Cerebral Hemispheres 2


Optogenetics, memories, and mind control


A few years ago (2010), the journal Nature Methods chose optogenetics as its "method of the year." The fact that optogenetics, in 2010, was already considered a viable approach to studying the brain is impressive in and of itself, considering that all of the seminal work with optogenetics has been done since the year 2000. Because the method is still a relatively recent development, however, it is probably true that the most intriguing work with optogenetics has yet to be done.

What is optogenetics?

Optogenetics incorporates methodology from the fields of optics and genetics in attempting to understand the activity of neurons. Specifically, optogenetic methods can be used to selectively activate individual neurons. This allows researchers to gain a better understanding of the function of these neurons by observing the effects of their activation.

There have been a few different approaches developed to activate neurons; one of the more common approaches was realized with the help of green algae. Green algae possess an ion channel that opens in response to light. When the channel is exposed to light it opens, allowing ions to rush into the cell and potentially causing an action potential to occur. The channel is called channelrhodopsin-2 (ChR2), and algae use its light sensitivity to grow towards sources of light.

Researchers in the early 2000s realized if they could get neurons to express light-sensitive ion channels like ChR2, then they could potentially control the activation of those neurons using pulses of light. So, they packaged the genes that encode for ChR2 into a viral vector and used it to infect neurons. The viral vector carries ChR2 genes into susceptible cells and "infects" them, causing the target cells to express the genes.

Once the genes for a light-sensitive ion channel become incorporated into a neuron, researchers can use light to activate that neuron. They can do this by inserting optical fibers into the brains of animals and using lasers or light emitting diodes (LEDs) to expose neurons to light. You can see this in action in the video below, which shows a mouse that (after being injected with a viral vector containing ChR2 genes) expresses ChR2 in its motor cortex. When researchers apply a burst of blue light to the mouse's brain, this causes a distinct pattern of movement.

What is optogenetics used for?

Optogenetics provides neuroscientists with a method to turn on specific neurons and then observe the effects. This gives researchers a way to make a strong connection between the activity of individual neurons and behavior. In other words, if researchers stimulate a particular area of the motor cortex (as seen in the video above) and this causes a mouse to move counterclockwise in circles, then we can hypothesize that the region stimulated plays a large role in that type of movement. Understanding the role of individual neuronal populations is crucial to understanding behavior and disease.

A study published this month in Nature provides a good example of influential optogenetics research. In the study, researchers (Nabavi et al.) used optogenetic methods to examine the behavior of neurons involved in conditioning fear responses. Normally, when you take a rodent and play a specific tone right before it receives an uncomfortable electric shock, it will begin to associate the tone with the shock; quickly it will come to fear the tone itself. In other words, it forms a memory of what normally follows the tone (a shock) and begins to anticipate it immediately upon hearing the tone.

It is thought that the mechanism of fear conditioning involves the amygdala, a region of the brain that plays an important role in fear processing of all kinds. In the case of associating fear with an auditory signal, the lateral amygdala receives auditory information from the thalamus. When there is an aversive stimulus associated with that auditory information, some neurons in the amygdala may undergo a process known as long-term potentiation, which is a term for the enhancement of synaptic communication thought to underlie memory formation (for more on this process, see this article). This enhancement allows those neurons in the amygdala to "remember" that the auditory information was followed by something aversive, and promotes avoidance behavior upon simply hearing the tone in the future.

Nabavi et al. injected a virus that expressed a variant of ChR2 into the brains of rats, and then waited until it was expressed in neurons of the lateral amygdala. Then, instead of pairing the shock with an auditory tone, they paired it with a burst of light that would hypothetically activate the same neurons in the amygdala that would be activated by a tone. This created a fear response that was similar to what was seen in rats who had the shock paired with a tone. So, the investigators essentially created a memory for an auditory stimulus in these rats, even though there was no auditory stimulus present.

The researchers went on to demonstrate that the memory formation was likely due to long-term potentiation. One way they did this was to use a method of optical stimulation thought to induce long-term depression, which is in some ways the opposite of LTP, as it acts to weaken the connection between synapses. By doing this, Nabavi et al. were able to abolish the memory. Amazingly, they were then able to reactivate it simply by re-stimulating the amygdala with light (foot shock was not needed again).

This experiment demonstrates how optogenetics can be used to activate specific neurons to help us to understand their role in behavior. In this case, researchers activated neurons in the amygdala to show how they are involved in fear conditioning, and expanded upon this by verifying that LTP is important to the fear conditioning process.

Optogenetics and mind control

While optogenetics gives us the ability to explore the functions of individual neurons, at the same time it provides us with the ability to modify the activity of those neurons. In this way, we can influence behavior, as can be seen in the video above when the mouse is prompted to move in a specific direction after optogenetic stimulation. Although tethering an animal to a cable for experimentation would seem to limit the possibilities that could be explored in terms of behavior, wireless optogenetic methods have already been introduced; their use will remove some of these limitations.

But how far can this technology go? Would it be possible to express ion channels sensitive to different wavelengths of light in different areas of the brain, thus giving scientists the capability of controlling a whole panoply of behavior? Indeed, work has already started to move in this direction. Will optogenetic technology one day be able to be applied to humans to influence things like addictive behavior or to treat disorders like depression, essentially modifying peoples' thought patterns in the process? Although this is not right around the corner, it is conceivable, and it is not a far stretch from approaches like deep-brain stimulation that are already being explored for these purposes. Thus, using optogenetics to exert some sort of control over the mind, albeit not of the devious sort that the phrase "mind control" seems to imply (hopefully), may be a distinct possibility at some point in the future.

Nabavi, S., Fox, R., Proulx, C., Lin, J., Tsien, R., & Malinow, R. (2014). Engineering a memory with LTD and LTP Nature DOI: 10.1038/nature13294


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