Researchers find counterintuitive way to reverse depression

U.S. researchers said Thursday they have found a conceptually novel, but also counterintuitive, therapeutic strategy for treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers from the Icahn School of Medicine in New York demonstrated for the first time that further activating these neurons can also help completely abolish depression in mice. The findings, published in the U.S. journal Science, were so surprising that the research team thinks it may lead to totally new therapies that promote a natural resilience to depression in humans. "There's a saying in Chinese: wu ji bi fan, which means things will develop in the opposite direction when they become extreme," lead author Ming-Hu Han, assistant professor at the Icahn School of Medicine, told Xinhua. "The classical therapeutic strategy is to identify the cause of an illness and then reverse it. Our study, however, found that we can also achieve the expected outcome by boosting depression- causing mechanisms even further." Previous studies have shown that when the currents of cation channels are elevated in mice, dopamine neurons in the ventral tegmental area (VTA) of their brains can become hyperactive and, in turn, the rodents become depressed. In the new study, the researchers were surprised to find that although dopamine neurons in the VTA of resilient (non-depressed) mice were normal, their ion channel currents were elevated much higher than those of their susceptible (depressed) counterparts. Yet neurons of these resilient mice also showed a simultaneous increase in inhibitory potassium channel currents, Han said. This prompted the researchers to hypothesize that in resilient animals the runaway excitatory currents triggers the boost in the inhibitory currents in a self-balancing mechanism, resulting in normal mood-related behaviors. By this logic, perhaps the susceptible mice just needed a boost in excitatory currents to activate their compensatory currents. "It's a crazy idea, but it works," Han said. To test this, Han's team repeatedly infused the VTA of susceptible mice, over five days, with a drug known to increase the excitatory currents. As hypothesized, the animals showed a profound reversal in behaviors and antidepressant-like effects -- they became more sociable and regained their sweet tooth. The once-hyperactive VTA neurons were also normalized. The researchers also achieved similar results using chronic optogenetic stimulation to drive up the neuronal activity. The findings "reveal a highly novel mechanism that controls an individual's susceptibility or resilience to chronic social stress, " said Eric Nestler, professor of the Icahn School of Medicine, who was not involved in the study. "The discoveries have important implications for the development of new treatments for depression and other stress- related disorders," Nestler added.