Optogenetics

Just a decade ago, some scientists were calling optogenetics a long shot, a crazy idea. Then it turned out to be not so crazy.

This relatively new technology allows neuroscientists to use light to probe the inner workings of the brain to study—and even control—pinpointed regions believed to be implicated in disorders like addiction, epilepsy, and autism.

The formula involves light-sensitive algae proteins, a detoxified virus (which acts as the rocketship that delivers the payload protein into the brain), and LED light (sometimes in multiple colors) administered via superfine fiber optic cables. 

With support from MnDRIVE—an infusion of research dollars by the Minnesota Legislature into brain sciences, among other areas, at the University of Minnesota—and the federal BRAIN Initiative, a group of University neuroscientists is now all in on this groundbreaking work.

“One of the most exciting things about optogenetics,” says Patrick Rothwell, Ph.D., assistant professor in the Department of Neuroscience,“is that it may, in and of itself, one day be used as a treatment strategy, but it may also be used to identify other interventions … based on our discovery of what is actually going wrong in the brain.” 

Targeting relapse

There’s a lot scientists still don’t know about the brain and its billions of neural connections. Over time, though, they have identified areas that seem to hold the key for disorders like addiction.

“If you think of the brain as a powerful computer, it has specific circuits dedicated to controlling particular functions,” explains Mark Thomas, Ph.D., associate professor in the Department of Neuroscience. “Studying morphine addiction in mice over time, we’ve identified brain circuits that are involved in a relapse-like phenomenon.”

Using optogenetics, Thomas has recently shown that he can retool those circuits, returning them to what he calls a “drug naïve state”—a discovery that could ultimately lead to treatments that would help people struggling with addiction avoid relapse.

“The challenge with addiction is to identify which circuits are really producing the addiction-like pattern of behavior so that, ultimately, we can target them with therapeutic intervention,” he says. “That’s what optogenetics, which is so exquisitely precise, allows us to do.”

Precise seizure control

Every day in the United States, doctors diagnose 500 people with epilepsy, a condition that causes recurrent seizures. Current treatments, says assistant professor of neuroscience Esther Krook-Magnuson, Ph.D., tend toward a “hammer” approach: drugs, surgical removal of brain tissue, and deep brain stimulation surgery, all of which can have unwelcome side effects because they can’t be focused intently on only the disordered circuits.

Using optogenetics, however, Krook-Magnuson can target the circuits with great specificity.  In her lab, she monitors mice using brain electrodes and software that detects epileptic seizures. As soon as the seizure begins, the investigators shine LED light directly on to the targeted circuits, stopping the seizure.

“That specificity—seizure control without negative side effects—is what attracted me to optogenetics,” Krook-Magnuson says. “It’s like a classroom full of kids where only one is misbehaving. It doesn’t make sense to discipline the whole class.”

Zeroing in on autism

Rothwell, new to the U’s faculty this year, uses a different metaphor to describe his optogenetics work involving autism and addiction.

“Imagine the brain as an orchestra, with all of the cells working together. You might hear a problem in, say, the strings section. But then you have to break it down further, to the cellos, the violas, the violins, to find out which is out of tune.”

Rothwell has pinpointed a particular group of malfunctioning synaptic connections—say, the violins—in the brain’s striatum that he believes plays a role in autism; now he wants to pluck each string to find the discordant notes.

“My previous work got us to the violins,” he explains. “Now, using optogenetics, we’re looking closer in hopes of being able to ‘tune’ those cells, to restore healthy function.”

Rothwell keeps a foot in two camps—both autism and addiction research—because the same area of the striatum appears to be problematic in both disorders, he says. Addiction research in general is further along, he says, so he can learn from that and apply it, where indicated, to his autism investigations. He now has philanthropic backing for this work, too.

On a roll

The MnDRIVE and BRAIN Initiative funding were critical to producing this body of optogenetics knowledge, says Thomas, which is being shared with multiple labs across campus.

Now scientists are focused on the next steps: developing improved viruses to deliver the optogenetics proteins into the brain and using functional magnetic resonance imaging to actually watch what happens as the photosensitive neurons are activated.

“There’s so much promise here,” Thomas says. “Optogenetics has been a transformative tool, allowing us to work in the brain in a whole new way, to tackle the unknowns. And is it possible that it could be used as a therapeutic tool for humans? Yes, I think that’s on the horizon.”

How optogenetics works

The roots of optogenetics can be traced back to the 1970s, when scientists discovered that certain types of algae contained photosensitive proteins.

Jump forward several decades, when neuroscientists wondered whether, if they somehow put that algae protein into specific neurons in the brain, they could become light-sensitive. And could the scientists then control those neurons with light? Vastly simplified, the answers were yes and yes.

To deliver the protein, scientists use a benign virus (one that won’t replicate or cause sickness), injecting it into the target cells of interest in the brain of a mouse. Those brain cells take up the virus—and thereby, the protein—while other neurons nearby remain unaffected.

Then, with a superfine fiber optic probe, the scientist shines LED light on to the target area and essentially turns on a particular set of neurons. Or they can use another protein that, once lit, inhibits the neurons from firing.

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