WEBVTT 00:00:00.090 --> 00:00:01.670 The following content is provided 00:00:01.670 --> 00:00:03.820 under a Creative Commons license. 00:00:03.820 --> 00:00:06.550 Your support will help MIT OpenCourseWare continue 00:00:06.550 --> 00:00:10.160 to offer high quality educational resources for free. 00:00:10.160 --> 00:00:12.700 To make a donation or to view additional materials 00:00:12.700 --> 00:00:16.620 from hundreds of MIT courses, visit MIT OpenCourseWare 00:00:16.620 --> 00:00:17.278 at ocw.mit.edu. 00:00:25.530 --> 00:00:29.490 PROFESSOR: All right, so now today, the topic 00:00:29.490 --> 00:00:34.930 we are going to discuss will be the ON and OFF channels 00:00:34.930 --> 00:00:36.230 in the retina. 00:00:36.230 --> 00:00:38.420 I will provide you with a brief overview 00:00:38.420 --> 00:00:41.250 again of what we have covered before about this, 00:00:41.250 --> 00:00:44.640 and then will go on and look at this in some depth. 00:00:44.640 --> 00:00:47.590 Now before I start on that, let me just 00:00:47.590 --> 00:00:54.120 very briefly mention again that the syllabus-- which 00:00:54.120 --> 00:00:55.390 all of you I presume have. 00:00:55.390 --> 00:00:59.420 If any of you doesn't have a syllabus-- any one of you 00:00:59.420 --> 00:01:04.330 doesn't have a syllabus, we can provide one for you. 00:01:04.330 --> 00:01:06.290 What I would like to encourage all of your 00:01:06.290 --> 00:01:09.450 again is that you do this so-called preparatory 00:01:09.450 --> 00:01:13.630 reading that appears for each session, which 00:01:13.630 --> 00:01:16.970 will make it easier for you to follow, 00:01:16.970 --> 00:01:20.190 and consequently, also memorize the basic facts 00:01:20.190 --> 00:01:21.950 that we are going to be dealing with. 00:01:24.150 --> 00:01:29.320 Alright, so therefore let me get started with the so-called ON 00:01:29.320 --> 00:01:30.970 and OFF channels. 00:01:30.970 --> 00:01:33.750 And what I would like to do first of all 00:01:33.750 --> 00:01:37.970 is to tell you what are the major questions we are going 00:01:37.970 --> 00:01:41.420 to pose in dealing with this very-- to me at least-- 00:01:41.420 --> 00:01:45.080 very interesting question of the ON and OFF channels. 00:01:45.080 --> 00:01:47.990 The first prime question you're going to ask 00:01:47.990 --> 00:01:52.295 is why did the ON and OFF channels evolve? 00:01:53.980 --> 00:01:55.650 What is their function? 00:01:56.660 --> 00:01:59.600 As I've already indicated before, 00:01:59.600 --> 00:02:07.100 it is rather complicated to have created these two channels, 00:02:07.100 --> 00:02:08.960 and therefore there must have been 00:02:08.960 --> 00:02:14.590 a great deal of evolutionary pressures to accomplish this. 00:02:14.590 --> 00:02:17.130 So that's the prime question we're going to ask. 00:02:17.130 --> 00:02:19.040 Now more specifically we're going 00:02:19.040 --> 00:02:23.600 to ask how the rods and the cones 00:02:23.600 --> 00:02:27.680 are involved in the creation of the ON and OFF channels. 00:02:28.840 --> 00:02:31.960 And then you're going to ask how do the ON and OFF 00:02:31.960 --> 00:02:34.040 channels contribute to the center 00:02:34.040 --> 00:02:38.340 and surround organization of retinal ganglion cells, 00:02:38.340 --> 00:02:42.080 because this has been a big issue among many investigators 00:02:42.080 --> 00:02:45.580 over the past 20 or so years. 00:02:45.580 --> 00:02:49.160 Then you're going to ask what role do these channels play 00:02:49.160 --> 00:02:52.295 in giving rise to the transforms that we had discussed 00:02:52.295 --> 00:02:54.780 the last time in visual cortex. 00:02:54.780 --> 00:02:56.550 And lastly we're going to ask what 00:02:56.550 --> 00:03:00.160 are the consequences of blocking the ON channel 00:03:00.160 --> 00:03:02.705 on neuronal activity and on perception. 00:03:03.990 --> 00:03:05.810 And this last question then will be 00:03:05.810 --> 00:03:08.710 successful in answering several of the questions 00:03:08.710 --> 00:03:13.650 that we pose as to why we have these curious arrangement of ON 00:03:13.650 --> 00:03:15.460 and OFF channels in the retina. 00:03:15.460 --> 00:03:16.000 All right. 00:03:16.000 --> 00:03:21.360 So now let me first of all talk about the neuronal responses-- 00:03:21.360 --> 00:03:25.850 sorry-- of the ON and OFF retinal ganglion cells. 00:03:28.020 --> 00:03:30.890 First of all, if you remember, I told you 00:03:30.890 --> 00:03:37.830 that back in the 19th century, Keffer Hartline 00:03:37.830 --> 00:03:40.510 was the first to record from single neurons 00:03:40.510 --> 00:03:44.430 by dissecting single fires in the optic nerve. 00:03:44.430 --> 00:03:47.720 And then what he did-- he shone light into the eye. 00:03:49.510 --> 00:03:51.740 And then subsequently-- especially when 00:03:51.740 --> 00:03:54.210 I talked the last time about Hubel and Wiesel-- 00:03:54.210 --> 00:03:57.010 what was done is to use reflected light. 00:03:57.010 --> 00:03:59.720 And most currently we using reflected light 00:03:59.720 --> 00:04:05.490 by presenting images on a computer monitor facing 00:04:05.490 --> 00:04:08.100 the animal or the human we are studying. 00:04:08.100 --> 00:04:10.610 Now when Keffer Hartline did this 00:04:10.610 --> 00:04:13.700 by shining light into the eye, he 00:04:13.700 --> 00:04:16.860 noticed that there are some says which are called ON cells, 00:04:16.860 --> 00:04:19.670 some cells that are OFF cells, and some cells which 00:04:19.670 --> 00:04:21.490 are both ON and OFF. 00:04:21.490 --> 00:04:25.040 Now his idea at that time was, using that method, 00:04:25.040 --> 00:04:28.570 that ON cells discharge when a stimulus came on 00:04:28.570 --> 00:04:30.430 in the visual field, and OFF cells 00:04:30.430 --> 00:04:32.430 signaled their termination. 00:04:32.430 --> 00:04:34.080 That was his idea, and that's why 00:04:34.080 --> 00:04:35.635 I call them ON and OFF cells. 00:04:36.790 --> 00:04:43.420 So subsequently, especially when reflected the light was used, 00:04:43.420 --> 00:04:48.130 a different view had emerged as to what 00:04:48.130 --> 00:04:51.030 might be the reason for having these kinds of cells. 00:04:51.030 --> 00:04:56.600 And this was further enhanced by the beautiful findings 00:04:56.600 --> 00:04:58.720 of Kuffler, when he noticed that there 00:04:58.720 --> 00:05:02.000 was center-surround organization in these cells 00:05:02.000 --> 00:05:05.280 at the so-called ON, OFF, and ON/OFF cells 00:05:05.280 --> 00:05:07.110 responded vigorously when a light was 00:05:07.110 --> 00:05:10.560 shown into the center, but responded less 00:05:10.560 --> 00:05:13.580 when the light shown into the surround. 00:05:13.580 --> 00:05:16.160 So then people began to do all kinds of experiments 00:05:16.160 --> 00:05:19.360 to try to study this in further detail, and one of them 00:05:19.360 --> 00:05:23.310 was to use reflected light, either by using a projector 00:05:23.310 --> 00:05:25.550 or by using a color monitor. 00:05:25.550 --> 00:05:29.020 And when they did that-- I'm going to show this to you 00:05:29.020 --> 00:05:31.640 schematically-- they found that if you 00:05:31.640 --> 00:05:34.740 had a certain lit background like we have here, 00:05:34.740 --> 00:05:36.770 you could present the stimulus either by virtue 00:05:36.770 --> 00:05:39.712 of light increment or by virtue of light decrement. 00:05:39.712 --> 00:05:43.000 And as I had mentioned to you before, 00:05:43.000 --> 00:05:44.740 the visual system is dramatically 00:05:44.740 --> 00:05:47.860 different from the other senses that we have in 00:05:47.860 --> 00:05:54.330 that we need to be able to see dark stimuli in a background, 00:05:54.330 --> 00:05:59.500 like letters on a page, as well as light incremental stimuli. 00:05:59.500 --> 00:06:03.530 And so this idea then, if it's selected that way 00:06:03.530 --> 00:06:05.080 schematically, looks like this. 00:06:05.080 --> 00:06:08.870 An ON cell will fire vigorously when a bright spot 00:06:08.870 --> 00:06:13.300 appears in the center, and will not fire to a dark spot. 00:06:13.300 --> 00:06:15.720 If anything, it'll be slightly inhibited. 00:06:15.720 --> 00:06:16.450 OK? 00:06:16.450 --> 00:06:20.910 By contrast, when you look at an OFF cell, you get inverse. 00:06:20.910 --> 00:06:21.945 It fires vigorously. 00:06:21.945 --> 00:06:26.030 If you would, it gets excited by a dark spot. 00:06:26.030 --> 00:06:29.090 It gets excited by the detriment in light illumination. 00:06:30.530 --> 00:06:33.780 Now if you did the same thing using a much larger spot 00:06:33.780 --> 00:06:38.040 of light-- that is shown here-- what you see here 00:06:38.040 --> 00:06:40.750 is that the center-surround antagonism 00:06:40.750 --> 00:06:42.760 that we talked about fully applies 00:06:42.760 --> 00:06:45.540 to this kind of stimulation conditions as well. 00:06:45.540 --> 00:06:48.890 Use a large spot, bright spot, or dark spot 00:06:48.890 --> 00:06:51.100 and you see that the over responses 00:06:51.100 --> 00:06:57.300 of the cells-- the responses are much more limited than when 00:06:57.300 --> 00:07:00.750 you confine the simulation to the center, only 00:07:00.750 --> 00:07:04.710 further emphasizing this important fact 00:07:04.710 --> 00:07:07.150 about center-surround antagonism-- 00:07:07.150 --> 00:07:11.860 this incredible increasing complexity of the organization 00:07:11.860 --> 00:07:15.120 of neurons that you see already in the retina. 00:07:15.120 --> 00:07:18.290 OK, so now we are going to next look 00:07:18.290 --> 00:07:21.550 at the anatomy of the ON and OFF ganglion cells. 00:07:21.550 --> 00:07:25.880 And as we look at these various ways of studying the ON and OFF 00:07:25.880 --> 00:07:30.200 channels, we are gradually going to understand 00:07:30.200 --> 00:07:33.830 what these two systems are really for. 00:07:33.830 --> 00:07:41.050 So the first thing is to use this method that I had also 00:07:41.050 --> 00:07:44.630 already described, namely that you can record intracellularly 00:07:44.630 --> 00:07:49.610 from a cell, understand its functional responses, 00:07:49.610 --> 00:07:52.380 and then you can inject a label, and then 00:07:52.380 --> 00:07:55.040 you can process that anatomically 00:07:55.040 --> 00:07:56.570 to see what it looks like. 00:07:56.570 --> 00:08:00.760 So when this was done, a very interesting new finding 00:08:00.760 --> 00:08:03.190 had emerged, which is depicted here. 00:08:03.190 --> 00:08:08.350 Here we have the photoreceptors-- 00:08:08.350 --> 00:08:10.810 just the tail end of them, if you will-- that 00:08:10.810 --> 00:08:13.510 connect to the bipolar cells. 00:08:13.510 --> 00:08:15.340 Two bipolar cells are shown. 00:08:15.340 --> 00:08:20.060 And then they project into the inner plexiform layer, which 00:08:20.060 --> 00:08:22.840 we often just refer to as IPL, which 00:08:22.840 --> 00:08:27.420 is subdivided into two parts-- A and B. 00:08:27.420 --> 00:08:32.559 And it was shown that the majority of cells 00:08:32.559 --> 00:08:37.299 arborize in either one or the other of these two sublamina 00:08:37.299 --> 00:08:40.495 in the inner plexiform layer. 00:08:41.570 --> 00:08:44.500 But there were also some cells, which is not shown here, 00:08:44.500 --> 00:08:49.360 that had arborization in both of these lamina, 00:08:49.360 --> 00:08:52.570 and that's to anticipate actually 00:08:52.570 --> 00:08:56.090 the property of those cells, which are called the ON/OFF 00:08:56.090 --> 00:08:57.200 cells. 00:08:57.200 --> 00:09:00.960 Now furthermore, it was found-- because these cells were 00:09:00.960 --> 00:09:05.840 labeled after recording-- that the cells that arborized 00:09:05.840 --> 00:09:08.980 in subliminal A, or the inner plexiform layer, 00:09:08.980 --> 00:09:13.260 were so-called OFF cells, and those that arborized 00:09:13.260 --> 00:09:15.860 in subliminal B, like this one here, 00:09:15.860 --> 00:09:20.490 and this one here, and this one here, were ON cells. 00:09:20.490 --> 00:09:21.690 OK? 00:09:21.690 --> 00:09:25.710 So there was a distinct spatial segregation 00:09:25.710 --> 00:09:30.350 into the lamina of those retinal ganglion cells that 00:09:30.350 --> 00:09:33.470 were ON and OFF, and also furthermore, 00:09:33.470 --> 00:09:35.570 those that were ON/OFF because they 00:09:35.570 --> 00:09:38.870 had arborization in both of them. 00:09:38.870 --> 00:09:40.890 So that was the basic finding. 00:09:40.890 --> 00:09:43.350 Now when that was discovered, people 00:09:43.350 --> 00:09:44.930 went on and asked the question, what 00:09:44.930 --> 00:09:49.050 is the spacial arrangement of these cells 00:09:49.050 --> 00:09:51.320 on the retinal surface, if you will. 00:09:51.320 --> 00:09:58.980 And so experiments were done in which cells were labeled, 00:09:58.980 --> 00:10:02.120 in most cases with the Golgi stain, 00:10:02.120 --> 00:10:05.850 and then the retina was looked at head on with a microscope. 00:10:05.850 --> 00:10:07.960 Now the interesting thing about a microscope is, 00:10:07.960 --> 00:10:09.610 which all of you I'm sure know, is 00:10:09.610 --> 00:10:12.220 that the higher the magnification 00:10:12.220 --> 00:10:18.670 that you use, the shorter the focus of the microscope. 00:10:18.670 --> 00:10:20.920 And in fact, what you can do here 00:10:20.920 --> 00:10:22.490 is when you look at his head I like 00:10:22.490 --> 00:10:28.690 that, if you can focus either in sublamina A or sublamina B, 00:10:28.690 --> 00:10:32.260 and if you do that, since we had gotten these results, 00:10:32.260 --> 00:10:39.180 you know that whatever focuses into sublamina A would be OFF 00:10:39.180 --> 00:10:42.340 cells, and whatever comes into focus 00:10:42.340 --> 00:10:44.590 and the [INAUDIBLE] is coming to focus in B, 00:10:44.590 --> 00:10:47.710 would be the ON cells. 00:10:47.710 --> 00:10:51.320 So then what was done by a fellow 00:10:51.320 --> 00:10:54.190 called Heinz Wesley is he asked a question, what 00:10:54.190 --> 00:10:56.960 is the spacial arrangement of these two? 00:10:56.960 --> 00:11:00.120 Do they respect each other, or what? 00:11:00.120 --> 00:11:02.870 And so when he did that, here is a good example 00:11:02.870 --> 00:11:04.090 of what that looks like. 00:11:04.090 --> 00:11:07.840 Here we have labeled both the ON and OFF cells using the two 00:11:07.840 --> 00:11:09.822 depth of [INAUDIBLE], and you can 00:11:09.822 --> 00:11:11.280 see they're kind of helter skelter. 00:11:12.310 --> 00:11:16.960 Then if he focus deeper, he focus only in the ON cells. 00:11:16.960 --> 00:11:20.230 It looks like a they're very, very nicely arranged, 00:11:20.230 --> 00:11:22.470 and that's also true for the OFF cells. 00:11:22.470 --> 00:11:24.600 And they respect each other. 00:11:24.600 --> 00:11:26.580 Looking at the dendritic arbors, there's 00:11:26.580 --> 00:11:30.030 a little overlap among the dendrites themselves 00:11:30.030 --> 00:11:31.330 of the cells. 00:11:31.330 --> 00:11:36.380 So what's this then said is that the ON cells respect each other 00:11:36.380 --> 00:11:39.680 but don't seem to give a damn about the OFF cells. 00:11:39.680 --> 00:11:42.170 And the reverse applied to the OFF cells. 00:11:42.170 --> 00:11:43.190 OK? 00:11:43.190 --> 00:11:46.325 So as if there were two independent entities. 00:11:47.350 --> 00:11:49.165 So that was a very interesting finding. 00:11:50.690 --> 00:11:54.250 And so that was one of the initial cues saying 00:11:54.250 --> 00:11:57.950 that these ON and OFF cells do different things, 00:11:57.950 --> 00:12:02.950 and each is a devoted entity to what it does. 00:12:02.950 --> 00:12:08.050 All right so now to understand this even better, let's go back 00:12:08.050 --> 00:12:12.380 and take a brief overview of the retinal connections 00:12:12.380 --> 00:12:14.990 so we can understand how these systems came about. 00:12:16.190 --> 00:12:20.080 And the first thing to do is to talk about the photoreceptor 00:12:20.080 --> 00:12:20.750 basics. 00:12:20.750 --> 00:12:23.530 And I told you many times-- by now I'm sure all of you 00:12:23.530 --> 00:12:27.026 know that already-- that all photoreceptors hyperpolarize 00:12:27.026 --> 00:12:28.230 to light. 00:12:28.230 --> 00:12:34.320 Then I also told you when photoreceptors depolarize-- 00:12:34.320 --> 00:12:36.915 that's when they release their neurotransmitter, which 00:12:36.915 --> 00:12:38.190 is glutamate. 00:12:38.190 --> 00:12:41.530 And that glutamate acts on both the horizontal cells 00:12:41.530 --> 00:12:43.100 and the bipolar cells. 00:12:43.100 --> 00:12:46.890 And then furthermore, just to look in the details-- 00:12:46.890 --> 00:12:50.499 this you don't need to remember exactly in these words-- photon 00:12:50.499 --> 00:12:52.790 absorption by the photopigment results in isomerization 00:12:52.790 --> 00:12:56.490 of the chromophore from 11-cis to all-trans. 00:12:56.490 --> 00:12:59.990 To all-trans this causes hyperpolarization, thereby 00:12:59.990 --> 00:13:02.280 reducing neurotransmitter release. 00:13:02.280 --> 00:13:05.040 But what you do need to remember is the next step, 00:13:05.040 --> 00:13:07.120 which says the same thing in much simpler words. 00:13:07.120 --> 00:13:10.340 It says that the two classes of bipolars, 00:13:10.340 --> 00:13:14.240 the ON and the OFF, synaptic junction of the OFF bipolars 00:13:14.240 --> 00:13:17.710 is sign conserving, and that of the ON bipolars 00:13:17.710 --> 00:13:19.600 is sign inverting. 00:13:19.600 --> 00:13:22.250 And so as I've told you the last time, as you hyperpolarize 00:13:22.250 --> 00:13:24.610 and depolarize the photoreceptor, 00:13:24.610 --> 00:13:27.520 an OFF bipolar cell does the same thing like this, 00:13:27.520 --> 00:13:30.300 but the ON bipolar does the opposite, OK? 00:13:30.300 --> 00:13:34.020 So you created a two-ended system-- 00:13:34.020 --> 00:13:37.603 a double-ended system, if you will-- from a single-ended one 00:13:37.603 --> 00:13:39.103 that you have in the photoreceptors. 00:13:40.290 --> 00:13:44.790 Now, yet another fact that is important to remember 00:13:44.790 --> 00:13:48.430 is that the ON bipolar cell receptor is mGluR6. 00:13:49.710 --> 00:13:55.770 That is a specific molecule that exists in most animals, 00:13:55.770 --> 00:14:00.710 only in the retina, created anew in the course of evolution, 00:14:00.710 --> 00:14:02.870 indicating what considerable pressure there 00:14:02.870 --> 00:14:06.650 had to be able to have an ON system. 00:14:06.650 --> 00:14:09.940 And lastly I should add here also that the OFF bipolar 00:14:09.940 --> 00:14:15.530 receptors are mGlueR1 and 2 and they follow, pretty much, 00:14:15.530 --> 00:14:19.000 the way the photoreceptors respond, 00:14:19.000 --> 00:14:20.850 which means that their activation leads 00:14:20.850 --> 00:14:23.070 to the opening of channels, causing depolarization. 00:14:24.610 --> 00:14:27.270 And of course you all know that-- I should restate maybe 00:14:27.270 --> 00:14:32.150 once more-- that when neurons in the retina that had greater 00:14:32.150 --> 00:14:35.100 potentials, when they depolarize, 00:14:35.100 --> 00:14:36.820 neurotransmitters released. 00:14:36.820 --> 00:14:40.280 When they hyperpolarize, they do not release them. 00:14:40.280 --> 00:14:42.110 In anything, they stop releasing them. 00:14:42.110 --> 00:14:42.610 OK. 00:14:42.610 --> 00:14:50.040 So now let's look at this wiring again in more graphic detail. 00:14:50.040 --> 00:14:52.905 Here we have a cone. 00:14:54.080 --> 00:14:57.630 And the fact is that in central retina, 00:14:57.630 --> 00:15:02.680 each cone connects with at least two bipolar cells. 00:15:02.680 --> 00:15:05.170 So in other words, in the retina there are many, many more 00:15:05.170 --> 00:15:08.090 bipolars than there are photoreceptors, 00:15:08.090 --> 00:15:10.240 which is amazing if you think about the numbers. 00:15:10.240 --> 00:15:12.010 I don't know if you remember the numbers. 00:15:12.010 --> 00:15:17.640 I told you there are more than 50 million cones, and maybe 00:15:17.640 --> 00:15:20.470 150 million rods, in the retina. 00:15:20.470 --> 00:15:23.620 So the retina is an unbelievably complex structure 00:15:23.620 --> 00:15:26.645 with millions and millions and millions of cells. 00:15:27.960 --> 00:15:28.460 All right. 00:15:28.460 --> 00:15:31.920 So what happens then-- you create these ON and OFF bipolar 00:15:31.920 --> 00:15:32.835 cells. 00:15:32.835 --> 00:15:36.490 The OFF ones, by virtue are sign conserving synapse. 00:15:36.490 --> 00:15:39.620 The OFF, by virtue, are sign conserving synapse. 00:15:39.620 --> 00:15:44.395 And they connect with two basic classes of ganglion cells-- 00:15:44.395 --> 00:15:46.620 the ON and the OFF. 00:15:46.620 --> 00:15:50.850 So the ON and OFF signals, in large part, 00:15:50.850 --> 00:15:53.310 then are sent separately, especially 00:15:53.310 --> 00:15:55.200 to the [INAUDIBLE] nucleus. 00:15:55.200 --> 00:15:57.000 But let's not forget that they also 00:15:57.000 --> 00:16:00.430 have the so-called ON/OFF cells. 00:16:00.430 --> 00:16:04.120 And many of them actually end up projecting the colliculus, 00:16:04.120 --> 00:16:06.140 as we'll talk about later on. 00:16:06.140 --> 00:16:08.120 So this is a very basic wiring. 00:16:08.120 --> 00:16:10.980 They can then add here, as I've already said. 00:16:10.980 --> 00:16:13.070 This is sign inverting synapse. 00:16:13.070 --> 00:16:15.290 This is sign-conserving sign conserving synapse. 00:16:15.290 --> 00:16:16.950 And then we can add the fact that we 00:16:16.950 --> 00:16:22.700 have horizontal cells that collect signals going sideways 00:16:22.700 --> 00:16:27.220 on the retinal surface, thereby creating-- 00:16:27.220 --> 00:16:32.700 hypothetically speaking, at least-- the surround effect, 00:16:32.700 --> 00:16:36.360 although that we will look at in just a minute in more detail 00:16:36.360 --> 00:16:39.800 because some people had proposed-- many hypotheses had 00:16:39.800 --> 00:16:41.720 emerged why we have ON and OFF channels-- 00:16:41.720 --> 00:16:43.910 and a lot of the hypotheses was to create 00:16:43.910 --> 00:16:46.940 this famous center-surround antagonism 00:16:46.940 --> 00:16:49.580 that you see in the retinal ganglion cells. 00:16:49.580 --> 00:16:51.960 I'll have a model for that in a minute. 00:16:51.960 --> 00:16:54.880 OK, so here we have the ON and OFF systems. 00:16:54.880 --> 00:16:56.510 And again I want to point out to you 00:16:56.510 --> 00:17:01.880 that they terminate in different sublamina, the inner plexiform 00:17:01.880 --> 00:17:07.170 layer-- the ON in sublamina B and the OFF in sublamina A, 00:17:07.170 --> 00:17:11.040 whereas the ON/OFF system looks something like this. 00:17:11.040 --> 00:17:13.240 It has dendritic arbors. 00:17:13.240 --> 00:17:17.130 They are ON/OFF ganglion cell in both layers, 00:17:17.130 --> 00:17:20.690 and connects to both the ON and the OFF like that. 00:17:20.690 --> 00:17:22.930 So that's how you create these three 00:17:22.930 --> 00:17:25.800 types of cells at the very simple level. 00:17:25.800 --> 00:17:30.700 Now the issue that I just to referred to 00:17:30.700 --> 00:17:33.710 is how is this surround mechanism created. 00:17:33.710 --> 00:17:37.310 One hypothesis is that it's created 00:17:37.310 --> 00:17:39.150 by virtue of the horizontal cells 00:17:39.150 --> 00:17:41.510 predominantly, as shown in this figure, which 00:17:41.510 --> 00:17:43.770 is pretty much what you had seen before. 00:17:43.770 --> 00:17:48.900 So the surround is created by the horizontal cell network. 00:17:48.900 --> 00:17:52.700 An alternative hypothesis that was for a while popular 00:17:52.700 --> 00:17:56.090 was that actually the reason we have ON or OFF channels 00:17:56.090 --> 00:17:59.590 is to create the surround antagonism in retinal ganglion 00:17:59.590 --> 00:18:02.355 cells by using this kind of wiring arrangement. 00:18:04.119 --> 00:18:05.910 I'm not going to go into details about this 00:18:05.910 --> 00:18:07.460 because to anticipate what I'm going 00:18:07.460 --> 00:18:13.180 to tell you is that this model does not seem to be correct, 00:18:13.180 --> 00:18:15.330 and that of course is often the case. 00:18:15.330 --> 00:18:17.220 We have many, many different models 00:18:17.220 --> 00:18:20.060 and then one of our tasks is to try 00:18:20.060 --> 00:18:22.305 to figure out which one is correct. 00:18:22.305 --> 00:18:23.937 And you know what often happens is 00:18:23.937 --> 00:18:25.520 that if three models are correct, well 00:18:25.520 --> 00:18:27.561 there's a fourth one you didn't even think about. 00:18:27.561 --> 00:18:30.870 So that sometimes happens, and especially 00:18:30.870 --> 00:18:32.460 when you study the brain. 00:18:32.460 --> 00:18:33.000 All right. 00:18:33.000 --> 00:18:35.615 So now we are going to move on. 00:18:37.260 --> 00:18:42.380 This is, unless you had read the preparatory material, 00:18:42.380 --> 00:18:45.730 is something that may puzzle you-- 00:18:45.730 --> 00:18:48.170 the effects of APB on the responses 00:18:48.170 --> 00:18:50.540 of neurons in the visual system. 00:18:50.540 --> 00:18:55.060 So now I'm going to ask you guys as to how many of you actually 00:18:55.060 --> 00:18:56.640 know what APB is. 00:18:58.370 --> 00:19:00.010 Oh, I see all these hands raised. 00:19:00.010 --> 00:19:00.635 Oh my goodness. 00:19:02.520 --> 00:19:03.060 All right. 00:19:03.060 --> 00:19:05.860 So nobody knows what the APB is. 00:19:05.860 --> 00:19:06.360 That's good. 00:19:06.360 --> 00:19:09.770 So that way you are going to learn something brand new. 00:19:09.770 --> 00:19:13.490 But if you get a chance and read the preparatory material, 00:19:13.490 --> 00:19:18.010 then it will be easier for to remember these many, many facts 00:19:18.010 --> 00:19:22.020 that I'm going to try to impart on you with each lecture. 00:19:22.020 --> 00:19:24.120 All right, so APB. 00:19:24.120 --> 00:19:30.100 APB stands for an artificial molecule called 00:19:30.100 --> 00:19:34.180 2-amino-4-phosphonobutyric acid. 00:19:34.180 --> 00:19:38.192 And to show that to you in some detail, it is shown here-- 00:19:38.192 --> 00:19:39.400 2-amino-4-phosphonobuterate . 00:19:42.670 --> 00:19:45.640 Butyrate-- "ate," as you know, stands for acid. 00:19:45.640 --> 00:19:46.390 OK? 00:19:46.390 --> 00:19:50.100 So this molecule, as I mentioned to you before, 00:19:50.100 --> 00:19:54.690 was invented, if you will, by Watkins and Evans 00:19:54.690 --> 00:19:57.640 in England, who are molecular biologists. 00:19:57.640 --> 00:20:03.600 And their game, as I mentioned, is to create new molecules-- 00:20:03.600 --> 00:20:07.216 and many of which are either analogs or antagonists 00:20:07.216 --> 00:20:08.090 of neurotransmitters. 00:20:09.110 --> 00:20:12.340 Now this is a glutamate neurotransmitter 00:20:12.340 --> 00:20:17.270 that is discharged by many, many cells in the brain, 00:20:17.270 --> 00:20:18.650 including your photoreceptors. 00:20:19.960 --> 00:20:21.650 So this is a variant of that. 00:20:21.650 --> 00:20:27.530 Now once this molecule was invented, or created, 00:20:27.530 --> 00:20:30.210 I should say perhaps, people began 00:20:30.210 --> 00:20:34.250 to ask the question, well what is this variant? 00:20:34.250 --> 00:20:35.940 What can they do for us? 00:20:35.940 --> 00:20:38.700 And that was the basic game they all played. 00:20:38.700 --> 00:20:41.360 You create molecule after molecule after molecule, 00:20:41.360 --> 00:20:45.400 and then you test them to see whether they can tell you 00:20:45.400 --> 00:20:49.610 something useful in studying the brain. 00:20:49.610 --> 00:20:53.160 And it turns out that there's-- I've mentioned before also-- 00:20:53.160 --> 00:20:56.480 most of those molecules you can throw into the waste paper 00:20:56.480 --> 00:20:57.370 basket. 00:20:57.370 --> 00:21:01.710 But the few of them come out and become very, very useful. 00:21:01.710 --> 00:21:03.460 And this one here-- that's the reason 00:21:03.460 --> 00:21:07.290 I'm mentioning it to you-- this APB turned out 00:21:07.290 --> 00:21:09.560 to be a magic bullet. 00:21:09.560 --> 00:21:12.860 First of all-- you should remember this-- 00:21:12.860 --> 00:21:15.290 that this a neurotransmitter analog. 00:21:17.220 --> 00:21:23.360 So what happens is in a way it acts like glutamate, 00:21:23.360 --> 00:21:29.270 but it acts really specifically on the neurotransmitter 00:21:29.270 --> 00:21:33.230 sites of the ON bipolar cells. 00:21:33.230 --> 00:21:41.180 And what it does-- it fills the receptor site, 00:21:41.180 --> 00:21:45.310 which then makes those neurons insensitive 00:21:45.310 --> 00:21:47.045 to subsequent light stimulation. 00:21:48.190 --> 00:21:48.770 All right? 00:21:48.770 --> 00:21:51.350 So this then is a remarkable molecule. 00:21:51.350 --> 00:21:55.350 And consequently, people began to do all sorts of experiments. 00:21:55.350 --> 00:21:59.450 And it was discovered that when this substance was applied 00:21:59.450 --> 00:22:06.710 to the retina, indeed shining light into the receptor 00:22:06.710 --> 00:22:11.750 fields of cells failed to elicit a response. 00:22:11.750 --> 00:22:17.750 But by contrast, when as part of dark stimulus 00:22:17.750 --> 00:22:20.040 was present in the receptor field, 00:22:20.040 --> 00:22:21.980 the cells continued to fire. 00:22:21.980 --> 00:22:26.130 So that was a basic finding, and so a method was developed 00:22:26.130 --> 00:22:28.490 to study this in the monkey. 00:22:28.490 --> 00:22:30.412 And let me show you what the method is 00:22:30.412 --> 00:22:31.870 so you can get a sense of what it's 00:22:31.870 --> 00:22:33.740 like to do experiments like this. 00:22:33.740 --> 00:22:36.770 So the method was to put two tubes 00:22:36.770 --> 00:22:40.640 into the eye of an anesthetized, paralyzed animal, through one 00:22:40.640 --> 00:22:43.510 of which you could infuse a substance, 00:22:43.510 --> 00:22:45.785 and through the other which the substance could exit. 00:22:46.970 --> 00:22:50.540 Because if there were no exiting and you fuse something in here, 00:22:50.540 --> 00:22:52.710 the eye would swell up, so to speak, 00:22:52.710 --> 00:22:54.575 and it would kill the cells in the eye. 00:22:54.575 --> 00:22:56.740 So you got to circulate it. 00:22:56.740 --> 00:23:00.480 So what you have to do also is to take the vitreous humor 00:23:00.480 --> 00:23:04.180 and make sure that-- you know that's a jelly-like substance-- 00:23:04.180 --> 00:23:08.890 to make it so that it was fluid enough to come out of this tube 00:23:08.890 --> 00:23:10.130 here, as well. 00:23:10.130 --> 00:23:17.890 So then you could present to the eye either a solution that 00:23:17.890 --> 00:23:21.390 had no effect on anything, because you made 00:23:21.390 --> 00:23:25.430 that solution with enough molecular substances 00:23:25.430 --> 00:23:28.050 similar to what's in the vitreous already. 00:23:28.050 --> 00:23:28.850 OK? 00:23:28.850 --> 00:23:30.540 And then what you could do is you 00:23:30.540 --> 00:23:33.050 could switch over using this same substance 00:23:33.050 --> 00:23:35.510 and add a little bit of APB. 00:23:35.510 --> 00:23:37.850 Now APB is a very powerful substance 00:23:37.850 --> 00:23:43.040 so you need only small amounts of it to have an effect. 00:23:43.040 --> 00:23:45.099 And then what you did is you recorded 00:23:45.099 --> 00:23:46.890 from either the lateral geniculate nucleus, 00:23:46.890 --> 00:23:49.300 in this case, or from the optic nerve fibers, 00:23:49.300 --> 00:23:51.450 or from the visual cortex. 00:23:51.450 --> 00:23:54.650 And so now you have this magic bullet, 00:23:54.650 --> 00:23:57.510 and first, however, you want to determine, is it true. 00:23:57.510 --> 00:24:01.370 What has been found originally in the mutt puppy-- is it also 00:24:01.370 --> 00:24:03.540 true in the monkey? 00:24:03.540 --> 00:24:07.860 If you inject this APB into the eye of a monkey, 00:24:07.860 --> 00:24:13.980 do you really stop the responses of ON-center cells 00:24:13.980 --> 00:24:16.206 to view light visual stimulation, 00:24:16.206 --> 00:24:17.455 light incremental stimulation. 00:24:18.780 --> 00:24:21.870 And the answer is lucky B-- because otherwise I 00:24:21.870 --> 00:24:23.810 wouldn't be telling you this, of course-- 00:24:23.810 --> 00:24:25.280 is that the answer is yes. 00:24:25.280 --> 00:24:29.720 So here is an example of taking a response. 00:24:29.720 --> 00:24:31.850 These are cumulative histograms, OK? 00:24:31.850 --> 00:24:34.760 You've turned the light on, and then turned it off. 00:24:34.760 --> 00:24:37.130 And you can see here's an ON-center cell responds 00:24:37.130 --> 00:24:39.380 vigorously under normal conditions. 00:24:39.380 --> 00:24:43.210 You put APB into the eye, the cell stops responding. 00:24:43.210 --> 00:24:46.100 And then when the animal recovers from this, 00:24:46.100 --> 00:24:48.980 you wash it out, so to speak, then the response returns. 00:24:50.350 --> 00:24:52.255 By contrast, we do same experiment 00:24:52.255 --> 00:24:55.090 in an OFF-center cell, shown on the right. 00:24:55.090 --> 00:24:57.580 You see that the cell continues to respond 00:24:57.580 --> 00:24:59.445 when you put APB into the eye. 00:24:59.445 --> 00:25:02.130 So this is indeed a magic bullet, 00:25:02.130 --> 00:25:06.540 which selectively blocks the ON system, 00:25:06.540 --> 00:25:10.330 and has no significant effect on the OFF system. 00:25:10.330 --> 00:25:14.550 So this then opened the gates to study 00:25:14.550 --> 00:25:19.850 what happens when you do these kinds of experiments-- 00:25:19.850 --> 00:25:25.300 in this case, in monkeys-- to determine 00:25:25.300 --> 00:25:31.010 what might be the function of these two systems. 00:25:31.010 --> 00:25:37.220 And so this then enabled one to test the various hypotheses, 00:25:37.220 --> 00:25:39.440 which I had mentioned to you briefly before. 00:25:39.440 --> 00:25:41.910 The first hypothesis you can ask, 00:25:41.910 --> 00:25:45.520 is it true-- as that model I've shown you the right-- 00:25:45.520 --> 00:25:49.270 that it is interaction between the ON or OFF systems 00:25:49.270 --> 00:25:52.920 that gives rise to the center-surround antagonism 00:25:52.920 --> 00:25:54.670 of cells in the retina. 00:25:54.670 --> 00:25:56.450 That's one thing you could test. 00:25:56.450 --> 00:25:59.020 So to assess that, let me show you 00:25:59.020 --> 00:26:02.370 what the experimental procedure is. 00:26:02.370 --> 00:26:05.490 What you do here-- here is a receptive field of a cell. 00:26:05.490 --> 00:26:09.290 And in this case, this cell-- the recording is taking place 00:26:09.290 --> 00:26:13.120 in the geniculate-- and this particular cell 00:26:13.120 --> 00:26:18.980 is one that is color selective. 00:26:18.980 --> 00:26:22.020 It responds best to a small red spot. 00:26:22.020 --> 00:26:25.540 And if you hit the surround with a different color, 00:26:25.540 --> 00:26:27.360 the cell is inhibited. 00:26:27.360 --> 00:26:30.270 So the way this is then done is you 00:26:30.270 --> 00:26:33.070 shine the light on the center, then 00:26:33.070 --> 00:26:35.480 you shine the light on the surround, 00:26:35.480 --> 00:26:37.430 and then you're in the OFF cycle-- 00:26:37.430 --> 00:26:39.750 you just hit the surround alone. 00:26:39.750 --> 00:26:46.390 So this then shown to you here over time. 00:26:46.390 --> 00:26:47.830 Here's a center stimulation. 00:26:47.830 --> 00:26:48.677 Turn it on. 00:26:48.677 --> 00:26:49.760 Then you hit the surround. 00:26:49.760 --> 00:26:51.470 Then you turn it off. 00:26:51.470 --> 00:26:53.610 So because-- and the center stays on, 00:26:53.610 --> 00:26:56.270 and during the OFF cycle, you hit the surround. 00:26:56.270 --> 00:26:58.600 So this shows the exact manner in which 00:26:58.600 --> 00:27:01.191 you turn these on and off. 00:27:01.191 --> 00:27:01.690 All right. 00:27:01.690 --> 00:27:08.190 So now the big question is, how do ON- and OFF-center cells 00:27:08.190 --> 00:27:10.185 respond to this stimulus arrangement. 00:27:11.500 --> 00:27:17.275 So say you have an ON cell, which would discharge to this. 00:27:19.440 --> 00:27:21.122 Then the response should decrease 00:27:21.122 --> 00:27:22.580 because of the surround inhibition. 00:27:23.764 --> 00:27:26.237 And you'll see the normal response. 00:27:26.237 --> 00:27:27.695 And the question now-- what's going 00:27:27.695 --> 00:27:32.167 to happen if you put in the APB? 00:27:32.167 --> 00:27:33.875 Well there are a number of possibilities. 00:27:35.167 --> 00:27:36.750 One is that nothing's going to happen. 00:27:36.750 --> 00:27:39.050 That's unlikely because I already showed you 00:27:39.050 --> 00:27:44.350 that APB blocks the ON response of the center. 00:27:44.350 --> 00:27:46.240 The other possibility is that you 00:27:46.240 --> 00:27:48.940 lose the center-surround antagonism, which 00:27:48.940 --> 00:27:56.440 would prove that the ON and OFF systems play a significant role 00:27:56.440 --> 00:27:59.330 in creating center-surround antagonism. 00:27:59.330 --> 00:27:59.830 All right. 00:27:59.830 --> 00:28:02.420 So those are some of the possibilities. 00:28:02.420 --> 00:28:04.150 And of course a third possibility 00:28:04.150 --> 00:28:10.366 is that the OFF cells also lose their surround antagonism, 00:28:10.366 --> 00:28:12.616 although their responses to the center are unaffected. 00:28:13.680 --> 00:28:15.130 So let's take a look at that. 00:28:16.570 --> 00:28:20.340 And here are the data under normal conditions. 00:28:20.340 --> 00:28:23.720 This again is the stimulation arrangement lined up, 00:28:23.720 --> 00:28:26.630 but you can see here there's a huge response when 00:28:26.630 --> 00:28:29.851 you hit the center with a red spot, 00:28:29.851 --> 00:28:31.600 and then when you hit the surround there's 00:28:31.600 --> 00:28:33.230 a huge inhibition. 00:28:33.230 --> 00:28:36.680 When you remove that, the response returns. 00:28:36.680 --> 00:28:38.670 And then during the OFF cycle, there's 00:28:38.670 --> 00:28:42.650 some spontaneous activity, but the surround activation even 00:28:42.650 --> 00:28:43.830 stops that. 00:28:43.830 --> 00:28:46.105 So there's very strong center-surround antagonism. 00:28:47.210 --> 00:28:47.710 All right. 00:28:47.710 --> 00:28:49.390 So now I want you to guess for a minute. 00:28:49.390 --> 00:28:51.890 What do you think is going to happen 00:28:51.890 --> 00:28:53.900 when we inject APB into the eye? 00:28:55.504 --> 00:28:57.420 Think about it for a minute and I'll tell you. 00:29:02.280 --> 00:29:03.910 I listed some of the alternatives, 00:29:03.910 --> 00:29:06.219 and you can have a hypothesis of your own 00:29:06.219 --> 00:29:07.510 of what you think might happen. 00:29:08.540 --> 00:29:10.933 All right let me show you what really happened, OK? 00:29:13.300 --> 00:29:17.940 When this happened, actually, the experimenter thought, 00:29:17.940 --> 00:29:21.855 my god, we lost a cell while we were recording. 00:29:23.520 --> 00:29:27.330 But then, subsequently when the APB was washed out, 00:29:27.330 --> 00:29:28.935 you got the same response as before. 00:29:29.990 --> 00:29:34.360 And so the cell wasn't lost, but the APB was so effective 00:29:34.360 --> 00:29:36.510 that it stopped the response of the cell 00:29:36.510 --> 00:29:39.375 completely, both of the center and to the surround. 00:29:41.020 --> 00:29:44.070 And now let's ask the question, what happens when you do this, 00:29:44.070 --> 00:29:46.740 not to an ON-center cell, but an OFF-center cell. 00:29:46.740 --> 00:29:48.630 Think about it again for a minute 00:29:48.630 --> 00:29:51.270 and ask what do you think would happen then. 00:29:52.320 --> 00:29:54.030 OK, so here it is. 00:29:54.030 --> 00:29:56.560 Here is an OFF-center ganglion cell. 00:29:56.560 --> 00:30:01.081 And it shows here, using the same stimulus conditions, that 00:30:01.081 --> 00:30:02.580 in this case, because there's an OFF 00:30:02.580 --> 00:30:05.960 cell, adding the surround decreases 00:30:05.960 --> 00:30:08.240 the degree of inhibition turning OFF cycle. 00:30:08.240 --> 00:30:10.780 And here again the same thing is happening. 00:30:10.780 --> 00:30:15.160 But the same thing happens under both normal conditions 00:30:15.160 --> 00:30:17.515 and after APB had been injected. 00:30:18.960 --> 00:30:21.560 So what this experiment then shows-- and of course one 00:30:21.560 --> 00:30:24.490 does this with many, many cells-- 00:30:24.490 --> 00:30:28.440 is to prove that the hypothesis, that the ON and OFF 00:30:28.440 --> 00:30:32.630 systems play a significant role in center-surround antagonism, 00:30:32.630 --> 00:30:33.900 is wrong. 00:30:33.900 --> 00:30:37.380 And because of that, that hypothesis has been eliminated. 00:30:38.331 --> 00:30:38.830 All right. 00:30:38.830 --> 00:30:42.830 So then we can move on and ask the next question. 00:30:42.830 --> 00:30:45.150 I mean, let me first draw this up again here. 00:30:45.150 --> 00:30:45.650 All right. 00:30:45.650 --> 00:30:49.720 Here we have the photoreceptors-- 00:30:49.720 --> 00:30:52.393 the cone photoreceptors-- the horizontal cells, and the ON 00:30:52.393 --> 00:30:53.440 and OFF cells. 00:30:53.440 --> 00:30:59.190 So this alternative hypothesis, that the surround inhibition 00:30:59.190 --> 00:31:01.860 is due to horizontal cells, therefore, 00:31:01.860 --> 00:31:04.285 has gained much greater acceptance. 00:31:05.221 --> 00:31:05.720 OK. 00:31:07.340 --> 00:31:09.580 So now we are going to move upstairs 00:31:09.580 --> 00:31:14.930 and we're going to go to area V1 where we can ask the question, 00:31:14.930 --> 00:31:21.500 well what were the transforms that we had seen in V1. 00:31:23.210 --> 00:31:25.430 I presume all of you remember. 00:31:25.430 --> 00:31:27.950 What are the three major transforms we talked about? 00:31:27.950 --> 00:31:28.610 Who remembers? 00:31:34.900 --> 00:31:35.980 Come on. 00:31:35.980 --> 00:31:39.070 Sure you remember that, don't you-- that we have cells-- 00:31:39.070 --> 00:31:42.205 most of the cells are orientation specific, right? 00:31:42.205 --> 00:31:43.955 Most of the cells are direction selective. 00:31:45.290 --> 00:31:47.550 And most of the cells are selective 00:31:47.550 --> 00:31:48.825 for spatial frequency. 00:31:49.870 --> 00:31:52.390 So those are three of the major transforms. 00:31:52.390 --> 00:31:55.820 The other two we talked about is a convergence of the ON and OFF 00:31:55.820 --> 00:31:59.330 channels onto single cells in the cortex. 00:32:01.250 --> 00:32:05.280 And the other was that there was a binocular input 00:32:05.280 --> 00:32:06.155 to many of the cells. 00:32:07.280 --> 00:32:08.820 So those were the major transforms 00:32:08.820 --> 00:32:10.300 we talked about the last time. 00:32:11.440 --> 00:32:14.890 And again I want to emphasize the importance of this 00:32:14.890 --> 00:32:17.560 by telling you that Hubel received the Nobel 00:32:17.560 --> 00:32:24.750 Prize for those discoveries of how V1 operates. 00:32:24.750 --> 00:32:25.760 OK? 00:32:25.760 --> 00:32:29.500 And of course I mentioned before that Keffer Hartline, 00:32:29.500 --> 00:32:33.320 when he discovered the ON and OFF systems using light 00:32:33.320 --> 00:32:35.990 that he shown into the eye-- he called them the ON and OFF 00:32:35.990 --> 00:32:39.570 cells-- he received the Nobel Prize as well. 00:32:39.570 --> 00:32:43.870 So those are truly, truly major, major discoveries 00:32:43.870 --> 00:32:48.010 and have triggered hundreds and hundreds of experiments 00:32:48.010 --> 00:32:49.830 trying to understand better. 00:32:49.830 --> 00:32:52.080 And certainly one of the questions that was raised 00:32:52.080 --> 00:32:57.100 is how does orientation, and direction cell activity, 00:32:57.100 --> 00:32:59.740 and special frequencies activity, for that matter, 00:32:59.740 --> 00:33:01.650 arise in area of V1. 00:33:02.850 --> 00:33:06.810 And one prominent hypotheses was indeed 00:33:06.810 --> 00:33:09.390 that the reason we have ON and OFF channels 00:33:09.390 --> 00:33:12.050 is to create these transforms in the visual cortex. 00:33:14.300 --> 00:33:17.090 So what we can then do, now that one 00:33:17.090 --> 00:33:21.540 has this magic bullet of the APB, 00:33:21.540 --> 00:33:24.610 that one can record from a cortical cell. 00:33:24.610 --> 00:33:33.140 See how it responds when you inject APB in contrast 00:33:33.140 --> 00:33:35.990 to before you injected it and after injected it. 00:33:35.990 --> 00:33:38.740 So that's the big question you're going to ask next. 00:33:38.740 --> 00:33:39.310 All right. 00:33:39.310 --> 00:33:43.880 So here is an example of what of cortical cell's response 00:33:43.880 --> 00:33:48.150 looks like using this kind of histogram when a bar of light, 00:33:48.150 --> 00:33:51.380 in this case, is moved across the receptive field. 00:33:51.380 --> 00:33:54.780 Now this is a complex cell. 00:33:54.780 --> 00:33:56.966 And you can see it gives a vigorous response when 00:33:56.966 --> 00:33:58.590 the light edge goes across, and then it 00:33:58.590 --> 00:34:01.650 gives a vigorous response when the dark edge goes across. 00:34:01.650 --> 00:34:05.010 I'm showing this only for one direction of motion. 00:34:05.010 --> 00:34:06.980 So that is a natural response. 00:34:06.980 --> 00:34:09.120 So now the question comes up, what 00:34:09.120 --> 00:34:12.394 happens when you inject APB into the eye. 00:34:14.302 --> 00:34:16.375 A number of possibilities exist. 00:34:18.230 --> 00:34:21.429 The most basic one I think most of you would buy 00:34:21.429 --> 00:34:26.230 is that the light edge response is produced predominantly 00:34:26.230 --> 00:34:28.600 by the ON channel, and the dark edge 00:34:28.600 --> 00:34:30.699 response by the OFF channel. 00:34:30.699 --> 00:34:33.650 And if that is the case, then this response 00:34:33.650 --> 00:34:38.949 should be eliminated by blocking it with APB in the eye. 00:34:38.949 --> 00:34:41.699 And if you do that, that's exactly what happens. 00:34:41.699 --> 00:34:44.060 You can see here under normal conditions, 00:34:44.060 --> 00:34:46.850 you get a vigorous response for both light and dark edges. 00:34:46.850 --> 00:34:50.270 After APB, only a dark edge response remains. 00:34:50.270 --> 00:34:54.909 So this then established that these responses 00:34:54.909 --> 00:34:57.890 to the different edges-- the light edges and dark edges-- 00:34:57.890 --> 00:35:02.050 are a product of the input from the retina to the geniculate, 00:35:02.050 --> 00:35:06.130 and then to the cortex from the ON and the OFF channels, which 00:35:06.130 --> 00:35:08.450 then converge in many cortical cells, 00:35:08.450 --> 00:35:13.120 as is the case in this particular cortical cell. 00:35:13.120 --> 00:35:16.610 So that then establishes this very basic fact. 00:35:16.610 --> 00:35:19.100 Now the next question we can ask-- 00:35:19.100 --> 00:35:22.310 what about those transforms you talked about? 00:35:22.310 --> 00:35:24.970 Let's first of all look at the transform 00:35:24.970 --> 00:35:28.240 of direction selectivity. 00:35:28.240 --> 00:35:31.310 So we can take a cell that is, in this case, 00:35:31.310 --> 00:35:33.300 directionally biased. 00:35:33.300 --> 00:35:35.550 And you can see what the response is before 00:35:35.550 --> 00:35:37.740 and after APB is injected. 00:35:37.740 --> 00:35:40.380 And what you see here-- we move the bar 00:35:40.380 --> 00:35:43.400 across in one direction, and then we move the bar back 00:35:43.400 --> 00:35:45.100 across the opposite direction. 00:35:45.100 --> 00:35:47.630 So the first half shows a downward movement-- 00:35:47.630 --> 00:35:50.180 the second half, the upward movement. 00:35:50.180 --> 00:35:52.840 Now what you see here that the cell responds 00:35:52.840 --> 00:35:53.870 is much more vigorous. 00:35:53.870 --> 00:35:55.990 It's not 100% direction selective. 00:35:55.990 --> 00:35:57.860 I showed you some of those the last time. 00:35:57.860 --> 00:36:01.200 This one is a bias-- about a four to one bias-- 00:36:01.200 --> 00:36:03.680 much more response to the downward movement 00:36:03.680 --> 00:36:05.120 than the upward movement. 00:36:05.120 --> 00:36:08.390 But the cell responds both the light and the dark edge 00:36:08.390 --> 00:36:10.390 in both directions, and it lines up 00:36:10.390 --> 00:36:12.910 with the temporal arrangement here, 00:36:12.910 --> 00:36:16.410 proving indeed that this is a complex cell. 00:36:16.410 --> 00:36:19.190 Now then when you inject APB into the eye, 00:36:19.190 --> 00:36:20.440 look what happens. 00:36:20.440 --> 00:36:23.680 You eliminate the light edge response here and here, 00:36:23.680 --> 00:36:29.790 but the cell is still directionally biased. 00:36:29.790 --> 00:36:32.570 So direction specificity was maintained. 00:36:32.570 --> 00:36:34.130 And when this was studied in many, 00:36:34.130 --> 00:36:36.870 many, many cells-- even cells that 00:36:36.870 --> 00:36:41.320 were 100% direction specific-- blocking the ON channel 00:36:41.320 --> 00:36:45.870 did not eliminate directionality in the cortex. 00:36:45.870 --> 00:36:49.540 So that then indicates that the ON and OFF channels did not 00:36:49.540 --> 00:36:56.390 arise to bring about direction selectivity in the cortex. 00:36:58.810 --> 00:37:02.820 And so that brings us to the second transform, 00:37:02.820 --> 00:37:04.680 which is orientation specificity. 00:37:05.700 --> 00:37:07.280 So we can do that next. 00:37:07.280 --> 00:37:10.530 And here we have an example using a very similar procedure. 00:37:10.530 --> 00:37:14.600 Again, a complex cell when the APB is injected. 00:37:14.600 --> 00:37:17.430 The light edge response disappears. 00:37:17.430 --> 00:37:20.220 You move the bar across the different orientations 00:37:20.220 --> 00:37:24.400 and this is the orientation specificity you get. 00:37:24.400 --> 00:37:28.530 Now this is calculated here on the basis of only the dark edge 00:37:28.530 --> 00:37:31.256 response because you want to keep it the same 00:37:31.256 --> 00:37:32.380 as you're going to do here. 00:37:32.380 --> 00:37:35.160 Since the light edge response is eliminated, 00:37:35.160 --> 00:37:39.950 you can see that the cells orientation specificity is also 00:37:39.950 --> 00:37:45.910 unaffected, meaning that the orientation 00:37:45.910 --> 00:37:49.880 specificity of the cortical cells 00:37:49.880 --> 00:37:54.130 is not due to the interaction between the ON and OFF channel. 00:37:58.990 --> 00:38:01.950 Similar experiments were also done with spatial frequency 00:38:01.950 --> 00:38:06.070 selectivity, and again, no effect was found. 00:38:06.070 --> 00:38:09.780 So this then led to the conclusion 00:38:09.780 --> 00:38:13.830 that the ON and OFF channels did not 00:38:13.830 --> 00:38:17.940 arise for the purpose of creating the transforms that we 00:38:17.940 --> 00:38:22.910 had denoted in our last lecture about single cells 00:38:22.910 --> 00:38:24.801 in the visual cortex. 00:38:24.801 --> 00:38:25.300 All right. 00:38:25.300 --> 00:38:28.140 So now what we can do is here-- we can come up 00:38:28.140 --> 00:38:32.430 with a silly model, just to make it memorable, 00:38:32.430 --> 00:38:34.260 which is to say that the ON and OFF 00:38:34.260 --> 00:38:37.020 channels flow into the cortex. 00:38:37.020 --> 00:38:39.760 And these attributes we talked about-- orientation, direction, 00:38:39.760 --> 00:38:41.740 and spacial frequencies selectivity-- 00:38:41.740 --> 00:38:44.640 are produced by cortical filters. 00:38:44.640 --> 00:38:47.430 What you have in the cortex are all 00:38:47.430 --> 00:38:51.300 kinds of inhibitory interneurons and the interactions 00:38:51.300 --> 00:38:53.600 among many, many neurons. 00:38:53.600 --> 00:38:56.380 And that kind of activity that you 00:38:56.380 --> 00:39:02.190 get there is the one that produces these attributes, 00:39:02.190 --> 00:39:06.150 not the interaction between the ON and OFF channels 00:39:06.150 --> 00:39:07.795 that flow into the visual cortex. 00:39:09.461 --> 00:39:09.960 All right. 00:39:09.960 --> 00:39:16.400 So now the next question we can ask, 00:39:16.400 --> 00:39:24.790 or what happens on APB under photopic viewing conditions. 00:39:24.790 --> 00:39:30.740 We'll talk about scotopic, as well as photopic, vision. 00:39:34.670 --> 00:39:42.070 To do this, and to answer how it affects our visual capacities, 00:39:42.070 --> 00:39:48.820 what we do is to turn to behavioral experiments. 00:39:48.820 --> 00:39:51.470 In behavioral experiments, what you can do 00:39:51.470 --> 00:39:53.740 is you can present various kinds of stimuli. 00:39:53.740 --> 00:39:55.720 You can train a monkey-- in this case, 00:39:55.720 --> 00:40:02.780 with monkeys-- to see how well they perceive a stimulus, 00:40:02.780 --> 00:40:05.900 and ask them to make an eye movement to that stimulus. 00:40:05.900 --> 00:40:10.290 So when you do this-- testing that 00:40:10.290 --> 00:40:13.550 hypothesis I've shown you earlier about light increment 00:40:13.550 --> 00:40:15.740 and light decrement-- what we can do 00:40:15.740 --> 00:40:19.650 is to train a monkey to first fixate. 00:40:19.650 --> 00:40:21.700 And then after the monkey fixated, 00:40:21.700 --> 00:40:25.480 you can present either a light incremental spot 00:40:25.480 --> 00:40:27.940 or a light decremental spot. 00:40:27.940 --> 00:40:31.220 The monkey's task is to make a saccade to that target. 00:40:31.220 --> 00:40:34.670 And of course, those spots will appear randomly 00:40:34.670 --> 00:40:37.130 in several different locations in each trial, 00:40:37.130 --> 00:40:40.350 so the monkey doesn't know where he's going to appear. 00:40:40.350 --> 00:40:42.710 And if he makes a correct saccade to it, 00:40:42.710 --> 00:40:45.500 he will get a drop of apple juice for a reward. 00:40:45.500 --> 00:40:47.420 So that is the procedure. 00:40:47.420 --> 00:40:49.710 And so now the question then comes up-- 00:40:49.710 --> 00:40:54.210 how well does the monkey do in being 00:40:54.210 --> 00:40:56.875 able to detect light increment and light decrement? 00:40:58.250 --> 00:41:03.010 So if you do that, luckily one gets a very clear cut 00:41:03.010 --> 00:41:05.350 and dramatic result. 00:41:05.350 --> 00:41:07.420 Here is the section that I will show 00:41:07.420 --> 00:41:09.660 you data for light increment, and here 00:41:09.660 --> 00:41:13.730 is a section showing data for light decrement. 00:41:13.730 --> 00:41:15.420 So here is an example. 00:41:15.420 --> 00:41:17.260 What you measure here are two things-- 00:41:17.260 --> 00:41:21.860 you measure the monkey's percent correct performance, 00:41:21.860 --> 00:41:25.060 and you measure what the saccadic latencies are 00:41:25.060 --> 00:41:27.730 to make a saccade to the target. 00:41:27.730 --> 00:41:30.170 So it shows here that under normal conditions, 00:41:30.170 --> 00:41:34.570 the monkey's performances is over 90%, 00:41:34.570 --> 00:41:37.560 and that he has a very nice distribution 00:41:37.560 --> 00:41:40.140 of saccadic latencies with a mean of about two 00:41:40.140 --> 00:41:41.860 in 53 milliseconds. 00:41:43.220 --> 00:41:47.830 Then when you apply APB to the eye, what happens 00:41:47.830 --> 00:41:50.670 is that the monkey's performance drops dramatically. 00:41:50.670 --> 00:41:55.890 He is just a little bit above probability, 00:41:55.890 --> 00:41:58.620 and his latencies are very, very late-- very, very, 00:41:58.620 --> 00:42:01.180 very long-- 406 milliseconds. 00:42:02.270 --> 00:42:04.550 So in other words, the monkey can barely 00:42:04.550 --> 00:42:07.560 perceive a light incremental stimulus 00:42:07.560 --> 00:42:10.840 by virtue of having blocked the ON channel in the retina 00:42:10.840 --> 00:42:11.590 by APB. 00:42:12.870 --> 00:42:14.950 Now if you do the same experiment 00:42:14.950 --> 00:42:19.320 with light decrement, what you see here 00:42:19.320 --> 00:42:21.020 is the monkey's performance remains 00:42:21.020 --> 00:42:24.940 normal-- about 95% correct. 00:42:24.940 --> 00:42:29.000 And the latency distribution is also 00:42:29.000 --> 00:42:33.380 about the same-- two in 49, versus two in 51 milliseconds. 00:42:34.980 --> 00:42:40.270 So that then says that indeed the ability 00:42:40.270 --> 00:42:43.700 to detect light incremental stimuli 00:42:43.700 --> 00:42:48.630 has been devastated by the injection of APB, 00:42:48.630 --> 00:42:53.280 and therefore raised the idea that the ON and OFF 00:42:53.280 --> 00:42:56.910 channels are for the purpose of quickly and efficiently 00:42:56.910 --> 00:43:01.080 detecting light increment, as well as light decrement. 00:43:02.120 --> 00:43:07.120 So that then was the basic finding 00:43:07.120 --> 00:43:14.050 that was obtained with this behavioral experiment studying 00:43:14.050 --> 00:43:17.030 the monkey's performance on being 00:43:17.030 --> 00:43:18.870 able to process visual stimuli. 00:43:20.645 --> 00:43:25.170 Now we are going to get a bit more complicated, 00:43:25.170 --> 00:43:27.080 because what we talked about so far 00:43:27.080 --> 00:43:30.360 was under photopic conditions, meaning 00:43:30.360 --> 00:43:33.670 when your cones were fully functional. 00:43:34.940 --> 00:43:40.270 So the question is what happens under scotopic conditions, 00:43:40.270 --> 00:43:42.350 meaning what happens when you're dark adapted. 00:43:43.370 --> 00:43:45.700 Now we have talked about this before. 00:43:46.820 --> 00:43:52.220 It was pointed out, initially by Schultze, 00:43:52.220 --> 00:43:56.520 that we have two basic classes of photoreceptors-- the rods 00:43:56.520 --> 00:44:00.275 and the cones-- and that the rods are for night vision. 00:44:02.020 --> 00:44:06.641 So now the question is, what happens under night vision 00:44:06.641 --> 00:44:07.140 conditions. 00:44:08.150 --> 00:44:11.920 And when this was found-- this was truly, truly baffling. 00:44:11.920 --> 00:44:14.070 And I'm going to show you the data. 00:44:14.070 --> 00:44:17.540 It showed here under light adapted conditions 00:44:17.540 --> 00:44:19.530 with the same kind of data-- but shown only 00:44:19.530 --> 00:44:22.810 as histograms in this case-- the monkey 00:44:22.810 --> 00:44:25.190 does equally well for light and dark. 00:44:25.190 --> 00:44:29.920 And when you apply APB, the monkey 00:44:29.920 --> 00:44:33.360 has difficulty seeing the light incremental stimulus, 00:44:33.360 --> 00:44:37.390 but has little loss in the light decremental stimulus. 00:44:37.390 --> 00:44:38.560 OK? 00:44:38.560 --> 00:44:41.870 But when you do the same thing under dark adapted conditions, 00:44:41.870 --> 00:44:44.050 when only the rods are operative, 00:44:44.050 --> 00:44:45.490 a curious thing happens. 00:44:45.490 --> 00:44:48.900 The monkey doesn't see either light increment or light 00:44:48.900 --> 00:44:49.400 decrement. 00:44:50.720 --> 00:44:53.475 In other words, and the way to put it shortly, 00:44:53.475 --> 00:44:58.120 is to say that the monkey has become night blind. 00:44:59.280 --> 00:45:05.230 Now there are, among humans, a small population of individuals 00:45:05.230 --> 00:45:08.160 individuals who are night blind, and what's 00:45:08.160 --> 00:45:09.350 the situation with them? 00:45:10.580 --> 00:45:12.570 It's called "night blind" because they just 00:45:12.570 --> 00:45:14.470 see very poorly at night. 00:45:14.470 --> 00:45:17.760 And, in fact, when that is known, 00:45:17.760 --> 00:45:21.730 they only get a special kind of driver's license-- one 00:45:21.730 --> 00:45:23.432 saying you can drive in the daytime, 00:45:23.432 --> 00:45:24.640 but you can't drive at night. 00:45:26.290 --> 00:45:29.180 So now we have a monkey here with APB 00:45:29.180 --> 00:45:30.810 injected-- that he's night blind. 00:45:30.810 --> 00:45:34.180 And also you see the same data reflected in the latencies, 00:45:34.180 --> 00:45:35.490 just like before. 00:45:35.490 --> 00:45:38.990 And it shows that the monkey is devastated 00:45:38.990 --> 00:45:41.460 both for light increment and light decrement 00:45:41.460 --> 00:45:43.300 by having a tremendous increase-- more 00:45:43.300 --> 00:45:48.035 than a tripling of latencies for the few trials 00:45:48.035 --> 00:45:50.290 that he did carry out correctly. 00:45:51.510 --> 00:45:55.780 So now this being the case, it raises a big question-- 00:45:55.780 --> 00:45:58.490 and I'm sorry that things are getting so complicated, 00:45:58.490 --> 00:46:01.510 but the brain is complicated-- as 00:46:01.510 --> 00:46:11.950 to just what is the nature and arrangement of the rods 00:46:11.950 --> 00:46:14.400 in the retina, and how does that relate 00:46:14.400 --> 00:46:16.320 to the arrangement of the cones? 00:46:16.320 --> 00:46:16.870 OK? 00:46:16.870 --> 00:46:21.100 So that brings me to an interesting point. 00:46:22.290 --> 00:46:25.390 Again, as so often happens, whenever 00:46:25.390 --> 00:46:27.812 you're confronted with a puzzle, you 00:46:27.812 --> 00:46:29.020 have all kinds of hypotheses. 00:46:30.050 --> 00:46:32.960 And then luckily if you do this instead of experiments, 00:46:32.960 --> 00:46:34.880 you come up with the right kinds of tools. 00:46:34.880 --> 00:46:38.250 You can eliminate most of them and come up with the right one. 00:46:38.250 --> 00:46:47.180 Now, so we can ask, first of all, 00:46:47.180 --> 00:46:52.670 without talking about APB at all now, 00:46:52.670 --> 00:46:55.070 simply ask a general question-- what 00:46:55.070 --> 00:47:02.480 happens to the receptive fields, or retinal ganglion cells, 00:47:02.480 --> 00:47:04.760 under dark adapted conditions? 00:47:04.760 --> 00:47:07.985 And what happens is that the receptive fields become larger. 00:47:10.030 --> 00:47:16.830 Now this initially-- discovered by Barlow in England-- 00:47:16.830 --> 00:47:20.580 was negated by the other individuals saying, 00:47:20.580 --> 00:47:23.790 you just got scattering of light-- that's why it's larger. 00:47:23.790 --> 00:47:26.600 So it was kind of dismissed, but in the end 00:47:26.600 --> 00:47:28.890 it turned that he was right, as you shall see. 00:47:30.110 --> 00:47:34.490 The other thing that happened is that the color selectivity 00:47:34.490 --> 00:47:40.360 response disappears in the retinal ganglion cells. 00:47:41.550 --> 00:47:44.470 And not only that, but it disappears behaviorally. 00:47:44.470 --> 00:47:46.240 So when you have a red rose, and you 00:47:46.240 --> 00:47:50.520 look at a red rose at night when only your rods are functional, 00:47:50.520 --> 00:47:52.140 it looks like a black rose. 00:47:53.740 --> 00:47:55.860 The rods cannot process color. 00:47:55.860 --> 00:47:56.360 OK? 00:47:56.360 --> 00:47:59.120 They can only process light increment and decrement. 00:48:00.760 --> 00:48:03.550 OK, again just to reiterate-- the receptive fields 00:48:03.550 --> 00:48:05.010 become larger. 00:48:05.010 --> 00:48:05.650 OK. 00:48:05.650 --> 00:48:08.930 So the big question is what on earth is happening, 00:48:08.930 --> 00:48:10.700 what kind of wiring is taking place, 00:48:10.700 --> 00:48:13.540 or what kind of connections are created 00:48:13.540 --> 00:48:16.510 to create these two things. 00:48:16.510 --> 00:48:19.960 Now the second one is the one that's the big puzzle. 00:48:19.960 --> 00:48:22.065 The first one we can understand because it's 00:48:22.065 --> 00:48:24.620 been shown that rods are only one type 00:48:24.620 --> 00:48:26.725 and that they don't carry color information. 00:48:27.900 --> 00:48:37.880 Now to study this further, way back when in the 1870s-- 1880s, 00:48:37.880 --> 00:48:41.280 Cajal did the large number of experiments of this sort. 00:48:41.280 --> 00:48:45.910 If you remember, I told you that Cajal played a central role 00:48:45.910 --> 00:48:49.260 in using the Golgi stain, and that he and Golgi received 00:48:49.260 --> 00:48:55.790 the Nobel Prize in 1906 for their major discoveries 00:48:55.790 --> 00:48:56.570 about this. 00:48:56.570 --> 00:49:01.470 So now he argued that the way this happens 00:49:01.470 --> 00:49:04.410 is that rods and the cones connect differently 00:49:04.410 --> 00:49:05.980 with the ganglion cells. 00:49:05.980 --> 00:49:09.580 And so here is a picture of Cajal. 00:49:09.580 --> 00:49:11.370 He spent most of his life like this, 00:49:11.370 --> 00:49:13.960 looking through a microscope, endlessly looking 00:49:13.960 --> 00:49:19.190 at brain slices, and studying the individual cells-- 00:49:19.190 --> 00:49:21.710 the shapes and drew them, as you can see his pencil. 00:49:21.710 --> 00:49:25.150 He is in the middle drawing, actually, a cell there. 00:49:26.210 --> 00:49:31.230 And so he speculated about this a great deal. 00:49:31.230 --> 00:49:34.070 And he was just a remarkable person. 00:49:34.070 --> 00:49:39.646 And he had written an autobiography. 00:49:41.130 --> 00:49:47.580 And the way he speaks in this-- translated from Spanish-- 00:49:47.580 --> 00:49:50.890 but he has an incredibly colorful way of talking-- 00:49:50.890 --> 00:49:52.830 "had," I guess I should say. 00:49:52.830 --> 00:49:55.610 And I want to quote some of this, 00:49:55.610 --> 00:49:58.300 because I think you'll find it interesting and amusing. 00:49:58.300 --> 00:50:00.930 So he said, "Since this impression received by the rods 00:50:00.930 --> 00:50:04.040 is different from that taken by the cone, 00:50:04.040 --> 00:50:06.850 it is necessary from every point of view 00:50:06.850 --> 00:50:09.360 that each of these specific impressions 00:50:09.360 --> 00:50:15.130 should be conveyed through the retina by a separate channel." 00:50:15.130 --> 00:50:19.370 The translation leaves a lot to be desired, but that's OK. 00:50:19.370 --> 00:50:21.070 So then he went on and said, "When 00:50:21.070 --> 00:50:25.060 we reason with common sense and lift a war club determined 00:50:25.060 --> 00:50:30.790 upon vigorous action, nature ultimately hears us." 00:50:30.790 --> 00:50:34.430 Very picturesque, as if nature had heard anyone, right? 00:50:34.430 --> 00:50:37.560 "Knowing what I was looking for--" meaning he 00:50:37.560 --> 00:50:42.730 had a hypothetical bias, right-- "I began to explore eagerly 00:50:42.730 --> 00:50:45.380 retina of fishes and mammals. 00:50:45.380 --> 00:50:48.600 Finally as a reward of my faith, there 00:50:48.600 --> 00:50:52.800 deigned to appear most clearly and brilliantly those two 00:50:52.800 --> 00:50:56.590 types of bipolar cells demanded by theory 00:50:56.590 --> 00:50:58.220 and guessed by reason." 00:50:58.220 --> 00:51:02.520 What he means by this is that there 00:51:02.520 --> 00:51:05.440 were two kinds of basic kinds of bipolar cells-- 00:51:05.440 --> 00:51:06.930 and not the ON and OFF. 00:51:06.930 --> 00:51:08.960 But in this case, what he was talking about, 00:51:08.960 --> 00:51:12.700 he was talking about rod bipolars and cone bipolars. 00:51:12.700 --> 00:51:17.570 He said the rod photoreceptors connect with rod bipolars, 00:51:17.570 --> 00:51:19.570 and the cone photoreceptors with cone bipolars. 00:51:21.690 --> 00:51:25.090 So that's what [INAUDIBLE] then established, 00:51:25.090 --> 00:51:27.550 and that finding was basically correct. 00:51:27.550 --> 00:51:33.790 But then he went on to say that these two kinds of bipolars 00:51:33.790 --> 00:51:37.050 hook up with two types of ganglion cells, 00:51:37.050 --> 00:51:39.490 thereby forming separate channels to the brain. 00:51:42.310 --> 00:51:45.190 So that was an interesting conclusion, and for many years 00:51:45.190 --> 00:51:46.530 that was accepted. 00:51:46.530 --> 00:51:49.040 And interestingly enough, as it so often happens 00:51:49.040 --> 00:51:52.880 with hypotheses, this conclusion-- 00:51:52.880 --> 00:51:56.184 even though you had the drawings looking 00:51:56.184 --> 00:51:58.100 through the microscope showing that there were 00:51:58.100 --> 00:52:00.740 these separate channels-- turned out to be largely 00:52:00.740 --> 00:52:02.630 not one-- almost entirely wrong. 00:52:03.750 --> 00:52:05.370 Now what do we mean by that? 00:52:05.370 --> 00:52:06.960 Well people began to do all sorts 00:52:06.960 --> 00:52:10.370 of very careful intercellular recordings in the retina, 00:52:10.370 --> 00:52:13.450 and using much more sophisticated 00:52:13.450 --> 00:52:16.230 anatomical procedures than Cajal was 00:52:16.230 --> 00:52:19.050 able to use, thanks to the new developments in the field. 00:52:19.050 --> 00:52:24.420 And they discovered, first of all-- let me back up a second. 00:52:24.420 --> 00:52:27.100 This is sort of the model that he had proposed. 00:52:27.100 --> 00:52:29.420 He had the cone model and the rod model, 00:52:29.420 --> 00:52:32.480 not distinguishing between the ON and OFF. 00:52:32.480 --> 00:52:35.350 And so the model that then subsequently emerged 00:52:35.350 --> 00:52:40.640 was that ganglion cells in most of the retina 00:52:40.640 --> 00:52:44.220 actually receive a convergent input- except in the fovia, 00:52:44.220 --> 00:52:47.500 because you don't have rods there-- so that you don't have 00:52:47.500 --> 00:52:53.080 a doubling of ganglion cells-- some for rods 00:52:53.080 --> 00:52:56.100 and some for cones-- but both the rods and the cones, 00:52:56.100 --> 00:53:00.450 through separate pathways, feed into the ganglion cell. 00:53:00.450 --> 00:53:03.610 So then this was analyzed in much, much more detail. 00:53:03.610 --> 00:53:08.240 And now I'm going to point this out to you by providing you 00:53:08.240 --> 00:53:11.241 with an overview of the retinal connections. 00:53:11.241 --> 00:53:11.740 OK. 00:53:11.740 --> 00:53:15.690 So here we have the three basic classes of cones. 00:53:15.690 --> 00:53:16.610 All right? 00:53:16.610 --> 00:53:18.711 And we have the rods. 00:53:18.711 --> 00:53:19.210 All right? 00:53:19.210 --> 00:53:23.870 Then, if you look at the cones, each cone 00:53:23.870 --> 00:53:28.890 gives rise to at least two bipolar cell-- an ON and OFF 00:53:28.890 --> 00:53:30.130 bipolar cell. 00:53:30.130 --> 00:53:36.730 But the rods in most species only 00:53:36.730 --> 00:53:40.260 have a single kind of bipolar cell, 00:53:40.260 --> 00:53:43.020 and they can refer to that as an ON bipolar cell, 00:53:43.020 --> 00:53:47.990 because the synapses are all sign-inverting synapses using 00:53:47.990 --> 00:53:53.480 the mGluR6 neurotransmitter receptor site. 00:53:53.480 --> 00:53:55.150 So that's what we have there. 00:53:55.150 --> 00:53:58.840 Now if you look further down here at the ganglion cells-- 00:53:58.840 --> 00:54:01.680 and what we have is of course, that we have the ON and OFF 00:54:01.680 --> 00:54:04.430 bipolar cells from the cones feed 00:54:04.430 --> 00:54:07.030 into the ON and OFF ganglion cells. 00:54:07.030 --> 00:54:10.021 So now the questions are what happens to the ON bipolar 00:54:10.021 --> 00:54:10.520 cells? 00:54:10.520 --> 00:54:16.120 How do they connect to these cells 00:54:16.120 --> 00:54:18.640 since they do not form a separate pathway? 00:54:18.640 --> 00:54:20.890 And this has been again-- things got 00:54:20.890 --> 00:54:26.120 very complicated in the course of evolution 00:54:26.120 --> 00:54:28.870 where it was very important to try to conserve things 00:54:28.870 --> 00:54:31.640 as much as possible, and that's why we do not 00:54:31.640 --> 00:54:34.690 have separate pathways for rods and cones. 00:54:34.690 --> 00:54:37.210 If we did we'd need a huge eye, and we'd 00:54:37.210 --> 00:54:41.199 need at least twice as many ganglion cells 00:54:41.199 --> 00:54:43.615 than we have at the present time, which is about a million 00:54:43.615 --> 00:54:44.860 in each eye. 00:54:44.860 --> 00:54:49.740 OK, so what really happened is-- dumb-founding almost-- 00:54:49.740 --> 00:54:55.860 is that a so-called amacrine cell -- 00:54:55.860 --> 00:54:58.830 I told you there are different classes of amacrine cells-- 00:54:58.830 --> 00:55:02.370 one of them is a so-called A2 amacrine cell. 00:55:02.370 --> 00:55:05.420 That is a cell that receives a direct input 00:55:05.420 --> 00:55:08.340 from the ON bipolar cells. 00:55:08.340 --> 00:55:14.250 Now that amacrine cell connects to ganglion cells 00:55:14.250 --> 00:55:15.750 in two different ways. 00:55:15.750 --> 00:55:20.060 It makes a gap junction connection with the ON bipolar 00:55:20.060 --> 00:55:24.890 cells, and it makes a glycinergic synaptic connection 00:55:24.890 --> 00:55:27.360 with the OFF ganglion cell. 00:55:27.360 --> 00:55:28.790 So let's label this. 00:55:30.220 --> 00:55:32.820 What we have here-- this is inner plexiform layer again, 00:55:32.820 --> 00:55:34.740 and here is the outer plexiform layer. 00:55:34.740 --> 00:55:37.580 And what we have here-- just to remind you, 00:55:37.580 --> 00:55:40.740 that already know-- we have a sign-inverting synapse 00:55:40.740 --> 00:55:44.800 for the ON, and sign-conserving for the OFF bipolars 00:55:44.800 --> 00:55:49.840 that connect with the cones. 00:55:49.840 --> 00:55:53.920 And now we have here-- let's proceed to the A2 amacrine 00:55:53.920 --> 00:55:58.910 cell that is feeding into these cells from the rods. 00:55:58.910 --> 00:56:03.380 And what we have here is a glycinergic synapse, so-called. 00:56:03.380 --> 00:56:04.770 That's a real synapse. 00:56:04.770 --> 00:56:06.200 It's inhibitory. 00:56:06.200 --> 00:56:08.660 And then here we have what is called a gap junction. 00:56:08.660 --> 00:56:10.920 I'm sure all of you know what these things are. 00:56:10.920 --> 00:56:16.830 Gap junction is what you call an electrical synapse. 00:56:16.830 --> 00:56:21.720 So they transform the signal without any neurotransmitters 00:56:21.720 --> 00:56:22.740 involved. 00:56:22.740 --> 00:56:27.720 So it directly activates-- in this case, this fiber here-- 00:56:27.720 --> 00:56:29.040 and drives it. 00:56:29.040 --> 00:56:31.700 So what you create in the inner retina 00:56:31.700 --> 00:56:35.310 then here is a double ended system 00:56:35.310 --> 00:56:40.550 for the rods that is created in the outer retina for the cones. 00:56:40.550 --> 00:56:43.030 So you create [INAUDIBLE]. 00:56:43.030 --> 00:56:47.060 Here are the OFF, and here are the ON inputs to the ON and OFF 00:56:47.060 --> 00:56:48.710 ganglion cells. 00:56:48.710 --> 00:56:51.390 Now because of this arrangement, what happens 00:56:51.390 --> 00:56:56.370 is that the size of the receptive 00:56:56.370 --> 00:56:59.170 fields under dark adaptive conditions 00:56:59.170 --> 00:57:04.300 is bigger because a bigger range of connections from the rods 00:57:04.300 --> 00:57:05.505 to the ganglion cells. 00:57:07.660 --> 00:57:09.950 So all this is nice wiring that finally, 00:57:09.950 --> 00:57:12.230 after many, many years of experiments, 00:57:12.230 --> 00:57:13.630 has been clarified. 00:57:13.630 --> 00:57:14.785 Sorry it is so complicated. 00:57:16.700 --> 00:57:18.950 That's just how it is. 00:57:18.950 --> 00:57:23.340 Explains then the claim that you have bigger receptive fields 00:57:23.340 --> 00:57:24.980 at night than in the daytime. 00:57:24.980 --> 00:57:27.015 And now that has been generally accepted. 00:57:28.210 --> 00:57:32.990 OK so now the central conclusions that we come to 00:57:32.990 --> 00:57:36.160 is that ON and OFF channels have emerged 00:57:36.160 --> 00:57:39.380 in the course of evolution to enable organisms 00:57:39.380 --> 00:57:44.040 to process light both incrementally and decrementally 00:57:44.040 --> 00:57:48.110 for being able to see things rapidly and quickly. 00:57:48.110 --> 00:57:48.870 All right? 00:57:48.870 --> 00:57:50.500 So that is the prime function. 00:57:50.500 --> 00:57:54.200 Nature has gone to incredible extent 00:57:54.200 --> 00:57:58.250 to modify the basic organization of the visual system 00:57:58.250 --> 00:58:01.170 and the retina to create a way to be 00:58:01.170 --> 00:58:03.510 able to process both light increment 00:58:03.510 --> 00:58:05.070 and decrement rapidly. 00:58:05.070 --> 00:58:08.900 Now that may provide you with a little cute mnemonic, 00:58:08.900 --> 00:58:10.550 if you will. 00:58:10.550 --> 00:58:11.830 Here we have a fish. 00:58:11.830 --> 00:58:15.645 Fish also, believe it or not, have ON and OFF channels. 00:58:16.794 --> 00:58:20.110 Now what happens is if below here there 00:58:20.110 --> 00:58:23.080 is a predator-- a large fish that 00:58:23.080 --> 00:58:28.570 is trying to catch this fish-- because of the sun shining 00:58:28.570 --> 00:58:30.530 on it, it reflects the light, and so 00:58:30.530 --> 00:58:33.910 this fish would see this particular predator 00:58:33.910 --> 00:58:35.740 by virtue of light increment. 00:58:35.740 --> 00:58:36.870 Got it? 00:58:36.870 --> 00:58:40.540 By contrast, if you have osprey up here 00:58:40.540 --> 00:58:42.520 that's trying to catch this fish, 00:58:42.520 --> 00:58:46.380 that osprey against the sky would be seen as a dark object. 00:58:46.380 --> 00:58:47.480 OK? 00:58:47.480 --> 00:58:54.490 And so now, since this fish has both ON and OFF cells 00:58:54.490 --> 00:58:57.730 in its retina, it's going to do this. 00:58:57.730 --> 00:58:58.400 You ready? 00:59:00.630 --> 00:59:02.750 He's going to escape, OK? 00:59:04.440 --> 00:59:08.680 So that then, in a nutshell, tells us 00:59:08.680 --> 00:59:16.670 why we have ON and OFF channels in the visual system-- namely 00:59:16.670 --> 00:59:20.460 to enable us to process both light increment and light 00:59:20.460 --> 00:59:21.390 decrement effectively. 00:59:22.530 --> 00:59:24.600 And as I've mentioned to you before, 00:59:24.600 --> 00:59:28.410 whenever you read or write, you see things 00:59:28.410 --> 00:59:32.770 mostly by virtue of your OFF system 00:59:32.770 --> 00:59:39.140 because you have dark print or a dark pen on a light background. 00:59:40.450 --> 00:59:42.795 But of course the obverse is also the case. 00:59:44.530 --> 00:59:48.320 So this was known for ages and ages. 00:59:48.320 --> 00:59:51.670 And that's why eventually, instead 00:59:51.670 --> 00:59:54.310 of having print in which you have 00:59:54.310 --> 00:59:58.170 a black page with white letters, you now 00:59:58.170 --> 01:00:00.880 a white page with black letters, because that's 01:00:00.880 --> 01:00:04.170 much more economical to achieve. 01:00:04.170 --> 01:00:06.940 And you can read both light incremental 01:00:06.940 --> 01:00:10.400 and light decremental letters equally well 01:00:10.400 --> 01:00:13.570 because we have these ON and OFF channels. 01:00:13.570 --> 01:00:14.230 OK. 01:00:14.230 --> 01:00:17.800 So on the basis of this then, we are 01:00:17.800 --> 01:00:24.460 ready to summarize why we have this remarkable duality 01:00:24.460 --> 01:00:30.540 in the retina, originating in the ON and OFF channels, 01:00:30.540 --> 01:00:32.820 whose circuits we by now, I presume, 01:00:32.820 --> 01:00:35.060 you understand pretty well. 01:00:35.060 --> 01:00:37.890 So just to reiterate for the umpteenth time, which 01:00:37.890 --> 01:00:40.622 is easy to remember by now, all photoreceptors 01:00:40.622 --> 01:00:42.510 hyperpolarize to light. 01:00:42.510 --> 01:00:47.390 Secondly, the cone driven ON and OFF channels 01:00:47.390 --> 01:00:51.120 originate at the level of the retinal bipolar cells. 01:00:51.120 --> 01:00:51.730 OK? 01:00:51.730 --> 01:00:54.270 For ON bipolars you have a system, 01:00:54.270 --> 01:00:56.785 which involves sign-inverting synapses. 01:00:57.870 --> 01:00:58.910 OK? 01:00:58.910 --> 01:01:03.686 The neuron transmitted by the way of the photoreceptors 01:01:03.686 --> 01:01:05.500 is glutamate. 01:01:05.500 --> 01:01:13.090 And you come to the receptor sites-- the mGluR6 receptor is 01:01:13.090 --> 01:01:20.050 the one that inverts the signal for the ON bipolar cells. 01:01:21.110 --> 01:01:27.450 And the mGluR1 and 2 is the neurotransmitter receptor site 01:01:27.450 --> 01:01:30.710 for the OFF bipolar cells. 01:01:30.710 --> 01:01:33.500 Now APB-- can important to remember 01:01:33.500 --> 01:01:35.880 this-- is that glutamate analog. 01:01:35.880 --> 01:01:38.980 A lot of people make a mistake and think it's an antagonist. 01:01:38.980 --> 01:01:40.900 It's a glutamate analog. 01:01:40.900 --> 01:01:44.515 So what happens is that it blocks the ON bipolar. 01:01:44.515 --> 01:01:47.850 Now let me say just a couple more words about this. 01:01:51.060 --> 01:01:54.960 We move our eyes about three times a second. 01:01:54.960 --> 01:02:02.560 Every time you move your eye some mechanisms in the retina 01:02:02.560 --> 01:02:05.690 wipe the slate clean, so to speak, 01:02:05.690 --> 01:02:09.339 because if it didn't, then the image that 01:02:09.339 --> 01:02:11.380 would fall on the retina after you moved your eye 01:02:11.380 --> 01:02:13.530 would interfere with the image that 01:02:13.530 --> 01:02:15.510 had fallen on the eye beforehand. 01:02:15.510 --> 01:02:18.010 So there's an incredibly rapid system 01:02:18.010 --> 01:02:21.530 that breaks down the molecular arrangement 01:02:21.530 --> 01:02:27.910 of glutamate and many other transmitters in the retina 01:02:27.910 --> 01:02:30.880 so that with each movement of the eye, 01:02:30.880 --> 01:02:32.620 you can see things clearly. 01:02:32.620 --> 01:02:34.830 Now there is an exception to that, of course, 01:02:34.830 --> 01:02:36.720 under extreme conditions. 01:02:36.720 --> 01:02:39.390 We have what is called "after images," 01:02:39.390 --> 01:02:41.450 like when you look at the sun for a while. 01:02:41.450 --> 01:02:45.996 Then you will see an after image lingering on in your eye. 01:02:45.996 --> 01:02:49.690 But under normal illumination conditions, 01:02:49.690 --> 01:02:53.910 the slate is wiped clean with every shift in the eye. 01:02:54.920 --> 01:02:56.290 Quite amazing. 01:02:56.290 --> 01:02:56.790 All right. 01:02:56.790 --> 01:03:00.300 Then APB blocks the ON response of retinal ganglion cells. 01:03:00.300 --> 01:03:02.970 The OFF response and center-surround antagonism 01:03:02.970 --> 01:03:03.990 are unaffected. 01:03:05.430 --> 01:03:08.630 APB blocks lighted responses in the cortex, 01:03:08.630 --> 01:03:11.540 but has no effect on orientation, direction, 01:03:11.540 --> 01:03:13.385 and spatial frequency selectivity. 01:03:15.500 --> 01:03:19.400 APB reduces the sensitivity for light increment, 01:03:19.400 --> 01:03:24.520 and the ON and OFF channels for rods arise in the inner retina. 01:03:24.520 --> 01:03:25.970 And I should add here that there's 01:03:25.970 --> 01:03:31.140 only one kind of rod bipolar, which is the ON-type. 01:03:31.140 --> 01:03:33.070 There are no OFF-type rod biopolars. 01:03:34.080 --> 01:03:41.650 Then in most primates there are only ON rod bipolars. 01:03:41.650 --> 01:03:44.170 The rod ON and OFF channels are created 01:03:44.170 --> 01:03:46.700 in the inner retina by the amacrine cells, 01:03:46.700 --> 01:03:49.750 predominately by the so-called A2 amacrine cell, 01:03:49.750 --> 01:03:50.970 as I told you. 01:03:50.970 --> 01:03:54.090 Lastly, excitatory signals are generated 01:03:54.090 --> 01:03:56.820 for both light increment and for light decrement 01:03:56.820 --> 01:04:00.280 by virtue of the ON and OFF channels. 01:04:00.280 --> 01:04:02.600 So those are the major conclusions 01:04:02.600 --> 01:04:10.380 that we need to make about this remarkable achievement of how 01:04:10.380 --> 01:04:13.780 the visual system works, by virtue of having created 01:04:13.780 --> 01:04:18.820 the ON and the OFF channels, by virtue of having then 01:04:18.820 --> 01:04:23.020 done this, by virtue of creating from a single-ended system 01:04:23.020 --> 01:04:26.050 of the photoreceptors, a double-ended system 01:04:26.050 --> 01:04:28.030 at the level of the bipolar cells. 01:04:28.030 --> 01:04:31.285 So that then is-- sorry how complicated 01:04:31.285 --> 01:04:35.830 it is-- the basic layout of the retina and the ON and OFF 01:04:35.830 --> 01:04:37.030 channels. 01:04:37.030 --> 01:04:42.790 Next time we are going to talk about yet another subdivision 01:04:42.790 --> 01:04:46.260 in retinal ganglion cells-- the so-called midget and parasol 01:04:46.260 --> 01:04:46.840 cells. 01:04:46.840 --> 01:04:49.240 I think I've mentioned to you before that we 01:04:49.240 --> 01:04:53.290 have several different classes of retinal ganglion cells-- 01:04:53.290 --> 01:04:54.320 not just ON and OFF. 01:04:56.030 --> 01:04:59.210 And the so-called midget and parasol cells 01:04:59.210 --> 01:05:01.257 have ON and OFF subdivisions. 01:05:01.257 --> 01:05:02.840 And then there are several other cells 01:05:02.840 --> 01:05:04.256 that do all kinds of other things. 01:05:04.256 --> 01:05:05.950 We will talk about some of those. 01:05:05.950 --> 01:05:09.410 But the overwhelming, largest number of cells in the retina 01:05:09.410 --> 01:05:12.120 are the midget and the parasol, and so they 01:05:12.120 --> 01:05:14.970 deserve the greatest scrutiny as to why 01:05:14.970 --> 01:05:17.040 we have those two systems. 01:05:17.040 --> 01:05:20.140 And that's we are going to discuss the next time. 01:05:20.140 --> 01:05:25.880 So that pretty well finishes what I had to cover today, 01:05:25.880 --> 01:05:28.060 and so if any of you have any questions, 01:05:28.060 --> 01:05:31.680 I will be happy to try to answer them for you, as long as it 01:05:31.680 --> 01:05:34.500 pertains, of course, to the ON and OFF channels. 01:05:34.500 --> 01:05:38.170 Anybody not clear on the rules of how 01:05:38.170 --> 01:05:42.890 APB works-- that it's an analog, that it fills the receptor 01:05:42.890 --> 01:05:46.690 sites of the ON bipolar cells, rendering 01:05:46.690 --> 01:05:50.795 them insensitive to subsequent light stimulation? 01:05:50.795 --> 01:05:53.230 Now I should add maybe one more thing here 01:05:53.230 --> 01:05:57.730 is that unlike the glutamate, which is broken down 01:05:57.730 --> 01:06:02.630 in milliseconds, this artificial substance-- APB-- 01:06:02.630 --> 01:06:05.260 there's no natural optic mechanism for it. 01:06:05.260 --> 01:06:10.810 And so it lingers on, and that's why it is so effective. 01:06:12.310 --> 01:06:15.260 And it has to be washed out of the eye-- you typically 01:06:15.260 --> 01:06:21.330 have to wait 10-- 15 minutes for the eye to return to normal 01:06:21.330 --> 01:06:25.950 because there's no rapid optic mechanism for the APB, 01:06:25.950 --> 01:06:27.765 in contrast to the glutamate. 01:06:33.220 --> 01:06:35.390 Well it sounds like I was reasonably clear. 01:06:36.540 --> 01:06:41.020 I hope you can absorb this and marvel 01:06:41.020 --> 01:06:45.980 at the inventiveness, if you will, of evolution 01:06:45.980 --> 01:06:48.960 to have created this incredible mechanisms that we 01:06:48.960 --> 01:06:49.815 see in the retina. 01:06:49.815 --> 01:06:52.300 It's just dumb-founding. 01:06:52.300 --> 01:06:53.500 Yes, it's just incredible. 01:06:55.500 --> 01:07:01.390 So that then is what we going to finish with today. 01:07:01.390 --> 01:07:03.360 And so I will see you Wednesday, and we 01:07:03.360 --> 01:07:06.600 talk about the midget and parasol systems, which 01:07:06.600 --> 01:07:08.610 is also very interesting, by the way. 01:07:08.610 --> 01:07:10.160 And I hope you've enjoyed hearing 01:07:10.160 --> 01:07:13.560 about what those two systems are for.