MITOCW | MIT9_14S09_lec36-mp3

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PROFESSOR: So this class, we will talk about some of the cell types in the neocortex and the way they're connected. We'll talk about different regions of neocortex, that is actually after it had experienced, in evolution, a lot of expansion, and we're just going to deal with mammalian cortex in small animals, like rodents, and human being. And then we'll talk a little bit about some of the major fibers in and out of the membrain. We've talked about those already, but I want to review them to make sure that they're in your mind.

And then we'll get, at least, to an introduction of thalamocortical connections, which again, you've had some because when we talked about visual system, we talked about the genicular body rejection in the visual area, primary visual cortex, the

auditory cortex. We talked about medial geniculate body, somatosensory has been talked about several times. We talked about the ventral nucleus. All right.

So what are the two most commonly encountered classes in the cortical cells? The

most characteristic cell type in the neocortex is the pyramidal cell, and this is what they look like. This is Brodel's simplification of the pyramidal cell that shows their major characteristics, a cell body with a sort of pyramidal shape in an apical

dendrite that goes up towards the surface, and many of these cells send their apical dendrite all the way up to the surface where they arborize right up in layer one. And this doesn't show the fine ramifications of that dendritic arbor that you really see in these cells. I think the next slide will show some of those.

And you see the largest ones are in layer five. Layer five is the layer where the large neurons project out of the cortex to subcortical regions. The longest one's going to the spinal cord from the motor cortex and from somasensory cortex, as well.

1 In layer three, also fairly large pyramidal cells. They're projecting mainly to the opposite side, the neocortex, and they're smaller pyramidal cells, mostly in layer two, that project transcortically, to the same hemisphere. And it's interesting that layers two and three, that give rise to these, what we can call, association connections, connect one part of the neocortex with another part, had expanded tremendously in higher animals.

And here's a layer six pyramidal cell. Some of them have dendrites that go all the way up to the surface. Some of the don't.

And here's the other major cell type, stellate cells. We'll see some cartoons of it, too, but these are actual drawings of Golgi stain. Here's a pyramidal cell here.

Here's a couple of stellate cells. Now, what you're seeing there is dendrites radiate in all directions, just like a motor neuron. But then you also see a somewhat thinner axon, and you can see that the axons and the stellate cells tend to arborize near the cell body, but not always in the same column. Often they're terminating in adjacent columns, but their major connections are actually within the same column, and we'll see some other pictures like this one.

Here's different types of stellate cells that Brodel drew these cartoons of to show you the variety of, not just dendritic arbors, but especially the axonal arbors. They're quite specialized. Like for example, this one, in layer four, that has axons that go up all within the column, terminating along this line, and then there's a small arbor way up in layer one. Here's another one with a totally different kind of arbor. It's not primarily within the column, but it's an adjacent columns.

We can be pretty sure this is an inhibitory interneuron. It's terminating on cell bodies of adjacent cells in adjacent columns, and you can see the little arbor for each cell body. And here you see an interneuron in layer five, but it's a stellate cell so it's right among all those big pyramidal cells. It's probably an inhibitory interneuron there.

OK now, when we talk about the major morphological characteristics of neocortex, one would be they've got these pre-pyramidal cells. That's certainly a morphological

2 characteristic, but the other characteristic that you would want to point out if you were asked about major morphological characteristics in the neocortex would be the layers, of course. The dorsal cortex of many species is not six layered. It's many fewer layers.

We've seen pictures of the-- I think, last time, I probably showed a frog cortex right at the end when we were looking at the different axon types coming in, and they were very few layers. But this is the way the layers are usually numbered in name, we saw this picture once before, you see in the fiber stain here that there's actually more layers if you want to subdivide it more. And often in the cell stain, for example, layer six has often at least three clear, very different, layers. And in primary sensory areas, layer four has often got at least three sublayers.

And the molecular layer here is often layered in different fibers, like here you see a lot of fibers in the upper part of layer one. But there's actually other fibers terminating in deeper parts, and we call them the multiform layer, the deepest layer.

These are considered the oldest layers, most similar to the layers in non-mammals, layers five and six. So the large pyramidal cells in layer five and then the multiform layer, which has pyramidal cells, stellate cells, a few [UNINTELLIGIBLE] cells, and other cell types.

And then the granular layer. Sometimes we just call that the granular layer, but more properly, it's the internal granular layer because there is another layer of small cells, often small pyramidal cells, but also stellate cells all in layer two. And then

Layer three is the external pyramidal layer, which is why the layer five here, with the biggest cells itself, is called the internal pyramidal cell layer.

OK, so you'll notice here in the fiber stain, we see these radial fascicles. Radial means it's perpendicular to the surface of the brain, which is up here, we call the pial surface. Down here, below the white matter, would be the ventricular surface.

And often the layer of white matter here is much thicker. This would go down much further before you get to the ventricle. Depends, of course, on the species how much white matter they show. The larger animals, larger brains, and more white 3 matter.

One of the reasons is the larger the brain, the fibers are thicker because they're traveling further. They've got more mile in their larger axons, so just for speed, you get larger axons. But there's also a lot more of it with the expansion of the cortex.

OK so I'm asking a question here. What are the radial fascicles? Well, we just saw picture of them. They run up and down and within the columns, or usually within the columns. And then I ask what are three major groups of cortical output axons found in these fascicles?

Well, why don't we start with just the input? So let's start a little further back. OK, here comes a fiber from the thalamus, and it's going up and terminating mainly, say, in layer four within a column, also up in layer one, with a few terminals in layer six, perhaps a few in the other layers as well. Well, that hybrid is one of those fibers in a radial fascicle, but it's an input. It's coming this way.

What other kind of fibers are coming in to a column like that? Somebody? What have we said? Well, they come from other parts of the hemisphere. They're transcortical axons. So they would be coming in, too, and terminating mostly up above layer four.

And then there's callosal axons, but the callosum doesn't go to all areas. It goes to most areas. For example, it doesn't interconnect the part of the cortex representing my hand, here, and fingertips doesn't get callosal projection. Most of the visual cortex doesn't get a callosal projection, with one exception, the cells that represent the midline because you have some receptive fields that cross from one half of the visual field to the other. So to make that work, you've got to have callosal axons because the right half of the visual field represented in the left hemisphere, and the left half of the visual field's represented in the right hemisphere.

So now in these radial fascicles, the output axons. So here's a layer five cell, and let's draw in red the output axons. OK, so there it goes, and it's going out to the corpus striatum, to the optic tectum, or to other areas.

4 [PHONE RINGS]

PROFESSOR: Sorry.

[PHONE STOPS RINGING]

PROFESSOR: That's somebody who should know I'm teaching, now. Right.

That's one type of output axon. Where else does this cortical column project? Subcortical regions? Well, we can go to another layer. We can go to cells here in

layer six, usually pyramidal cells also.

Where do they go? Well, one of the main areas of long axons coming out layer six go just like these, but they're going to the thalamus from layer six. So that's another type.

And do you remember where we said these cells up in layer three and layer two go? Does anybody remember?

AUDIENCE: [INAUDIBLE]

PROFESSOR: What?

AUDIENCE: [INAUDIBLE]

PROFESSOR: Yeah, association axons. Exactly. Where do the association axons go? Well, either within the hemisphere to another cortical area, like for example, if this is a striate cortex, we're going to go to the prestriate cortex, the cortex just near the striate cortex. The striate cortext projects to a number of areas like that, and the association areas are heavily interconnected.

And then the callosal axons. Similar kind of axon, but it's going to be opposite side. They're usually U-fibers. So they go down into the white matter and over and then up into another area. OK, so all of those fibers you see are going down the white

matter, so all of those are part of those radial fascicles. These radial fascicles that are found within a column.

5 OK now, we get to another type of axon, and these axons, for example, cause this appearance in the striate cortex we call the line of gennari, the stripe in the striate cortex. And first of all, let's look at it. This is the border between human area 17, or striate area, and area 18, next to the striate area. You can see the border there quite clearly.

I mean, look at the big change in layer four. Suddenly, many more granule cells. This is all layer four, from about here all the way down to here. It's very thick in the striate cortex.

These are the layer pre-pyramidal cells up here. Here's the layer five pyramidal cells, down here. And these are cells within layer six, the multiform layer, which you can see has got several sublayers.

So see in the middle of layer four, you see this whiter area? Well, whenever you see a lighter area like that, where more space, it appears to be more space, and in this this whole stain, it's because there's a lot of fibers there. OK, so this is the line of gennari, and if we look at a myelin section, you can see my arrows almost identical place here, there's a lot of fibers there.

Well, [UNINTELLIGIBLE] points out that if you take a live animal and do this experiment, where you undercut one region of the striate cortex, so you cause the axons to degenerate that are coming in and out of that cortex through the deeper layers, which means you're cutting all the axons coming in from the thalamus, because after all those could be arborising axons coming from the thalamus. But it turns out most of them are not, because the line of gennari stays. So most of them are, in fact, caused by cells that have tangential association fibers that don't go down through a radial fascicle. They just connect tangentially to an adjoining area of cortex. So that's the line of gennari, mostly connecting within striate cortex.

OK now, when we're talking about these columns, columns can be of various widths, and they have different functional roles. So they're not precisely defined anatomically in any single way, and then uniform across the cortex, although there is a columnar organization throughout the cortex. So for example, we talk about the 6 columns of cells that are dominated by the right eye or the left eye in the striate cortex, the eye dominance columns. And now we're more likely to call them stripes because of the way they're organized.

So I'm asking how could you discover that? How would you find out how they're organized? How can you visualize them? What's the experiment you could do?

Well, you could inject one eye of a monkey or a cat-- You can try it in a rat, too, but you won't get eye dominance columns in the rat. But if you can do it in a monkey or a cat, and use a tag, like radioactive proline, where at least a small amount of it will go transsynaptically-- small amount of the protein that's incorporating in the proline.

--will go transsynaptically.

OK, then what does that mean? You inject it in the eye, you make the eye very hot, you inject quite a bit of proline. It goes to the layers of the genicular body that get input, say, in this genicular body from the right eye, and this genicular body from the left eye. OK, and then the ipsilateral layers, of course, will get it-- it'll stay on the same side.

Anyway, some of the proline will get across the synapse in the radioactive proteins that originated in the retina, and they will be transported up to the cortex. So if you just wait awhile, you'll get transdermal transport all the way up to the cortex, and then you can reconstruct the cortex, as was done here, and you get the zebra stripe pattern. So you're looking down at the surface of the cortex, because of the way they reconstructed.

And actually, you're not looking at the surface. You're looking at mostly layer four because they've cut the sections tangentially to the surface, and then they've put enough sections together so they could reconstruct the pattern. And the light areas there are labeled, this is a dark field picture, that's what they saw the radioactivity, and the dark areas didn't have it. And if you had injected the other eye, you would fill in the dark stripes there.

And that's been verified. You label both eyes that way. The whole cortex is labeled 7 [INAUDIBLE]. So those are eye dominance stripes.

What other kinds of columns in the visual cortex do we know about? You've had

901. You've had some exposure to this. What-- Yeah?

AUDIENCE: [INAUDIBLE]

PROFESSOR: Sorry?

AUDIENCE: [INAUDIBLE]

PROFESSOR: Orientation? That's right. They're [UNINTELLIGIBLE] columns in these eye dominance columns. It would be quite a few orientation columns within one of these,

so it shows you that these columns are not all the same width.

And we can get other things, other kind of columns, too, some of which we don't

know. For example, these are columns of terminating fibers that came from the prefrontal cortex that is that the frontal pole of the monkey brain, and they're

traveling here. They come through the white matter, and they're terminating in the

retrosplenial association areas--

[PHONE RINGS]

PROFESSOR: Oh, my. Should have turned this off.

[PHONE STOPS RINGING]

PROFESSOR: David? Hung up. OK, so the question here is, we get this termination in the columns, what's in between?

And it looks like they're coming from the other side. So this kind of finding has made

people realize that a lot of, maybe the whole, cortex has got this kind of columnar termination of axons, but we in fact don't know it for every area. Columns are

probably quite variable in their functional nature.

So now I'm asking what the different types of cortex, and how do different regions of

neocortex differ from each other? Well, the major types we talked about is 8 neocortex, and then the allocortex, which just means the other cortex. And the allocortex is the-- sometimes we call it paleocortex because it appears to be older.

It's cortex that was around before mammals, and it includes what's sometimes called the archicortex, which is just another name for hippocampus, one-layered cortex.

So one-layered cortex that's got two to four layers, and then the six-layered neocortex. These are major types, major groups just neocortex and allocortex. And then neocortex--

Oh, I point out here that are in-between types, too. Much of the four-layered cortex is called juxta-allocortex, which just means next to the allocortex. It's actually cortex that's transitional between, say, the alembic cortex, the paralimbic areas, and the neocortex.

And then there's regional differences, so I've got a couple of pictures here, this one and this one. This is one I showed you before that shows a medial view of the hemisphere where the paralimbic areas are darkened. Paralimbic areas are the areas that project heavily to, say, hippocampal formation. This is parahippocampal gyrus, retrosplenial cortex and the rest of the cingluate, and then there's a region up front we call the parolfactory area, but it's all hippocampus-centric in that all of these areas project into the hippocampus, often indirectly. Many of them project to the entorhinal area, for example.

OK, and then if you go around the ring further, you're in the insular cortex, the temporal pole, medial part of the orbitofrontal cortex. [UNINTELLIGIBLE] called them olfactor-centric, probably because they were originally olfactory. There is olfactory cortex there, but not all of it's olfactory. It also includes the taste cortex, and I related it to, because of very early functions of those senses, to object perception and perception of space, but in fact both of these types of regions get a lot of inputs from all the major senses.

Let's look here, just stick with neocortex now, just the neocortical types. The extremes are sometimes called heterotypic cortex. And there at the ends here, one 9 extreme is the motor cortex, which has no very discernible layer four at all, it doesn't have the granule cells.

So if you look there, you'll see that the association layers here, two and three, are very well developed. Layers five, five here has actually got two major sublayers. It's well developed.

Layer six is pretty well developed. It's the agranular cortex. Frontal agranular cortex is another name for motor cortex because of the structure.

And then at the other extreme, it's actually thinner cortex, is the primary sensory cortex like area 17 or striate cortex, or like the primary auditory or somatosensory cortex. It has very well developed layer four. Layer five, it's not as thick, but there are still a very clearly discernible large pyramidal cells in layer five, there.

OK, so that's granular cortex. These areas that don't look like the rest are, because of these specializations, are sometimes called heterotypical cortex. Types one and five of the anatomist who's method they're using, and the rest of the cortex he grouped together is homotypical, and he just had three major types. They're all fairly similar to each other, a frontal type, a parietal type, and one that you see near the poles of the cortex. All right.

So layer four is most different in motor cortex and primary visual, so what are those differences? We look back here, the major difference was in layer four, simply the presence of a lot of granule cells. And what do the granule cells do? Well, they're receiving input from the thalamus.

And then those cells, actually their major connection, is within the column, and we'll see that in a minute. We mentioned that last time. But the other difference, of course, is the much greater development of the output layer in the motor cortex.

And here is the connections of the different layers, but we're only talking about, of course, the cell bodies in those layers. Remember, these inputs I've indicated here, axons coming from the thalamus that determinate primarily in these three layers, but more here than any place, layer four. In some species, there's quite in layer 10 one, as well. There's always some in layer six.

These are not just terminating in the cell bodies there, remember. They're terminating on those apical dendrites, so that means a layer five or six pyramidal cell could be getting input from the thalamus in any of these layers. But then, if you look at where layer four projects-- these are stellate cells remember, and I said they project mainly within a column. Well, they mainly project up to layers two and three, and I've indicated that with a heavy arrow here.

And layers two and three, we're not talking about their output axons to other cortical areas here, but within the column, they project onto layer five. They also project across the callosum. They also project transcortically in the same hemisphere. And then layer five projects to layer six, a major source of input to layer six, which projects to the thalamus. But remember those apical dendrites are getting input at other layers, as well.

OK, and this was the earlier picture where you see a more realistic picture of the cells. And this is a little better, to look at the cartoon here just to show you how these connections are formed. Like here's a big pyramidal cell in layer five, and you see its axon going out, like to the tectum or to the corpus striatum. But then you see these collaterals that form in the cortex that are projecting heavily to layer six, and we see that here, five to six.

OK, and here's a layer three cell, and you can see it has collaterals, too, that are projecting, especially, to layer five. But it also has axons going back up to its own layer and probably layer two as well. Here's a layer two cell, this is the axon in blue, going up to its own layer, terminating heavily in layer five, as well as going out to the other areas of the cortex.

Another point about neocortical areas is the varying amount of convergence.

Convergence simply means there's a lot of different inputs coming into the same cells. Remember that many cells won't fire unless they get quite a bit of convergence with spatial summation, and one interesting, quantitative way to look at the relative amount of convergence in different cortical areas is actually just to count 11 the synapses. It leaves a lot of questions unanswered, but it gave an interesting numbers.

This was the fellow, Craig, who did this with the electron microscope, taking little pieces of cortex, counting every single synapse on the dendrites and cell bodies of the cells in that little column of tissue. He went all the way from the pia down to the white matter, and then he separately counted the neurons. And he did it for a large enough piece that he gives a fair estimate of the average number of synapses per neuron in the cortex. And when he did it for area 17 of the rhesus macaque, he got 4,000 synapses per neuron. When he did it for the primary motor cortex, he got

60,000.

And I'm just pointing out that the synapses include synapses of thalamocortical axons, the intracolumnar association axons, the local transcortical axons within the layers, and transcortical new fibers coming from other cortical regions and from the callosum. So I ask a question here, what are probably the dominant one in areas 17 and four? What would you guess?

I would guess that geniculate body projects so heavily to layer four, and layer four's quite thick in the visual cortex, that that's probably dominant input to that area, whereas the motor cortex, even though there certainly is a thalamic input, the thalamic input isn't terminating primarily on granule cells at all. It's terminating right on the dendrites of pyramidal cells. But we know it gets tremendous amount of transport projections. Now, how all those transcortical projections reach the motor cortex, we'll be dealing with here later today and tomorrow and Monday.

When we talk about functional types of neocortical areas, I talked about the-- now, I just want to refer to neocortex, which was only one type we talked about before.

And then we talked about different regions within the neocortex, and those regions are the primary sensory to motor, those were the heterotypic areas. And then the association areas and limbic areas, but actually that can be a little misleading because most of the limbic areas are not actually neocortical. But there are areas close to the limbic areas in the frontal region.

12 Oh, then I'm asking about Brodmann's area and the basis of their differentiation. This was the early map of the human neocortex, and also the cortex of many others animals that became most popular for people studying cortex, and it's still used today. I know you can't see the numbers. You'd have to blow it up, and you can actually read them if you blow this up, but you'll see area 17, striate cortex there.

You'll see area 41, primary auditory cortex.

You see areas three, one, and two that are the primary somatosensory areas there, and then you'll see parietal areas like seven and five. You'll see the motor cortex here, which is area four, and premotor in front of it, which is area six. And frontal eye fields, which is area eight. Those are the numbers that most people studying cortex will still use Brodmann's numbers for because other ways to refer to cortical areas have also been developed, and different people depending on their emphasis and studying cortex will use these different names. So I'm not asking people to memorize such numbers, but if you work with cortex, of course, then you will have to refer to these different regions in some way.

Now, we talked about temporalization and about axons coming to and from your neocortex. Let's just review those. When neocortex expanded so much in larger animals, we got temporalization in many of them. And I'm asking here, where would you look for the rodent equivalent of primate infratemporal?

And we did this once before. If we just draw this edge here, in the primate or in the human, where's is that cortex in the rodent? Well, it would be right here, just like it's right here in the cat. So it's this cortex which has expanded so much and formed that protrusion, and then it just sort of folded up like a glove, like the thumb of a mitten, actually, with temporalization.

This is [UNINTELLIGIBLE] picture, which I won't be spending more time on now because I want to talk about the axons to and from neocortex. And these are the terms that are used. We've not used the term corona radiata very much, the radiating crown of fibers. You can see, there's the corona radiata.

The internal capsule, which we've used a lot. That's those fibers from the cortex that 13 are coming down through the corpus striatum. It's also a lot of fibers going the opposite direction there.

And then the cerebral peduncle. Same fibers, but now they're a little further down, alongside the thalamus and the base of the midbrain. So the same fibers. And then they continue through the pons. Now, they become the pyramidal tract. Of course, the bundle's getting thinner because a lot of them are terminating, and then they're just corticospinal fibers in the spinal cord.

And this is the picture that we used before, showing the fibers in the white matter, the hemisphere, there it is in the frontal section. Here, it's coming down through the striatum, so it's internal capsule, there. Here, it's cerebral peduncle, which is alongside the tweenbrain or at the base of the midbrain. This is the cerebral peduncle.

There it is at the base of the hindbrain, so now it's called the pyramidal track because the pyramidal shape of the axon bundle. And then after the crossing here, they're just called corticospinal fibers in the spinal cord. And here, I ask you to name one type of axon which is present all those structures? Got different names at different points, and I list them again here at these different levels. From up here to down here, you start with these two, then these two, then these two, going down the spinal cord.

OK so what's one type that you find in all? Well, a fiber that starts in the cortex and ends up in the spinal cord, so corticospinal axon is found in all levels. What are fibers within this whole line of fibers here that you don't find all along? After all, the bundle's a lot smaller in the pyramidal tract than it is up there the peduncle.

So why? What's leading it? Give me an axon type. How about the cortical ponte fibers? It's a huge number of fibers terminating in the pons. That's the way the input from cortex gets through-- activity from cortex reaches the cerebellum.

What's another type? Give me one going in the opposite direction. How about thalamocortical? Well, that goes through the internal capsule and the white matter 14 of the hemisphere, too, but it's only part of it. It's all those other axon types that are shorter that just go between thalamus and cortex or midbrain and cortex, cortex and midbrain mostly, in that direction. That's why these bundles up here are so thick compared to the bundles down here.

And then I say here, this is just one of two major axon bundles leading in and out of the mammalian forebrain. What's the other one? Well, we talked about it early on. All these things that we just talked about as part of the lateral forebrain bundle that show how it originates in neocortex and also the striatum here.

But there's the medial forebrain bundle. That's the other one coming out. It originates in the limbic areas, as I'm show there, and then follows this route the hypothalamus. The longest one's don't get passed the midbrain.

So those are the two major bundles, but that term, lateral forebrain bundle, is not commonly used when we talk about the adult anatomy. It's used in the embryo a lot, but we don't usually refer to it that way. Instead we're referring to it with these names in the adult.

But the medial forebrain bundle, we still call that, even in the adult, unless we're talking about just one part of it, like the fornix fibers coming from hippocampus. But the fornix fibers coming from the hippocampus and going to the coronal hypothalamus is part of the medial forebrain bundle. And so this is just that listing of the origins of these two major bundles. And I thought we would get started with the other one today, but we didn't. So we'll take up the next class next time.

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