The most complicated thing in the universe is sitting on your shoulders.
The mere 1.5 kg or 3-pound organ sitting inside your skull contains a vast and unfathomable universe of information and connections.
What humans use to reason the unknown is the unknown.
Scientists have been struggling to understand how the brain works for centuries. In 1664, an English doctor named Thomas Willis published the “Anatomy of the Brain,” which described reflexes and epilepsy and coined the term “neurology” for the first time. In 1837, J. E. Purkyně, a Czech scientist, was the first man to describe a neuron. By 1992, functional magnetic resonance imaging (fMRI) was first used to map activity in the human brain, thus beginning a new era of neuroscience.
Despite centuries-old research and the new technological advancements of the 21st century, scientists still have a long way to go. We can observe and measure brain activity through fMRI’s and analyze connections between cortical regions through classical EEGs and MEGs. While these technologies give us a basic understanding of the brain and help us classify the functions of larger sections, we really don’t know a lot about the roles of smaller subsets of neurons and their individual connections. We don’t have a comprehensive map of the billions of neurons in our own brains, nor do we have no way to isolate certain neurons or groups of neurons to find their specific function(s) and role in everyday activity and disease.
Let’s Take A Step Back
Let’s take a step back and talk about neurons for a second. You may have heard about them briefly in Biology class or read about them in an article, but what exactly are they?
Neurons are specialized cells in the brain and nervous system that largely differ from your somatic cells. They are the basic working unit of your brain as they transmit information to other nerve, muscle, or gland cells. Most neurons have a cell body, an axon, and dendrites.
The cell body contains the nucleus, or the control center, and the cytoplasm, which is the clear, viscous fluid composing the bulk of the cellular material. The axon extends from the cell body, splitting into many smaller branches and ending at nerve terminals. Dendrites extend from the neuron cell body, receiving messages from the other neurons.
The dendrites are covered with synapses, points where one neuron touches another to communicate. The synapses occur between the dendrites of one neuron and the ends of the axons of another. At synapses, neurons can exchange neurotransmitters, chemicals traveling minuscule distances across the synapses to relay a message.
These connections are, quite literally, your train of thought.
Action Potentials → Electrical Activity
When a neuron “spikes”, it produces an electrical stimulation called an action potential.
The action potential is the explosion of electrical activity, which is caused by a depolarizing current as sodium channels open (positively charged sodium ions rush into the neuron → accumulation of positive charge).
Action potentials are the basic currency of the brain, allowing neurons to communicate with each other, perform computations, and process information. At the neuron’s action potential, neurotransmitters are released from hundreds of its synapses, resulting in communication with hundreds of other neurons. However, the majority of neurons are thought to be able to only release one type of neurotransmitter.
Where did this all start?
In the mid-18th century, an Italian biologist named Luigi Galvani made a shocking discovery. Galvani was walking in a market during a lightning storm and saw some frog legs for sale. However, he happened to notice that they were twitching. Galvani hypothesized that the electricity of the lightning was somehow activating the nerves in the frog legs. Galvani performed many experiments on the frog legs using an electric charge. He found that a charge applied to the spinal cord of a frog could generate muscular spasms throughout its body even if the legs were no longer attached to a frog. This was one of the first electrical stimulation studies in all of neuroscience.
From these findings, Galvani concluded that neurons could use electrical signals to pass information, but it wasn’t until the early 20th century until scientists began to use electrical stimulation as a way to map the human brain.
In the 1930s, Dr. Wilder Penfield, a brain surgeon, was working with patients who had epilepsy. Epilepsy is a dangerous disorder in which nerve cell activity in the brain is disturbed, causing seizures. As Dr. Penfield needed to surgically operate on the brains of his patients with severe cases, he wanted to map their brains to distinguish the most important areas, thus finding which aspects of the brain he should not operate on.
To do this, Dr. Penfield used electrical stimulation, similar to Galvani.
He lowered a small electrode into the motor areas of the brain, controlling movement, and then sent a small electrical signal. Then, he observed the patient’s movements. He realized that stimulation in one area of the brain caused different body parts to twitch and he realized that certain areas of the brain control very specific areas of the body. However, Dr. Penfield also noticed that the motor areas of the brain were similar across all of his patients. Through the patterns he observed, Dr. Penfield created functional maps of the motor areas of the brain which are still used today.
However, brain stimulation experiments and research have drastically changed since the 1930s. In addition to the influx of new technology and networking we now have, traditional brain stimulation poses many dangers to the human brain. It is quite easy for the brain to get damaged at the insertion of an electrode. In addition, electrical stimulation activates larger groups of cells rather than small subsets of or singular neurons as mentioned above. In general, traditional electrical stimulation is not very precise nor is it careful.
In 2005, a new technique called optogenetics was pioneered by Stanford University’s Karl Deisseroth and MIT’s Ed Boyden, inspired by the work and novel ideas of Francis Crick, one of the most influential molecular biologists in history specifically for his work with the structure of the DNA molecule. Optogenetics uses a combination of light and genetic engineering (changing the genetic information of a living organism by inserting/deleting genetic code) to control specific cells in the brain.
What exactly is Optogenetics?
Specifically, optogenetics is a method for controlling neuron activity using both light and genetic engineering. Genetic engineering is a process in which scientists change the add or remove segments of DNA, the genetic code of an organism, as a way to alter it. In optogenetics, scientists can take the DNA of the specific neurons they want to study and add a piece of genetic code to it. The new code causes the neurons to produce a new type of protein, called opsins, which naturally respond to light. The production of opsins by certain types of neurons allows scientists to isolate the neurons they want to study, and determine their activity, function, and/or role in disease.
How do opsins and neurons work together?
Opsins are naturally occurring proteins that were first discovered in algae. Algae use opsins to help them move towards the light. In neuroscience, the most frequently used opsin is channelrhodopsin-2 (ChR2), which comes from the green algae Chlamydomonas reinhardtii. ChR2 is activated by blue light, meaning that it only responds to that specific wavelength; it is not activated by any other type of light. Therefore, when ChR2 is produced by neurons, those neurons can only be turned on with blue light.
Opsins are produced by the neuron once the neuron has been genetically engineered to do so. Because we have a much larger understanding of the genetic code, we can choose where to put the opsin. Depending on the location that the code is inserted, we can trigger a specific type of neuron or neurons in a specific area of the brain to produce opsins, allowing scientists to choose exactly which neurons they want to control.
Opsins are delivered through a local injection of adeno-associated viral plasmids, known as AAV. These plasmids contain small insertions of genetic code producing a low immune response with low toxicity. AAV’s deliver opsins through stereotaxic surgery, a minimally invasive form of surgery. Following surgery, scientists can measure the neural activity and neurochemistry of singular or small groups of neurons, as well as manipulate their activity to determine the role of these specific neurons in brain physiology and behavior.
How is optogenetic stimulation different from electrical stimulation?
It all comes down to structural versus functional mapping.
When you look at the structural map of a city, you’re given all the possible options. On the map, you see all of the cars going from Point A to Point B and all the possible ways that the cars can get to their desired location through a jumble of roads, highways, and intersections. However, this map does not tell you which route is the most popular, if a specific type of car likes to go down a certain route, or any other patterns in regards to the cars and the routes they take. It shows you a jumble of cars traveling and around this busy city, giving you the big picture of all the cars, but nothing more specific.
On the other hand, functional maps show which roads are being used by which cars. It shows patterns that are undetectable in a structural map, such as the fact that red cars tend to travel down Road Y versus Road Z. In this map, you can choose which vehicles you want to see. You can even choose where the cars begin and where the cars end their journey.
Electrical stimulation allows scientists to create a structural map of the brain. Although we can control when the neurons (represented as cars) are traveling, we cannot choose which neurons or traveling, or monitor a certain neuron traveling from Point A to Point B. Electrical stimulation is very general and fails to provide specific information about the activity of a certain neuron or a subset of neurons.
On the other hand, the functional map represents optogenetic stimulation. Through optogenetic stimulation, we have much more control over what we want to see mapped. We can choose exactly which neurons go out and when. We can choose to activate neurons by location or type, resulting in a selective stimulation process that reveals specific information about the operation of a smaller group of neurons.
Why do we want to know the specifics?
Sure, optogenetics might allow scientists to control the activity of any neurons they want with extraordinary precision, but in what ways does that enhance neuroscience?
Well, optogenetics has allowed scientists to make remarkable advancements in neuroscience because it allows scientists to link neural behavior, circuits, and function.
Knowing the specifics is crucial to finding the role of certain neurons and types of neurons in cognitive behavior, function, and disease.
Through optogenetics, scientists have been able to make massive strides in understanding diseases such as Parkinson’s disease, epilepsy, strokes, and even cardiac arrhythmia (irregular heartbeat), when optogenetic techniques are used in the myocardium, or the muscular tissue of the heart.
Let’s take Parkinson’s disease as an example, a disease that affects over 10 million people worldwide. Parkinson’s is a disorder in the Central Nervous System that leads to shaking, stiffness, and difficulty with walking, balance, and coordination. It is caused by a degeneration of nerve cells in a part of the brain called the substantia nigra. These nerve cells are responsible for producing dopamine, which is a neurotransmitter that helps control and coordinate body movements. The substantia nigra works with the striatum, a central area of the brain. The striatum feeds into another part of the brain, called the basal ganglia, whose function is to regular motor control, motor learning, speech, and other large roles.
Through this pathway, the degeneration of nerve cells in the substantia nigra has an effect on the basal ganglia. When the substantia nigra isn’t producing enough dopamine, the dopamine receptors in the striatum aren’t properly stimulated, causing parts of the basal ganglia to be either under- or over-stimulated, resulting in tremors.
However, optogenetic research looks promising in reducing symptoms caused by Parkinson’s, and potentially even eradicating it altogether. Scientists have been able to employ the same techniques described above to treat Parkinson’s in mice. Specifically, the gene of a light-activated ion channel is introduced into certain cells. This allows for the activation or inhibition of neurons through depolarization (positive ion accumulation) or hyperpolarization (negative ion accumulation) of the neuron under a certain wavelength of light. The cellular activity can be adjusted to various levels by fine-tuning the parameters of the illumination on the neurons, such as frequency and width.
In a recent study, scientists introduced an opsin similar to channelrhodopsin, called halorhodopsin (NpHR), which actively pumps negative Chlorine (Cl-) ions into cells in response to yellow light. Scientists introduced NpHR into the subthalamic nucleus of mice, which is a small, lens-shaped structure that is an important moderator in the basal ganglia system, shown in the image above. When introduced, scientists found a reduction in the hyperactivity of the subthalamic nucleus in the mice, which is a major contributor to Parkinson’s Disease.
Over the past decade and a half, Optogenetics has accomplished the unfathomable. Not only has it given scientists a completely new perspective on the role of individual neurons, but it has also given them a level of control that had only been dreamt of for centuries. With this revolutionary technology, we can only imagine the information we will be able to decode over the next few years about the most complicated thing in the universe.
- Although the brain is the most complicated thing in the universe, humans know the least about it.
- Current technologies give us a very basic understanding of the brain, but don’t allow us to see the roles and functions of singular neurons or subsets of neurons in everyday activity and disease
- Traditional electrical brain stimulation poses many dangers. Optogenetics, which uses gene editing and light to activate singular neurons or smaller groups of neurons, is a much safer option.
- Opsins, light-sensitive proteins, are introduced into the brain through local injections of plasmids, producing a low immune response. Scientists can manipulate and observe neurons by varying the wavelength and frequency of the light on the neurons.
- Optogenetics shows a lot of potential in reducing the symptoms and potentially eradicating diseases such as Parkinson’s disease, epilepsy, strokes, and even cardiac arrhythmia (irregular heartbeat).
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