Welcome to this tutorial about the non-neuronal cells of the central nervous system. We have three learning objectives today. We want to again simply describe the basic classes of cells found in the central nervous system. And now, in this tutorial, we want to focus specifically on the glial cells. So I want you to be able to describe the basic functions of the three types of glial cells found in the central nervous system. One of those types of cells has an important role to plain in a particular kind of physiological barrier called the blood-brain barrier. So we'll spend a little bit of time thinking together about that, and I want you to be able to discuss it or characterize it with a friend or a study partner. So let's begin by again, looking deeply into the brain, as we did in our first tutorial. Here again, is a view of the motor cortex, as seen in the histological slide. That reminds us that, again, the cortex is a very complicated place. There's lots of different kinds of cells that are found here. And specifically, what we find here are neurons, which was the subject of our first tutorial. Neuroglial cells, and that's what we're going to focus on today, or sometimes we'll just call them glia for short. So we'll talk in more detail in just a few minutes about all of their various functions. And I would just remind you again that there are also vascular endothelial cells found in this tissue as well. Given the fact that the brain requires such a steady and, abundant supply of the cardiac output in order to maintain the functions of the brain. Okay so let's think now about the neuroglial cells. And the neuroglial cells provide a variety of functions for brain tissue. Perhaps the broadest summary statement that captures a variety of their functions would be to simply state that they support the metabolic and the signaling functions of neurons. Which often involves both electrical and chemical signals. Neuroglia participate in the forming of neural circuits and in a variety of forms of synaptic plasticity. This is a very exciting, new aspect of glial cell biology that's just now beginning to open up. And we're coming to see glial cells as really being active participants in the process of making new synaptic connections in the brain. Certain types of glia, they make myelin, which is a form of insulation around axons that aids significantly in the propagation of electrical signals along this component of the neuron. Glia contribute to the formation of the blood-brain barrier, we'll have more to say about that in the end of the tutorial. Glia participate in the inflammatory response in injured neural tissue, and that includes phagocytosis of cellular debris. Other types of glial cells contribute to the formation of scar tissue in damaged brain and spinal cord, and so this is part of the way that the brain responds to injury. Alright, now let's consider different types of glial cells. Beginning with what is, in some respects, the most complex of the three major types of glial cells, the astrocyte. So here is an illustration of an astrocyte from your textbook. And astrocytes are primarily found in gray matter. And the reason is, is that they're closely associated with the cell bodies, the dendrytes and the synaptic connections of neurons, and as you'll recall from our first tutorial, these are all, cellular components that are found in gray matter. Glial cells help to maintain the ionic balance of the extracellular fluids that surround neurons and that's very important for maintaining the capacity of those neurons to generate and maintain electrical signaling. One additional role of astrocytes is to take up and process neurotransmitters. Those are the special chemical molecules that are released by presynaptic terminals and the process of intercellular communication from one neuron to the next. So Astrocytes have a role to play in processing neurotransmitters. As I mentioned, astrocytes are the glial element that assists in the formation of new synapses and new circuits within gray matter. This is a, again a newly discovered property of astocytes and it's one that is opening up new for research as well as potentially new therapies for intervention for individuals who've had damage to their brain or spinal cord. Atrocytes are that category of glial cell that contributes to the formation of the blood-brain barrier. As well as the barrier between the brain and the ventricular system within the brain called the brain ependymal barrier. And astrocytes are that type of glia that can differentiate into a type of cell that can form fibrillary scar tissue. With in injured brain and so this is important if there has been injury and that injury is evolves in time to form let's say a small cavity as cellular debris is removed, then that cavity can be filled up by astrocytes that will grow in and form a kind of scar tissue to occupy that space in damaged brain. Okay, the next type of glial cell to consider is the oligodendrocyte, and the oligodendrocyte is more of a specialist. Its functions seem to be much more limited than that of the astrocyte. Specifically, the oligodendrocyte is found in white matter because this is the cell that forms the insulation around axons in the central nervous system. And that insulation is called myelin. Now if we were talking about a peripheral nerve in the peripheral nervous system, we'd be talking about a different type of myelin forming cell called a Schwann cell. So, I just wanted to make that distinction between the oligodendrocyte and the Schwann cell. They both make myelin, they both insulate axons, but the oligodendrocyte is the one found in the brain and the spinal cord. Whereas the Schwann cells found in the nerves of our body. So what good is myelin? Well myelin aids in the propogation of neural signals along myelinated axions and we'll say more about that in just a moment. But before we do, I'll also mention that the oligodendrocytes add antigens that influence the growth of axions both in the developing brain and in the recovering brain that's undergoing a process by which it will try to re-generate connections that have been lost due to injury. Now, unfortunately the oligodendrocyte also presents antigens that are subject to immunological attack in certain diseases of the central nervous system. A preeminent example of which would be multiple sclerosis in which oligodendrocytes are the subject of the immunological attack, and myelin can break down, and with the breakdown of myelin, is a loss in the efficiency of the conduction of neural signals along axons, and that can lead to neurological dysfunction. Okay. Let's come back to this point about oligodendrocytes making myelin and what that does for, the efficiency of information transfer along the length of an axon. So here's an illustration from your book showing you two portions of an oligodendrocyte that are coming together forming myelin. Myelin would be this wrapping of membrane that surrounds this axion here so these mini-concentric rings of membrane, that's what we call myelin wraps or myelin sheaths. And so, here is the cell body of one oligodendrocyte, there'll be the cell body of another somewhere off screen here with it's nucleus. So, these two oligodendrocytes are coming together and there's a small gap between them called the node of Ranvier. Okay, so what these oligodencrocytes are doing is that they're insulating axons by generating layers of membrane that wrap around those axon segments. And this has the important function of decreasing the leakiness of the membrane of that axle. And so this allows the passive flow of current along the length of the axon to be much more efficient. Now, as I mentioned, there are gaps between these myelin segments contributed by different oligodendrocyte, and those gaps are called nodes of Ranvier. And these nodes are, are quite important, because they provide a place Whereby ion channels and ion pumps can be concentrated. And so the benefit here is really twofold, the electrical signal is regenerated. Here in this node of Ranvier and the signal can be regenerated across these segments of myelin that are contributed by different oligodendrocytes and the signal can essentially jump from one node to the next. We call that saltatory conduction, more on that in a later tutorial. But there's another advantage of having nodes of Ranvier, and that is that one can populate these nodes with the proteins in the membranes. Here, of the axon with great efficiency. So, you end up having to, create and populate fewer ion channels and pumps in a smaller region of axonal membrane than you would otherwise if there were no myelin. One would have to have channels and pumps along the entire length of that axonal membrane in order to keep that electrical signal propagating, but with nodes of Ranvier and myelin segments between the nodes we can be much more efficient. Both in the electrical properties of the conducting tissue but also in the bio-synthetic, requirements to create that machinery that's necessary to generate those signals. So, these are all great advantages of having myelin, insulating axons. Okay, and our third type of glial cell that we'll talk about in this tutorial is called the microglial cell. Now, this is a really fascinating cell. It's actually a cell that is a special type of mononuclear phagocyte that resides in the central nervous system. Although it's actually derived from hematopoietic precursor cells that migrate into the brain. During early embryonic development. So these cells enter the brain and they take up residence in one of two forms. In the dormant state, this microglial cell Is called a ramified cell and that's what's illustrated over here to the left. So this is a ramified microglia cell. It has lots filamentus processes that extend away from the cell body and here below we have a photomicrograph that shows a population of ramified microglia. Well, these ramified cells are dormant, they are lying in wait, and in the event of injury or inflammation, then these cells will retract their processes and convert to what's called an amoeboid state. Which is what we see over here in the right-hand figure. So these are all activited microglial cells that are now on the move. So the amoeboid form is the activated, mobile state when microglial cells are mobilized and engaged in phagocytic activity. And this is one principle function of microglias, that they phagocytize cellular debris that is found at the site of injury in the nervous system. But they also sigal, signaling molecules numerous kinds of cytokines, for example, that can modulate local inflammatory responses. Now, one further type of glial cell that is worthy of some mention, is actually not a mature cell at all. It's a stem cell. So, within the central nervous system, we now know that there are stem cells that have the capacity to multiply and to differentiate, and these stem cells resemble glial cells of the astrocyte and lygagindrocite forms. So, here's an illustration of glial stem cells. And these seem to be a subset of immature astrocytes that are located near the ventricles, often adjacent to blood vessels, as we see here in this illustration. And these glial stem cells can give rise to more stem cells or they can mature into astrocytes, oligodendrocytes, and even neurons. So these cells exhibit the key properties of somatic stem cells. They can proliferate, they can renew their populations. That is, they can form other stem cells. And they have the potential, the potency to make all the cells of a given tissue. In this case, of course, we're thinking about the central nervous system. Now there's also a glial stem cell that more resembles the oligodendrocyte and this oligodendrocyte precursor is found scattered throughout the white matter of the central nervous system. And when this cell differentiates, it mainly gives rise to mature oligodendrocytes. Although under certain conditions it might give rise to astrocytes, and perhaps even neurons. Okay, now let's return to this concept of the blood-brain barrier as we conclude today's tutorial. The blood-brain barrier is a specialized permeability barrier between the capillary endothelium and the extra cellular space within neural tissue. And it's formed by tight junctions between capillary endothelial cells. So, for example, here is the, nucleus of a capillary endothelial cell, which is otherwise wrapping around, forming a capillary wall. And where the processes of this cell overlap, we find the histological feature know as tight junction. So, tight junctions seal up the spaces, between These overlapping regions of this endothelial cell as it forms the capillary. Surrounding this endothelial cell are the foot processes, or the end feet of astrocytes. That completely envelop this capillary endothelial cell. So together the endothelial with its tight junctions and the astrocytic foot processes form a limiting barrier around the vascular compartment. So, this has some very important consequences. This barrier excludes large water soluable molecules from freely diffusing into the central nervous system. As well as certain pathological microbes and certain toxic compounds that might otherwise enter the brain. So, a very important protective function formed by this limiting barrier. Of course, there are some molecules that must enter the brain, such as glucose and a variety of amino acids. Such molecules typically are transported across this barrier by both active And passive means. Now unfortunately, this barrier also provides a limitation for certain pharmaceutical agents that we might want to provide patients in the health care setting. So certain drugs, for example might be engineered in a way to circumvent this barrier because otherwise passage of such compounds would not be facilitated by the presence of this blood brain barrier. Now across the lifespan, this blood and brain barrier is present in most places throughout the central nervous system with a few important exceptions. Essentially, wherever there are special populations of neurons that are secreting proteins that need to enter the blood in order to have a hormone affect throughout the body. Then this blood brain barrier tends to be porous; that is to say the tight junctions are not present. And there are openings that allow substances to diffuse across this junction between brain and blood stream. And so, that's important, for example, at the base of the fore brain, where we find the hypothalamus. Where there are neurons that are secreting peptides into the blood that will affect the anterior pituitary. There are other places in the brain, such as in the pineal gland, where hormones such as melatonin are secreted and enter the blood stream. So wherever there is a hormone secretory function, there is going to be some loosening of this blood-brain barrier. But with those exceptions, this barrier is present at birth and it's maintained throughout the lifespan in normal, healthy brain. There are some diseases and some conditions that can infect the integrity of this barrier and when that integrity is challenged, then the brain is more susceptible to the entrance of molecules that might alter its physiology and decrease its function. Well, let's conclude this tutorial with a study question. I want you to think about a patient that is had a stroke. And that stroke causes some small region of the brain to be damaged. I want you to think about the glial cells that are present in the brain, around that region of damaged brain and think about which activity of glial cells do you think happens first. Well, think about these activities and the sequence in which they might unfold and go ahead and record your response. . Well, thanks for your attention. I hope you enjoyed this tutorial on the non-neuronal cells of the central nervous system. For our next tutorial, we'll get back to talking about neurons and focusing on the means by which they generate electrical signals. I'll see you then.
