Released Today: Foundation-Funded Team Identifies Malfunctioning Circuitry in Depression

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Scientific Council Member Karl Deisseroth, M.D., Ph.D. and NARSAD Young Investigator Grantee Melissa R. Warden, Ph.D. of Stanford University, Experts in Optogenetics and Depression
Karl Deisseroth, M.D., Ph.D.

A team of neuroscientists led by NARSAD Young Investigator Grantee and Scientific Council Member Karl Deisseroth, M.D., Ph.D., has demonstrated for the first time how dopamine neurons are linked to depression. The team at Stanford also includes NARSAD Young Investigator Grantees, Melissa R. Warden, Ph.D. and Kimberly R. Thompson, Ph.D., and the results of their experiments were reported today in the prestigious journal Nature.

With the use of optogenetics, they discovered that dopamine neurons are involved in circuitry whose malfunction gives rise to symptoms of depression, including hopelessness and the loss of the ability to feel pleasure (anhedonia). While many theories about depression have been advanced over the years, it has been technologically impossible to manipulate individual neurons in carefully targeted brain areas in order to conclusively demonstrate the nature of their involvement in brain disorders like depression. This is now becoming possible owing to several advances in technology, including the revolutionary technology optogenetics that Dr. Deisseroth developed with the support of his NARSAD Young Investigator Grant in 2005.

The research team worked with mice as a model as the circuitry of the brain closely resembles that of humans and optogenetics cannot be used on live human subjects. The mice were exposed to chronic mild stress to induce symptoms of depression and optogenetics was used to switch off or on specific dopamine neurons in the midbrain (specifically in the VTA, the ventral tegmental area). The team discovered that within seconds they could either induce or eliminate the symptoms. They were also able to trace alterations in key downstream brain circuitry caused by the switching of the dopamine neurons. They observed altered neuronal representations of the animal’s motivated actions in the nucleus accumbens, which is intimately involved in regulating emotions, motivation and behavior.

In reporting the findings, the team 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.” Depression and its treatment are “likewise exceedingly complex,” they said. They point out, for example, that serotonin neurons—whose action is targeted by popular antidepressant drugs—are also involved in malfunctioning circuitry that leads to depression.  

“This underscores the fact that psychiatric diseases [including depression] that are defined by a constellation of different classes of symptoms are likely influenced by multiple neural circuit processes,” the researchers note. These latest discoveries of Dr. Deisseroth’s team add to the continuing assemblage of ‘building blocks’ in understanding the complex circuitry of the brain, that will enable the development of more effective treatment strategies for mental illness.

Read more about this research in Nature

Read about this and a companion study done by Ming-Hu Han, Ph.D., NARSAD Young Investigator Grantee and Brain & Behavior Research Foundation Scientific Council Member Eric Nestler, M.D., Ph.D., at the Mount Sinai School of Medicine

Read a blog written about these two studies in Discover Magazine

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