2010 NARSAD Young Investigator Grantee Bo Li, Ph.D., has solved an important mystery about depression that helps explain at least one of its causes. The same research, published May 28th 2014 in the Journal of Neuroscience, also sheds new light on the effectiveness of a powerful experimental treatment for therapy-resistant depression called deep brain stimulation (DBS).

Dr. Li, of Cold Spring Harbor Laboratory, and colleagues, wanted to learn more about why some people are resilient when they are placed under severe stress, while others develop mood disorders, including depression. The team conducted behavioral tests in animal models in which mice were confronted over a three-day period with stress that they could neither control nor escape. This “learned helplessness” model, as expected, was endured by many of the mice, which proved resilient under stress, but was not well endured by some others. These mice exhibited the mouse equivalent of depression.

Knowing that imaging studies of depressed people (and mice) have shown hyperactivity in a part of the brain called the medial prefrontal cortex (mPFC), Dr. Li paid particular attention to neurons in this region. The team found that in mice that developed depression as a result of the learned helplessness, a specific group of neurons in the mPFC were indeed hyperactive. In the majority of animals, which proved resilient, signaling among this same set of neurons was unusually weak.

When the scientists artificially made this same set of mPFC neurons hyperactive in the resilient mice, says Dr. Li, “the results were remarkable: once-strong and resilient mice became helpless, showing all the classic signs of depression.”

These results were especially exciting because the group of neurons pinpointed in the team’s experiments is found in the brain region (also called Brodmann Area 25) targeted in DBS. Foundation Scientific Council member and three-time NARSAD Grantee Helen Mayberg, M.D., of Emory University, pioneered the use of DBS in patients with major, life-threatening depression that did not respond to known treatments. Many of these patients experienced a rapid lifting of depressive symptoms when DBS was targeted to this region that she had earlier identified as a key locus of pathology in depression. The technique involves brain surgery and is still experimental.

Dr. Li says his work could lead to more precise targeting of DBS. His team is now investigating why neurons in the mPFC become hyperactive in brains susceptible to stress-induced depression. He hypothesizes that nearby inhibitory neurons are either failing or being abnormally bypassed.

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