A Light Revolution in Neuroscience
New Technique Sheds Light on the Function Of Specific Neurons
Over the last few years, a new technology termed “optogenetics” has led to a minor revolution in systems neuroscience, a field that studies how networks and circuits give rise to brain function. This new technique has opened the door to a better understanding of how specific groups of neurons and their activity contribute to the complex interactions that underlie perception and behavior.
Historically, neuroscientists have had a range of tools to manipulate and observe neural circuits in the brain. These techniques, however, have often lacked the ability to isolate the contribution of specific neurons or types of neurons to the overall network. With optogenetics, researchers can now discretely control neuronal activity by using pulses of light to activate or inactivate specific populations of neurons. These tools are giving neuroscientists the potential to unlock many of the remaining mysteries of how individual groups of cells in the brain control perception and behavior.
The term optogenetics was first coined by one of its pioneers, Karl Deisseroth at Stanford. The technique, which recently won the 2010 Nature Methods method of the year award, makes use of a group of ion channels and other proteins discovered in bacteria and algae called “opsins.” These proteins are light sensitive and can therefore be activated by pulses of light of an appropriate wavelength. Depending on the opsin expressed, this will either excite or inhibit the neurons. The expression of opsins in mammalian neurons is achieved by inserting the encoding DNA into the target cells, which then produce the opsin proteins. The process of DNA addition is called transfection, and is typically accomplished by using a specially selected virus as a carrier to deliver the new DNA. Variants in the viral delivery and DNA coding sequence allow for specific subtypes of neurons to be targeted. Once opsins are expressed in the neurons, the firing rate can then be controlled in vivo by light from an implanted fiber-optic cable or through a small window in the skull.
This technique gives researchers enormous flexibility and control of the behavior of specific cell types in a given brain region. Spatial resolution comes from the location of the injection and the neural cell-type specificity of the viral vector. Temporal control is produced by the frequency of the delivered light pulses, which via the opsins drives the cells to fire at the same frequency as the pulses of light, or alternatively prevents them from firing at specific times.
“…it is important that we keep in mind the essential role of federal funding in facilitating scientific advances”
For example, a group of neurons in a specific area of the brain could be transfected with an opsin that excites the cells, and then is activated at various frequencies to see how this changes the animal’s perception of a stimulus directed to this area of the brain. It can also be used to completely silence a set of neurons during specific behavioral tasks in order to determine the effect of those neurons on that behavior. With this level of precise control, many systems neuroscience questions that had imprecise answers previously can now be addressed by observing awake, behaving animals.
Some of the recent articles published using this technique have demonstrated new insights into previously vexing problems in neuroscience. For example, there has been a tremendous amount of debate about the mechanism of deep brain stimulation, or DBS, utilized to treat movement disorders resulting from Parkinson’s disease.
This treatment uses electrical stimulation targeted to a region of the brain involved in motor output and control, and its mechanism of action is not well understood. It has previously been difficult to assess whether this intervention affects the neurons nearby the electrode directly, the inputs to those neurons, or the targets of the output from these neurons in this circuit.
Researchers utilized a mouse model of Parkinson’s disease and optogenetics to dissect the circuits of the brain involved in the response to electrical stimulation of the targeted area. Their results suggest that rather than leading to a simple excitation or inhibition of the neurons in the targeted area, DBS is activating connections arising from another area, and that this activation is necessary for the effectiveness of the treatment.
Another recent article demonstrated the importance of a single type of neuron to cocaine addiction in mice, suggesting a target for future clinical interventions. Because this particular type of neuron represents only 1 percent of the cells in the investigated area (the Nucleus accumbens), they have been difficult to study up until now, and their function has been the subject of much debate in scientific literature. The precise genetic targeting of the opsins allowed for just this population of neurons to be manipulated during the experiment.
The implications of this new technology for the field of systems neuroscience are profound. Its potential is being realized as the technique is implemented more broadly and more difficult circuits and systems are teased apart. A better understanding of the circuits underlying psychiatric and neurological disorders will hopefully also lead to improved clinical treatments.
One question for the future is whether or not these new techniques may be directly used to treat some human disorders as well. For example, a future version of DBS might be coupled with optogenetics to provide more specific targeting of cells in the basal ganglia, directly affecting the firing patterns of the cells responsible for disrupted movement in Parkinson’s disease. In addition, research efforts in the past year have successfully demonstrated the feasibility of utilizing optogenetics in nonhuman primates. Use of this technology in humans, however, would combine the ethical dilemmas of gene therapy with those of brain-machine interfaces such as DBS. While the road to safe and efficacious use of this technology for treatment in humans is uncertain, it is already providing great benefits to scientists in understanding circuits and their complex regulation in the brain.
As Congress turns back this week to the continuing resolution to fund the government through the end of fiscal year 2011, it is important that we keep in mind the essential role of federal funding in facilitating scientific advances like optogenetics. The original project in Dr. Deisseroth’s laboratory, the first attempt to integrate the microbial opsins into mammalian cells, was funded by a grant awarded by the National Institutes of Mental Health and National Institutes of Health, as are many of the above-mentioned projects that followed. The first scientists describing the light-sensitive proteins in 1971 could not have predicted that their findings would lead to such a profound change in neuroscientific research. These discoveries are one of the best arguments for continuing to fund basic biological research as well as more translational research: We often don’t know where the breakthroughs are going to come from that will be the basis for the next generation of treatments for disease, or that will allow us to better understand the complex systems that make up our daily habits, thoughts, and decisions.
John A. Wolf, Ph.D., is a neuroscientist at the Center for Brain Injury and Repair in the Department of Neurosurgery at the University of Pennsylvania.
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