Researchers Shed Light On Depression By Curing Depressed, Stressed-Out Mice

This fact surprised us too, but according to the World Health Organization (WHO), depression is “the leading cause of disability worldwide.” It turns out the condition causes more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined. In fact, every year, five to seven percent of the world’s population experiences a major depressive episode, and one in six people will at some point experience this condition.

In recent years, research has culminated into some progress in understanding depression.  However, scientists’ understanding of the biological mechanisms behind it remains lacking, preventing the delivery of effective prevention and therapy. One of the possible reasons behind this is that almost all research focuses on the brain’s neurons, leaving the involvement of other brain cells unexamined.

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Depressed mice

In experiments with animals, researchers at the Hebrew University of Jerusalem have now demonstrated that changes in one type of non-neuronal brain cells (called microglia) are behind the depressive symptoms caused by exposure to chronic stress.

The scientists carried out the research by mimicking chronic unpredictable stress in humans (a leading cause of depression) by placing mice in similar conditions, exposing them to repeated and unpredictable stress over a five-week span. The mice developed the same behavioral and neurological symptoms as depressed humans, being manifested in a reduction of pleasurable activity and social interaction, as well as a reduced generation of new brain cells (neurogenesis), an important biological marker of depression.

Depression kills brain cells

Researchers discovered that during the first week of exposure to stress, microglia cells undergo a phase of proliferation and activation, shown by increased size and production of specific inflammatory molecules, after which some microglia begin to die. After five weeks of stress exposure, this phenomenon escalated to a total reduction in the number of microglia and to a degenerated appearance of some microglia cells, particularly in the brain’s specific region of stress response.

“Our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular,” explained Professor Raz Yirmiya, one of the leading researchers of the experiment. “This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”

The researchers examined the role of microglia brain cells in the development of depression following chronic exposure to stress. It was already known that microglia cells are the representatives of the immune system in the brain, comprising roughly 10 percent of all brain cells. However, recent studies have shown that these cells also play a role in physiological processes which aren’t directly linked to infection and injury, such as stress responses.

Prevention and treatment

Using drugs or genetic manipulation, the researchers were able to block the initial stress-induced activation of microglia among non-stressed mice. In turn, this also stopped subsequent microglia cell death and decline, as well as depressive symptoms and led to increased neurogenesis. However, these treatments failed to alleviate the condition of “depressed” mice, since they had already been exposed to the five-week stress period and therefore had a lower number of microglia. Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.

“We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment,” said Yirmiya.

The Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.

The research was conducted by Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with researchers at Yirmiya’s laboratory and at the University of Colorado in Boulder, USA. The findings were recently published in the journal Molecular Psychiatry. 

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