Let There Be Light
The Manipulation of Neurons through Optogenetics
What if I told you there could be a remote control for your brain? That at the click of a button, you may be able to control your stress eating when finals season hits, overwrite terrible memories of your shitty ex, or cure your seasonal depression?
It’s called optogenetics, and its revolutionizing neuroscience. This technology sits at the intersection of neurology and engineering, allowing scientists to hijack the mechanisms that naturally activate or silence genetically modified neurons in the brain, using nothing but light. And though it hasn’t been tested on humans just yet, scientists have been pretty successful on mice. The technique involves genetically altering particular cells to make them produce light-sensitive proteins, which when exposed to controlled amounts of light, impacts the output of neural circuits.
Too much, too fast? To understand optogenetics, I’ll walk you through the following:
I. General Overview of Neurons and Ionic Channels (you can skip this if you have a basic understanding of how the brain works)
II. Let’s Get Technical: How Does Optogenetics Really Work?
III. How Optogenetics is Being Used Today
IV. What’s Next?
I. General Overview of Neurons and Ionic Pathways
Think of it this way. Neurons are tiny homes in the brain playing telephone with each other. If a message is loud enough, these neurons will open their doors through the dendrites, process that message in the center of the house — or the cell body — and eventually send that message through the house via the axon. The axon terminal sends the message to the next house (see Figure 1). When a neuron is successful in sending a message to the next neuron, it has fired a signal and an electrical current has been generated. When these tiny homes play a successful game of telephone with each other, we get to live, experiencing memories, emotions and behaviors.
Neurons send messages electrochemically, which means that chemicals in the body send messages through the neurons when they are electrically charged. Chemicals carrying electric charge are called “ions”. The most important ions that exist in these nerve cells are sodium and potassium (both have 1 positive charge, +), calcium (has two positive charges, ++) and chloride (has a negative change, -). Neurons are encompassed by a membrane that permits the flow or blockage of the passage of ions through the neuron. The flow/blockage of ions into the membrane is dictated by ionic channels, as shown below.
When a neuron is not sending a signal to the next neuron, it is at resting potential (-70 milliVolts). At rest, there are relatively more sodium ions outside the neuron and more potassium ions inside the neuron. An action potential occurs when a neuron sends information down an axon, away from the cell body. In this case, the ionic pathways are stimulated, causing the membrane to let sodium ions rush in and later potassium ions rush out. An action potential is triggered when it spikes the neuron’s threshold level, as seen below. This sudden burst in activity resulting from different ion channels opening and closing is also called an impulse.
Optogenetics hijacks this process by trying to create an impulse of its own, usually by embedding a light-processing protein — an opsin — in the membrane.
II. Let’s Get Technical: How Does Optogenetics Really Work?
There is so much scientists have discovered to successfully target and manipulate a set of neurons so it can be light responsive. The story of optogenetic discovery dates back to 2003 (ancient, I know, back when we didn’t have iPhones). A group of Stanford scientists observed that a green algae called Chlamydomonas Reinhardtii (C. Reinhardtii) uses light to propel the photosynthetic process and create energy for itself.
Targeting Neural Circuits for Optogenetic Use
-Activating Opsins: ChR2
After further delving in, scientists saw that in order for the algae to activate this activity, it needed to be exposed to light. When the correct wavelength of light hit these channels, they became stimulated, automatically allowing ions to flow across the membrane. The membrane protein — or opsin — that responded to light within this algae, was called Channelrhodopsin-2, or ChR2.
Scientists started to get even more curious. They found that when illuminated by 470 mm blue light, ChR2 generated an even larger photocurrent capable of stimulating an action potential, which caused an influx of Na+ ions inside the cell. This suggested that this kind of current can also be mimicked in the brain. The most commonly used ion channel for stimulation in optogenetics is ChR2.
-Inhibiting Opsins: NpHR
If you can excite a neuron, can you get it to chill? In other words, is inhibition of neural activity possible through optogenetics? Yes. And the answer is Halorhodopsin, or NpHR.
A couple years after identifying ChR2 as the holy grail to neural circuit activation, scientists found that NpHR can be used to inhibit neural activity. When exposed to 580 nm light, NpHR can be used to inhibit neural activity by pumping negatively charged chloride ions into the cell.
Credit- Optogenetics: Shining Light on the Brain
Since their discovery though, upgraded versions of both ChR2 and NpHR have been produced to improve localization and further refine the ability of light to penetrate and impact these opsins.
Ok so now what? How did scientists go from algae to the brain, targeting nerve cells?
Manipulating Neural Circuits for Optogenetic Use
-Viral Vectors
In order to get these ion channels expressed within the brain, a genetically modified virus was created. This virus, when injected into the brain, genetically modified host cells in order to create a light receptor gene. By combining its DNA with the host cell genome, the virus is used as a vector to introduce the light-specific transgene into the cells of interest.
In the game of telephone, the hinges of the neuron “doors” are changed with something more open and transparent that would accept light under certain frequencies and pulses. Think of the virus as a handyman that manipulates host neurons to change the hinges on their doors with a brand new gene. Once the DNA is recombined, all of the cell dynamics and machinery necessary to express the ion channel gene is available, and the cell will begin expressing the channels on its cell membrane.
You might be thinking the more hinges, the more light, the more impulse creation, the more control, right? Nope. The problem with viral vectors is that they can only produce so many light-responsive proteins at one time, limiting transgene expression in the target neurons. In other words, you can only put so much of that virus into a rat before it stops working.
Viral vectors have a limited packaging capacity, which results in weak expression levels and directly limits the impact of optogenetics. Scientists are working on other forms of optogenetic targeting — such as Cre-dependent expression systems like ChRmine — to strengthen expression levels within mice. More on the development of these tools here.
III. How it’s Being Used Today
Since optogenetics acts as a bridge between the diverse molecular systems that make up brains and the complex neural circuits that enable these systems, it has provided many answers for experimental mysteries in neurology.
To recap, the point of optogenetics is not mind control. Scientists are using this technology today to learn what specific cells in the brain do, or to treat specific conditions such as curing blindness, regulating glucose levels in diabetics, fighting Parkinson’s disease and manipulating memories.
Curing Blindness
Optogenetics provides scientists the unique opportunity to treat blindness. When there is vision loss, the retinal opsins that convert light entering the eye into electrical signals often fail. To combat this, scientists are creating and implanting viruses to deliver opsin-producing genes into targeted cells that have been damaged within the eye. Through the targeting of these neural pathways, there is a possibility of restoring light sensitivity in the eyes.
Regulating Glucose Levels in Diabetics
In a 2011 study, a Zurich-based team set out to optogenetically manipulate gene expression in diabetic mice in order to regulate blood glucose levels. During this study, the team activated a protein known to regulate blood glucose levels using blue light. The experiments in this study showed a direct relationship between the application of blue light into the neurons of these mice, resulting in increased insulin levels and reduced glucose sensitivity.
But wait- there’s more. Over the last decade, this team has been working on using wirelessly powered LED lights to control blood glucose levels in mice via a smartphone app. Imagine being able to control your blood sugar levels by adjusting light intensity and duration from your phone?
SO. FREAKING. COOL.
Fighting Parkinson’s
Classic symptoms of Parkinson’s include tremors, slow movement, rigid muscles and an overall disability with loss of motions. Some recent studies have shown that controlling transplanted dopamine-releasing neurons within the brain using light can help define motion in the body.
Scientists started to play around with the transplant of fetal neural cells into the brains of Parkinson’s patients beginning in the 1990’s. Since then, they discovered that Parkinson’s is caused by the degeneration of midbrain dopamine neurons, which then became the target neurons for optogenetic therapy. So far, optogenetics has proven to be a powerful tool to fight Parkinson’s in mice, and scientists are hopeful of the application of this gene therapy in humans too.
Manipulating Memories
A particular use case that is awe-inspiring for the future (and also a bit freaky) is the potential of optogenetics to create and manipulate memories. In this TED talk, MIT scientists Steve Ramirez and Xu Liu demonstrate how optogenetics could be leveraged to build and manipulate fear in rats. (If you want to click any hyperlink in this article, click this one — seriously. Shit’s cray.)
At the flip of a switch, these scientists were able to take a previously conditioned fear and make it reappear in a new environment, using blue light on target neurons in the hippocampus — the part of the brain that stores and processes memories. In fact, they also inhibited that same fear using NpHR.
IV. What’s Next?
If you’re inspired but also creeped out — same.
The implications of optogenetic discovery till date are massive. Studies discussed above suggest that with once gene therapy is perfected for humans, we could control emotions, behaviors and memories, something so fundamental to our understanding of the world. And while the neuroethics of this should be interesting (we’ll cross that bridge when we get there), I’m most excited to see how these scientific discoveries will help vulnerable populations such as PTSD/trauma survivors, people battling drug addictions, new mothers experiencing postpartum depression and students with severe social anxiety.
My hope is that in the next 20–30 years, scientists will unlock the ability to use optogenetics in human beings, making the world a more equitable place for those living through adversity. And though this science is not yet perfect, there is no doubt we’re making leaps into the future. You just gotta let there be light.
