Optogenetics proven to work in the primate brain

Neuroscientists at Brown University (Providence, RI) have shown that optogenetics, a technique that uses pulses of visible light to genetically alter brain cells to be excited or silenced, works as well in complex and large brains as it has in rodent models.

A new study in the journal Current Biology may be the most definitive demonstration yet that the technique can work in nonhuman primates as well as, or even a little better than, the tried-and-true method of perturbing brain circuits with small bursts of electrical current. The researchers directly compared the two techniques to test how well they could influence the visual decision-making behavior of two primates. 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.

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With that in mind, senior author David Sheinberg, lead author Ji Dai, and second author Daniel Brooks designed their experiments to determine whether and how much optical or electrical stimulation in a particular area of the brain called the lateral intraparietal area (LIP) would affect each subject’s decision making when presented with a choice between a target and a similar-looking, distracting character.

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 beginning those trials, the researchers had carefully 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. Then, they mapped where on the screen an object should be in order for them to detect a response in those cells. They called that area 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 stimulating 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. Generally, accuracy was unchanged when neither character was in the receptive field; 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 could therefore make the subjects more accurate or effectively distract them from making the right choice.

The magnitude of the difference made by either stimulation method compared to no stimulation were small, but statistically significant. When the T was in the receptive field, one research subject became 10 percentage points more accurate (80 percent vs. 70 percent) when optically stimulated and eight points more accurate when electrically stimulated. The subject was five points less accurate (73 percent vs. 78 percent) with optical stimulation and six percentage points less accurate with electrical stimulation when the distracting character was in the receptive field.

The other subject showed similar differences. 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.

Electrical stimulation appeared to be less precise in the cells it reached, a possibility suggested by a reduction in electrically stimulated subjects’ reaction time when the T appeared outside the receptive field. Optogenetic stimulation, Sheinberg says, did not produce such unintended effects and allows for easier simultaneous electrical recording of neural activity.

Sheinberg is planning a new study in which his group will look at memory of visual cues in the LIP. To read the study in Current Biology, please visit http://www.cell.com/current-biology/abstract/S0960-9822%2813%2901397-3.

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