Optogenetics illuminates pathways of motivation through brain, study shows

November 18, 2012 in Neuroscience

Whether you are an apple tree or an antelope, survival depends on using your energy efficiently. In a difficult or dangerous situation, the key question is whether exerting effort—sending out roots in search of nutrients in a drought or running at top speed from a predator—will be worth the energy.

In a paper to be published online Nov. 18 in Nature, Karl Deisseroth, MD, PhD, a professor of and of psychiatry and at Stanford University, and postdoctoral scholar Melissa Warden, PhD, describe how they have isolated the neurons that carry these split-second decisions to act from the higher brain to the brain stem. In doing so, they have provided insight into the causes of severe such as depression.

In organisms as complex as humans, the that help answer the question, "Is it worth my effort?" can fail, leading to debilitating . , for instance, which affects nearly 20 percent of people at some point in life, is correlated with underperformance in the involved in motivation. But researchers have struggled to work out the exact cause and effect.

"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. "This is the level of the mystery we face in this field."

Clinicians refer to this slowing down of motivation in as "psychomotor retardation." According to Deisseroth, who is also a practicing psychiatrist, patients may experience this symptom mentally, finding it hard to envision the positive results of an action, or, he said, they may feel physically heavy, like their limbs just do not want to move.

"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," said Deisseroth, who also holds the D.H. Chen Professorship.

Light coercion

Psychiatrists, Deisseroth included, believe the will to act may be born in the prefrontal cortex—the foremost part of the brain that helps plan and coordinate action. It then zips through the brain as a series of electrical signals, passing from neuron to neuron along countless branching pathways until it reaches the nerves that directly implement movement. Until this study, however, it was not clear which of these pathways 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, which has since revolutionized the fields of bioengineering and neuroscience.

The secret is as old as green algae. These single-celled organisms produce a protein called channelrhodopsin that makes them sensitive to sunlight. Borrowing and engineering the gene for this protein, Deisseroth has been able to create neurons that respond to light delivered from fiber-optic cables. He can turn the neurons on and off by sending bursts of light to activate different areas of the brain and then observe the effects on behavior.

Working backward

Surprisingly, the researchers found that simply stimulating the prefrontal cortices of rodents didn't motivate them to try any harder in a laboratory challenge. 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. Some neurons excite motivated activity and others inhibit it. Broadly stimulating the executive part of the brain will not generate a simple effect on behavior.

"It's one step more subtle" said Deisseroth, "but this is something that optogenetics was very well-suited to resolve."

An optogenetic method called projection targeting allowed the scientists to work backward from the brain stem and find the exact pathway from neurons in the prefrontal cortex that signal motivation.

The researchers first introduced their light-sensitive protein into cells in the prefrontal cortex. 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 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.

Mapping motivation

The researchers suspected that one part of the brain stem in particular, the dorsal raphe nucleus, might be crucial to behaviors that control effort. This cluster of cells is a production hub for serotonin—a chemical messenger that changes the firing behavior of other cells. Serotonin is associated with mood modulation; many antidepressant drugs, for instance, may act by increasing serotonin concentration in the brain.

When the pathway between the prefrontal cortex and the dorsal raphe nucleus was stimulated, rodents facing a challenge in the lab showed an immediate and dramatic surge in motivation.

Curiously, however, when the rodents were relaxing in their home environment, the same stimulation had no effect. The pathway was not merely linked to any action, or to agitation; it was, more specifically, helping to "set the effort that the organism was willing to put forth to meet a challenge," Deisseroth said.

Researchers were also able to produce the opposite effect—reduced effort in response to challenge—by stimulating prefrontal that project to the lateral habenula, a region perched atop the brain stem that is thought to play a role in depression. When this region was getting signals driven optogenetically from the prefrontal cortex, rodents put forward less effort.

Larger puzzles

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.

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.

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.

Journal reference: Nature search and more info website

Provided by Stanford University Medical Center search and more info website

5 /5 (4 votes)  

Rank 5 /5 (4 votes)
Relevant PhysicsForums posts

More news stories

New neuron formation could increase capacity for new learning, at the expense of old memories

New research presented today shows that formation of new neurons in the hippocampus - a brain region known for its importance in learning and remembering - could cause forgetting of old memories by causing a reorganization ...

Neuroscience created May 24, 2013 | popularity 4 / 5 (4) | comments 0

Help at hand for people with schizophrenia

How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.

Neuroscience created May 24, 2013 | popularity 4 / 5 (2) | comments 2

Japanese research organizations contribute to Human Brain Project

One of the major frontiers of modern science is a comprehensive understanding of the human brain and its functions to guide the development of new technologies in information and communication. In a major announcement for ...

Neuroscience created May 24, 2013 | popularity 3.7 / 5 (3) | comments 0

Controlling mood through the motions of mitochondria

(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...

Neuroscience created May 23, 2013 | popularity 4.9 / 5 (9) | comments 0 | with audio podcast report

Brain uses internal 'average voice' prototype to identify who is talking

(Medical Xpress)—The human brain is able to identify individuals' voices by comparing them against an internal 'average voice' prototype, according to neuroscientists.

Neuroscience created May 23, 2013 | popularity 3.7 / 5 (3) | comments 3 | with audio podcast


First drug to improve heart failure mortality in over a decade

Coenzyme Q10 decreases all cause mortality by half, according to the results of a multicentre randomised double blind trial presented today at Heart Failure 2013 congress. It is the first drug to improve heart failure mortality ...

Hormone levels may provide key to understanding psychological disorders in women

Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.

Heart failure accelerates male 'menopause'

Heart failure accelerates the aging process and brings on early andropausal syndrome (AS), according to research presented today at the Heart Failure Congress 2013. AS, also referred to as male 'menopause', was four times ...

Researchers identify first drug targets in childhood genetic tumor disorder

Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...

Feds fight morning-after pill age ruling in NY

(AP)—Department of Justice lawyers have again asked a federal appeals court in New York to delay lifting age restrictions and prescription requirements on an emergency contraceptive popularly known as the morning-after ...

Death highest in heart failure patients admitted in January, on Friday, and overnight

Mortality and length of stay are highest in heart failure patients admitted in January, on Friday, and overnight, according to research presented today at the Heart Failure Congress 2013. The analysis of nearly 1 million ...