Welcome back and welcome to this tutorial in which I hope to provide you with an overview of the cerebral cortex and cortical circuits. I know I've said this repeatedly so far in the course, but we truly are dealing with the most complex organ to be found in the human body. And when we talk about the organization of the cerebral cortex and cortical circuits, we're largely looking at the product of genetic instructions that are determining how these circuits are going to form. And how they provide for the foundation of all the amazing functions that our cortical networks perform for us. One of them is we are endowed with curiosity, with a sense of wonderment, and I hope that capacity is being well-exercised so far in this course. As we turn our consideration to the cerebral cortex and cortical networks, we can't help but to be reminded of the importance of this part of the human nervous system for health and wellness, and optimal functioning. And we can't help but to be reminded of the hundreds of thousands of people that are living worldwide with neurological disability because of some problem in the development or in the ongoing health status of the cerebral cortex and its networks. With a reminder of those core concepts in the field of neuroscience that are at stake today let me point you to our learning objectives for this session. I want you to be able to discuss the embryological origins of the cerebral cortex. I want you to be able to discuss differences in the cellular architecture that we find from one region of the cortex to another. And I want you to be able to discuss, not only what's different from one region to another but what's conserved. And that would be the anatomical organization of what we'll call the cortical microcircuit. And lastly, I want to give you a bit of an acronym that might help you remember what are some of the principle functions of that microcircuit and I call that the ACC of the cortical microcircuit. Okay well let's begin with just a bit of embryology. Now the cerebral cortex and all the networks contained therein, arise from the most anterior swelling that develops in early embryonic life. And that anterior swelling of the developing neural tube, is called the prosencephalon. I'll just remind you, that the nervous system is derived from the walls of a tube. And the anterior end of that tube is closed. And that's what we call the prosencephalon, or the forebrain. So, it's going to be a massive swelling that will form at the anterior end of this developing neural tube. As we proceed on with gestation, this prosencephalon further subdivides into a diencephalon and a telencephalon. And it's from this telencephalic vesicle that the cerebral cortex will develop. The cerebral cortex basically becomes this outer rind of tissue, this outer wall of this developing telencephalon. As we progress in human gestation into the third trimester, the outer wall begins to take the shape that we are more familiar with from our journeys into the adult human brain. So what we see now is a cerebral hemisphere with some of the primary sulci or fissures beginning to take shape. So in the third trimester of pregnancy is when we begin to appreciate the central sulcus, the lateral fissure. And many of our other primary that we saw when we looked at the human brain together in the lab. And as we look inside this brain, if we were to take a cross section, what we would observe is an outer cortex. Which means bark, like the bark on a tree. The outer rind of tissue, so the cerebral cortex is this outermost layer that we observe when we look through our cross section through the forebrain. Well it's really incredible to consider that the closed anterior end of the neural tube eventually takes this marvelous shape of the cerebral cortex in the human brain. So, it really is one of the grand achievements, both in the evolution of the mammalian nervous system but also in the development of each of you. We should just never forget the just incredible achievement and mammalian biology that's represented by the human cerebral cortex. Well part of the story of how that cortex came to be has to do with many cycles of cell division. And early nervous system development and so there is, as you might imagine, an exquisite set of control mechanisms that are responsible for producing the neurons that are needed to populate the nervous system. And for reasons that are not fully understood, it seems as though the strategy for creating the nervous system and largely that cerebral cortex is to create about twice as many neurons that will actually survive the process of brain development into early childhood. And believe it or not you've had about twice as many neurons in your brain during early embryonic life than what you now have and that true of those of you that are younger and true of those of you that may be older, certainly. So, there is a process in brain development that we'll talk about in due course whereby cells are programmed to die. And some of that cell death seems to be the result of the failure of some competitive mechanism. Some of it occurs for reasons that no one quite understands. But be that as it may the proliferation of cells is obviously a key component in building a brain. So this happens in a region of the central nervous system that's very close to the ventricles, very close to that lumen of the developing neural tube. There's an interesting dance that we'll come to talk about in a little while as the cell cycle proceeds, where nuclei divide and DNA is replicated in different zones within the wall of that neural tube. But eventually cells exit the cell cycle, and become what we call neuroblasts. These neuroblasts go on to differentiate into neurons and glia, meanwhile a progenitor cell is left behind that can continue to divide. Or perhaps differentiate eventually into a stem cell that may remain competent to reenter the cell cycle at some later point across the lifespan. Well, after many cycles of mitotic activity, the neuroblasts that result will migrate over some vast territory within the central nervous system. And for the building up of a cerebral cortex, that is an outer bark, there must be a migration of cells from this inner region close to the ventricle, to this outer bark where a cortex is going to be built. And we call that developing cortex the cortical plate. So here, very close to the ventricle, is the site where the cells divide and the neuroblasts first exit the cell cycle. Well in order for these neuroblasts to get from the ventricular zone to the presumptive cortex, that is the cortical plate, they migrate. And they migrate along a scaffold provided by radial glial cells. Radio glial cells extend to process from the pial surface, down to the ventricular region of the wall of the neural tube and it provides a means by which a neuroblast then can migrate by shimmying along this fiber. So through this migratory stream, the neurons that are the process of differentiating can come to populate this cortical plate. And as a consequence of this grand migration of neuroblasts from deep within the walls of the tube to this outer bark, this outer cortical plate, we end up developing a sheet of cells. That reside out here in this outer region of the developing wall of the neural tube. Now this sheet is actually continuous across the entire cerebral mantle. You might not appreciate that, if all we had in view was the adult form of the human brain. But everywhere you see cerebral cortex we have a continuous sheet of cells. And as I've told you elsewhere, if we take the amount of cortex that can be found in one cerebral hemisphere and flatten it all out we have something about the dimensions of what in most countries is a medium sized pizza dough. Or a medium sized pizza. Now that, the dough of that pizza would have to be very thin. Here in the United States we call that a New York style pizza with a very thin crust because after all the cerebral mantle, the cerebral gray matter is only a few millimeters thick. In some parts of the world, the pizza is made in deep dish styles. So, that wouldn't be a good model for the cortex of the hemisphere. We'd have to travel to Manhattan and enjoy that crispy thin crust pizza that's characteristic of that part of the world. Well anyway, I hope you can resonate with this picture of a single sheet of cells that is folded into the shape of the four lobes of the cerebral hemisphere. So, I want to emphasize for the purposes of this tutorial that this sheet of cells, it's not just one cell thick, of course. There are actually many hundreds, perhaps even thousands of neurons that constitute the thickness of that sheet. And we can appreciate that when we look under the microscope at the cerebral cortex in its adult form, that has been stained in various ways to demonstrate the presence of neurons. So I'd like to show you some images that I've prepared myself in my own lab, and on the left what we have is preparation that shows us the presence that's called nissl substance. Within the cell bodies of the neurons and the glial cells that populate the cerebral cortex. And on the right we have a stain for a neurofilament that is especially enriched in large neurons. There are a variety of ways that we can prepare stains of the cerebral cortex that highlight its features, and they all show a similar theme and that is an abundance of neurons that populate that cortical sheet. But those neurons are ordered and they're structured into layers. Now sometimes those layers are not so easy to appreciate, but nevertheless, histologists over the years have agreed that it is possible to recognize typically six layers in most divisions of the cerebral cortex. The first layer is considered just this outer layer, which is right up against the peel service. So, this is the peel layer out here, and just below the peel layer is a region where we don't find a whole lot of neurons. What we find here is actually a whole bunch of axons and myelinated axons. So we can think of this as a little bit of white matter at the very extreme edge of our cerebral cortex. Well just below that layer one, where we don't have many cells, we tend to have a pretty distinct population of neurons that have a particular shape and form that are not particularly obvious to us here in this stain. But through other staining methods we might see them stand out just a little bit better. So that's what we call cortical layer two. Cortical layer three is actually a broad layer that extends for some distance here and people have subdivided this layer in various ways in different parts of the brain. We won't worry about that here, I'll just highlight that this is one place where we find these larger pyramidal neurons that have enriched concentrations of this nerve filament protein that stands out here to the right. But in stark contrast, we come to the next layer of cortex, which is called layer four. Now, layer four is really important, and I hope that you can recognize its importance as we talk through our sensory systems. Layer four is the target of our first order or our principle thalamic nuclei that are sending signals into this cortical network. So each of our sensory systems for example, will have a region of the thalamus that sends its inputs into layer four. So layer four is what we call the thalamic recipient zone. It's the first place that gets information from the thalamus that then cortical networks can operate upon. And as we see in the stain to the left, layer four is populated by smaller cells. These cells are often called stellate cells because of their star-like appearance and sometimes they can be so dense that they sort of look like grains of sand or grains of salt in the salt shaker. So we sometimes call layer four the granular layer of the cortex because of the appearance of these grains of sand. Now notice that layer four is almost completely devoid of large neurons expressing this neurofilaments, so layer four actually stands out perhaps a little bit better in the units to the right then the units to the left. Well right below layer four is of course layer five, and layer five is home to some of the largest pyramidal cells that we have in the cerebral cortex. These pyramidal cells stain beautifully with this SMI-32 stain, we see their cell bodies and their dendrites heading out towards the peel surface. And there is more space that is evident between the cell bodies that we see in the Nissl stain. That space isn't empty. It's actually filled up with synaptic connections. So layer five is a place where there is rich synaptic connectivity among its neurons. Well just below layer five, finally we have layer six. Layer six in some respects resembles layer four. There's a concentration of small cells that are more densely pact, sort of the way we have here in layer four. And with respect to this SMI-32 stain, layer six is like layer four, devoid of cellular staining. And finally below layer six, we have the white matter that underlies the cerebral cortex.
