Scientific Council Member Karl Deisseroth, M.D., Ph.D. and NARSAD Young Investigator Grantee Melissa R. Warden, Ph.D. led a team of researchers that used optogenetics to identify the pathways in our brains that prompt us to act. This new research provides insight into how brain disorders such as depression can occur due to a malfunction in the brain signaling involved in motivation. The findings were published online in Nature on November 18th.

Dr. Deisseroth explains that in organisms as complex as humans, the neural mechanisms that help answer the question, ‘Is it worth my effort?’ can fail, leading to debilitating mental illnesses. "It's challenging because we do not have a fundamental understanding of the circuitry that controls this sort of behavioral pattern selection. We don't understand what the brain is doing wrong when these behaviors become dysfunctional, or even what the brain is supposed to be doing when things are working right," he commented. "This is the level of the mystery we face in this field."

Until this study, it was not clear which pathways in the brain might control the willingness to meet challenges, or the anticipation that action might be worthwhile in a difficult situation. To isolate these pathways relevant to depression, Deisseroth's team needed to stimulate specific brain cells in rodents and observe changes in their behavior. They used optogenetics, a technique Deisseroth developed at Stanford in 2005 with the support of a NARSAD Young Investigator Grant, which has since revolutionized the fields of bioengineering and neuroscience.

It turns out that motivation is not as simple as stimulating a region of the brain. Instead of one switch in the prefrontal cortex that turns motivation on, multiple switches work in concert. Optogenetics allowed the researchers to work backward from the brain stem and find the exact pathway from neurons in the prefrontal cortex that signal motivation. They could see not only which cells are possibly involved in motivation, but the way motivation moves from one brain region to another.

Connecting depressive symptoms with brain pathways may be helpful in the development of new medications explains Deisseroth, but the most important part of this research is its insight into how motivation works in both depressed and healthy people. As a practicing psychiatrist, he has observed that simply knowing that a biological reality underlies the lack of motivation experienced by depressed patients can be a motivational force in itself.

Kimberly R. Thompson, Ph.D., another NARSAD Young Investigator Grantee, was also part of the research team.

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