From The Quarterly, Winter 2013

Two research teams independently led by members of our Scientific Council have made important new discoveries about how stress impacts the circuitry in the brain and is linked to depression. The two teams, using some of the same advanced experimental techniques in mouse models of depression, obtained seemingly opposing results.



Yet, the results are complementary, and together appear to reveal more about the stress-depression relationship than either study does by itself. Dr. Karl Deisseroth of Stanford University led one team with NARSAD Young Investigator Grantees, Melissa R. Warden, Ph.D. and Kimberly R. Thompson, Ph.D. In a study published in Nature in December 2012, that team demonstrated for the first time how brain cells activated by the neurotransmitter dopamine are involved in depression.



The Stanford team used the new technology optogenetics, developed by Dr. Deisseroth with the support of a NARSAD Young Investigator Grant in 2005, that enables scientists to turn specific neurons on and off using beams of colored laser light. They did experiments with mice showing symptoms of depression after exposure to mild, chronic stress. Within seconds of switching off dopamine neurons in a part of the midbrain called the ventral tegmental area (VTA), the symptoms in the depressed mice vanished. When the same cells were switched on again, symptoms of depression returned.



At Mount Sinai School of Medicine in New York, a team led by Dr. Ming-Hu Han, a NARSAD Young Investigator Grantee, and Dr. Eric Nestler, was performing similar experiments, but with mice exposed to severe stress—a model Dr. Nestler calls ‘social defeat.’ After being bullied for ten days by much stronger mice, many of the ‘defeated’ mice showed several depression-like behavioral abnormalities. But some proved resilient and held up well under the repeated stress.



When this resilient subset was exposed to optogenetic stimulation of dopamine neurons in the VTA—the same area stimulated in the Deisseroth experiments—they became more susceptible to the stress. Essentially the same stimulation to the same type of neurons in the same part of the brain instantly lifted the depression of the mice that were chronically, mildly stressed, but made the severely, socially stressed mice more depressed, or more likely to become depressed. These results were also published in Nature in December 2012. Dr. Nestler says of the results, “These studies highlight the complexity of microcircuits in the brain, the unique ability of optogenetic approaches to study circuits, and the importance of characterizing the function of those circuits in multiple animal models of mental illness.”



Dr. Deisseroth’s team also emphasized that the effects of stress on affected parts of the brain “are highly complex, as different stressors can cause very different responses from neurons.” Simultaneously, depression and its treatment are “exceedingly complex,” they said. These studies represent one more step forward in decoding this complexity—and point toward the development of more effective treatments for those suffering.

Karl Deisseroth, M.D., Ph.D.

Scientific Council Member

2005 NARSAD Young Investigator Grantee

Associate Professor of Bioengineering and Psychiatry

Stanford University

Eric J. Nestler, M.D., Ph.D.

Scientific Council Member

1996 NARSAD Distinguished Investigator Grantee

Nash Family Professor of Neuroscience

Chair, Department of Neuroscience

Director, Friedman Brain Institute

Mount Sinai School of Medicine