of mitochondrial DNA.”
Scientists examined the behaviour of these mutant mice models and found that, in a way similar to human patients with mitochondrial diseases, the mice underwent spontaneous episodes of depression. They would express signs and symptoms described in the DSM-5 criteria of major depressive episode in humans. Scientists were actually surprised to discover that many of the female mutant mice used in the study showed symptoms similar to human depression patients.
One may wonder, how scientists can notice depression symptoms in mice. It is actually rather simple. These mice, when experiencing random and reoccurring episodes of depression, would run in their wheels less extensively, which indicates that they had a lack of pleasure-seeking behaviour, which is usually considered to be core feature of depression.
These episodes would appear around every six months and lasted for two or three weeks. Scientists also had means to control these episodes – doses of an SSRI—a common type of antidepressant drug would mitigate depression episodes, while lithium withdrawal induced them. These participants of the study also had higher levels of corticosterone (an equivalent of cortisol in humans), which is also considered a sign of depression.
Mice expressed other symptoms too, such as weight gain, slow running speed, and increased fatigue. Then researchers analysed which part of the brain was being affected by the mitochondrial abnormalities and found that there was a particularly high ratio of deleted mitochondrial DNAs in the paraventricular thalamus. It is a part of the brain that has not been previously linked to depression.
Scientists examined brain slices from two deceased patients who had suffered from a mitochondrial disease coupled with mood symptoms and found similar abnormalities in the paraventricular thalamus. Team wanted to test the potential association that they discovered so they blocked the transmission of signals from the paraventricular thalamus to other parts of the brain of mouse models. During this experiments mice exhibited similar episodes.
This is a very significant discovery. If depression turns out to be a brain disease rather than a psychological illness, treatments have to be revised from the ground up. It is still not clear and results are not final, but further research should help to create new innovative therapies for depression patients. It is not only a condition tremendously lowering quality of life, but it also costs a lot for health care systems around the world.