OPTOGENETICS: BACKGROUND AND CONCEPTS FOR NEUROSURGERY

The human brain is one of the last frontiers of our collective intellectual pursuit. Through the ages, its complexity has intrigued great thinkers from all walks of life, including scientists, philosophers, theologians, and artists. Our zeal for studying this marvelous organ has led to the development of complex and subtle techniques ranging from detailed anatomical studies to the manipulation of single molecules. Nevertheless, despite hundreds of years of devoted efforts and advances in technology, many questions about the brain remain unanswered. A major contributor of the brain’s complexity stems from the numerous and intricate connections among its member cells, neurons, and glia, which form the network that is ultimately responsible for all the phenotypes, macroscopic or microscopic, that are observable to us. Unfortunately, because of this complexity, traditional tools such as electrical stimulation, pharmacological intervention, and even sophisticated neuroimaging studies are not capable of further dissecting the circuitry of interest with the needed resolution, either on temporal or spatial scales. Take electrical stimulation as an example: It is a temporally very fast tool, and clinically it is an indispensable therapeutic modality, a notable example of which is deep brain stimulation (DBS) for movement disorders. However, it affects all electrically excitable elements, including axons, cell bodies, dendrites, and glia in the vicinity of where the stimulation is delivered without any discrimination for cells of interest. Pharmacological modulation, on the other hand, does not possess the same temporal precision as electrical stimulation, but is able to achieve some specificity secondary to the target cells’ receptor profiles. Even this cell-type specificity is seldom perfect because of the overlapping expression of target receptors by many different types of cells, both neurons and glia included. The aforementioned limitations had led the Nobel laureate Francis Crick, in his essay published in Scientific American in 1979, to produce a ‘‘wish list’’ of techniques needed to improve our understanding of the way the brain processes information. High on his list was a method of controlling specific groups of neurons while, he wrote, ‘‘leaving the others more or less unaltered. ’’ Given the fact that almost all cells in the central nervous system have overlapping electrical and pharmacological response profiles, it seems logical that a more precise tool will be based on a different physical entity that does not natively affect the neurons or glia. Crick later speculated that such a tool would involve the use of light. Lacking an expression of innate photoreceptors, it remained unclear to neuroscientists for many years how to make mammalian neurons or glia to respond to light. Microbiology, on the other hand, the existence of microbial membrane proteins that react to light with ionic fluxes, had been known for decades. 2,3 Nevertheless, it took more than 30 years for neuroscientists to make the connection that these microbial opsins could be the long-sought-after tool for rapid and specific neuronal control. Early attempts involved the use of multiple components, including cascades of multiple proteins or chemicals, without exploiting the potential of microbial opsins as a single-component control. However, in 2005, it was demonstrated that the introduction of a microbial opsin into mammalian neurons, without any additional components, rendered these neurons precisely reactive to light. Subsequently, it has been shown that multiple different opsins, including bacteriorhodopsins and halorhodopins, can be safely expressed in mammalian neurons and rapidly turn on or off neurons upon activation by different colors of light. All-trans retinal is naturally present in vertebrate tissues and, as a result, such a strategy of optical control using microbial opsins is even feasible in intact mammalian brains or freely moving animals. Microbial opsins are rapidly becoming the tools of choice for single-component neuronal control, and the term ‘‘optogenetics’’ was coined to describe this new technology.