Optogenetics: How to Control the brain

Updated: Aug 18, 2021

Recently, scientists have been using a technique called optogenetics to control the brain. By turning on a light, the nerve cells in this mouse's brain are activated, casuing it to run in circles...

Scientists can use optogenetics to make this mouse run in circles whenever the blue light is turned on.

Decoding the brain

Our brains are made of tens of billions of neurons, all interconnected in a very complex and intricate system. Up until recently, it was difficult to isolate neurons, as well as neuron groups, and determine their function. We would be able to observe these groups if we could find a method that would super-quickly fire specific neuron subsets.

The most obvious way to speedily stimulate neurons, which communicate via electrical signals, is to use an electrical stimulus. Electricity is speedy by nature, and it's how neurons naturally communicate, making it the most logical way for early scientists to map the brain. The problem with that is, not only could it fry the brain, usually something that you don’t want, but activated cells all around the stimulus zone, making it hard to isolate specific neurons.

Now, what if we used drugs? The problem with drugs is not only that, just like electrical stimuli, they spread everywhere, but also that they take a long time to make it into your brain.

We need to find an extremely fast way to control neurons.

Well, it turns out that light travels extremely fast. Since normal neurons aren’t light-sensitive, we can also selectively pick which neurons we do want to be light-sensitive, and will be specifically activated when we shine a laser on them.

So what if we use light? First, we would have to figure out how we can turn that light into an electrical impulse. Turns out that nature holds the key…

Opsins are sensory proteins that convert light into electrical signals, and are found in all sorts of places, from algae to our very own retinas. In 2002, it was discovered that a certain algae called Chlamydomonas reinhardtii had a protein called channelrhodopsin (ChR) that made it respond to light. ChRs, more specifically channelrhodopsin-2 (ChR2), are ion channels that open when they detect blue light, and let positively charged sodium (Na+) ions into the cell. This sudden rush of positive ions fires the electrical impulse, or action potential, that neurons use to communicate. Similarly, we can also turn off neurons by using opsins like halorhodopsin (NpHR). NpHR is an ion channel responsive to yellow light which lets in negative charges, making it harder for neurons to fire. If we could get these proteins onto a human neuron, that specific cell could be turned on and off manually at the speed of light.

But wait? How do we get these proteins, like ChR2, out of the algae, and into another animal? The most common way is to pack the genetic blueprint (of ChR2 in this case) and the DNA of a promoter into a virus. The virus infects all of the neurons, but due to the nature of the promoter, certain cells can start to make their own ChR2.

Now that the opsins are in the brain, to activate them, we need to find a way to get light in. To do this, we use a fiber-optic cable implanted into the head.

The ability to control specific neurons via light, in living animals, makes this technique, called optogenetics, extremely viable and impactful in our quest to understand the brain.

The power of optogenetics

Optogenetics has now become a super helpful tool in furthering the fundamental understanding of our brain. This technique has the potential to treat major brain disorders, like helping with Parkinson’s disease go from stumbling to walking. It has the potential to drastically increase the effectiveness of drugs by giving them the ability to figure out exactly which neural circuits they want to target. It has given us insight into to the neural code of autism, schizophrenia, depression, drug abuse, obesity and more. It has even given blind people partial recovery of vision.

But with such a powerful tool, there’s always a catch. Because optogenetics has given us the power to target specific regions in the brain, we can manually control behaviors in animals, from complete immobilization, to aggression. Anytime. Anywhere. Recently, we have even been able to make flies flirt with little balls of wax, without the need of an optic-fiber implant. Recently, scientists have even been able to use optogenetics to modify memories...

Using optogenetics to manipulate memories

Before we start, let's discuss memories. Memories are the activities of specific neurons in various regions across the brain. Because our memories are caused by actual cells, shouldn’t we be able to use optogenetics to tinker with them? If we can actually stimulate the active cells that were used to form a memory, then maybe we can recreate it. But how would it work?

Well, first we have to find a memory. When a new memory is formed, one of the most active brain regions is the hippocampus (shown above), which is crucial in memory creation, emotions, and learning. When a memory is formed, biological sensors can actually tell us when cells in the hippocampus are active.

These sensors are attached to the opsin of choice, which in our case is ChR2. The opsin and sensors are packed into an engineered virus which will infect our target brain. Now when a memory is formed, the active cells have the built in control button in them. Implanting an optic-fiber laser into their head enables us to turn those neurons on, which lets us manually recreate that memory.

Let’s test it! For our experiment, we will use mice, because their brains, though not as complex as ours, are genetically similar to us. We'll put this mouse inside a box and give it a small foot shock. When it receives this shock, the neurons in its head will fire, and develop a fear memory of the box. In this process, the set of neurons that fired to make the memory have now developed ChR2. Being a mouse, its natural defense mechanism will be to freeze in place, trying to main as inconspicuous as possible. So when it’s placed back into the box, it will freeze in place, remembering the previous fear memory.

If we put it into another box, the mouse, having nothing to fear from it, will curiously explore the box. But if we trigger the laser, and so fire the neurons, the mice will relive the memory, and freeze in the new box.

The optogenetic process of memory recreation
Note: The green blob in frame 2 is the Hippocampus, not the whole brain

Now that we’ve recreated a memory, we can take it to the next level: changing a memory. To do this, we put the mouse into a blue box. As the mouse explores, the neurons that encode the memory of this blue box develop ChR2. Then, we move the mouse to a different box, a red box. When the mouse is in this red box, we simultaneously activate the laser, triggering the memory of the blue box, and give the mouse the foot shock. The mouse freezes. Now, if you place the mouse back into the blue box, instead of exploring it like it used to, the mouse freezes again. The mouse has actually incorporated the 2 experiences together, and thinks the false memory that the blue box gave it the fear shock. Yep, that’s right, we just recreated a fake memory.

Using optogenetics to combine different experiences and create and manipulate memories
Creating a false-memory

Editing memories has continued to take steps forward from making a mouse scared of blue boxes to actually taking a fear memory, and make it into a happy memory. Scientists have even been able to transplant memories from a female mouse to a male mouse.

Now this entire time, we’ve been using ChR2, an ion channel that turns on neurons, thus recalling memories. If we use inhibitory proteins, like halorhodopsin (NPhR), we can turn off and actually delete a memory, remotely, and immediately.

Optogenetics has not been used in humans yet, due to the usage of gene therapy to get the virus into the body. Gene therapy in the U.S. is strictly regulated, and mostly only usable in a research setting. In Europe, the case is similar.

Tool or power?

As time goes on, the stuff of science fiction becomes more and more real. From the first genetically cloned sheep, to the manipulation of memories. As science continues to dig deeper and deeper into the wonders of our world, the more responsibility is put into our hands. Who decides how we use optogenetics? How do we make sure it stays a valuable tool for helping people and not controlling them?


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