Motivation Pathways In The Brain Can Fail And Cause Depression
November 19, 2012

Optogenetics Study Shines New Light On Biological Causes Of Depression

redOrbit Staff & Wire Reports - Your Universe Online

Researchers from Stanford University have isolated the neurons responsible for determining whether or not exerting effort in order to complete a task is worth the energy that said effort will require -- a discovery which could help medical professionals better deal with depression and other brain-related disorders.

According to the university, many psychiatrists believe that a person's "will to act" originates from the prefrontal cortex, "the foremost part of the brain that helps plan and coordinate action." It then travels through the brain, moving from neuron to neuron, until it reaches the nerves responsible for directly controlling the desired movement or reaction.

However, experts did not know which of the brain's neural pathways were in charge of deciding whether or not the body should act, or determine whether or not a particular reaction or movement might be a worthwhile response to a challenging situation. That was what Stanford bioengineering, psychiatry, and behavioral sciences professor Dr. Karl Deisseroth and colleagues set to find out.

"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," Deisseroth said in a statement. "This is the level of the mystery we face in this field."

"To isolate these pathways relevant to depression, Deisseroth's team needed to stimulate specific brain cells in rodents and observe changes in their behavior," the university said. They used a method known as optogenetics, which integrates optics and genetics in order to control specific events that occur within the cells of living tissue and was first developed by Deisseroth in 2005.

Using the gene for channelrhodopsin, a protein derived from green algae, Deisseroth has been able to create neurons which respond to light originating from fiber-optic cables. Using that light, he has developed a technique which allows him to essentially activate or deactivate neurons by sending bursts to different parts of the brain, and then studying the effects that the technique has on the subject's behavior.

In the latest study, the Stanford team attempted to stimulate the prefrontal cortices of rodents, but found that doing so did not actually motivate them to expend any more effort than usual when completing a laboratory challenge. They used the optogenetic method known as projection to work backwards, starting at the brain stem, and discovered the specific pathway which oversees effort and motivation.

"The researchers first introduced their light-sensitive protein into cells in the prefrontal cortex," officials from the university explained. "The light sensitivity then spread out like the branches of a tree through all the outgoing connections and eventually made its way to the brain stem, making those regions light sensitive, too."

"Then, illuminating the newly light-sensitive regions of the brain stem thought to control motivational movement, Deisseroth and [postdoctoral scholar Melissa] Warden watched the behavioral effects as a subgroup of neurons in the prefrontal cortex that sent connections to brain stem were activated. They could see not only which cells are possibly involved in motivation, but the way motivation moves from one brain region to another," they added.

So what makes these findings, which were published in Sunday's edition of the journal Nature, so important? According to the researchers, it's because failure of the pathways responsible for motivating the brain, spurring a person on to action, is one of the causes of depression and other severe mental illnesses.

"This is one of the most debilitating aspects of depression, and motivation to take action is something that we can model in animals. That's the exciting opportunity for us as researchers," Deisseroth said.

"These findings are part of a larger puzzle that Deisseroth and his team have pieced together by using optogenetics to model human behavior in animal subjects. The work has already helped clinicians and researchers to better understand what is going on in a patient's brain," the university added.

"Connecting depressive symptoms with brain pathways may be helpful in the development of drugs, but according to Deisseroth, the most important part of this research is its insight into how motivation works in both depressed and healthy people," they said. "He has observed that this insight alone can be helpful to those dealing with mental illness and seeking an explanation for troubling symptoms that feel deeply personal. For those patients, he said, simply knowing that a biological reality underlies their experience can be a motivational force in itself."