Wednesday, May 18, 2016


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.


  1. Krook-Magnuson E, Gelinas JN, Soltesz I, Buzsáki G. Neuroelectronics and Biooptics: Closed-Loop Technologies in Neurological Disorders. JAMA Neurol. 2015 Jul;72(7):823-9.

    Brain-implanted devices are no longer a futuristic idea. Traditionally, therapies for most neurological disorders are adjusted based on changes in clinical symptoms and diagnostic measures observed over time. These therapies are commonly pharmacological or surgical, requiring continuous or irreversible treatment regimens that cannot respond rapidly to fluctuations of symptoms or isolated episodes of dysfunction. In contrast, closed-loop systems provide intervention only when needed by detecting abnormal neurological signals and modulating them with instantaneous feedback. Closed-loop systems have been applied to several neurological conditions (most notably epilepsy and movement disorders), but widespread use is limited by conceptual and technical challenges. Herein, we discuss how advances in experimental closed-loop systems hold promise for improved clinical benefit in patients with neurological disorders.

  2. Nagaraj V, Lee ST, Krook-Magnuson E, Soltesz I, Benquet P, Irazoqui PP, Netoff TI. Future of seizure prediction and intervention: closing the loop. J Clin Neurophysiol. 2015 Jun;32(3):194-206.

    The ultimate goal of epilepsy therapies is to provide seizure control for all patients while eliminating side effects. Improved specificity of intervention through on-demand approaches may overcome many of the limitations of current intervention strategies. This article reviews the progress in seizure prediction and detection, potential new therapies to provide improved specificity, and devices to achieve these ends. Specifically, we discuss (1) potential signal modalities and algorithms for seizure detection and prediction, (2) closed-loop intervention approaches, and (3) hardware for implementing these algorithms and interventions. Seizure prediction and therapies maximize efficacy, whereas minimizing side effects through improved specificity may represent the future of epilepsy treatments.

  3. Krook-Magnuson E, Soltesz I. Beyond the hammer and the scalpel: selective circuit control for the epilepsies. Nat Neurosci. 2015 Mar;18(3):331-8.

    Current treatment options for epilepsy are inadequate, as too many patients suffer from uncontrolled seizures and from negative side effects of treatment. In addition to these clinical challenges, our scientific understanding of epilepsy is incomplete. Optogenetic and designer receptor technologies provide unprecedented and much needed specificity, allowing for spatial, temporal and cell type-selective modulation of neuronal circuits. Using such tools, it is now possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies. Such specificity of intervention also has the potential for direct therapeutic benefits, allowing healthy tissue and network functions to continue unaffected. In this Perspective, we discuss promising uses of these technologies for the study of seizures and epilepsy, as well as potential use of these strategies for clinical therapies.

  4. Krook-Magnuson E, Ledri M, Soltesz I, Kokaia M. How might novel technologies such as optogenetics lead to better treatments in epilepsy? Adv Exp Med Biol. 2014;813:319-36.

    Recent technological advances open exciting avenues for improving the understanding of mechanisms in a broad range of epilepsies. This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures. Optogenetics is a technique which, through cell-type selective expression of light-sensitive proteins called opsins, allows temporally precise control via light delivery of specific populations of neurons. Therefore, it is now possible not only to record interictal and ictal neuronal activity, but also to test causality and identify potential new therapeutic approaches. We first discuss the benefits and caveats to using optogenetic approaches and recent advances in optogenetics related tools. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research.

  5. Liu S, Li C, Xing Y, Wang Y, Tao F. Role of neuromodulation and optogenetic manipulation in pain treatment. Curr Neuropharmacol. 2016 Mar 2. [Epub ahead of print]

    Neuromodulation, including invasive and non-invasive stimulation, has been used to treat intractable chronic pain. However, the mechanisms by which neuromodulation produces antinociceptive effect still remain uncertain. Optogenetic manipulation, a recently developed novel approach, has already proven its value to clinicians by providing new insights into mechanisms of current clinical neuromodulation methods as well as pathophysiology of nervous system diseases at the circuit level. Here, we discuss the principles of two neuromodulation methods (deep brain stimulation and motor cortex stimulation) and their applications in pain treatment. More important, we summarize the new information from recent studies regarding optogenetic manipulation in neuroscience research and its potential utility in pain study.

    The field of optogenetics has revolutionized neuroscience research. This technology, pioneered by researchers at Memorial Sloan-Kettering Cancer Center in 2002 and further developed by scientists at Stanford in 2005, described in two landmark articles, how activity of genetically engineered neurons can be controlled by light.

    Neurons expressing light-sensitive ion channels (modified microbial opsins) can be excited or inhibited in vivo in a cell-specific manner and with high temporal precision using flashes of light delivered by fiber optic threads. Blue and yellow light activating channelrhodopsin and halorhodopsin respectively produces activation and inhibition respectively of neurons modified to express these ion channels.

    Applications of optogenetics span several fields and the technology is leveraged to study mechanisms of addiction, depression, anxiety disorders among others. In an article recently published in Current Neuropharmacology, Feng Tao, MD, PhD discusses how optogenetic manipulation can also be used for the study and treatment of pain, including migraine-related pain. Targeting neural networks involved in migraine pathophysiology using this technology shows great promise to reduce migraine-related headaches. “This technology won't just be used for biomedical research,” Dr Tao said in a statement. “We hope we will be able to move it into clinical trials to treat intractable pain.”

    Further improvements of the technology will be necessary for human applications to allow for wireless control with sensors implanted in the brain.
    Courtesy of Doximity