The researchers examined the involvement of microglia brain cells in the development of depression following chronic exposure to stress. Comprising roughly 10% of brain cells, microglia are the representatives of the immune system in the brain; but recent studies have shown that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.
The researchers mimicked chronic unpredictable stress in humans - a leading cause of depression - by exposing mice to repeated, unpredictable stressful conditions over a period of 5 weeks. The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis) - an important biological marker of depression.
The researchers found that during the first week of stress exposure, microglia cells undergo a phase of proliferation and activation, reflected by increased size and production of specific inflammatory molecules, after which some microglia begin to die. Following the 5 weeks of stress exposure, this phenomenon led to a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in responding to stress.
When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis. However, these treatments were not effective in "depressed" mice, which were already exposed to the 5-weeks stress period and therefore had 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.
Prof. Yirmiya said, "We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants