Written by Dominic Javonillo and Edited by Lauren Cho
For most of the 20th century, the predominant method of identifying neural circuits that wire the brain was through the administration of various drug compounds such as lidocaine, a local anesthetic. If one imagines the brain as a network of wires that connect different regions together, then one can visualize the widespread effects that occur when a drug inactivates a group of wires in a particular region of the brain network. By inhibiting a group of neurons in one region of the brain, researchers can record consequential changes in neural activity in neighboring regions and observe behavioral effects when these connections are inactivated. For decades, this method of drug administration has helped determine the neurobiology of behavior. However, the main issue with this method is the lack of specificity—that is, it is hard to administer a drug like lidocaine that targets a specific cellular type of neuron in a specific region of the brain to determine its narrow network of neural circuitry. It would just flood a particular region of the brain with limited spatial control. Fortunately, throughout the past ten years there has been an incline of using a revolutionary method for attaining this desired specificity in neuroscience: optogenetics [1].
Optogenetics is a method by which scientists shine a wavelength of light onto a region in the brain to either activate or inactivate it. Through this method, neuroscientists were able to genetically implement a switch in the brains of mice that either activates or inactivates the desired type of neuron with a high degree of specificity [2]. Essentially, optogenetics provide neuroscientists with the opportunity to control specific neurons by using light and recording the resulting activity of neighboring neurons. Although researchers only began using optogenetics since 2005, its technology and conceptual application has been around for much longer–so why hasn’t optogenetics been used earlier?
The issue was bringing various technologies together in this way: finding a light-activated protein, maintaining genetic control over the neuron, and delivering light to the desired brain region [3]. The first problem was finding naturally occurring opsins, which are light-sensitive membrane proteins that activate the neuron and the genes that direct its production. These proteins were discovered to naturally occur in microbial organisms, which were then reverse-engineered to determine the genes that encode them [1]. By determining the opsin gene that provides the instructions for its production, researchers can engineer neurons to express and produce the opsin proteins themselves. Once the neuron can produce these microbial opsins, it will respond to a specific wavelength of light and change shape within the membrane. This opens a channel that allows electric current to enter, thus activating the neuron [2]. The second problem was delivering the opsin gene into the neuron’s nucleus, where its genetic information is stored. One method of optogenetics utilizes viral vector targeting, which engineers a virus to contain the opsin gene and injects the virus into a specific part of the brain [2]. However, the small size of the virus limits the length of the opsin gene. Therefore, researchers enable a specific neuron type to produce a special enzyme that flips the genetic code of the opsin gene in the viral vector [4]. This allows for the production of these opsin proteins within these specific neuron types without limiting the length of the opsin gene [4]. The final problem was somehow delivering light to activate the opsin protein in specific neurons in a specific brain region. Using lasers and optical fibers, researchers can apply a narrow wavelength of light that activates the particular opsin protein in neurons located in the outer and deeper regions of the brain [2]. With the relative ease of delivering a laser or optical fiber to a specific region of the brain, the specific neuron type that produces the light-sensitive opsin proteins may be activated or inactivated to observe its causal relationships with other neighboring neurons.
While optogenetics has been commonly used for basic scientific research, its contribution to our knowledge of neural circuits over the past 13 years cannot be underestimated. Just to name a few benefits it has brought to the medical field, optogenetics allowed researchers to learn of the neural circuits attributed to mood disorders, addiction, Parkinson’s disease, and reward-motivated behaviors [2]. Since its first implementation in 2005, optogenetics has designed tools for more unique studies. A plethora of different opsin proteins are now available to activate neurons at different wavelengths of light, allowing for multiple alterations of different types of neurons within the same neural network [2]. Some of the future directions for optogenetics include imaging the brain using light-sensitive optogenetic control in defined neural populations [2]. Indeed, with the upcoming developments and innovative use of optogenetics, the future of neuroscientific research looks bright.
References:
- Deisseroth, K. 2015. Optogenetics: 10 years of microbial opsins in neuroscience. Nature Neuroscience. 18:1213-25.
- Guru, A., Post R.J., Ho Y., Warden M.R. 2015. Making Sense of Optogenetics. International Journal of Neuropsychopharmacology. 1:1-8.
- Deisseroth K. 2011. Optogenetics. Nature Methods. 8:26-9.
- Yizhar O., Fenno L.E., Davidson T.J., Mogri M., Deisseroth K. 2011. Optogenetics in Neural Systems. Neuron. 71:9-34.