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The Growth of Optogenetics in Neuroscience Research

By: Sai Srihaas Potu

Optogenetics is a powerful and rapidly expanding set of techniques that use genetically encoded light-sensitive proteins such as opsins. Through the selective expression of these exogenous light-sensitive proteins, researchers gain the ability to modulate neuronal activity, intracellular signaling pathways, or gene expression with spatial, directional, temporal, and cell-type specificity. Optogenetics provides a versatile toolbox and has significantly advanced a variety of neuroscience fields.


In a new study, researchers from Brown University have shown that optogenetics, a technique that uses pulses of visible light to alter the behavior of brain cells, can be as good as or possibly better than the older technique of using small bursts of electrical current. Optogenetics had been used in small rodent models. Research has shown that optogenetics works effectively in larger, more complex brains.


Neuroscientists are eagerly, but not always successfully, looking for proof that optogenetics, a celebrated technique that uses pulses of visible light to genetically alter brain cells to be excited or silenced, can be as successful in complex and large brains as it has been in rodent models.


This study 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. Brown University researchers directly compared the two techniques to test how well they could influence the visual decision-making behavior of two primates.


Ultimately 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.


With that in mind, Professor David Sheinberg, lead author Ji Dai, 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 researchers believe that this is an area of the brain involved in registering the location of salient objects in the visual world. They added 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 the 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 character presented on opposite ends of the screen.


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 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 that 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.


In other words, 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 was small but statistically significant. When the T was in the receptive field, one research subject became 10 percentage points more accurate when optically stimulated and eight points more accurate when electrically stimulated. The subject was five points less accurate 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 statistical analysis, electrical and optical stimulation showed essentially similar effects in biasing the decisions.


Although the two methods performed at parity on the main measure of accuracy, the optogenetic method had a couple of advantages. 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. Electrical stimulation also makes simultaneous electrical recording very difficult. That makes it hard to understand what neurons do when they are stimulated. Optogenetics allows for easier simultaneous electrical recording of neural activity.


Optogenetics is a quickly growing field that provides researchers with the ability to manipulate neurons with unprecedented specificity. It is also a versatile tool, easily used in combination with other techniques to answer diverse experimental questions. Continued development and sharing of new methods, including for selective opsin expression, ensure the further expansion of optogenetics’ utility in epilepsy research.



References:

1. Boyden E. S. Optogenetics and the future of neuroscience. Nature Neuroscience. 2015.

2. Chen S., Weitemier A. Z., Zeng X., He L., Wang X., Tao Y. Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics. Science. 2018.

3. Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nature Neuroscience. 2015.

4. Ji Dai, Daniel I. Brooks, David L. Sheinberg. Optogenetic and Electrical Microstimulation Systematically Bias Visuospatial Choice in Primates. Current Biology. 2013.

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