NDD: What are Neurons/Glia and History of the Neuron Doctrine

Ethan Intro: In this segment, first Jaime gives us a little bit of background on some of the brain cells that we'll be discussing, and then we transition into my explanation on the history of the neuron doctrine.

Ethan: Let's dive into some basic neuroanatomy for a little bit more comprehensive understanding. Jaime, since you're the neurologist, I'm gonna let you take over on this one.

Jaime: You can essentially break down the nervous system into 2 components. You have your central and your peripheral nervous system. Your central nervous system is gonna include things like your brain and your spinal cord, whereas your peripheral nervous system is gonna be [1:00] everything else outside of that. So your nerves, all of the sensory information that's coming in, as well as kind of the motor output from the spinal cord onward. You can further kind of delineate these different anatomic considerations in terms of myelinated versus the gray structures, or the non-myelinated. The myelinated regions are basically wiring, so the impulses aren't necessarily being derived from those regions, but the information is being transmitted over distances, and the myelination helps to keep that signal within those constructs, whereas the generation of those impulses, starts from the gray structures or the non-myelinated regions.

Ethan: So does the myelination help to speed up or slow down?

Jaime: It speeds up basically. And it also makes it just a much more efficient process. Thinking of the human [2:00] brain and the development of it, the first structures to kind of myelinate are your vision centers in the back of your brain. That's the first information that comes in and then needs to be processed efficiently. The cells called Oligodendrocytes are helping to coat the pathways that are being used more often so that energy can be more efficiently transmitted between different cells.

Ethan: You just think about it on a very basic or general level, you want your arm to move in a certain direction, it seems to happen instantaneously. Or, obviously in the processing of vision, I don't perceive any time lapse in what I see and then processing it.

Jaime: Exactly. We need it to be as efficient as possible, and I think it's somewhat beautiful how the process of myelination occurs from the back of our brain going forward. It really speaks to the different tasks that we learn [3:00] as we develop as humans. We start with our vision centers and then we start to incorporate more of our sensory regions and then further on our motor tracts, getting down to the frontal lobe, which is more of the fine-tuning of our behaviors.

Ethan: Which doesn't really fully develop until, I don't know… Is yours fully developed at this point?

Jaime: I, they tell me it is, but it develops much later, typically, I think average is around 27, 28. But full development kind of starts, or really accelerates, the development process with puberty, the frontal cortex, the prefrontal cortex a little bit later. And you can explain some of the stupidity of youth from it.

Ethan: Tell us more about the cells in the brain.

Jaime: We can further break down the different types of cells into neurons, which are the communicating cells themselves. That's where the [4:00] impulses are derived. That's where the information is stored, in between those connections. And they're connected through things called synapses. And there's information that's shared between those synapses using neurotransmitters. Different neurotransmitters help to change the excitation or the inhibition of the post-synaptic regions. You can think of the oligodendrocytes as the myelinating cells. They wrap up those neurons so that you can be more efficient in the transmission of that energy into different regions of the brain. You also have glial cells, which can be broken down into your microglial cells, as well as your astrocytes, both of which have roles in maintaining the synapse, clearing the synapse of any sort of excitatory overflow so that you can reset that signal and [5:00] be able to do it again. The microglia are important for one, synaptic pruning, getting rid of synapses that you don't need anymore, because, energetically, that is costly to maintain. Normal human development of the brain occurs when you start taking away synapses that you don't need anymore and maintaining the ones that you do need and that you wanna strengthen.

Ethan: So, the microglia are like the garbage collectors, scooping up everything that has been deemed unnecessary for brain function.

Jaime: Exactly. And there's ways that the synapse, the astrocyte, and the microglia are working all three together in order to maintain a homeostasis or a balance.

Ethan: The tripartite theory… how those all kind of work together. Astrocytes? What do you know about those?

Jaime: Our brain cells are neurons. They don't have the capacity to replicate. The information they have is [6:00] based off of that cell surviving as long as the organism can survive. Because you can't divide these cells to get rid of toxic accumulation or cellular breakdown products, you need to make sure these neurons are protected. The astrocytes set up a barrier system, the blood brain barrier, so that selective things can get to the neurons. Other things, like toxic metabolites, they don't get there. We need to have a controlled environment for our brain cells. They're vulnerable. They can't replicate. The worth of each cell is inherent to that ability to maintain that cell. So, the blood brain barrier has to be tightly controlled and activate neuro-inflammation when it's necessary so that the brain can last as long as possible.

Ethan: Essentially, you've got this kind of neuron network surrounded by so many [7:00] more astrocytes. All of these glial cells together maybe have a little bit more, or a lot more, importance than we have given them in the last 150 years.

Jaime: Absolutely. And I, would be remiss in not mentioning some of the other cells in the brain that are very important and also contribute to this homeostasis are ependymal cells. So, the ability to create a circulatory system in our brain, being able to make cerebral spinal fluid that is a distinct entity outside of blood, and is able to kind of cushion the brain as well as get rid of toxic accumulation during the day, which our sleep is very important for. If you didn't have that, then your brain would essentially collapse on itself, without the outward pressure of the CerebroSpinal Fluid in the ventricles. It also wouldn't be able to get rid of a lot of toxins in a rapid fashion.

Ethan: Before [8:00] we get off the neuroanatomy, Jaime, can you give us a global view of what a neuron looks like versus astrocytes.

Jaime: So neurons you can break down into input, output, and then the cell body, which, contains the genetic information and allows for the synthesis of the different chemicals that need to be produced by the brain in the nucleus. So, the cell body is that hub, and then you have extensions outward being the axon, that sends the signal to another place. And the dendrites being kind of the receiving end, and there's multiple inputs that then go towards the cell body and allow for the propagation of the signal towards the axon. Now, astrocytes are a little bit different. They have extensions that kind of envelope the vessels, and create this blood-brain barrier. And additionally [9:00] have a cell body that creates the different proteins and things through the genes of those cells in order to create the places near the synapse so that you can clear excitatory material.

Ethan: So ‘Astro-’ refers to them being star-shaped, and more of a central cell body with projections going in every different direction, not so much having a receiving end or ascending end but going in every direction. For a long time, we thought that neurons communicated with each other at the synapse, and that was the basis of brain communication. I'm trying to remind myself not to say neuronal because the fact that we call it neurology is even doing a disservice to the other 90% of the cells in the brain. For a long time, we neglected the fact that at the synapse, we could see the 2 [10:00] neurons. But, there are always astrocytes located directly adjacent to that synapse, and are releasing their own, they would be termed, I guess, GLIAtransmitters.

Jaime: Absolutely. And they are in constant communication with those neurons as well as with some of the other tissues, like the microglia, in order to maintain that synapse. Yes, the communication from one neuron to another is occurring through that synapse, but the maintenance of those connections, there's really an intricate balance between all of these cells that we're talking about.

Ethan: There was a historical stunting of the theory of how the brain works due to what's called The Neuron Doctrine, which I wanna give you a little bit of history about in our next segment.

Ethan: Have you ever heard that you only used [11:00] 10% of your brain? That's a myth. It's total bullshit. It comes from a historical dick measuring contest in the late 1800s/early 1900s, between a couple of scientific researchers, Camillo Golgi and Santiago Ramon e Cajal. Golgi believed that the brain worked like a continuous syncytium, or a net, where all the structures and all the cells were interconnected like a network of highways and cities, while Cajal thought that the structures were contiguous as opposed to continuous, sitting next to each other, but not actually physically connected. These 2 researchers despised each other. They constantly worked to disprove each other early in their careers and were comically duly awarded the Nobel Prize in Physiology in 1906. Their feud ultimately was very detrimental to the field of neurology and the understanding of brain function in general. Cajal’s efforts to [12:00] disprove what he considered to be a scientifically inferior Golgi stunted the growth of the field for nearly 100 years in his haste for scientific vindication. Cajal declared victory when he microscopically proved that brain cells were not interconnected, but rather adjacent to each other. And he used this platform to label the neuron as being of utmost importance to brain function at the expense of other glial cells, ‘glial’ being Latin for glue. These were delegated to the back burner as only providing support to the holy neurons. Metaphorically speaking, he failed to appreciate the forest through the trees.

So just a little background here about both of these gentlemen. Camillo Golgi was the less antagonistic of the two. He was an Italian teacher and physician, but he never actually practiced medicine, much more of a researcher and kind of a lifelong learner, [13:00] a little bit of a Renaissance man. He became a Senator in his older age, but in the late 1800s, he was designated as the Chief Medical Officer at the Hospital for the Chronically Sick in Abbiategrasso, Italy, I think is how you pronounce it, aka the Fertile Valley. He took a small kitchen, and converted it into a laboratory, and he began studying disease processes. He's the one who is credited for determining 3 unique forms of the malaria parasite and correlating that clinically to their distinct types of fever, and eventually discovered a way to photograph malaria's different phases. However, his greatest invention came years later when he revealed a method of staining cells called The Black Reaction, which used silver nitrate to illuminate nerve cells and gave us the ability to distinguish the dendrites from the axons, from the cell bodies, including the nucleus. It's not [14:00] known exactly when he discovered this staining method, as he was notably modest, self-critical, and kind of shy about his research, but it occurred sometime in the late 1800s.

Santiago Ramon e Cajal was a Golgi contemporary. He was a Spanish neuroscientist, pathologist, and histologist with a rebellious and somewhat anti-authoritarian attitude and had a certain machismo about him. He reportedly destroyed his neighbor's yard gate with a homemade cannon at age 11. His father was an anatomy teacher, used to take him to the graveyards to dig up human remains for anatomical study. You know he was crazy cuz he had 7 daughters and 5 sons, which is way too many kids. But in 1887, he moved to Barcelona where he learned about Golgi’s staining method. He actually improved upon it by introducing silver nitrate in 2 shorter soaks rather than 1 long soak [15:00] improving the color and the detail, and removing some of the artifact of the stain. This helped him to experimentally demonstrate that the relationship between the nerve cells was not continuous, but rather contiguous. Using that knowledge, he is highly credited for developing what's called The Neuron Doctrine, stating that the neuron was the basic signaling unit of the nervous system, and that they were separate discrete cells with processes arising out of the cell body, that they were primarily responsible for brain cell function.

Apparently Cajal disliked Golgi so much as it was so obvious to him that his stain showed the brain was comprised of incremental cells just like the rest of the body, that he fought tooth and nail for his doctrine to win out in terms of the scientific community’s acceptance of how the brain works. He felt neurons extended [16:00] longer distances, they went from the central nervous system to the peripheral nervous system, and therefore they must have much greater importance. Both Golgi and Cajal believed in a secondary role for glial cells. Golgi proposed what's called the Reticular Theory, saying that the brain works like that syncytium, where everything is floating around in the same goop and attached together in some way, working holistically to produce specific functions. Cajal opposed GOGI and supported a fiber-centric theory that neurons were primarily responsible for signaling each other and producing effects through rapid transmission of information, like electricity may be connected in a city. Cajal looked at Golgi as lesser than with no clinical experience and likely took personal offense to Golgi's opposing views of brain function. After disproving Golgi’s reticular theory, [17:00] Golgi receded into the background of the scientific community, pursued a 2^nd career in Italian politics and became a Senator. He did continue to work in his private lab until his death in 1926.

Unfortunately, Santiago continued to advance his neuron doctrine theory. Many years later, his own younger brother, Pedro, put forth the idea that persisted into our medical training years later, that glial cells were simply glue, there to support and insulate neurons. It wasn't until many, many years later that Carl Schleich, who was actually a prominent student of Rudolph Virchow, a pathologist that was credited for Cell Theory, the idea that cells arise from other cells. Carl Schleich was the first to go out on a limb and propose that glia and neurons were actually able to signal to each other, but his ideas weren't widely accepted at the time. [18:00] The impact of this story is that Cajal was so caught up in disproving Golgi and being scientifically superior that he missed the point in advancing scientific understanding of brain structure and function. He utilized one important detail and extrapolated it to most brain functions, neglecting the impact and the importance of glial cells, leading to a nearly century-long abandonment of astrocyte and glial cell research and propagating a bunch of myths.

Jaime: I think it's fascinating how single individuals like this can shape the way that we even perceive how something is working, to the point that it changes history entirely and how we view, one, how our brains work, and how can we fix when the brain goes wrong when there's disease. We are working, [19:00] a lot of times, off of incomplete pictures.

Ethan: Yeah, us humans don't like that uncertainty that comes with saying, actually I don't know if I do understand everything. My theory is comprehensive, and explains every detail of brain function. Obviously, they wouldn't have said that even back then, but it's the insinuation, I think, and just the kind of vehement pronouncement of my theory being correct. I mean, look what happened to Golgi. He had to recede into the background in terms of the scientific community and go be a Senator. I guess he was embarrassed that he had been disproven. So, there are several myths that are propagated by this neuron doctrine. The biggest of which is that you only use 10% of your brain, which, I don't think a lot of neurobiologists have ever really ascribed to that myth, but just so the general public knows that is completely and absolutely false. The [20:00] other idea, that neurons are molded into their final form in early childhood and cease to regenerate or change significantly throughout one's life, they do not regenerate in the vast majority of the brain, but we'll talk a little bit about certain areas where they can be told to regenerate. And they certainly do change throughout life.

Jaime: Plasticity being that process by which you can change how the brain's connected, and that's an important thing to make note of. Sure, we may not have a great capacity to make new neurons, but we certainly can change the way that we think. It's the combination of not only the neurons, but all of the cells in the brain that allow that process to occur.

Ethan: Other myths… that glia have these 2 functions, provide support or nutrition to neurons and insulate, to prevent [21:00] the undesirable spread of neuronal impulses, one example, seizures. The whole idea that The Neuron Doctrine supports (is) that these synapses create a disconnected neural network. If you look at the structure of an astrocyte, they form a bunch of different gap junctions at all of these areas where they coexist with neurons and with other astrocytes. You really could argue that everything is interconnected in some way.

Jaime: It's something that we haven't been able to fully understand how the different genetic processes that are occurring intersect at those different communication points between the astrocyte and the glial cells.

Ethan: Another one that, again, I don't think your typical leading neurobiologist believes this, but that astrocytes are one cell type, (that) they have clearly defined functions and roles when, in actuality, astrocytes [22:00] look different and behave different depending on which region of the brain that they're in. So it's quite plausible that specific subpopulations with distinct structure and molecular equipment help to dictate different neural functions. Any other myths related to that neuron doctrine?

Jaime: One prevailing theory that the Neuron Doctrine kind of promotes is that disease states in the brain are moreso the communication deficits between the synapses, and so most of the medicines that we use target just that process, only looking at the communication between pre- and post-synaptic transmission, whereas a more comprehensive look at the kind of homeostasis that the astrocyte entails, as well as the microglia entails, means there are many different ways that breaks down. And if we're treating a disease [23:00] state the same as only between these two neurons, we're missing a large portion of diseases that we're just not even focusing on.

Ethan: Yeah, I mean talk about missing the forest through the trees. I missed on including the part that almost all of our medications are directed at neurons and neuronal function, and that glial cells as a whole, whether it be microglia or astrocytes, or other cell types, there's a huge therapeutic potential there that, maybe we could better affect some of the disease processes that we haven't found a cure for or haven't found really good preventive or reversible agents that could be useful in so many different debilitating conditions.