From The Quarterly, Summer 2014

Can too much of a bad thing lead to a good outcome? In new research at the Icahn School of Medicine at Mount Sinai, this paradoxical question is at the heart of a surprising new discovery that could lead to a novel approach for treating stress-induced depression.

Working with mice, the research team, led by 2007 NARSAD Young Investigator Grantee Ming-Hu Han, Ph.D. and including 2010 NARSAD Young Investigator Grantee Vincent F. Vialou, Ph.D., found that by boosting overactive neuronal activity during a simulation of “social defeat stress”—a behavioral situation akin to repeated bullying—a self-stabilizing response was eventually triggered in animals susceptible to developing depression. By accentuating the flaw in activity, they found that it eventually corrected itself. Out-of-balance electrical activity in the brain was stabilized and behavioral symptoms of depression, such as social withdrawal, anxiety and listlessness were reversed.

The results of this new work were published online April 18th in the journal Science. Dr. Han and his team knew from prior studies that in mice naturally susceptible to developing stress-induced depression, the electrical current is elevated in cation channels, which enable positively charged ions to enter dopamine neurons*. This is thought to contribute to pathology. When susceptible mice are bullied they become depressed.

But the first unexpected finding made by Dr. Han’s team was that in mice naturally resilient to bullying—mice that don’t get depressed after experiencing social defeat stress—the level of current in cation channels was even higher than that seen in the susceptible mice. Oddly enough, these neurons were stable; unlike those of the depression-prone mice, they fired at a normal rate. A counterintuitive idea was born: perhaps if cation channels in dopamine neurons* were even more highly activated in susceptible mice, the neurons would become hyperactive, but then stabilize.

Using beams of laser light to control individual dopamine neurons* in the mice susceptible to developing depression—with the new technology optogenetics*—the team increased the overactive neuronal activity in these mice. This produced the second surprise: not only did the firing of the neurons stabilize; depression-related behaviors were “completely reversed.” At a certain point, the elevated neuronal activity triggered its own compensatory ion channel* adaptation to stabilize the out-of-balance electrical activity and produced resilience.

Dr. Han and his colleagues believe that if a medication could accentuate this neuronal hyperactivity until it self-corrects, essentially pushing depressed individuals past a certain tipping point, it could work as a more natural antidepressant by promoting resilience and cause fewer side effects.

Foundation Scientific Council member Eric Nestler, M.D., Ph.D., Chair of the Department of Neuroscience at Mount Sinai, praised the research, saying the team “reveals a highly novel mechanism that controls an individual’s susceptibility or resilience to chronic social stress. The discoveries have important implications for development of new treatments for depression and other stress-related disorders.”