The most definitive demonstration yet that optogenetics can be safe and effective in brains larger and more complex than those of rodents could incorporate the use of light pulses to genetically alter brain cells in primates. Neuroscientists at Brown University showed that optogenetics performs just as well as the tried-and-true method of perturbing brain circuits with small bursts of electrical current, and directly compared the two techniques to see how well they could influence the visual decision-making behavior of two primates. This hair-thin combination of electrode and optical fiber allows researchers to deliver stimulating light and current to a neuron and to measure the electrical activity of each. Courtesy of Sheinberg Lab/Brown University. “For most of my colleagues in neuroscience to say ‘I’ll be able to incorporate [optogenetics] into my daily work with nonhuman primates,’ you have to get beyond ‘It does seem to sort of work,’” said David Sheinberg, a professor of neuroscience affiliated with the Brown Institute for Brain Science. “In our comparison, one of the nice things is that in some ways we found quite analogous effects between electrical and optical [stimulation], but in the optical case it seemed more focused.” If it consistently proves safe and effective in the large, complex brains of primates, optogenetics could eventually be used in humans, where it could provide a variety of potential diagnostic and therapeutic benefits, the team said. With that in mind, Sheinberg, Ji Dai and Daniel Brooks designed their experiments to determine whether and how much optical or electrical stimulation in the lateral intraparietal area (LIP) of the brain would affect each subject’s decision making when given a choice between a target and a similar-looking, distracting character. “This is an area of the brain involved in registering the location of salient objects in the visual world,” Sheinberg said, adding that the experimental task was more cognitively sophisticated than those tested in optogenetics experiments in nonhuman primates before. The main task for the subjects was to fixate on a central point in middle of the screen and then to look toward the letter “T” when it appeared around the edge of the screen. In some trials, they had to decide quickly between the T and a similar-looking “+” or “†” character presented on opposite ends of the screen. They were rewarded if they glanced toward the T. Before trials began, the researchers placed a very thin combination sensor of an optical fiber and an electrode amid a small population of cells in the LIP of each subject. They then mapped where on the screen an object should be in order for them to detect a response in those cells, an area they called the receptive field. With this information, they could then look to see what difference either optical or electrical stimulation of those cells would have on the subject’s inclination to look when the T or the distracting character appeared at various locations in visual space. They found that stimulation with either method increased both subjects’ accuracy in choosing the target when it appeared in their receptive field. They also found the primates became less accurate when the distracting character appeared in their receptive field, but generally accuracy was unchanged when neither character was in the receptive field. That meant the stimulation of a particular group of LIP cells significantly biased the subjects to look at objects that appeared in the receptive field associated with those cells. Either stimulation method, then, could make the subjects more accurate or effectively distract them from making the right choice. In all, the two primates made thousands of choices over scores of sessions between the T and the distracting character with either kind of stimulation or none. Compared head to head in a statistical analysis, electrical and optical stimulation showed essentially similar effects in biasing the decisions. However, the optogenetics method had a couple of advantages, Sheinberg said. Electrical stimulation appeared to be less precise in the cells it reached, a possibility suggested by a reduction in the electrically stimulated subjects’ reaction time when the T appeared outside the receptive field. Optogenetic stimulation, Sheinberg said, did not produce such unintended effects. Electrical stimulation also makes simultaneous electrical recording very difficult, he said, making it hard to understand what neurons do when they are stimulated. Optogenetics, he said, allows for easier simultaneous electrical recording of neural activity. Sheinberg added that he is encouraged about using optogenetics to investigate even more sophisticated questions of cognition. “Our goal is to be able to now expand this and use it again as a daily tool to probe circuits in more complicated paradigms,” Sheinberg said. He plans a new study in which his group will look at memory of visual cues in the LIP. The study was funded through a DARPA grant called REPAIR meant to lay the basic neuroscience groundwork for ultimately addressing traumatic brain injury and other damage. An article on the work appears in Current Biology; Sheinberg is study senior author, Dai is lead author and Brooks is second author. For more information, visit: www.brown.edu