We May Have Misunderstood Myelin

The brain is made of living cells, not insulated wires

Myelin is classically known as an insulator that increases the speed of action potential propagation. Myelin is dynamically produced and maintained by cells called oligodendrocytes (or Schwann cells in the peripheral nervous system). Unfortunately, it is often pictured as inanimate sheathing, like pieces of rubber wrapped around conductive wire. Image Credit: Wikimedia Commons

The nervous tissue in our spinal cords and brains is visibly divided into gray and white matter. While these two kinds of tissue look quite different, they are both composed of similar populations of living cells. The difference comes from a type of biological insulation known as myelin. In other words, white matter is like an electrical wire that is insulated and gray matter is just naked wiring. It is tempting to describe nerves as little bundles of electrical wires encased in insulation. But is that really the best way to think about them? In this article, we’ll explore how you may have been misled about myelin as an inert insulator.

The Law of the Instrument, or The Golden Computer

The scientific revolution of the 16th century brought with it the idea that the universe (and by extension, life itself) is a mechanical artifact. As Thomas Hobbes wrote in his 1651 book Leviathan:

Why may we not say, that all “automata” (engines that move themselves by springs and wheels as doth a watch) have an artificial life? For what is the “heart,” but a “spring;” and the “nerves,” but so many “strings;” and the “joints,” but so many “wheels,” giving motion to the whole body, such as was intended by the artificer?

A psychological principle known as the Law of the Instrument, or the golden hammer, can help us understand the idea that biology operates like a mechanical watch. In his 1964 book, The Conduct of Inquiry, Abraham Kaplan formulated the Law of the Instrument like this: “Give a small boy a hammer, and he will find that everything he encounters needs pounding.” In other words, we are cognitively restricted by the functionality of our tools. The passage by Thomas Hobbes is a perfect example of this principle, as the popularity of the pocket-watch was spreading throughout Europe while Hobbes was comparing the heart to a spring and the joints to cogwheels.

Recently, the Law of the Instrument has been validated with modern technology. The advent of the computer has catalyzed the birth of a historic period called The Information Age. The ever-expanding power of computing is revolutionizing the way we perceive our realities and, in particular, the way we think about our own bodies.

The robot in this GIF (Sophia) is explicitly designed to evoke the comparison between mechanical automata and biological organisms. Image Credit: Giphy

As we learn more about the information processing power of our nervous systems, we can’t help comparing our brains to the dominant instrument of our time. But conceptualizing brains as computers diminishes the overwhelming complexity of our biology. I’ve described one instance of this common oversimplification in a previous article in which I explain why it is misleading to visualize neuronal signaling as a static, electrical phenomenon. Unlike the motionless information processing in a computer, the activity in a brain is embedded within an extremely messy and active biological context: a living creature.

Neuroscience — It’s Not All About The Neurons

A brain is a feature that can only be found in a multi-cellular organism. Therefore, just like everything in a multi-cellular organism, a brain is composed of cells. But neurons get a disproportionate share of the love when it comes to the study of brains (it is called neuroscience after all). So, in this article, I want to focus on a different type of brain cell: the oligodendrocyte.

Oligodendrocytes make myelin, which can wrap around 40–50 different axons. Image Credit: Gyfcat

Oligodendrocytes are a type of glial cell, which are often called the “support cells” of the brain (again, neurons get all the love). Glial cells do all sorts of important things, like clean up waste, fight off invaders, and provide vital nutrients to neurons. As glial cells, oligodendrocytes have a special trick up their sleeves: they can create a highly functional structure called myelin. To do this, an oligodendrocyte stretches out its processes (like little arms) and wraps itself very tightly around the axons of the surrounding neurons. The cute little animated oligodendrocyte in the GIF above is shown hugging the axons of three neurons. But, in a real brain, these glial cells myelinate upwards of 50 different axons and the myelin of an oligodendrocyte encircles each axon hundreds of times. In this way, myelin encases the length of an axon in discrete segments of tightly wrapped spirals.

One oligodendrocyte wraps many myelin sheaths around segments of many axons. This structure is often deceptively depicted as something like a Swiss cake roll. But cross-sectional electron microscope images (see image in the right panel) show that myelin is actually made of hundreds of tightly wrapped layers. Image Credits: Nature Reviews Neuroscience (Left); Cooking By Moonlight (Middle); Systems Cell Biology at Yale (Right)

Myelin is often referred to as an insulator because it drastically increases the speed of action potential propagation; an axon ensheathed in myelin can send signals up to 300x faster than its unmyelinated counterparts. This enhanced conduction speed allows rapid communication to occur between distal parts of a spread out body plan. For example, a nerve impulse travels a great distance — from your foot to your brain and back to your foot — in a tiny fraction of a second. And this is a highly valuable feature of a living body — your chances of survival in dangerous situations depend largely on your reaction time. For this reason, myelin is a feature found in every vertebrate and may be an evolutionary requirement for the existence of vertebrates in general.

Myelin: More Than A Golden Insulator

Referring to myelin as an “insulating sheath” evokes an inaccurate equivalence between the brain and a modern electronic device, as if myelin is a piece of non-conductive material that wraps around an electrical wire. But myelin does so much more than function as an inert piece of insulation. As I mentioned before, the brain’s glial cells play the vital role of providing nutrients to power-hungry neurons. This is extremely important for oligodendrocytes because the insulating nature of myelin also isolates axons from the extracellular space. Whereas many types of cells can simply collect their own food from the environment, myelinated neurons have no access to the outside world. Oligodendrocytes are in the perfect position to spoon-feed neurons that constantly need to meet the energy demands of their firing axons.

Oligodendrocytes traffic RNA across microtubules (which are lit up in this GIF) to maintain myelin through local translation. They also transport energy substrates, like lactate, through myelin into actively firing axons. Image Credit: @Meng2fu

The importance of this this relationship between oligodendrocytes and neurons cannot be understated — proper myelination is absolutely necessary for our health. Evidence has linked abnormalities in myelin structure and function to a wide range of diseases. For example,

• Multiple sclerosis is caused when the immune system selectively attacks and degrades myelin
• Cognitive disturbances in schizophrenia seem to be related to oligodendrocyte and myelin dysfunction
• Post-mortem observations have seen that people with major depression show changes in myelinated regions of the brain
• Children with autism show an antibody response to myelin, which is similar to the etiology of multiple sclerosis
• Veterans with post-traumatic stress disorder (PTSD) actually show increased myelination in parts of the brain

Clearly, oligodendrocytes need to maintain a delicate balance of myelination to ensure neuronal health and brain function. Even beyond disease and dysfunction, myelination is a highly dynamic process that is constantly changing in response to the growth and behavior of an organism. For example, action potential conduction delays remain the same throughout development despite a huge increase in the distance that nerve impulses are required to travel (as the body gets bigger over time). In addition, extensive piano practice induces large-scale myelination changes in specific brain regions as a resulting of learning a new motor skill.

But how can oligodendrocytes respond so dynamically to the needs of individual axons, the growth of a body, and the behavior of an organism? It had been hypothesized that a form of rapid communication between neurons and oligodendrocytes must be maintained in order to support these dynamic and responsive changes in myelin structure. And indeed, such a structure was recently discovered underneath the many layers of the myelin sheath: a hidden synapse between an axon and its myelin.

The Axo-Myelinic Synapse

Synapses are considered to be the major form of information processing in the brain. They are defined by Oxford Lexico as “a junction between two nerve cells, consisting of a minute gap across which impulses pass by diffusion of a neurotransmitter.” But synapses aren’t found only between nerve cells. The evidence is mounting that axo-myelinic synapses are formed within every segment of myelin and its underlying axon. These synapses seem to work in exactly the same way as a synapse between two neurons: an action potential causes the fusion of vesicles with the cell membrane, which dumps the contents of the vesicles (neurotransmitters) into the synaptic cleft. Then, protein receptors on the post-synaptic neuron sense the incoming chemical signal and respond accordingly.

Action potentials induce the release of neurotransmitter at the synapse, which binds to post-synaptic receptors to induce a response in the receiving neuron. Image Credit: Wikimedia Commons

In the case of neuron-to-neuron synapses, neurotransmitters will sometimes induce an action potential in the post-synaptic cell. But this doesn’t really apply to axo-myelinic synapses, because oligodendrocytes don’t produce action potentials. However, there are many other downstream effects that occur when neurotransmitters bind to receptors on any post-synaptic cell. Unlike a computer, brain cells don’t need to use electrical signals to transmit important information; cellular signaling often happens through vastly complicated networks of cascading chemical reactions. In this way, axo-myelinic synapses are a completely untapped therapeutic target that are likely involved in all myelin-related diseases. But practically nothing is known about the function of these newly discovered synapses. Despite the lack of hard evidence, we can make some educated speculations about the role of axo-myelinic communication in our brains. (I won’t dig too deeply into the details here, so if you want more information about the possible molecular mechanisms you can check out my qualifying exam and its associated figures).

There are three probable ways in which axo-myelinic synapse activity could affect neurons and oligodendrocytes. We’ve already briefly touched on the first: the activity-dependent delivery of vital nutrients. As we discussed, myelin prevents axons from taking in vital nutrients, so oligodendrocytes deliver the food directly to the neuron. It seems extraordinarily likely that the amount of energy delivered to a given neuron would depend on the activity level of specific axons. And this information would be easily communicated through axo-myelinic synapses (see the top portion of the figure below). Secondly, axo-myelinic synapses are an attractive mechanism to explain how oligodendrocytes determine the thickness of their myelin wrappings. By using axo-myelinic synapses as a read-out of neuronal activity, an oligodendrocyte could fine tune the structure of each individual myelin sheath to modulate the speed of neuronal signaling (see the bottom portion of the figure below).

This is a figure I created to visualize the hypothetical ways in which axo-myelinic synapses might function. Top part of the figure: PKC is immediately activated by low frequency action potential firing which perfuses lactate into myelin through monocarboxylate transporter 1 (MCT) where it is delivered to actively firing axons through MCT2. Bottom part of the figure: High frequency action potentials cause a delayed inhibition of MAPK through myelinic NMDA receptor activation which enhances mRNA translation in myelin.

Finally, the interplay of these two mechanisms raises other fascinating possibilities. Because oligodendrocytes myelinate up to 60 different axons, they are in a perfect position to control the activity of an entire neuronal network. By receiving information from hundreds of axo-myelinic synapses, an oligodendrocyte could selectively provide nutrients to certain axons while also changing the structure of individual myelin sheaths. The combination of these abilities provides oligodendrocytes with an immense power to orchestrate the information processing of a group of neurons. An oligodendrocyte could starve out specific neurons by withholding nutrients, or it could alter the myelination on particular axons to synchronize activity across a network. We don’t really know if any of this happens, but the mere possibilities are mind-boggling. Whatever the actual functions of axo-myelinic synapses turn out to be, oligodendrocytes clearly play a much more important role in the brain than they receive credit for.

The dynamic and responsive ability of oligodendrocytes to control myelination is a great example of The Law of the Instrument leading us astray. Nothing even remotely similar happens within a computer. It’s okay if you can’t stop yourself from comparing brains to computers — the Law of the Instrument is going to restrict our cognition no matter how hard we try to fight it, so we may as well use it to our advantage. By studying the brain in its full and incomprehensible glory, we will certainly find innovative ways to design our technology. Indeed, there has been a recent push to create transistors that mimic the operations of neurons.

A compter-rendered image of oligodendrocytes myelinating neurons. Image Credit: Searching for the Mind

Using the complexity of the brain to advance our technology is a noble goal, but be wary of anyone who says things like this: “So Neuralink I think at first will solve a lot of brain-related diseases. So could be anything from like autism, schizophrenia, memory loss…” These promises may sound good, but just consider the intricacies of myelin: the axo-myelinic synapse, the role of myelin in diseases, and how little we understand about oligodendrocytes. Then realize that myelin is just one small piece of a much bigger picture: the immense complexity of the brain. And then, realize that the brain is just one small organ embedded within an even bigger context: the holistic unity of a living being. Don’t let the Law of the Instrument distort your perspective on human progress. Our technology has a long way to go before it can match even a fraction of the power displayed by our biology.

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