Brain Mechanisms of Vision
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Transcript: English(auto-generated)
00:16
Thank you very much for the introduction and I appreciate to be invited to participate in this meeting.
00:23
I'm also very grateful to Jack Echols who have made it possible for me to just make a few comments about the visual system. And it's true that by working on a system like the visual system, you may learn some of the principles that are used also by other areas of the brain.
00:44
And for those of us who are brain scientists, it often pays off to focus your attention on one particular subject, which I have done for about 30 years, and that is on the primary visual cortex in a cat and a monkey.
01:00
And I'd like here to present work that first David Hubel and I did in the 60s and 70s, and then discuss work that Charles Gilbert and some other colleagues have done more recently at Harvard and at the Rockefeller University. I will sort of try to, for the students' sake, show, illustrate something about how cells in the brain
01:25
respond to visual stimuli and give you a sense of how it is to be a neurobiologist. We hope, obviously, that Charles seduced you to the fact that the brain is a very interesting structure
01:41
and we know something about it and there is a great deal more to learn. One amusing thing is that the first slide is by the same, if I can have the first slide and the light down, is by the same painter as Jack Echols. That means that in the field, think alike.
02:06
So this is a painting of Seurat, maybe Jack's have a better choice than this, but the point I like to make in addition to the fact that these painters used small points to make their images,
02:23
it's also, if you think about this painting, when it falls on your retina, it's going to stimulate single-foot receptors which absorb the light and then convert that into electrical energy, and then it's being processed by the eye and by the higher visual centers, and there are about 200 million receptors in your eyes
02:45
and only one million optic nerve fibers, so already in the eye there is some processing occurring. So let's first take a picture, or could I have the next slide? I don't know if I can control it myself. So this is a picture then of the human brain with the eye, and outlined here is a visual pathway.
03:06
As you know, the retinal ganglion cells project into the thalamus to a nucleus called the lateral geniculate nucleus, which in turn synapse there and then send their fibers up to the primary visual cortex. And Jack Eccles pointed out these cells in the primary visual cortex send fibers to higher visual areas,
03:24
V2 and V4 and V5, et cetera. I'm only going to discuss what happens in V1. It's a complicated enough structure for me to try to understand. There are many people now, Zeki and many others, who are recording from higher visual centers,
03:40
both in anesthetized animals and also in wide-awake monkeys with implanted electrodes. So you can record single-cell activity in a behaving monkey and correlate the behavior of the monkey and response what the monkey sees with a single-cell activity. The fundamental assumption here in this work is that by recording from single cells
04:03
and study their response properties, you can indeed learn something about how the brain works. When I left Sweden to go to the United States to Steve Kuffler's laboratory, I was warned by my colleagues to be unnamed that this may be a useful task to try to understand the structure with billions and billions of cells by looking at one cell at a time.
04:25
But as you will see, this has, over the last 30 years in many laboratories, turned out to be a fruitful way of looking at things and it's still profitable and will for many more years, I believe, be a useful approach to trying to probe out the secrets of the brain.
04:42
Of course, large part of this structure, our knowledge is still very primitive. Now if you look at the visual pathway, the next slide, could you have the next slide? This is looking at the human brain from underside and just to make the point that the projection from the two eyes and the crossing here, so each left side of the brain
05:03
projects to the left hemisphere and the right to the right. And this makes it possible and then these each hemisphere then receive input from the contralateral visual field. This crossing makes it possible for binocular vision, depth perception, fusion of images, etc. which I won't have time to discuss today.
05:23
The other important fact of the organization of this visual system is called topography and that is it's a very orderly projection of E5 retina onto that genetically and onto the visual cortex. So that the peripheral part of the retina or the visual field objects to this part and the most central part here.
05:44
So if you record from cells in this part of the brain, you have to stimulate this part of the retina. If you record more in this part, you have to stimulate more peripheral parts. So this is one of the fundamental organization of all our sensory system is topography. The laying out of this here, the visual field in a very highly orderly fashion.
06:06
The next slide shows the processing that already, if you could have the next slide, in the eye. So here we have the eye with all these beautiful optics and a piece of the retina has been enlarged and here you can see the photoreceptors, the bipolar cells, the second order neurons
06:23
and the retinal ganglion cells that project centrally into the central nervous system. Now there are also fibrous cells, horizontal cells and amacrine cells that make horizontal, interconnect these cell lines and they are often inhibitory neurons.
06:41
So with this circuit here, it's possible to interact spatially excitatory and inhibitory influences. And my mentor Steve Kuffler was the first to show in the mammalian retina what happened. And he showed that if you stimulate photoreceptors in the center here
07:01
and then there is a direct excitatory pathway for some cells into the retinal ganglion cells into the brain. Then he stimulated the receptors on the side, the cell was inhibited rather than excited. So there was then the spatial separation, these cells, excitatory and inhibitory.
07:23
And if you could imagine that you are looking down on the retina from above in the next slide, you will have then the area over which the cell responds. This is the center, you stimulate here, you excite the cell. If you still excite the receptors in the surrounding area, the ganglion cell you record from is inhibited.
07:42
Now all these recordings are done with microelectrode extracellularly and you can then record action potential. Now I will show you an example in the film in a few minutes of a cell like this, excited in the center and is inhibited when you stimulate the surround. And these cells are built, this is a very sophisticated type of processing,
08:03
but now cells not only respond to light that falls on the retina, but the pattern of light, the contrast is very important in order to optimally activate the cell. The bar here is to show that this is a circular symmetric thing and this is just to make a contrast with the way cells in the visual cortex respond.
08:22
The size of these varies in the fovea, there can only be a minute of arc that is very, very small and this is when you go to the eye doctor, the smallest distance between the bar of the E for example and in the periphery there could be a degree or more in the central area. So the high acuity region is small and in the periphery larger.
08:45
There it's larger because you have a larger area and you have higher sensitivity, whereas in the center you have higher acuity and lower sensitivity. This type of cell organization, this scopular also showed that you have the reverse arrangement and also about half of the cells have inhibitory centers and excitatory surrounds.
09:05
In the film I will only show this kind of cell. Now the cells in the visual cortex which receive projection from lateral geniculate cells which have exactly the same organization, the center symmetric surround is quite different.
09:20
It's a major transformation that occurs in the way cells respond to visual stimuli and this is illustrated in the next slide which is a diagrammatic illustration. This is the visual field, here is the fovea and this is the cell that is then in the left hemisphere with the visual field in the right.
09:42
This is the size of the area over which the cell responds called the receptive field. This is a more square form and here in the center we are moving a dark bar across the receptive field in different orientations and we get the best response at the one o'clock orientation moving to the right.
10:01
If you change the orientation the response declines and you can plot this sensitivity through different orientations in the tuning curve shown here. The remarkable thing and I will show you, you see that in the film is that here we stimulate the same area, the same receptors in the retina and the only difference we make is that we change the orientation of the stimulus
10:21
and the cell doesn't see that. It only sees the cell, the bar of a particular or a contour of a particular orientation. Now I'd like to show you the film of a few cells just to get you feeling and the first cell is then a recording from the lachet in eclat body in the cat.
10:43
The animal is asleep and it's like you looking onto the screen onto which we project spots of light and map the receptive field and see the small area in the center where you get a response and we will then stimulate the surround and the whole field.
11:00
After that there will be two cortical cells with properties quite different. So this change from the first cell into the cell sensitive to orientation of contour is through specific wiring in the cortex, specific circuitry that is make it possible to generate these kind of.
11:21
So maybe we can have the film now. So this is the center of the receptive field. We could increase the sound a little bit more, it would be better. More dramatic. So this is stimulating the whole field center and surround cell response.
11:41
This is a surround only, see, response when you turn the light off. We are not eliminating the skies at the center. When you turn it off, you release inhibition and the cell fires. Also when you have a big spot contracted, this is now the center only,
12:03
big spot contracted, you remove the inhibition and the cell fires. So again, it's quite powerful inhibition and this is just to illustrate that these cells are symmetric.
12:21
The orientation of the bar is of no consequence. We can move from this orientation to any other. This is very important because this is not seen at the cortical level. So now we have a cortical cell and we first map the receptive field,
12:42
map the area of the individual field over which the cell responds. So the animal is looking at the screen, it's anesthetized, but the cells are still active even if this animal is asleep. And you then try to determine then the area over which you can invoke these sort of impulse discharges.
13:03
As you know, cells communicate with each other through, it's like a Morse code in a way. Frequency tells you about the intensity.
13:21
So this is a rough map, as we say, of the receptive field. This is then the area over which the cell responds. As you can see, the orientation isn't quite right and the field is a little smaller than it ought to be because its longer slit has actually turned out to be more effective. This cell responds best to left but also to the right.
13:48
So now we are stimulating the same receptive area in the eye by the visual field and there's no response. So again, you have to understand that it's through specific wiring
14:01
in the retina and in the cortex that this happens. And this is a very robust thing, you can take an ordinary paintbrush and then move it across in different orientation and you will see.
14:22
Moving stimuli, just like we do, our eyes are constantly moving so if you stabilize the visual image, which is possible to do technically, you go blind within three to five seconds and then if you move the stimulus,
14:40
and these cells similarly stop firing if you don't move the stimulus after a while. Now this is another cortical cell which I show because it has similar properties to the one you just saw but still an additional quality that is, again, an elegant demonstration or a demonstration of the elegant wiring, I should say, in the cortex.
15:00
I didn't build it. So we have a map here and then we have a very directional cell. It varies, some cells are very directional, some cells respond to both directions. Now the last, first one is here.
15:23
And this is a punchline of the cell. So here what happens is that you have inhibitory flanks here. You get no response here but there are flanks here that make it possible, that inhibit the cell from firing. And it's only when you stimulate the center alone.
15:42
This is what we now call an end-inhibited cell. And I like to, in this talk, to try to give you some feeling. Can you turn this off now and turn down the sound for the next part? So this, I hope, give you then a feeling for the... Yeah, that's fine. Let's leave the slide on.
16:01
Now it turns out that the organization of the cortex, what we call the functional architecture, is highly specific. And you can keep in mind what Jack Eckert talked about, enderons, that is, the cells close to each other have common properties. And what you find when you record from the visual cortex,
16:23
make a perpendicular penetration and record from cell after cell after cell, is if it goes through all the cells in the given path, it will have the same orientation preference that's preferred, the same orientation of a contour crossing the receptive field. And this is how we define an orientation columns.
16:41
That is, our columns of cells have the same orientation preference. Now, these really is a term column that we use from a term that Werner Markhausen had used some years ago, but it turns out that they aren't really columns or have the structure like Jack showed with circular, but they're a long, narrow band going through.
17:03
Now, if you make many penetrations, then you can get a feeling for the organization of the orientation columns in the cortex, and that's illustrated in the next slide. I don't know if you can see it in the back. If you can have the next slide. Here is the visual cortex surface, white matter,
17:21
and here is one penetration, perpendicular penetration here. All the cell had more or less vertical orientation preference, and here is another penetration. Also, the cell had the same vertical impression. The receptive fields you record from ten or so cells in this penetration all had overlap in the receptive field. Now, because of the topography,
17:41
as you move from this point to this point, there is a shift in the receptive field position, so all the cells we recorded here had their receptive fields here. In fact, you have to move about one to two millimeter in order to get the fields not to overlap anymore. Now, the main point here is to show that as you make an oblique penetration,
18:01
so you go and record from several columns, and these are steps, about 50 micrometer steps, there is a shift in orientation preference, as you can see here from counterclockwise back to after. Actually, in real life, it's about 18 shifts. It's hard to draw from one vertical orientation column to the next.
18:23
The highly orderly sequence of this change in orientation is shown here as you go from vertical to counterclockwise over many steps back to the vertical again. This is a distance of cortex about between half a millimeter then. That is a chunk of cortex that deals with
18:40
a small part of the visual field in terms of all the analysis orientation of contours. What David Hubel and I have called a hyper column type of organization. Now, when we had come to this stage, Charles Gilbert and I started to collaborate, and we were interested to understand
19:00
the wiring of the cells within a given column. And what the approach we used was to record intracellular, maybe micropipette electrodes, which were filled with the dye, horseradish peroxidase, AHRP. And this next slide shows a cell filled with horseradish peroxidase. You can have the next slide.
19:21
This is a cell here. The dark is a pyramidal cell. You can see the dendrite, apical dendrite, and basal dendrite, and also axons. This AHRP stain is wonderful because it fills axons over long distances and also myelinated, the fibers, which the Golgi method does not do.
19:41
It's a counter stain just to show all the other cells in the surrounding area. And it's to see how big a single cell is. You may think these are small cells, but in fact, most of them have this spread over several hundred mu with the dendrites. Now, in order to get this cell reconstructed, you have to do serial section,
20:02
and then the camera loses the tracing, and the two-dimensional reconstruction is shown in the next slide of a pyramidal cell. So if you can have the next slide, this then are very beautiful cells, cell body, basal dendrite, apical dendrite, and then axon, leaving the cortex. This cell is in layer six.
20:21
As Jack said, there are six layers. This is layer six, and it leaves the cortex, go back to the latrogenic body. But it also has a very important as you see, projection up to layer four to have a very specific function. Now, Charles Gilbert and I, we have a recording from hundreds of cells in different layers,
20:41
and this has led us to draw a circuit diagram of the connections across the cortex, and that's shown in the next slide. I don't want you, could I have the next slide? I don't want you to, too much attention to the details, but it's a nice picture that you get which very much confirm the classical histology
21:02
with some additions, that the projection is primarily into the middle of the cortex of layer four, where uniculate fibers with circular symmetric fields make contact with spiny stellate cells in this layer, and they have the simple cell property, the simplest properties you find in the cortex. These cells in turn project to superficial layers,
21:23
pyramidal cells, for example, which have more complex properties in larger receptive fields, and these cells are the ones that project to higher visual centers. They leave the cortex and go to V2 and V3 and V4, et cetera. But they, on their way out, also have a very important projection
21:40
down to cells in layer five, where we have these beautiful pyramidal cells that Jack mentioned, and these are cells that project subcortically to the superior colliculus, for example, which is an important structure for control of eye movement and things of that sort. But they also, on their way out, give collateral to cells in layer six.
22:00
Now, the receptive fields of these cells are large, again, as you go from step to step, the fields get larger and larger, and in layer six cells that receive input from layer five cells, they are particularly large, as I will come back to in a little bit, and then this recurrent projection. Then each layer, about 80% of the cells in the cortex
22:22
are either pyramidal or spinostellate cells, and about 20% to 25% are inhibitory GABAergic cells, and these are illustrated here. I don't want to go into the details of that, but you have to keep in mind that at each stage, in each layer, there is an interaction, again, between excitatory input and inhibitory circuitry.
22:42
Now, the one discovery that we made with this method of intracellular injection, with HIP, is illustrated in the next couple of slides. Could I have the next? This is a cell in superficial. Could I have the next slide? This is then pyramidal cells in layer two and three, apical dendrite, basal dendrite.
23:01
It looks sort of messy, but if you do a three-dimensional reconstruction with a computer graphics system of the axonal projection, you can see what's shown in the next slide, and here is more or less axonal projection in the same plane which you saw before, and this is rotated 90 degrees. I have to look in my hand
23:21
in one orientation and in the other, and this is very interesting. You have a cluster of axonal collaterals around the cell body here, and then there is a distance, and then there's another cluster of endings at a distance away, and here too, and the projection to layer five, you have the same thing. You have a cluster of endings here and here, and they are beautifully lined up.
23:41
Now, these sort of projections and this distance here in this case is the distance you would expect from going from one column to the next, so if this was cell with a vertical orientation preference, our hypothesis from seeing pictures like this would be that they are projecting the cell with the same orientation columns, which is the thesis of this talk.
24:01
Now, I'd like to show you the three dimensions of this film, and if the sound is off, we can have the last part of the film. This is, unfortunately, I have no sound for this, so this is a cell in the superficial layers. The cell body is here, and then these are axonal processes,
24:20
and it's just to see, show you the complex organization of the cell and how they project not across the cortex but along the cortical surface and they have these very typical clustered endings, which we believe then our connection to cell with the same orientation preference that the cell is here.
24:40
And you can see, this is then looking across the layer, and you can see how it's like a flat sheet within the cortex. This is a cell that you saw before, the dendrites, and here are the axons, and as you rotate it, you can see the, and it's a little bit like a chip,
25:02
a majestic chip, sailing in the, and you can see again how the clusters are lined up very beautifully in a columnar fashion. So if you make a penetration through here and record for themselves, they will all have the same orientation preference. So maybe that's enough of the film, just to give you a sense.
25:21
We can turn off the film and turn on the slide projector. So this is in the general scheme, which we have evidence, and I always like to present evidence, particularly since students are here, but time is not made possible, so I took out those slides. But this is in the scheme we ended up with.
25:40
Here are the highlighted cells you may be able to see from the back, or a cell all with the same orientation preference, in this case, vertical orientation. And the proposal is that these cells then are interconnected. They don't connect with cells with different orientation preference. And we can show that by physiological means by recording from this as a reference cell
26:00
and determine its orientation, and then record from cell after cell after cell and correlate their firing, and we find the only cells that are correlated are cells with the same, or very close to the same orientation preference. The other method we have used is an atomical one. You can inject a retrogate tracer. You inject the tracer in the region with the cell with vertical orientation,
26:21
and the retrogate tracer will then go back to and fill cells that project to this area. And we have shown that the cell that projected this area by this anatomical method are all within the vertical orientation, the same orientation as the cell to which they project. So we believe that we have good evidence
26:41
for this very highly precise horizontal connection. So the next slide then shows the general diagram. Could we have the next slide? And so this is then the vertical connections that I talked about first between the different lamina, and then there is a horizontal connections which make it possible for cell with the same orientation preference to interconnect.
27:03
Now, these connections go over many millimeters, and it makes possible then to integrate the visual area not only to have an atomistic, very small representation, but that cells connect and talk to each other over wide regions.
27:21
Now, I'd like to end up with a demonstration of how we tried to illustrate the importance of the circuitry, and the next slide is just the same. Could we have the next slide? This is a cell, what I showed on the film. The last one is end-stopped. It gives a good response to a short bar
27:41
moved back and forth across the receptive field, and with a long bar, it gives a very poor response. So this is then what we call an end-stopped cell. The next slide shows the circuit that we proposed to explain this circuit, and that is, as I mentioned, there's a projection from layer 6 cells back to layer 4,
28:00
and we have shown by EM studies that the 80% of connections are with GABAergic inhibitory neurons, and they in turn project to the spiny stellate cells. Now, the spiny stellate cells respond very well to a short bar, as shown here, and poorly to a long bar, whereas a cell in layer 6 and this inhibitory neuron respond very well to a long bar
28:24
because it needs summation over this area, but very little at all to a short bar. And the experiment to test this circuit is shown in the next slide, in which we have the cortical layers. We have a recording electrode, one from spiny stellate cells here, and another recording electrode in layer 6,
28:43
which also have a GABA electrode, so we can inject GABA, and GABA is an inhibitory substance, so you can silence this area of the cortex without interfering directly with this cell, and if you do such an experiment, which is shown in the next slide, you have then our same cell,
29:01
an uninhibited cell. Before injection of the GABA, you get poor response to a long bar, good response to a short bar, and when we inject the GABA and activate layer 6, the inhibitory, you get as good response to a long bar as to a short bar, and then it recovers within a few minutes. The next slide shows the role of cells of this type
29:23
to detect curvatures, a cell with no end inhibition, see no difference between a short bar, a long bar, or a curved bar, whereas a cell with end inhibition responds well to a long bar, to a short bar, and not at all to a long bar, and reasonably well to a curved bar, because the curvature here,
29:41
the enzymes here, have the same orientation sensitivity as the center region, and the late David Marr used these sort of cells as a building block. We have the next slide to think about how perception works, so this is from a teddy bear, and you imagine that individual cells then in the primary racial cortex,
30:02
here cells respond in the vertical contour, will be activated, and here the horizontal contours, and in this way you could more or less draw a complex picture like a teddy bear quite well. So this then is the concept, I like to think that cells of the kind that I've showed you
30:20
are important for form vision, and that they are building blocks. The last slide is, could I have the last slide, is a picture that J.C. Young, a well-known British neuroanatomist, neuroscientist, sent to me when David Lublin and I published original papers on oriented,
30:42
cells in the cortex for sensitive oriented lines, and he said, this is all very interesting work, but nothing new. It's clear that Van Gogh knows about the importance of oriented lines. So I interpret this to mean that perhaps visual, that artists have a deeper,
31:01
more profound understanding of the mind than individual neuroscientists who record from single cells. Thank you.