1 00:00:00,090 --> 00:00:01,670 The following content is provided 2 00:00:01,670 --> 00:00:03,820 under a Creative Commons license. 3 00:00:03,820 --> 00:00:06,550 Your support will help MIT OpenCourseWare continue 4 00:00:06,550 --> 00:00:10,160 to offer high quality educational resources for free. 5 00:00:10,160 --> 00:00:12,700 To make a donation or to view additional materials 6 00:00:12,700 --> 00:00:16,620 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:16,620 --> 00:00:17,278 at ocw.mit.edu. 8 00:00:25,530 --> 00:00:29,490 PROFESSOR: All right, so now today, the topic 9 00:00:29,490 --> 00:00:34,930 we are going to discuss will be the ON and OFF channels 10 00:00:34,930 --> 00:00:36,230 in the retina. 11 00:00:36,230 --> 00:00:38,420 I will provide you with a brief overview 12 00:00:38,420 --> 00:00:41,250 again of what we have covered before about this, 13 00:00:41,250 --> 00:00:44,640 and then will go on and look at this in some depth. 14 00:00:44,640 --> 00:00:47,590 Now before I start on that, let me just 15 00:00:47,590 --> 00:00:54,120 very briefly mention again that the syllabus-- which 16 00:00:54,120 --> 00:00:55,390 all of you I presume have. 17 00:00:55,390 --> 00:00:59,420 If any of you doesn't have a syllabus-- any one of you 18 00:00:59,420 --> 00:01:04,330 doesn't have a syllabus, we can provide one for you. 19 00:01:04,330 --> 00:01:06,290 What I would like to encourage all of your 20 00:01:06,290 --> 00:01:09,450 again is that you do this so-called preparatory 21 00:01:09,450 --> 00:01:13,630 reading that appears for each session, which 22 00:01:13,630 --> 00:01:16,970 will make it easier for you to follow, 23 00:01:16,970 --> 00:01:20,190 and consequently, also memorize the basic facts 24 00:01:20,190 --> 00:01:21,950 that we are going to be dealing with. 25 00:01:24,150 --> 00:01:29,320 Alright, so therefore let me get started with the so-called ON 26 00:01:29,320 --> 00:01:30,970 and OFF channels. 27 00:01:30,970 --> 00:01:33,750 And what I would like to do first of all 28 00:01:33,750 --> 00:01:37,970 is to tell you what are the major questions we are going 29 00:01:37,970 --> 00:01:41,420 to pose in dealing with this very-- to me at least-- 30 00:01:41,420 --> 00:01:45,080 very interesting question of the ON and OFF channels. 31 00:01:45,080 --> 00:01:47,990 The first prime question you're going to ask 32 00:01:47,990 --> 00:01:52,295 is why did the ON and OFF channels evolve? 33 00:01:53,980 --> 00:01:55,650 What is their function? 34 00:01:56,660 --> 00:01:59,600 As I've already indicated before, 35 00:01:59,600 --> 00:02:07,100 it is rather complicated to have created these two channels, 36 00:02:07,100 --> 00:02:08,960 and therefore there must have been 37 00:02:08,960 --> 00:02:14,590 a great deal of evolutionary pressures to accomplish this. 38 00:02:14,590 --> 00:02:17,130 So that's the prime question we're going to ask. 39 00:02:17,130 --> 00:02:19,040 Now more specifically we're going 40 00:02:19,040 --> 00:02:23,600 to ask how the rods and the cones 41 00:02:23,600 --> 00:02:27,680 are involved in the creation of the ON and OFF channels. 42 00:02:28,840 --> 00:02:31,960 And then you're going to ask how do the ON and OFF 43 00:02:31,960 --> 00:02:34,040 channels contribute to the center 44 00:02:34,040 --> 00:02:38,340 and surround organization of retinal ganglion cells, 45 00:02:38,340 --> 00:02:42,080 because this has been a big issue among many investigators 46 00:02:42,080 --> 00:02:45,580 over the past 20 or so years. 47 00:02:45,580 --> 00:02:49,160 Then you're going to ask what role do these channels play 48 00:02:49,160 --> 00:02:52,295 in giving rise to the transforms that we had discussed 49 00:02:52,295 --> 00:02:54,780 the last time in visual cortex. 50 00:02:54,780 --> 00:02:56,550 And lastly we're going to ask what 51 00:02:56,550 --> 00:03:00,160 are the consequences of blocking the ON channel 52 00:03:00,160 --> 00:03:02,705 on neuronal activity and on perception. 53 00:03:03,990 --> 00:03:05,810 And this last question then will be 54 00:03:05,810 --> 00:03:08,710 successful in answering several of the questions 55 00:03:08,710 --> 00:03:13,650 that we pose as to why we have these curious arrangement of ON 56 00:03:13,650 --> 00:03:15,460 and OFF channels in the retina. 57 00:03:15,460 --> 00:03:16,000 All right. 58 00:03:16,000 --> 00:03:21,360 So now let me first of all talk about the neuronal responses-- 59 00:03:21,360 --> 00:03:25,850 sorry-- of the ON and OFF retinal ganglion cells. 60 00:03:28,020 --> 00:03:30,890 First of all, if you remember, I told you 61 00:03:30,890 --> 00:03:37,830 that back in the 19th century, Keffer Hartline 62 00:03:37,830 --> 00:03:40,510 was the first to record from single neurons 63 00:03:40,510 --> 00:03:44,430 by dissecting single fires in the optic nerve. 64 00:03:44,430 --> 00:03:47,720 And then what he did-- he shone light into the eye. 65 00:03:49,510 --> 00:03:51,740 And then subsequently-- especially when 66 00:03:51,740 --> 00:03:54,210 I talked the last time about Hubel and Wiesel-- 67 00:03:54,210 --> 00:03:57,010 what was done is to use reflected light. 68 00:03:57,010 --> 00:03:59,720 And most currently we using reflected light 69 00:03:59,720 --> 00:04:05,490 by presenting images on a computer monitor facing 70 00:04:05,490 --> 00:04:08,100 the animal or the human we are studying. 71 00:04:08,100 --> 00:04:10,610 Now when Keffer Hartline did this 72 00:04:10,610 --> 00:04:13,700 by shining light into the eye, he 73 00:04:13,700 --> 00:04:16,860 noticed that there are some says which are called ON cells, 74 00:04:16,860 --> 00:04:19,670 some cells that are OFF cells, and some cells which 75 00:04:19,670 --> 00:04:21,490 are both ON and OFF. 76 00:04:21,490 --> 00:04:25,040 Now his idea at that time was, using that method, 77 00:04:25,040 --> 00:04:28,570 that ON cells discharge when a stimulus came on 78 00:04:28,570 --> 00:04:30,430 in the visual field, and OFF cells 79 00:04:30,430 --> 00:04:32,430 signaled their termination. 80 00:04:32,430 --> 00:04:34,080 That was his idea, and that's why 81 00:04:34,080 --> 00:04:35,635 I call them ON and OFF cells. 82 00:04:36,790 --> 00:04:43,420 So subsequently, especially when reflected the light was used, 83 00:04:43,420 --> 00:04:48,130 a different view had emerged as to what 84 00:04:48,130 --> 00:04:51,030 might be the reason for having these kinds of cells. 85 00:04:51,030 --> 00:04:56,600 And this was further enhanced by the beautiful findings 86 00:04:56,600 --> 00:04:58,720 of Kuffler, when he noticed that there 87 00:04:58,720 --> 00:05:02,000 was center-surround organization in these cells 88 00:05:02,000 --> 00:05:05,280 at the so-called ON, OFF, and ON/OFF cells 89 00:05:05,280 --> 00:05:07,110 responded vigorously when a light was 90 00:05:07,110 --> 00:05:10,560 shown into the center, but responded less 91 00:05:10,560 --> 00:05:13,580 when the light shown into the surround. 92 00:05:13,580 --> 00:05:16,160 So then people began to do all kinds of experiments 93 00:05:16,160 --> 00:05:19,360 to try to study this in further detail, and one of them 94 00:05:19,360 --> 00:05:23,310 was to use reflected light, either by using a projector 95 00:05:23,310 --> 00:05:25,550 or by using a color monitor. 96 00:05:25,550 --> 00:05:29,020 And when they did that-- I'm going to show this to you 97 00:05:29,020 --> 00:05:31,640 schematically-- they found that if you 98 00:05:31,640 --> 00:05:34,740 had a certain lit background like we have here, 99 00:05:34,740 --> 00:05:36,770 you could present the stimulus either by virtue 100 00:05:36,770 --> 00:05:39,712 of light increment or by virtue of light decrement. 101 00:05:39,712 --> 00:05:43,000 And as I had mentioned to you before, 102 00:05:43,000 --> 00:05:44,740 the visual system is dramatically 103 00:05:44,740 --> 00:05:47,860 different from the other senses that we have in 104 00:05:47,860 --> 00:05:54,330 that we need to be able to see dark stimuli in a background, 105 00:05:54,330 --> 00:05:59,500 like letters on a page, as well as light incremental stimuli. 106 00:05:59,500 --> 00:06:03,530 And so this idea then, if it's selected that way 107 00:06:03,530 --> 00:06:05,080 schematically, looks like this. 108 00:06:05,080 --> 00:06:08,870 An ON cell will fire vigorously when a bright spot 109 00:06:08,870 --> 00:06:13,300 appears in the center, and will not fire to a dark spot. 110 00:06:13,300 --> 00:06:15,720 If anything, it'll be slightly inhibited. 111 00:06:15,720 --> 00:06:16,450 OK? 112 00:06:16,450 --> 00:06:20,910 By contrast, when you look at an OFF cell, you get inverse. 113 00:06:20,910 --> 00:06:21,945 It fires vigorously. 114 00:06:21,945 --> 00:06:26,030 If you would, it gets excited by a dark spot. 115 00:06:26,030 --> 00:06:29,090 It gets excited by the detriment in light illumination. 116 00:06:30,530 --> 00:06:33,780 Now if you did the same thing using a much larger spot 117 00:06:33,780 --> 00:06:38,040 of light-- that is shown here-- what you see here 118 00:06:38,040 --> 00:06:40,750 is that the center-surround antagonism 119 00:06:40,750 --> 00:06:42,760 that we talked about fully applies 120 00:06:42,760 --> 00:06:45,540 to this kind of stimulation conditions as well. 121 00:06:45,540 --> 00:06:48,890 Use a large spot, bright spot, or dark spot 122 00:06:48,890 --> 00:06:51,100 and you see that the over responses 123 00:06:51,100 --> 00:06:57,300 of the cells-- the responses are much more limited than when 124 00:06:57,300 --> 00:07:00,750 you confine the simulation to the center, only 125 00:07:00,750 --> 00:07:04,710 further emphasizing this important fact 126 00:07:04,710 --> 00:07:07,150 about center-surround antagonism-- 127 00:07:07,150 --> 00:07:11,860 this incredible increasing complexity of the organization 128 00:07:11,860 --> 00:07:15,120 of neurons that you see already in the retina. 129 00:07:15,120 --> 00:07:18,290 OK, so now we are going to next look 130 00:07:18,290 --> 00:07:21,550 at the anatomy of the ON and OFF ganglion cells. 131 00:07:21,550 --> 00:07:25,880 And as we look at these various ways of studying the ON and OFF 132 00:07:25,880 --> 00:07:30,200 channels, we are gradually going to understand 133 00:07:30,200 --> 00:07:33,830 what these two systems are really for. 134 00:07:33,830 --> 00:07:41,050 So the first thing is to use this method that I had also 135 00:07:41,050 --> 00:07:44,630 already described, namely that you can record intracellularly 136 00:07:44,630 --> 00:07:49,610 from a cell, understand its functional responses, 137 00:07:49,610 --> 00:07:52,380 and then you can inject a label, and then 138 00:07:52,380 --> 00:07:55,040 you can process that anatomically 139 00:07:55,040 --> 00:07:56,570 to see what it looks like. 140 00:07:56,570 --> 00:08:00,760 So when this was done, a very interesting new finding 141 00:08:00,760 --> 00:08:03,190 had emerged, which is depicted here. 142 00:08:03,190 --> 00:08:08,350 Here we have the photoreceptors-- 143 00:08:08,350 --> 00:08:10,810 just the tail end of them, if you will-- that 144 00:08:10,810 --> 00:08:13,510 connect to the bipolar cells. 145 00:08:13,510 --> 00:08:15,340 Two bipolar cells are shown. 146 00:08:15,340 --> 00:08:20,060 And then they project into the inner plexiform layer, which 147 00:08:20,060 --> 00:08:22,840 we often just refer to as IPL, which 148 00:08:22,840 --> 00:08:27,420 is subdivided into two parts-- A and B. 149 00:08:27,420 --> 00:08:32,559 And it was shown that the majority of cells 150 00:08:32,559 --> 00:08:37,299 arborize in either one or the other of these two sublamina 151 00:08:37,299 --> 00:08:40,495 in the inner plexiform layer. 152 00:08:41,570 --> 00:08:44,500 But there were also some cells, which is not shown here, 153 00:08:44,500 --> 00:08:49,360 that had arborization in both of these lamina, 154 00:08:49,360 --> 00:08:52,570 and that's to anticipate actually 155 00:08:52,570 --> 00:08:56,090 the property of those cells, which are called the ON/OFF 156 00:08:56,090 --> 00:08:57,200 cells. 157 00:08:57,200 --> 00:09:00,960 Now furthermore, it was found-- because these cells were 158 00:09:00,960 --> 00:09:05,840 labeled after recording-- that the cells that arborized 159 00:09:05,840 --> 00:09:08,980 in subliminal A, or the inner plexiform layer, 160 00:09:08,980 --> 00:09:13,260 were so-called OFF cells, and those that arborized 161 00:09:13,260 --> 00:09:15,860 in subliminal B, like this one here, 162 00:09:15,860 --> 00:09:20,490 and this one here, and this one here, were ON cells. 163 00:09:20,490 --> 00:09:21,690 OK? 164 00:09:21,690 --> 00:09:25,710 So there was a distinct spatial segregation 165 00:09:25,710 --> 00:09:30,350 into the lamina of those retinal ganglion cells that 166 00:09:30,350 --> 00:09:33,470 were ON and OFF, and also furthermore, 167 00:09:33,470 --> 00:09:35,570 those that were ON/OFF because they 168 00:09:35,570 --> 00:09:38,870 had arborization in both of them. 169 00:09:38,870 --> 00:09:40,890 So that was the basic finding. 170 00:09:40,890 --> 00:09:43,350 Now when that was discovered, people 171 00:09:43,350 --> 00:09:44,930 went on and asked the question, what 172 00:09:44,930 --> 00:09:49,050 is the spacial arrangement of these cells 173 00:09:49,050 --> 00:09:51,320 on the retinal surface, if you will. 174 00:09:51,320 --> 00:09:58,980 And so experiments were done in which cells were labeled, 175 00:09:58,980 --> 00:10:02,120 in most cases with the Golgi stain, 176 00:10:02,120 --> 00:10:05,850 and then the retina was looked at head on with a microscope. 177 00:10:05,850 --> 00:10:07,960 Now the interesting thing about a microscope is, 178 00:10:07,960 --> 00:10:09,610 which all of you I'm sure know, is 179 00:10:09,610 --> 00:10:12,220 that the higher the magnification 180 00:10:12,220 --> 00:10:18,670 that you use, the shorter the focus of the microscope. 181 00:10:18,670 --> 00:10:20,920 And in fact, what you can do here 182 00:10:20,920 --> 00:10:22,490 is when you look at his head I like 183 00:10:22,490 --> 00:10:28,690 that, if you can focus either in sublamina A or sublamina B, 184 00:10:28,690 --> 00:10:32,260 and if you do that, since we had gotten these results, 185 00:10:32,260 --> 00:10:39,180 you know that whatever focuses into sublamina A would be OFF 186 00:10:39,180 --> 00:10:42,340 cells, and whatever comes into focus 187 00:10:42,340 --> 00:10:44,590 and the [INAUDIBLE] is coming to focus in B, 188 00:10:44,590 --> 00:10:47,710 would be the ON cells. 189 00:10:47,710 --> 00:10:51,320 So then what was done by a fellow 190 00:10:51,320 --> 00:10:54,190 called Heinz Wesley is he asked a question, what 191 00:10:54,190 --> 00:10:56,960 is the spacial arrangement of these two? 192 00:10:56,960 --> 00:11:00,120 Do they respect each other, or what? 193 00:11:00,120 --> 00:11:02,870 And so when he did that, here is a good example 194 00:11:02,870 --> 00:11:04,090 of what that looks like. 195 00:11:04,090 --> 00:11:07,840 Here we have labeled both the ON and OFF cells using the two 196 00:11:07,840 --> 00:11:09,822 depth of [INAUDIBLE], and you can 197 00:11:09,822 --> 00:11:11,280 see they're kind of helter skelter. 198 00:11:12,310 --> 00:11:16,960 Then if he focus deeper, he focus only in the ON cells. 199 00:11:16,960 --> 00:11:20,230 It looks like a they're very, very nicely arranged, 200 00:11:20,230 --> 00:11:22,470 and that's also true for the OFF cells. 201 00:11:22,470 --> 00:11:24,600 And they respect each other. 202 00:11:24,600 --> 00:11:26,580 Looking at the dendritic arbors, there's 203 00:11:26,580 --> 00:11:30,030 a little overlap among the dendrites themselves 204 00:11:30,030 --> 00:11:31,330 of the cells. 205 00:11:31,330 --> 00:11:36,380 So what's this then said is that the ON cells respect each other 206 00:11:36,380 --> 00:11:39,680 but don't seem to give a damn about the OFF cells. 207 00:11:39,680 --> 00:11:42,170 And the reverse applied to the OFF cells. 208 00:11:42,170 --> 00:11:43,190 OK? 209 00:11:43,190 --> 00:11:46,325 So as if there were two independent entities. 210 00:11:47,350 --> 00:11:49,165 So that was a very interesting finding. 211 00:11:50,690 --> 00:11:54,250 And so that was one of the initial cues saying 212 00:11:54,250 --> 00:11:57,950 that these ON and OFF cells do different things, 213 00:11:57,950 --> 00:12:02,950 and each is a devoted entity to what it does. 214 00:12:02,950 --> 00:12:08,050 All right so now to understand this even better, let's go back 215 00:12:08,050 --> 00:12:12,380 and take a brief overview of the retinal connections 216 00:12:12,380 --> 00:12:14,990 so we can understand how these systems came about. 217 00:12:16,190 --> 00:12:20,080 And the first thing to do is to talk about the photoreceptor 218 00:12:20,080 --> 00:12:20,750 basics. 219 00:12:20,750 --> 00:12:23,530 And I told you many times-- by now I'm sure all of you 220 00:12:23,530 --> 00:12:27,026 know that already-- that all photoreceptors hyperpolarize 221 00:12:27,026 --> 00:12:28,230 to light. 222 00:12:28,230 --> 00:12:34,320 Then I also told you when photoreceptors depolarize-- 223 00:12:34,320 --> 00:12:36,915 that's when they release their neurotransmitter, which 224 00:12:36,915 --> 00:12:38,190 is glutamate. 225 00:12:38,190 --> 00:12:41,530 And that glutamate acts on both the horizontal cells 226 00:12:41,530 --> 00:12:43,100 and the bipolar cells. 227 00:12:43,100 --> 00:12:46,890 And then furthermore, just to look in the details-- 228 00:12:46,890 --> 00:12:50,499 this you don't need to remember exactly in these words-- photon 229 00:12:50,499 --> 00:12:52,790 absorption by the photopigment results in isomerization 230 00:12:52,790 --> 00:12:56,490 of the chromophore from 11-cis to all-trans. 231 00:12:56,490 --> 00:12:59,990 To all-trans this causes hyperpolarization, thereby 232 00:12:59,990 --> 00:13:02,280 reducing neurotransmitter release. 233 00:13:02,280 --> 00:13:05,040 But what you do need to remember is the next step, 234 00:13:05,040 --> 00:13:07,120 which says the same thing in much simpler words. 235 00:13:07,120 --> 00:13:10,340 It says that the two classes of bipolars, 236 00:13:10,340 --> 00:13:14,240 the ON and the OFF, synaptic junction of the OFF bipolars 237 00:13:14,240 --> 00:13:17,710 is sign conserving, and that of the ON bipolars 238 00:13:17,710 --> 00:13:19,600 is sign inverting. 239 00:13:19,600 --> 00:13:22,250 And so as I've told you the last time, as you hyperpolarize 240 00:13:22,250 --> 00:13:24,610 and depolarize the photoreceptor, 241 00:13:24,610 --> 00:13:27,520 an OFF bipolar cell does the same thing like this, 242 00:13:27,520 --> 00:13:30,300 but the ON bipolar does the opposite, OK? 243 00:13:30,300 --> 00:13:34,020 So you created a two-ended system-- 244 00:13:34,020 --> 00:13:37,603 a double-ended system, if you will-- from a single-ended one 245 00:13:37,603 --> 00:13:39,103 that you have in the photoreceptors. 246 00:13:40,290 --> 00:13:44,790 Now, yet another fact that is important to remember 247 00:13:44,790 --> 00:13:48,430 is that the ON bipolar cell receptor is mGluR6. 248 00:13:49,710 --> 00:13:55,770 That is a specific molecule that exists in most animals, 249 00:13:55,770 --> 00:14:00,710 only in the retina, created anew in the course of evolution, 250 00:14:00,710 --> 00:14:02,870 indicating what considerable pressure there 251 00:14:02,870 --> 00:14:06,650 had to be able to have an ON system. 252 00:14:06,650 --> 00:14:09,940 And lastly I should add here also that the OFF bipolar 253 00:14:09,940 --> 00:14:15,530 receptors are mGlueR1 and 2 and they follow, pretty much, 254 00:14:15,530 --> 00:14:19,000 the way the photoreceptors respond, 255 00:14:19,000 --> 00:14:20,850 which means that their activation leads 256 00:14:20,850 --> 00:14:23,070 to the opening of channels, causing depolarization. 257 00:14:24,610 --> 00:14:27,270 And of course you all know that-- I should restate maybe 258 00:14:27,270 --> 00:14:32,150 once more-- that when neurons in the retina that had greater 259 00:14:32,150 --> 00:14:35,100 potentials, when they depolarize, 260 00:14:35,100 --> 00:14:36,820 neurotransmitters released. 261 00:14:36,820 --> 00:14:40,280 When they hyperpolarize, they do not release them. 262 00:14:40,280 --> 00:14:42,110 In anything, they stop releasing them. 263 00:14:42,110 --> 00:14:42,610 OK. 264 00:14:42,610 --> 00:14:50,040 So now let's look at this wiring again in more graphic detail. 265 00:14:50,040 --> 00:14:52,905 Here we have a cone. 266 00:14:54,080 --> 00:14:57,630 And the fact is that in central retina, 267 00:14:57,630 --> 00:15:02,680 each cone connects with at least two bipolar cells. 268 00:15:02,680 --> 00:15:05,170 So in other words, in the retina there are many, many more 269 00:15:05,170 --> 00:15:08,090 bipolars than there are photoreceptors, 270 00:15:08,090 --> 00:15:10,240 which is amazing if you think about the numbers. 271 00:15:10,240 --> 00:15:12,010 I don't know if you remember the numbers. 272 00:15:12,010 --> 00:15:17,640 I told you there are more than 50 million cones, and maybe 273 00:15:17,640 --> 00:15:20,470 150 million rods, in the retina. 274 00:15:20,470 --> 00:15:23,620 So the retina is an unbelievably complex structure 275 00:15:23,620 --> 00:15:26,645 with millions and millions and millions of cells. 276 00:15:27,960 --> 00:15:28,460 All right. 277 00:15:28,460 --> 00:15:31,920 So what happens then-- you create these ON and OFF bipolar 278 00:15:31,920 --> 00:15:32,835 cells. 279 00:15:32,835 --> 00:15:36,490 The OFF ones, by virtue are sign conserving synapse. 280 00:15:36,490 --> 00:15:39,620 The OFF, by virtue, are sign conserving synapse. 281 00:15:39,620 --> 00:15:44,395 And they connect with two basic classes of ganglion cells-- 282 00:15:44,395 --> 00:15:46,620 the ON and the OFF. 283 00:15:46,620 --> 00:15:50,850 So the ON and OFF signals, in large part, 284 00:15:50,850 --> 00:15:53,310 then are sent separately, especially 285 00:15:53,310 --> 00:15:55,200 to the [INAUDIBLE] nucleus. 286 00:15:55,200 --> 00:15:57,000 But let's not forget that they also 287 00:15:57,000 --> 00:16:00,430 have the so-called ON/OFF cells. 288 00:16:00,430 --> 00:16:04,120 And many of them actually end up projecting the colliculus, 289 00:16:04,120 --> 00:16:06,140 as we'll talk about later on. 290 00:16:06,140 --> 00:16:08,120 So this is a very basic wiring. 291 00:16:08,120 --> 00:16:10,980 They can then add here, as I've already said. 292 00:16:10,980 --> 00:16:13,070 This is sign inverting synapse. 293 00:16:13,070 --> 00:16:15,290 This is sign-conserving sign conserving synapse. 294 00:16:15,290 --> 00:16:16,950 And then we can add the fact that we 295 00:16:16,950 --> 00:16:22,700 have horizontal cells that collect signals going sideways 296 00:16:22,700 --> 00:16:27,220 on the retinal surface, thereby creating-- 297 00:16:27,220 --> 00:16:32,700 hypothetically speaking, at least-- the surround effect, 298 00:16:32,700 --> 00:16:36,360 although that we will look at in just a minute in more detail 299 00:16:36,360 --> 00:16:39,800 because some people had proposed-- many hypotheses had 300 00:16:39,800 --> 00:16:41,720 emerged why we have ON and OFF channels-- 301 00:16:41,720 --> 00:16:43,910 and a lot of the hypotheses was to create 302 00:16:43,910 --> 00:16:46,940 this famous center-surround antagonism 303 00:16:46,940 --> 00:16:49,580 that you see in the retinal ganglion cells. 304 00:16:49,580 --> 00:16:51,960 I'll have a model for that in a minute. 305 00:16:51,960 --> 00:16:54,880 OK, so here we have the ON and OFF systems. 306 00:16:54,880 --> 00:16:56,510 And again I want to point out to you 307 00:16:56,510 --> 00:17:01,880 that they terminate in different sublamina, the inner plexiform 308 00:17:01,880 --> 00:17:07,170 layer-- the ON in sublamina B and the OFF in sublamina A, 309 00:17:07,170 --> 00:17:11,040 whereas the ON/OFF system looks something like this. 310 00:17:11,040 --> 00:17:13,240 It has dendritic arbors. 311 00:17:13,240 --> 00:17:17,130 They are ON/OFF ganglion cell in both layers, 312 00:17:17,130 --> 00:17:20,690 and connects to both the ON and the OFF like that. 313 00:17:20,690 --> 00:17:22,930 So that's how you create these three 314 00:17:22,930 --> 00:17:25,800 types of cells at the very simple level. 315 00:17:25,800 --> 00:17:30,700 Now the issue that I just to referred to 316 00:17:30,700 --> 00:17:33,710 is how is this surround mechanism created. 317 00:17:33,710 --> 00:17:37,310 One hypothesis is that it's created 318 00:17:37,310 --> 00:17:39,150 by virtue of the horizontal cells 319 00:17:39,150 --> 00:17:41,510 predominantly, as shown in this figure, which 320 00:17:41,510 --> 00:17:43,770 is pretty much what you had seen before. 321 00:17:43,770 --> 00:17:48,900 So the surround is created by the horizontal cell network. 322 00:17:48,900 --> 00:17:52,700 An alternative hypothesis that was for a while popular 323 00:17:52,700 --> 00:17:56,090 was that actually the reason we have ON or OFF channels 324 00:17:56,090 --> 00:17:59,590 is to create the surround antagonism in retinal ganglion 325 00:17:59,590 --> 00:18:02,355 cells by using this kind of wiring arrangement. 326 00:18:04,119 --> 00:18:05,910 I'm not going to go into details about this 327 00:18:05,910 --> 00:18:07,460 because to anticipate what I'm going 328 00:18:07,460 --> 00:18:13,180 to tell you is that this model does not seem to be correct, 329 00:18:13,180 --> 00:18:15,330 and that of course is often the case. 330 00:18:15,330 --> 00:18:17,220 We have many, many different models 331 00:18:17,220 --> 00:18:20,060 and then one of our tasks is to try 332 00:18:20,060 --> 00:18:22,305 to figure out which one is correct. 333 00:18:22,305 --> 00:18:23,937 And you know what often happens is 334 00:18:23,937 --> 00:18:25,520 that if three models are correct, well 335 00:18:25,520 --> 00:18:27,561 there's a fourth one you didn't even think about. 336 00:18:27,561 --> 00:18:30,870 So that sometimes happens, and especially 337 00:18:30,870 --> 00:18:32,460 when you study the brain. 338 00:18:32,460 --> 00:18:33,000 All right. 339 00:18:33,000 --> 00:18:35,615 So now we are going to move on. 340 00:18:37,260 --> 00:18:42,380 This is, unless you had read the preparatory material, 341 00:18:42,380 --> 00:18:45,730 is something that may puzzle you-- 342 00:18:45,730 --> 00:18:48,170 the effects of APB on the responses 343 00:18:48,170 --> 00:18:50,540 of neurons in the visual system. 344 00:18:50,540 --> 00:18:55,060 So now I'm going to ask you guys as to how many of you actually 345 00:18:55,060 --> 00:18:56,640 know what APB is. 346 00:18:58,370 --> 00:19:00,010 Oh, I see all these hands raised. 347 00:19:00,010 --> 00:19:00,635 Oh my goodness. 348 00:19:02,520 --> 00:19:03,060 All right. 349 00:19:03,060 --> 00:19:05,860 So nobody knows what the APB is. 350 00:19:05,860 --> 00:19:06,360 That's good. 351 00:19:06,360 --> 00:19:09,770 So that way you are going to learn something brand new. 352 00:19:09,770 --> 00:19:13,490 But if you get a chance and read the preparatory material, 353 00:19:13,490 --> 00:19:18,010 then it will be easier for to remember these many, many facts 354 00:19:18,010 --> 00:19:22,020 that I'm going to try to impart on you with each lecture. 355 00:19:22,020 --> 00:19:24,120 All right, so APB. 356 00:19:24,120 --> 00:19:30,100 APB stands for an artificial molecule called 357 00:19:30,100 --> 00:19:34,180 2-amino-4-phosphonobutyric acid. 358 00:19:34,180 --> 00:19:38,192 And to show that to you in some detail, it is shown here-- 359 00:19:38,192 --> 00:19:39,400 2-amino-4-phosphonobuterate . 360 00:19:42,670 --> 00:19:45,640 Butyrate-- "ate," as you know, stands for acid. 361 00:19:45,640 --> 00:19:46,390 OK? 362 00:19:46,390 --> 00:19:50,100 So this molecule, as I mentioned to you before, 363 00:19:50,100 --> 00:19:54,690 was invented, if you will, by Watkins and Evans 364 00:19:54,690 --> 00:19:57,640 in England, who are molecular biologists. 365 00:19:57,640 --> 00:20:03,600 And their game, as I mentioned, is to create new molecules-- 366 00:20:03,600 --> 00:20:07,216 and many of which are either analogs or antagonists 367 00:20:07,216 --> 00:20:08,090 of neurotransmitters. 368 00:20:09,110 --> 00:20:12,340 Now this is a glutamate neurotransmitter 369 00:20:12,340 --> 00:20:17,270 that is discharged by many, many cells in the brain, 370 00:20:17,270 --> 00:20:18,650 including your photoreceptors. 371 00:20:19,960 --> 00:20:21,650 So this is a variant of that. 372 00:20:21,650 --> 00:20:27,530 Now once this molecule was invented, or created, 373 00:20:27,530 --> 00:20:30,210 I should say perhaps, people began 374 00:20:30,210 --> 00:20:34,250 to ask the question, well what is this variant? 375 00:20:34,250 --> 00:20:35,940 What can they do for us? 376 00:20:35,940 --> 00:20:38,700 And that was the basic game they all played. 377 00:20:38,700 --> 00:20:41,360 You create molecule after molecule after molecule, 378 00:20:41,360 --> 00:20:45,400 and then you test them to see whether they can tell you 379 00:20:45,400 --> 00:20:49,610 something useful in studying the brain. 380 00:20:49,610 --> 00:20:53,160 And it turns out that there's-- I've mentioned before also-- 381 00:20:53,160 --> 00:20:56,480 most of those molecules you can throw into the waste paper 382 00:20:56,480 --> 00:20:57,370 basket. 383 00:20:57,370 --> 00:21:01,710 But the few of them come out and become very, very useful. 384 00:21:01,710 --> 00:21:03,460 And this one here-- that's the reason 385 00:21:03,460 --> 00:21:07,290 I'm mentioning it to you-- this APB turned out 386 00:21:07,290 --> 00:21:09,560 to be a magic bullet. 387 00:21:09,560 --> 00:21:12,860 First of all-- you should remember this-- 388 00:21:12,860 --> 00:21:15,290 that this a neurotransmitter analog. 389 00:21:17,220 --> 00:21:23,360 So what happens is in a way it acts like glutamate, 390 00:21:23,360 --> 00:21:29,270 but it acts really specifically on the neurotransmitter 391 00:21:29,270 --> 00:21:33,230 sites of the ON bipolar cells. 392 00:21:33,230 --> 00:21:41,180 And what it does-- it fills the receptor site, 393 00:21:41,180 --> 00:21:45,310 which then makes those neurons insensitive 394 00:21:45,310 --> 00:21:47,045 to subsequent light stimulation. 395 00:21:48,190 --> 00:21:48,770 All right? 396 00:21:48,770 --> 00:21:51,350 So this then is a remarkable molecule. 397 00:21:51,350 --> 00:21:55,350 And consequently, people began to do all sorts of experiments. 398 00:21:55,350 --> 00:21:59,450 And it was discovered that when this substance was applied 399 00:21:59,450 --> 00:22:06,710 to the retina, indeed shining light into the receptor 400 00:22:06,710 --> 00:22:11,750 fields of cells failed to elicit a response. 401 00:22:11,750 --> 00:22:17,750 But by contrast, when as part of dark stimulus 402 00:22:17,750 --> 00:22:20,040 was present in the receptor field, 403 00:22:20,040 --> 00:22:21,980 the cells continued to fire. 404 00:22:21,980 --> 00:22:26,130 So that was a basic finding, and so a method was developed 405 00:22:26,130 --> 00:22:28,490 to study this in the monkey. 406 00:22:28,490 --> 00:22:30,412 And let me show you what the method is 407 00:22:30,412 --> 00:22:31,870 so you can get a sense of what it's 408 00:22:31,870 --> 00:22:33,740 like to do experiments like this. 409 00:22:33,740 --> 00:22:36,770 So the method was to put two tubes 410 00:22:36,770 --> 00:22:40,640 into the eye of an anesthetized, paralyzed animal, through one 411 00:22:40,640 --> 00:22:43,510 of which you could infuse a substance, 412 00:22:43,510 --> 00:22:45,785 and through the other which the substance could exit. 413 00:22:46,970 --> 00:22:50,540 Because if there were no exiting and you fuse something in here, 414 00:22:50,540 --> 00:22:52,710 the eye would swell up, so to speak, 415 00:22:52,710 --> 00:22:54,575 and it would kill the cells in the eye. 416 00:22:54,575 --> 00:22:56,740 So you got to circulate it. 417 00:22:56,740 --> 00:23:00,480 So what you have to do also is to take the vitreous humor 418 00:23:00,480 --> 00:23:04,180 and make sure that-- you know that's a jelly-like substance-- 419 00:23:04,180 --> 00:23:08,890 to make it so that it was fluid enough to come out of this tube 420 00:23:08,890 --> 00:23:10,130 here, as well. 421 00:23:10,130 --> 00:23:17,890 So then you could present to the eye either a solution that 422 00:23:17,890 --> 00:23:21,390 had no effect on anything, because you made 423 00:23:21,390 --> 00:23:25,430 that solution with enough molecular substances 424 00:23:25,430 --> 00:23:28,050 similar to what's in the vitreous already. 425 00:23:28,050 --> 00:23:28,850 OK? 426 00:23:28,850 --> 00:23:30,540 And then what you could do is you 427 00:23:30,540 --> 00:23:33,050 could switch over using this same substance 428 00:23:33,050 --> 00:23:35,510 and add a little bit of APB. 429 00:23:35,510 --> 00:23:37,850 Now APB is a very powerful substance 430 00:23:37,850 --> 00:23:43,040 so you need only small amounts of it to have an effect. 431 00:23:43,040 --> 00:23:45,099 And then what you did is you recorded 432 00:23:45,099 --> 00:23:46,890 from either the lateral geniculate nucleus, 433 00:23:46,890 --> 00:23:49,300 in this case, or from the optic nerve fibers, 434 00:23:49,300 --> 00:23:51,450 or from the visual cortex. 435 00:23:51,450 --> 00:23:54,650 And so now you have this magic bullet, 436 00:23:54,650 --> 00:23:57,510 and first, however, you want to determine, is it true. 437 00:23:57,510 --> 00:24:01,370 What has been found originally in the mutt puppy-- is it also 438 00:24:01,370 --> 00:24:03,540 true in the monkey? 439 00:24:03,540 --> 00:24:07,860 If you inject this APB into the eye of a monkey, 440 00:24:07,860 --> 00:24:13,980 do you really stop the responses of ON-center cells 441 00:24:13,980 --> 00:24:16,206 to view light visual stimulation, 442 00:24:16,206 --> 00:24:17,455 light incremental stimulation. 443 00:24:18,780 --> 00:24:21,870 And the answer is lucky B-- because otherwise I 444 00:24:21,870 --> 00:24:23,810 wouldn't be telling you this, of course-- 445 00:24:23,810 --> 00:24:25,280 is that the answer is yes. 446 00:24:25,280 --> 00:24:29,720 So here is an example of taking a response. 447 00:24:29,720 --> 00:24:31,850 These are cumulative histograms, OK? 448 00:24:31,850 --> 00:24:34,760 You've turned the light on, and then turned it off. 449 00:24:34,760 --> 00:24:37,130 And you can see here's an ON-center cell responds 450 00:24:37,130 --> 00:24:39,380 vigorously under normal conditions. 451 00:24:39,380 --> 00:24:43,210 You put APB into the eye, the cell stops responding. 452 00:24:43,210 --> 00:24:46,100 And then when the animal recovers from this, 453 00:24:46,100 --> 00:24:48,980 you wash it out, so to speak, then the response returns. 454 00:24:50,350 --> 00:24:52,255 By contrast, we do same experiment 455 00:24:52,255 --> 00:24:55,090 in an OFF-center cell, shown on the right. 456 00:24:55,090 --> 00:24:57,580 You see that the cell continues to respond 457 00:24:57,580 --> 00:24:59,445 when you put APB into the eye. 458 00:24:59,445 --> 00:25:02,130 So this is indeed a magic bullet, 459 00:25:02,130 --> 00:25:06,540 which selectively blocks the ON system, 460 00:25:06,540 --> 00:25:10,330 and has no significant effect on the OFF system. 461 00:25:10,330 --> 00:25:14,550 So this then opened the gates to study 462 00:25:14,550 --> 00:25:19,850 what happens when you do these kinds of experiments-- 463 00:25:19,850 --> 00:25:25,300 in this case, in monkeys-- to determine 464 00:25:25,300 --> 00:25:31,010 what might be the function of these two systems. 465 00:25:31,010 --> 00:25:37,220 And so this then enabled one to test the various hypotheses, 466 00:25:37,220 --> 00:25:39,440 which I had mentioned to you briefly before. 467 00:25:39,440 --> 00:25:41,910 The first hypothesis you can ask, 468 00:25:41,910 --> 00:25:45,520 is it true-- as that model I've shown you the right-- 469 00:25:45,520 --> 00:25:49,270 that it is interaction between the ON or OFF systems 470 00:25:49,270 --> 00:25:52,920 that gives rise to the center-surround antagonism 471 00:25:52,920 --> 00:25:54,670 of cells in the retina. 472 00:25:54,670 --> 00:25:56,450 That's one thing you could test. 473 00:25:56,450 --> 00:25:59,020 So to assess that, let me show you 474 00:25:59,020 --> 00:26:02,370 what the experimental procedure is. 475 00:26:02,370 --> 00:26:05,490 What you do here-- here is a receptive field of a cell. 476 00:26:05,490 --> 00:26:09,290 And in this case, this cell-- the recording is taking place 477 00:26:09,290 --> 00:26:13,120 in the geniculate-- and this particular cell 478 00:26:13,120 --> 00:26:18,980 is one that is color selective. 479 00:26:18,980 --> 00:26:22,020 It responds best to a small red spot. 480 00:26:22,020 --> 00:26:25,540 And if you hit the surround with a different color, 481 00:26:25,540 --> 00:26:27,360 the cell is inhibited. 482 00:26:27,360 --> 00:26:30,270 So the way this is then done is you 483 00:26:30,270 --> 00:26:33,070 shine the light on the center, then 484 00:26:33,070 --> 00:26:35,480 you shine the light on the surround, 485 00:26:35,480 --> 00:26:37,430 and then you're in the OFF cycle-- 486 00:26:37,430 --> 00:26:39,750 you just hit the surround alone. 487 00:26:39,750 --> 00:26:46,390 So this then shown to you here over time. 488 00:26:46,390 --> 00:26:47,830 Here's a center stimulation. 489 00:26:47,830 --> 00:26:48,677 Turn it on. 490 00:26:48,677 --> 00:26:49,760 Then you hit the surround. 491 00:26:49,760 --> 00:26:51,470 Then you turn it off. 492 00:26:51,470 --> 00:26:53,610 So because-- and the center stays on, 493 00:26:53,610 --> 00:26:56,270 and during the OFF cycle, you hit the surround. 494 00:26:56,270 --> 00:26:58,600 So this shows the exact manner in which 495 00:26:58,600 --> 00:27:01,191 you turn these on and off. 496 00:27:01,191 --> 00:27:01,690 All right. 497 00:27:01,690 --> 00:27:08,190 So now the big question is, how do ON- and OFF-center cells 498 00:27:08,190 --> 00:27:10,185 respond to this stimulus arrangement. 499 00:27:11,500 --> 00:27:17,275 So say you have an ON cell, which would discharge to this. 500 00:27:19,440 --> 00:27:21,122 Then the response should decrease 501 00:27:21,122 --> 00:27:22,580 because of the surround inhibition. 502 00:27:23,764 --> 00:27:26,237 And you'll see the normal response. 503 00:27:26,237 --> 00:27:27,695 And the question now-- what's going 504 00:27:27,695 --> 00:27:32,167 to happen if you put in the APB? 505 00:27:32,167 --> 00:27:33,875 Well there are a number of possibilities. 506 00:27:35,167 --> 00:27:36,750 One is that nothing's going to happen. 507 00:27:36,750 --> 00:27:39,050 That's unlikely because I already showed you 508 00:27:39,050 --> 00:27:44,350 that APB blocks the ON response of the center. 509 00:27:44,350 --> 00:27:46,240 The other possibility is that you 510 00:27:46,240 --> 00:27:48,940 lose the center-surround antagonism, which 511 00:27:48,940 --> 00:27:56,440 would prove that the ON and OFF systems play a significant role 512 00:27:56,440 --> 00:27:59,330 in creating center-surround antagonism. 513 00:27:59,330 --> 00:27:59,830 All right. 514 00:27:59,830 --> 00:28:02,420 So those are some of the possibilities. 515 00:28:02,420 --> 00:28:04,150 And of course a third possibility 516 00:28:04,150 --> 00:28:10,366 is that the OFF cells also lose their surround antagonism, 517 00:28:10,366 --> 00:28:12,616 although their responses to the center are unaffected. 518 00:28:13,680 --> 00:28:15,130 So let's take a look at that. 519 00:28:16,570 --> 00:28:20,340 And here are the data under normal conditions. 520 00:28:20,340 --> 00:28:23,720 This again is the stimulation arrangement lined up, 521 00:28:23,720 --> 00:28:26,630 but you can see here there's a huge response when 522 00:28:26,630 --> 00:28:29,851 you hit the center with a red spot, 523 00:28:29,851 --> 00:28:31,600 and then when you hit the surround there's 524 00:28:31,600 --> 00:28:33,230 a huge inhibition. 525 00:28:33,230 --> 00:28:36,680 When you remove that, the response returns. 526 00:28:36,680 --> 00:28:38,670 And then during the OFF cycle, there's 527 00:28:38,670 --> 00:28:42,650 some spontaneous activity, but the surround activation even 528 00:28:42,650 --> 00:28:43,830 stops that. 529 00:28:43,830 --> 00:28:46,105 So there's very strong center-surround antagonism. 530 00:28:47,210 --> 00:28:47,710 All right. 531 00:28:47,710 --> 00:28:49,390 So now I want you to guess for a minute. 532 00:28:49,390 --> 00:28:51,890 What do you think is going to happen 533 00:28:51,890 --> 00:28:53,900 when we inject APB into the eye? 534 00:28:55,504 --> 00:28:57,420 Think about it for a minute and I'll tell you. 535 00:29:02,280 --> 00:29:03,910 I listed some of the alternatives, 536 00:29:03,910 --> 00:29:06,219 and you can have a hypothesis of your own 537 00:29:06,219 --> 00:29:07,510 of what you think might happen. 538 00:29:08,540 --> 00:29:10,933 All right let me show you what really happened, OK? 539 00:29:13,300 --> 00:29:17,940 When this happened, actually, the experimenter thought, 540 00:29:17,940 --> 00:29:21,855 my god, we lost a cell while we were recording. 541 00:29:23,520 --> 00:29:27,330 But then, subsequently when the APB was washed out, 542 00:29:27,330 --> 00:29:28,935 you got the same response as before. 543 00:29:29,990 --> 00:29:34,360 And so the cell wasn't lost, but the APB was so effective 544 00:29:34,360 --> 00:29:36,510 that it stopped the response of the cell 545 00:29:36,510 --> 00:29:39,375 completely, both of the center and to the surround. 546 00:29:41,020 --> 00:29:44,070 And now let's ask the question, what happens when you do this, 547 00:29:44,070 --> 00:29:46,740 not to an ON-center cell, but an OFF-center cell. 548 00:29:46,740 --> 00:29:48,630 Think about it again for a minute 549 00:29:48,630 --> 00:29:51,270 and ask what do you think would happen then. 550 00:29:52,320 --> 00:29:54,030 OK, so here it is. 551 00:29:54,030 --> 00:29:56,560 Here is an OFF-center ganglion cell. 552 00:29:56,560 --> 00:30:01,081 And it shows here, using the same stimulus conditions, that 553 00:30:01,081 --> 00:30:02,580 in this case, because there's an OFF 554 00:30:02,580 --> 00:30:05,960 cell, adding the surround decreases 555 00:30:05,960 --> 00:30:08,240 the degree of inhibition turning OFF cycle. 556 00:30:08,240 --> 00:30:10,780 And here again the same thing is happening. 557 00:30:10,780 --> 00:30:15,160 But the same thing happens under both normal conditions 558 00:30:15,160 --> 00:30:17,515 and after APB had been injected. 559 00:30:18,960 --> 00:30:21,560 So what this experiment then shows-- and of course one 560 00:30:21,560 --> 00:30:24,490 does this with many, many cells-- 561 00:30:24,490 --> 00:30:28,440 is to prove that the hypothesis, that the ON and OFF 562 00:30:28,440 --> 00:30:32,630 systems play a significant role in center-surround antagonism, 563 00:30:32,630 --> 00:30:33,900 is wrong. 564 00:30:33,900 --> 00:30:37,380 And because of that, that hypothesis has been eliminated. 565 00:30:38,331 --> 00:30:38,830 All right. 566 00:30:38,830 --> 00:30:42,830 So then we can move on and ask the next question. 567 00:30:42,830 --> 00:30:45,150 I mean, let me first draw this up again here. 568 00:30:45,150 --> 00:30:45,650 All right. 569 00:30:45,650 --> 00:30:49,720 Here we have the photoreceptors-- 570 00:30:49,720 --> 00:30:52,393 the cone photoreceptors-- the horizontal cells, and the ON 571 00:30:52,393 --> 00:30:53,440 and OFF cells. 572 00:30:53,440 --> 00:30:59,190 So this alternative hypothesis, that the surround inhibition 573 00:30:59,190 --> 00:31:01,860 is due to horizontal cells, therefore, 574 00:31:01,860 --> 00:31:04,285 has gained much greater acceptance. 575 00:31:05,221 --> 00:31:05,720 OK. 576 00:31:07,340 --> 00:31:09,580 So now we are going to move upstairs 577 00:31:09,580 --> 00:31:14,930 and we're going to go to area V1 where we can ask the question, 578 00:31:14,930 --> 00:31:21,500 well what were the transforms that we had seen in V1. 579 00:31:23,210 --> 00:31:25,430 I presume all of you remember. 580 00:31:25,430 --> 00:31:27,950 What are the three major transforms we talked about? 581 00:31:27,950 --> 00:31:28,610 Who remembers? 582 00:31:34,900 --> 00:31:35,980 Come on. 583 00:31:35,980 --> 00:31:39,070 Sure you remember that, don't you-- that we have cells-- 584 00:31:39,070 --> 00:31:42,205 most of the cells are orientation specific, right? 585 00:31:42,205 --> 00:31:43,955 Most of the cells are direction selective. 586 00:31:45,290 --> 00:31:47,550 And most of the cells are selective 587 00:31:47,550 --> 00:31:48,825 for spatial frequency. 588 00:31:49,870 --> 00:31:52,390 So those are three of the major transforms. 589 00:31:52,390 --> 00:31:55,820 The other two we talked about is a convergence of the ON and OFF 590 00:31:55,820 --> 00:31:59,330 channels onto single cells in the cortex. 591 00:32:01,250 --> 00:32:05,280 And the other was that there was a binocular input 592 00:32:05,280 --> 00:32:06,155 to many of the cells. 593 00:32:07,280 --> 00:32:08,820 So those were the major transforms 594 00:32:08,820 --> 00:32:10,300 we talked about the last time. 595 00:32:11,440 --> 00:32:14,890 And again I want to emphasize the importance of this 596 00:32:14,890 --> 00:32:17,560 by telling you that Hubel received the Nobel 597 00:32:17,560 --> 00:32:24,750 Prize for those discoveries of how V1 operates. 598 00:32:24,750 --> 00:32:25,760 OK? 599 00:32:25,760 --> 00:32:29,500 And of course I mentioned before that Keffer Hartline, 600 00:32:29,500 --> 00:32:33,320 when he discovered the ON and OFF systems using light 601 00:32:33,320 --> 00:32:35,990 that he shown into the eye-- he called them the ON and OFF 602 00:32:35,990 --> 00:32:39,570 cells-- he received the Nobel Prize as well. 603 00:32:39,570 --> 00:32:43,870 So those are truly, truly major, major discoveries 604 00:32:43,870 --> 00:32:48,010 and have triggered hundreds and hundreds of experiments 605 00:32:48,010 --> 00:32:49,830 trying to understand better. 606 00:32:49,830 --> 00:32:52,080 And certainly one of the questions that was raised 607 00:32:52,080 --> 00:32:57,100 is how does orientation, and direction cell activity, 608 00:32:57,100 --> 00:32:59,740 and special frequencies activity, for that matter, 609 00:32:59,740 --> 00:33:01,650 arise in area of V1. 610 00:33:02,850 --> 00:33:06,810 And one prominent hypotheses was indeed 611 00:33:06,810 --> 00:33:09,390 that the reason we have ON and OFF channels 612 00:33:09,390 --> 00:33:12,050 is to create these transforms in the visual cortex. 613 00:33:14,300 --> 00:33:17,090 So what we can then do, now that one 614 00:33:17,090 --> 00:33:21,540 has this magic bullet of the APB, 615 00:33:21,540 --> 00:33:24,610 that one can record from a cortical cell. 616 00:33:24,610 --> 00:33:33,140 See how it responds when you inject APB in contrast 617 00:33:33,140 --> 00:33:35,990 to before you injected it and after injected it. 618 00:33:35,990 --> 00:33:38,740 So that's the big question you're going to ask next. 619 00:33:38,740 --> 00:33:39,310 All right. 620 00:33:39,310 --> 00:33:43,880 So here is an example of what of cortical cell's response 621 00:33:43,880 --> 00:33:48,150 looks like using this kind of histogram when a bar of light, 622 00:33:48,150 --> 00:33:51,380 in this case, is moved across the receptive field. 623 00:33:51,380 --> 00:33:54,780 Now this is a complex cell. 624 00:33:54,780 --> 00:33:56,966 And you can see it gives a vigorous response when 625 00:33:56,966 --> 00:33:58,590 the light edge goes across, and then it 626 00:33:58,590 --> 00:34:01,650 gives a vigorous response when the dark edge goes across. 627 00:34:01,650 --> 00:34:05,010 I'm showing this only for one direction of motion. 628 00:34:05,010 --> 00:34:06,980 So that is a natural response. 629 00:34:06,980 --> 00:34:09,120 So now the question comes up, what 630 00:34:09,120 --> 00:34:12,394 happens when you inject APB into the eye. 631 00:34:14,302 --> 00:34:16,375 A number of possibilities exist. 632 00:34:18,230 --> 00:34:21,429 The most basic one I think most of you would buy 633 00:34:21,429 --> 00:34:26,230 is that the light edge response is produced predominantly 634 00:34:26,230 --> 00:34:28,600 by the ON channel, and the dark edge 635 00:34:28,600 --> 00:34:30,699 response by the OFF channel. 636 00:34:30,699 --> 00:34:33,650 And if that is the case, then this response 637 00:34:33,650 --> 00:34:38,949 should be eliminated by blocking it with APB in the eye. 638 00:34:38,949 --> 00:34:41,699 And if you do that, that's exactly what happens. 639 00:34:41,699 --> 00:34:44,060 You can see here under normal conditions, 640 00:34:44,060 --> 00:34:46,850 you get a vigorous response for both light and dark edges. 641 00:34:46,850 --> 00:34:50,270 After APB, only a dark edge response remains. 642 00:34:50,270 --> 00:34:54,909 So this then established that these responses 643 00:34:54,909 --> 00:34:57,890 to the different edges-- the light edges and dark edges-- 644 00:34:57,890 --> 00:35:02,050 are a product of the input from the retina to the geniculate, 645 00:35:02,050 --> 00:35:06,130 and then to the cortex from the ON and the OFF channels, which 646 00:35:06,130 --> 00:35:08,450 then converge in many cortical cells, 647 00:35:08,450 --> 00:35:13,120 as is the case in this particular cortical cell. 648 00:35:13,120 --> 00:35:16,610 So that then establishes this very basic fact. 649 00:35:16,610 --> 00:35:19,100 Now the next question we can ask-- 650 00:35:19,100 --> 00:35:22,310 what about those transforms you talked about? 651 00:35:22,310 --> 00:35:24,970 Let's first of all look at the transform 652 00:35:24,970 --> 00:35:28,240 of direction selectivity. 653 00:35:28,240 --> 00:35:31,310 So we can take a cell that is, in this case, 654 00:35:31,310 --> 00:35:33,300 directionally biased. 655 00:35:33,300 --> 00:35:35,550 And you can see what the response is before 656 00:35:35,550 --> 00:35:37,740 and after APB is injected. 657 00:35:37,740 --> 00:35:40,380 And what you see here-- we move the bar 658 00:35:40,380 --> 00:35:43,400 across in one direction, and then we move the bar back 659 00:35:43,400 --> 00:35:45,100 across the opposite direction. 660 00:35:45,100 --> 00:35:47,630 So the first half shows a downward movement-- 661 00:35:47,630 --> 00:35:50,180 the second half, the upward movement. 662 00:35:50,180 --> 00:35:52,840 Now what you see here that the cell responds 663 00:35:52,840 --> 00:35:53,870 is much more vigorous. 664 00:35:53,870 --> 00:35:55,990 It's not 100% direction selective. 665 00:35:55,990 --> 00:35:57,860 I showed you some of those the last time. 666 00:35:57,860 --> 00:36:01,200 This one is a bias-- about a four to one bias-- 667 00:36:01,200 --> 00:36:03,680 much more response to the downward movement 668 00:36:03,680 --> 00:36:05,120 than the upward movement. 669 00:36:05,120 --> 00:36:08,390 But the cell responds both the light and the dark edge 670 00:36:08,390 --> 00:36:10,390 in both directions, and it lines up 671 00:36:10,390 --> 00:36:12,910 with the temporal arrangement here, 672 00:36:12,910 --> 00:36:16,410 proving indeed that this is a complex cell. 673 00:36:16,410 --> 00:36:19,190 Now then when you inject APB into the eye, 674 00:36:19,190 --> 00:36:20,440 look what happens. 675 00:36:20,440 --> 00:36:23,680 You eliminate the light edge response here and here, 676 00:36:23,680 --> 00:36:29,790 but the cell is still directionally biased. 677 00:36:29,790 --> 00:36:32,570 So direction specificity was maintained. 678 00:36:32,570 --> 00:36:34,130 And when this was studied in many, 679 00:36:34,130 --> 00:36:36,870 many, many cells-- even cells that 680 00:36:36,870 --> 00:36:41,320 were 100% direction specific-- blocking the ON channel 681 00:36:41,320 --> 00:36:45,870 did not eliminate directionality in the cortex. 682 00:36:45,870 --> 00:36:49,540 So that then indicates that the ON and OFF channels did not 683 00:36:49,540 --> 00:36:56,390 arise to bring about direction selectivity in the cortex. 684 00:36:58,810 --> 00:37:02,820 And so that brings us to the second transform, 685 00:37:02,820 --> 00:37:04,680 which is orientation specificity. 686 00:37:05,700 --> 00:37:07,280 So we can do that next. 687 00:37:07,280 --> 00:37:10,530 And here we have an example using a very similar procedure. 688 00:37:10,530 --> 00:37:14,600 Again, a complex cell when the APB is injected. 689 00:37:14,600 --> 00:37:17,430 The light edge response disappears. 690 00:37:17,430 --> 00:37:20,220 You move the bar across the different orientations 691 00:37:20,220 --> 00:37:24,400 and this is the orientation specificity you get. 692 00:37:24,400 --> 00:37:28,530 Now this is calculated here on the basis of only the dark edge 693 00:37:28,530 --> 00:37:31,256 response because you want to keep it the same 694 00:37:31,256 --> 00:37:32,380 as you're going to do here. 695 00:37:32,380 --> 00:37:35,160 Since the light edge response is eliminated, 696 00:37:35,160 --> 00:37:39,950 you can see that the cells orientation specificity is also 697 00:37:39,950 --> 00:37:45,910 unaffected, meaning that the orientation 698 00:37:45,910 --> 00:37:49,880 specificity of the cortical cells 699 00:37:49,880 --> 00:37:54,130 is not due to the interaction between the ON and OFF channel. 700 00:37:58,990 --> 00:38:01,950 Similar experiments were also done with spatial frequency 701 00:38:01,950 --> 00:38:06,070 selectivity, and again, no effect was found. 702 00:38:06,070 --> 00:38:09,780 So this then led to the conclusion 703 00:38:09,780 --> 00:38:13,830 that the ON and OFF channels did not 704 00:38:13,830 --> 00:38:17,940 arise for the purpose of creating the transforms that we 705 00:38:17,940 --> 00:38:22,910 had denoted in our last lecture about single cells 706 00:38:22,910 --> 00:38:24,801 in the visual cortex. 707 00:38:24,801 --> 00:38:25,300 All right. 708 00:38:25,300 --> 00:38:28,140 So now what we can do is here-- we can come up 709 00:38:28,140 --> 00:38:32,430 with a silly model, just to make it memorable, 710 00:38:32,430 --> 00:38:34,260 which is to say that the ON and OFF 711 00:38:34,260 --> 00:38:37,020 channels flow into the cortex. 712 00:38:37,020 --> 00:38:39,760 And these attributes we talked about-- orientation, direction, 713 00:38:39,760 --> 00:38:41,740 and spacial frequencies selectivity-- 714 00:38:41,740 --> 00:38:44,640 are produced by cortical filters. 715 00:38:44,640 --> 00:38:47,430 What you have in the cortex are all 716 00:38:47,430 --> 00:38:51,300 kinds of inhibitory interneurons and the interactions 717 00:38:51,300 --> 00:38:53,600 among many, many neurons. 718 00:38:53,600 --> 00:38:56,380 And that kind of activity that you 719 00:38:56,380 --> 00:39:02,190 get there is the one that produces these attributes, 720 00:39:02,190 --> 00:39:06,150 not the interaction between the ON and OFF channels 721 00:39:06,150 --> 00:39:07,795 that flow into the visual cortex. 722 00:39:09,461 --> 00:39:09,960 All right. 723 00:39:09,960 --> 00:39:16,400 So now the next question we can ask, 724 00:39:16,400 --> 00:39:24,790 or what happens on APB under photopic viewing conditions. 725 00:39:24,790 --> 00:39:30,740 We'll talk about scotopic, as well as photopic, vision. 726 00:39:34,670 --> 00:39:42,070 To do this, and to answer how it affects our visual capacities, 727 00:39:42,070 --> 00:39:48,820 what we do is to turn to behavioral experiments. 728 00:39:48,820 --> 00:39:51,470 In behavioral experiments, what you can do 729 00:39:51,470 --> 00:39:53,740 is you can present various kinds of stimuli. 730 00:39:53,740 --> 00:39:55,720 You can train a monkey-- in this case, 731 00:39:55,720 --> 00:40:02,780 with monkeys-- to see how well they perceive a stimulus, 732 00:40:02,780 --> 00:40:05,900 and ask them to make an eye movement to that stimulus. 733 00:40:05,900 --> 00:40:10,290 So when you do this-- testing that 734 00:40:10,290 --> 00:40:13,550 hypothesis I've shown you earlier about light increment 735 00:40:13,550 --> 00:40:15,740 and light decrement-- what we can do 736 00:40:15,740 --> 00:40:19,650 is to train a monkey to first fixate. 737 00:40:19,650 --> 00:40:21,700 And then after the monkey fixated, 738 00:40:21,700 --> 00:40:25,480 you can present either a light incremental spot 739 00:40:25,480 --> 00:40:27,940 or a light decremental spot. 740 00:40:27,940 --> 00:40:31,220 The monkey's task is to make a saccade to that target. 741 00:40:31,220 --> 00:40:34,670 And of course, those spots will appear randomly 742 00:40:34,670 --> 00:40:37,130 in several different locations in each trial, 743 00:40:37,130 --> 00:40:40,350 so the monkey doesn't know where he's going to appear. 744 00:40:40,350 --> 00:40:42,710 And if he makes a correct saccade to it, 745 00:40:42,710 --> 00:40:45,500 he will get a drop of apple juice for a reward. 746 00:40:45,500 --> 00:40:47,420 So that is the procedure. 747 00:40:47,420 --> 00:40:49,710 And so now the question then comes up-- 748 00:40:49,710 --> 00:40:54,210 how well does the monkey do in being 749 00:40:54,210 --> 00:40:56,875 able to detect light increment and light decrement? 750 00:40:58,250 --> 00:41:03,010 So if you do that, luckily one gets a very clear cut 751 00:41:03,010 --> 00:41:05,350 and dramatic result. 752 00:41:05,350 --> 00:41:07,420 Here is the section that I will show 753 00:41:07,420 --> 00:41:09,660 you data for light increment, and here 754 00:41:09,660 --> 00:41:13,730 is a section showing data for light decrement. 755 00:41:13,730 --> 00:41:15,420 So here is an example. 756 00:41:15,420 --> 00:41:17,260 What you measure here are two things-- 757 00:41:17,260 --> 00:41:21,860 you measure the monkey's percent correct performance, 758 00:41:21,860 --> 00:41:25,060 and you measure what the saccadic latencies are 759 00:41:25,060 --> 00:41:27,730 to make a saccade to the target. 760 00:41:27,730 --> 00:41:30,170 So it shows here that under normal conditions, 761 00:41:30,170 --> 00:41:34,570 the monkey's performances is over 90%, 762 00:41:34,570 --> 00:41:37,560 and that he has a very nice distribution 763 00:41:37,560 --> 00:41:40,140 of saccadic latencies with a mean of about two 764 00:41:40,140 --> 00:41:41,860 in 53 milliseconds. 765 00:41:43,220 --> 00:41:47,830 Then when you apply APB to the eye, what happens 766 00:41:47,830 --> 00:41:50,670 is that the monkey's performance drops dramatically. 767 00:41:50,670 --> 00:41:55,890 He is just a little bit above probability, 768 00:41:55,890 --> 00:41:58,620 and his latencies are very, very late-- very, very, 769 00:41:58,620 --> 00:42:01,180 very long-- 406 milliseconds. 770 00:42:02,270 --> 00:42:04,550 So in other words, the monkey can barely 771 00:42:04,550 --> 00:42:07,560 perceive a light incremental stimulus 772 00:42:07,560 --> 00:42:10,840 by virtue of having blocked the ON channel in the retina 773 00:42:10,840 --> 00:42:11,590 by APB. 774 00:42:12,870 --> 00:42:14,950 Now if you do the same experiment 775 00:42:14,950 --> 00:42:19,320 with light decrement, what you see here 776 00:42:19,320 --> 00:42:21,020 is the monkey's performance remains 777 00:42:21,020 --> 00:42:24,940 normal-- about 95% correct. 778 00:42:24,940 --> 00:42:29,000 And the latency distribution is also 779 00:42:29,000 --> 00:42:33,380 about the same-- two in 49, versus two in 51 milliseconds. 780 00:42:34,980 --> 00:42:40,270 So that then says that indeed the ability 781 00:42:40,270 --> 00:42:43,700 to detect light incremental stimuli 782 00:42:43,700 --> 00:42:48,630 has been devastated by the injection of APB, 783 00:42:48,630 --> 00:42:53,280 and therefore raised the idea that the ON and OFF 784 00:42:53,280 --> 00:42:56,910 channels are for the purpose of quickly and efficiently 785 00:42:56,910 --> 00:43:01,080 detecting light increment, as well as light decrement. 786 00:43:02,120 --> 00:43:07,120 So that then was the basic finding 787 00:43:07,120 --> 00:43:14,050 that was obtained with this behavioral experiment studying 788 00:43:14,050 --> 00:43:17,030 the monkey's performance on being 789 00:43:17,030 --> 00:43:18,870 able to process visual stimuli. 790 00:43:20,645 --> 00:43:25,170 Now we are going to get a bit more complicated, 791 00:43:25,170 --> 00:43:27,080 because what we talked about so far 792 00:43:27,080 --> 00:43:30,360 was under photopic conditions, meaning 793 00:43:30,360 --> 00:43:33,670 when your cones were fully functional. 794 00:43:34,940 --> 00:43:40,270 So the question is what happens under scotopic conditions, 795 00:43:40,270 --> 00:43:42,350 meaning what happens when you're dark adapted. 796 00:43:43,370 --> 00:43:45,700 Now we have talked about this before. 797 00:43:46,820 --> 00:43:52,220 It was pointed out, initially by Schultze, 798 00:43:52,220 --> 00:43:56,520 that we have two basic classes of photoreceptors-- the rods 799 00:43:56,520 --> 00:44:00,275 and the cones-- and that the rods are for night vision. 800 00:44:02,020 --> 00:44:06,641 So now the question is, what happens under night vision 801 00:44:06,641 --> 00:44:07,140 conditions. 802 00:44:08,150 --> 00:44:11,920 And when this was found-- this was truly, truly baffling. 803 00:44:11,920 --> 00:44:14,070 And I'm going to show you the data. 804 00:44:14,070 --> 00:44:17,540 It showed here under light adapted conditions 805 00:44:17,540 --> 00:44:19,530 with the same kind of data-- but shown only 806 00:44:19,530 --> 00:44:22,810 as histograms in this case-- the monkey 807 00:44:22,810 --> 00:44:25,190 does equally well for light and dark. 808 00:44:25,190 --> 00:44:29,920 And when you apply APB, the monkey 809 00:44:29,920 --> 00:44:33,360 has difficulty seeing the light incremental stimulus, 810 00:44:33,360 --> 00:44:37,390 but has little loss in the light decremental stimulus. 811 00:44:37,390 --> 00:44:38,560 OK? 812 00:44:38,560 --> 00:44:41,870 But when you do the same thing under dark adapted conditions, 813 00:44:41,870 --> 00:44:44,050 when only the rods are operative, 814 00:44:44,050 --> 00:44:45,490 a curious thing happens. 815 00:44:45,490 --> 00:44:48,900 The monkey doesn't see either light increment or light 816 00:44:48,900 --> 00:44:49,400 decrement. 817 00:44:50,720 --> 00:44:53,475 In other words, and the way to put it shortly, 818 00:44:53,475 --> 00:44:58,120 is to say that the monkey has become night blind. 819 00:44:59,280 --> 00:45:05,230 Now there are, among humans, a small population of individuals 820 00:45:05,230 --> 00:45:08,160 individuals who are night blind, and what's 821 00:45:08,160 --> 00:45:09,350 the situation with them? 822 00:45:10,580 --> 00:45:12,570 It's called "night blind" because they just 823 00:45:12,570 --> 00:45:14,470 see very poorly at night. 824 00:45:14,470 --> 00:45:17,760 And, in fact, when that is known, 825 00:45:17,760 --> 00:45:21,730 they only get a special kind of driver's license-- one 826 00:45:21,730 --> 00:45:23,432 saying you can drive in the daytime, 827 00:45:23,432 --> 00:45:24,640 but you can't drive at night. 828 00:45:26,290 --> 00:45:29,180 So now we have a monkey here with APB 829 00:45:29,180 --> 00:45:30,810 injected-- that he's night blind. 830 00:45:30,810 --> 00:45:34,180 And also you see the same data reflected in the latencies, 831 00:45:34,180 --> 00:45:35,490 just like before. 832 00:45:35,490 --> 00:45:38,990 And it shows that the monkey is devastated 833 00:45:38,990 --> 00:45:41,460 both for light increment and light decrement 834 00:45:41,460 --> 00:45:43,300 by having a tremendous increase-- more 835 00:45:43,300 --> 00:45:48,035 than a tripling of latencies for the few trials 836 00:45:48,035 --> 00:45:50,290 that he did carry out correctly. 837 00:45:51,510 --> 00:45:55,780 So now this being the case, it raises a big question-- 838 00:45:55,780 --> 00:45:58,490 and I'm sorry that things are getting so complicated, 839 00:45:58,490 --> 00:46:01,510 but the brain is complicated-- as 840 00:46:01,510 --> 00:46:11,950 to just what is the nature and arrangement of the rods 841 00:46:11,950 --> 00:46:14,400 in the retina, and how does that relate 842 00:46:14,400 --> 00:46:16,320 to the arrangement of the cones? 843 00:46:16,320 --> 00:46:16,870 OK? 844 00:46:16,870 --> 00:46:21,100 So that brings me to an interesting point. 845 00:46:22,290 --> 00:46:25,390 Again, as so often happens, whenever 846 00:46:25,390 --> 00:46:27,812 you're confronted with a puzzle, you 847 00:46:27,812 --> 00:46:29,020 have all kinds of hypotheses. 848 00:46:30,050 --> 00:46:32,960 And then luckily if you do this instead of experiments, 849 00:46:32,960 --> 00:46:34,880 you come up with the right kinds of tools. 850 00:46:34,880 --> 00:46:38,250 You can eliminate most of them and come up with the right one. 851 00:46:38,250 --> 00:46:47,180 Now, so we can ask, first of all, 852 00:46:47,180 --> 00:46:52,670 without talking about APB at all now, 853 00:46:52,670 --> 00:46:55,070 simply ask a general question-- what 854 00:46:55,070 --> 00:47:02,480 happens to the receptive fields, or retinal ganglion cells, 855 00:47:02,480 --> 00:47:04,760 under dark adapted conditions? 856 00:47:04,760 --> 00:47:07,985 And what happens is that the receptive fields become larger. 857 00:47:10,030 --> 00:47:16,830 Now this initially-- discovered by Barlow in England-- 858 00:47:16,830 --> 00:47:20,580 was negated by the other individuals saying, 859 00:47:20,580 --> 00:47:23,790 you just got scattering of light-- that's why it's larger. 860 00:47:23,790 --> 00:47:26,600 So it was kind of dismissed, but in the end 861 00:47:26,600 --> 00:47:28,890 it turned that he was right, as you shall see. 862 00:47:30,110 --> 00:47:34,490 The other thing that happened is that the color selectivity 863 00:47:34,490 --> 00:47:40,360 response disappears in the retinal ganglion cells. 864 00:47:41,550 --> 00:47:44,470 And not only that, but it disappears behaviorally. 865 00:47:44,470 --> 00:47:46,240 So when you have a red rose, and you 866 00:47:46,240 --> 00:47:50,520 look at a red rose at night when only your rods are functional, 867 00:47:50,520 --> 00:47:52,140 it looks like a black rose. 868 00:47:53,740 --> 00:47:55,860 The rods cannot process color. 869 00:47:55,860 --> 00:47:56,360 OK? 870 00:47:56,360 --> 00:47:59,120 They can only process light increment and decrement. 871 00:48:00,760 --> 00:48:03,550 OK, again just to reiterate-- the receptive fields 872 00:48:03,550 --> 00:48:05,010 become larger. 873 00:48:05,010 --> 00:48:05,650 OK. 874 00:48:05,650 --> 00:48:08,930 So the big question is what on earth is happening, 875 00:48:08,930 --> 00:48:10,700 what kind of wiring is taking place, 876 00:48:10,700 --> 00:48:13,540 or what kind of connections are created 877 00:48:13,540 --> 00:48:16,510 to create these two things. 878 00:48:16,510 --> 00:48:19,960 Now the second one is the one that's the big puzzle. 879 00:48:19,960 --> 00:48:22,065 The first one we can understand because it's 880 00:48:22,065 --> 00:48:24,620 been shown that rods are only one type 881 00:48:24,620 --> 00:48:26,725 and that they don't carry color information. 882 00:48:27,900 --> 00:48:37,880 Now to study this further, way back when in the 1870s-- 1880s, 883 00:48:37,880 --> 00:48:41,280 Cajal did the large number of experiments of this sort. 884 00:48:41,280 --> 00:48:45,910 If you remember, I told you that Cajal played a central role 885 00:48:45,910 --> 00:48:49,260 in using the Golgi stain, and that he and Golgi received 886 00:48:49,260 --> 00:48:55,790 the Nobel Prize in 1906 for their major discoveries 887 00:48:55,790 --> 00:48:56,570 about this. 888 00:48:56,570 --> 00:49:01,470 So now he argued that the way this happens 889 00:49:01,470 --> 00:49:04,410 is that rods and the cones connect differently 890 00:49:04,410 --> 00:49:05,980 with the ganglion cells. 891 00:49:05,980 --> 00:49:09,580 And so here is a picture of Cajal. 892 00:49:09,580 --> 00:49:11,370 He spent most of his life like this, 893 00:49:11,370 --> 00:49:13,960 looking through a microscope, endlessly looking 894 00:49:13,960 --> 00:49:19,190 at brain slices, and studying the individual cells-- 895 00:49:19,190 --> 00:49:21,710 the shapes and drew them, as you can see his pencil. 896 00:49:21,710 --> 00:49:25,150 He is in the middle drawing, actually, a cell there. 897 00:49:26,210 --> 00:49:31,230 And so he speculated about this a great deal. 898 00:49:31,230 --> 00:49:34,070 And he was just a remarkable person. 899 00:49:34,070 --> 00:49:39,646 And he had written an autobiography. 900 00:49:41,130 --> 00:49:47,580 And the way he speaks in this-- translated from Spanish-- 901 00:49:47,580 --> 00:49:50,890 but he has an incredibly colorful way of talking-- 902 00:49:50,890 --> 00:49:52,830 "had," I guess I should say. 903 00:49:52,830 --> 00:49:55,610 And I want to quote some of this, 904 00:49:55,610 --> 00:49:58,300 because I think you'll find it interesting and amusing. 905 00:49:58,300 --> 00:50:00,930 So he said, "Since this impression received by the rods 906 00:50:00,930 --> 00:50:04,040 is different from that taken by the cone, 907 00:50:04,040 --> 00:50:06,850 it is necessary from every point of view 908 00:50:06,850 --> 00:50:09,360 that each of these specific impressions 909 00:50:09,360 --> 00:50:15,130 should be conveyed through the retina by a separate channel." 910 00:50:15,130 --> 00:50:19,370 The translation leaves a lot to be desired, but that's OK. 911 00:50:19,370 --> 00:50:21,070 So then he went on and said, "When 912 00:50:21,070 --> 00:50:25,060 we reason with common sense and lift a war club determined 913 00:50:25,060 --> 00:50:30,790 upon vigorous action, nature ultimately hears us." 914 00:50:30,790 --> 00:50:34,430 Very picturesque, as if nature had heard anyone, right? 915 00:50:34,430 --> 00:50:37,560 "Knowing what I was looking for--" meaning he 916 00:50:37,560 --> 00:50:42,730 had a hypothetical bias, right-- "I began to explore eagerly 917 00:50:42,730 --> 00:50:45,380 retina of fishes and mammals. 918 00:50:45,380 --> 00:50:48,600 Finally as a reward of my faith, there 919 00:50:48,600 --> 00:50:52,800 deigned to appear most clearly and brilliantly those two 920 00:50:52,800 --> 00:50:56,590 types of bipolar cells demanded by theory 921 00:50:56,590 --> 00:50:58,220 and guessed by reason." 922 00:50:58,220 --> 00:51:02,520 What he means by this is that there 923 00:51:02,520 --> 00:51:05,440 were two kinds of basic kinds of bipolar cells-- 924 00:51:05,440 --> 00:51:06,930 and not the ON and OFF. 925 00:51:06,930 --> 00:51:08,960 But in this case, what he was talking about, 926 00:51:08,960 --> 00:51:12,700 he was talking about rod bipolars and cone bipolars. 927 00:51:12,700 --> 00:51:17,570 He said the rod photoreceptors connect with rod bipolars, 928 00:51:17,570 --> 00:51:19,570 and the cone photoreceptors with cone bipolars. 929 00:51:21,690 --> 00:51:25,090 So that's what [INAUDIBLE] then established, 930 00:51:25,090 --> 00:51:27,550 and that finding was basically correct. 931 00:51:27,550 --> 00:51:33,790 But then he went on to say that these two kinds of bipolars 932 00:51:33,790 --> 00:51:37,050 hook up with two types of ganglion cells, 933 00:51:37,050 --> 00:51:39,490 thereby forming separate channels to the brain. 934 00:51:42,310 --> 00:51:45,190 So that was an interesting conclusion, and for many years 935 00:51:45,190 --> 00:51:46,530 that was accepted. 936 00:51:46,530 --> 00:51:49,040 And interestingly enough, as it so often happens 937 00:51:49,040 --> 00:51:52,880 with hypotheses, this conclusion-- 938 00:51:52,880 --> 00:51:56,184 even though you had the drawings looking 939 00:51:56,184 --> 00:51:58,100 through the microscope showing that there were 940 00:51:58,100 --> 00:52:00,740 these separate channels-- turned out to be largely 941 00:52:00,740 --> 00:52:02,630 not one-- almost entirely wrong. 942 00:52:03,750 --> 00:52:05,370 Now what do we mean by that? 943 00:52:05,370 --> 00:52:06,960 Well people began to do all sorts 944 00:52:06,960 --> 00:52:10,370 of very careful intercellular recordings in the retina, 945 00:52:10,370 --> 00:52:13,450 and using much more sophisticated 946 00:52:13,450 --> 00:52:16,230 anatomical procedures than Cajal was 947 00:52:16,230 --> 00:52:19,050 able to use, thanks to the new developments in the field. 948 00:52:19,050 --> 00:52:24,420 And they discovered, first of all-- let me back up a second. 949 00:52:24,420 --> 00:52:27,100 This is sort of the model that he had proposed. 950 00:52:27,100 --> 00:52:29,420 He had the cone model and the rod model, 951 00:52:29,420 --> 00:52:32,480 not distinguishing between the ON and OFF. 952 00:52:32,480 --> 00:52:35,350 And so the model that then subsequently emerged 953 00:52:35,350 --> 00:52:40,640 was that ganglion cells in most of the retina 954 00:52:40,640 --> 00:52:44,220 actually receive a convergent input- except in the fovia, 955 00:52:44,220 --> 00:52:47,500 because you don't have rods there-- so that you don't have 956 00:52:47,500 --> 00:52:53,080 a doubling of ganglion cells-- some for rods 957 00:52:53,080 --> 00:52:56,100 and some for cones-- but both the rods and the cones, 958 00:52:56,100 --> 00:53:00,450 through separate pathways, feed into the ganglion cell. 959 00:53:00,450 --> 00:53:03,610 So then this was analyzed in much, much more detail. 960 00:53:03,610 --> 00:53:08,240 And now I'm going to point this out to you by providing you 961 00:53:08,240 --> 00:53:11,241 with an overview of the retinal connections. 962 00:53:11,241 --> 00:53:11,740 OK. 963 00:53:11,740 --> 00:53:15,690 So here we have the three basic classes of cones. 964 00:53:15,690 --> 00:53:16,610 All right? 965 00:53:16,610 --> 00:53:18,711 And we have the rods. 966 00:53:18,711 --> 00:53:19,210 All right? 967 00:53:19,210 --> 00:53:23,870 Then, if you look at the cones, each cone 968 00:53:23,870 --> 00:53:28,890 gives rise to at least two bipolar cell-- an ON and OFF 969 00:53:28,890 --> 00:53:30,130 bipolar cell. 970 00:53:30,130 --> 00:53:36,730 But the rods in most species only 971 00:53:36,730 --> 00:53:40,260 have a single kind of bipolar cell, 972 00:53:40,260 --> 00:53:43,020 and they can refer to that as an ON bipolar cell, 973 00:53:43,020 --> 00:53:47,990 because the synapses are all sign-inverting synapses using 974 00:53:47,990 --> 00:53:53,480 the mGluR6 neurotransmitter receptor site. 975 00:53:53,480 --> 00:53:55,150 So that's what we have there. 976 00:53:55,150 --> 00:53:58,840 Now if you look further down here at the ganglion cells-- 977 00:53:58,840 --> 00:54:01,680 and what we have is of course, that we have the ON and OFF 978 00:54:01,680 --> 00:54:04,430 bipolar cells from the cones feed 979 00:54:04,430 --> 00:54:07,030 into the ON and OFF ganglion cells. 980 00:54:07,030 --> 00:54:10,021 So now the questions are what happens to the ON bipolar 981 00:54:10,021 --> 00:54:10,520 cells? 982 00:54:10,520 --> 00:54:16,120 How do they connect to these cells 983 00:54:16,120 --> 00:54:18,640 since they do not form a separate pathway? 984 00:54:18,640 --> 00:54:20,890 And this has been again-- things got 985 00:54:20,890 --> 00:54:26,120 very complicated in the course of evolution 986 00:54:26,120 --> 00:54:28,870 where it was very important to try to conserve things 987 00:54:28,870 --> 00:54:31,640 as much as possible, and that's why we do not 988 00:54:31,640 --> 00:54:34,690 have separate pathways for rods and cones. 989 00:54:34,690 --> 00:54:37,210 If we did we'd need a huge eye, and we'd 990 00:54:37,210 --> 00:54:41,199 need at least twice as many ganglion cells 991 00:54:41,199 --> 00:54:43,615 than we have at the present time, which is about a million 992 00:54:43,615 --> 00:54:44,860 in each eye. 993 00:54:44,860 --> 00:54:49,740 OK, so what really happened is-- dumb-founding almost-- 994 00:54:49,740 --> 00:54:55,860 is that a so-called amacrine cell -- 995 00:54:55,860 --> 00:54:58,830 I told you there are different classes of amacrine cells-- 996 00:54:58,830 --> 00:55:02,370 one of them is a so-called A2 amacrine cell. 997 00:55:02,370 --> 00:55:05,420 That is a cell that receives a direct input 998 00:55:05,420 --> 00:55:08,340 from the ON bipolar cells. 999 00:55:08,340 --> 00:55:14,250 Now that amacrine cell connects to ganglion cells 1000 00:55:14,250 --> 00:55:15,750 in two different ways. 1001 00:55:15,750 --> 00:55:20,060 It makes a gap junction connection with the ON bipolar 1002 00:55:20,060 --> 00:55:24,890 cells, and it makes a glycinergic synaptic connection 1003 00:55:24,890 --> 00:55:27,360 with the OFF ganglion cell. 1004 00:55:27,360 --> 00:55:28,790 So let's label this. 1005 00:55:30,220 --> 00:55:32,820 What we have here-- this is inner plexiform layer again, 1006 00:55:32,820 --> 00:55:34,740 and here is the outer plexiform layer. 1007 00:55:34,740 --> 00:55:37,580 And what we have here-- just to remind you, 1008 00:55:37,580 --> 00:55:40,740 that already know-- we have a sign-inverting synapse 1009 00:55:40,740 --> 00:55:44,800 for the ON, and sign-conserving for the OFF bipolars 1010 00:55:44,800 --> 00:55:49,840 that connect with the cones. 1011 00:55:49,840 --> 00:55:53,920 And now we have here-- let's proceed to the A2 amacrine 1012 00:55:53,920 --> 00:55:58,910 cell that is feeding into these cells from the rods. 1013 00:55:58,910 --> 00:56:03,380 And what we have here is a glycinergic synapse, so-called. 1014 00:56:03,380 --> 00:56:04,770 That's a real synapse. 1015 00:56:04,770 --> 00:56:06,200 It's inhibitory. 1016 00:56:06,200 --> 00:56:08,660 And then here we have what is called a gap junction. 1017 00:56:08,660 --> 00:56:10,920 I'm sure all of you know what these things are. 1018 00:56:10,920 --> 00:56:16,830 Gap junction is what you call an electrical synapse. 1019 00:56:16,830 --> 00:56:21,720 So they transform the signal without any neurotransmitters 1020 00:56:21,720 --> 00:56:22,740 involved. 1021 00:56:22,740 --> 00:56:27,720 So it directly activates-- in this case, this fiber here-- 1022 00:56:27,720 --> 00:56:29,040 and drives it. 1023 00:56:29,040 --> 00:56:31,700 So what you create in the inner retina 1024 00:56:31,700 --> 00:56:35,310 then here is a double ended system 1025 00:56:35,310 --> 00:56:40,550 for the rods that is created in the outer retina for the cones. 1026 00:56:40,550 --> 00:56:43,030 So you create [INAUDIBLE]. 1027 00:56:43,030 --> 00:56:47,060 Here are the OFF, and here are the ON inputs to the ON and OFF 1028 00:56:47,060 --> 00:56:48,710 ganglion cells. 1029 00:56:48,710 --> 00:56:51,390 Now because of this arrangement, what happens 1030 00:56:51,390 --> 00:56:56,370 is that the size of the receptive 1031 00:56:56,370 --> 00:56:59,170 fields under dark adaptive conditions 1032 00:56:59,170 --> 00:57:04,300 is bigger because a bigger range of connections from the rods 1033 00:57:04,300 --> 00:57:05,505 to the ganglion cells. 1034 00:57:07,660 --> 00:57:09,950 So all this is nice wiring that finally, 1035 00:57:09,950 --> 00:57:12,230 after many, many years of experiments, 1036 00:57:12,230 --> 00:57:13,630 has been clarified. 1037 00:57:13,630 --> 00:57:14,785 Sorry it is so complicated. 1038 00:57:16,700 --> 00:57:18,950 That's just how it is. 1039 00:57:18,950 --> 00:57:23,340 Explains then the claim that you have bigger receptive fields 1040 00:57:23,340 --> 00:57:24,980 at night than in the daytime. 1041 00:57:24,980 --> 00:57:27,015 And now that has been generally accepted. 1042 00:57:28,210 --> 00:57:32,990 OK so now the central conclusions that we come to 1043 00:57:32,990 --> 00:57:36,160 is that ON and OFF channels have emerged 1044 00:57:36,160 --> 00:57:39,380 in the course of evolution to enable organisms 1045 00:57:39,380 --> 00:57:44,040 to process light both incrementally and decrementally 1046 00:57:44,040 --> 00:57:48,110 for being able to see things rapidly and quickly. 1047 00:57:48,110 --> 00:57:48,870 All right? 1048 00:57:48,870 --> 00:57:50,500 So that is the prime function. 1049 00:57:50,500 --> 00:57:54,200 Nature has gone to incredible extent 1050 00:57:54,200 --> 00:57:58,250 to modify the basic organization of the visual system 1051 00:57:58,250 --> 00:58:01,170 and the retina to create a way to be 1052 00:58:01,170 --> 00:58:03,510 able to process both light increment 1053 00:58:03,510 --> 00:58:05,070 and decrement rapidly. 1054 00:58:05,070 --> 00:58:08,900 Now that may provide you with a little cute mnemonic, 1055 00:58:08,900 --> 00:58:10,550 if you will. 1056 00:58:10,550 --> 00:58:11,830 Here we have a fish. 1057 00:58:11,830 --> 00:58:15,645 Fish also, believe it or not, have ON and OFF channels. 1058 00:58:16,794 --> 00:58:20,110 Now what happens is if below here there 1059 00:58:20,110 --> 00:58:23,080 is a predator-- a large fish that 1060 00:58:23,080 --> 00:58:28,570 is trying to catch this fish-- because of the sun shining 1061 00:58:28,570 --> 00:58:30,530 on it, it reflects the light, and so 1062 00:58:30,530 --> 00:58:33,910 this fish would see this particular predator 1063 00:58:33,910 --> 00:58:35,740 by virtue of light increment. 1064 00:58:35,740 --> 00:58:36,870 Got it? 1065 00:58:36,870 --> 00:58:40,540 By contrast, if you have osprey up here 1066 00:58:40,540 --> 00:58:42,520 that's trying to catch this fish, 1067 00:58:42,520 --> 00:58:46,380 that osprey against the sky would be seen as a dark object. 1068 00:58:46,380 --> 00:58:47,480 OK? 1069 00:58:47,480 --> 00:58:54,490 And so now, since this fish has both ON and OFF cells 1070 00:58:54,490 --> 00:58:57,730 in its retina, it's going to do this. 1071 00:58:57,730 --> 00:58:58,400 You ready? 1072 00:59:00,630 --> 00:59:02,750 He's going to escape, OK? 1073 00:59:04,440 --> 00:59:08,680 So that then, in a nutshell, tells us 1074 00:59:08,680 --> 00:59:16,670 why we have ON and OFF channels in the visual system-- namely 1075 00:59:16,670 --> 00:59:20,460 to enable us to process both light increment and light 1076 00:59:20,460 --> 00:59:21,390 decrement effectively. 1077 00:59:22,530 --> 00:59:24,600 And as I've mentioned to you before, 1078 00:59:24,600 --> 00:59:28,410 whenever you read or write, you see things 1079 00:59:28,410 --> 00:59:32,770 mostly by virtue of your OFF system 1080 00:59:32,770 --> 00:59:39,140 because you have dark print or a dark pen on a light background. 1081 00:59:40,450 --> 00:59:42,795 But of course the obverse is also the case. 1082 00:59:44,530 --> 00:59:48,320 So this was known for ages and ages. 1083 00:59:48,320 --> 00:59:51,670 And that's why eventually, instead 1084 00:59:51,670 --> 00:59:54,310 of having print in which you have 1085 00:59:54,310 --> 00:59:58,170 a black page with white letters, you now 1086 00:59:58,170 --> 01:00:00,880 a white page with black letters, because that's 1087 01:00:00,880 --> 01:00:04,170 much more economical to achieve. 1088 01:00:04,170 --> 01:00:06,940 And you can read both light incremental 1089 01:00:06,940 --> 01:00:10,400 and light decremental letters equally well 1090 01:00:10,400 --> 01:00:13,570 because we have these ON and OFF channels. 1091 01:00:13,570 --> 01:00:14,230 OK. 1092 01:00:14,230 --> 01:00:17,800 So on the basis of this then, we are 1093 01:00:17,800 --> 01:00:24,460 ready to summarize why we have this remarkable duality 1094 01:00:24,460 --> 01:00:30,540 in the retina, originating in the ON and OFF channels, 1095 01:00:30,540 --> 01:00:32,820 whose circuits we by now, I presume, 1096 01:00:32,820 --> 01:00:35,060 you understand pretty well. 1097 01:00:35,060 --> 01:00:37,890 So just to reiterate for the umpteenth time, which 1098 01:00:37,890 --> 01:00:40,622 is easy to remember by now, all photoreceptors 1099 01:00:40,622 --> 01:00:42,510 hyperpolarize to light. 1100 01:00:42,510 --> 01:00:47,390 Secondly, the cone driven ON and OFF channels 1101 01:00:47,390 --> 01:00:51,120 originate at the level of the retinal bipolar cells. 1102 01:00:51,120 --> 01:00:51,730 OK? 1103 01:00:51,730 --> 01:00:54,270 For ON bipolars you have a system, 1104 01:00:54,270 --> 01:00:56,785 which involves sign-inverting synapses. 1105 01:00:57,870 --> 01:00:58,910 OK? 1106 01:00:58,910 --> 01:01:03,686 The neuron transmitted by the way of the photoreceptors 1107 01:01:03,686 --> 01:01:05,500 is glutamate. 1108 01:01:05,500 --> 01:01:13,090 And you come to the receptor sites-- the mGluR6 receptor is 1109 01:01:13,090 --> 01:01:20,050 the one that inverts the signal for the ON bipolar cells. 1110 01:01:21,110 --> 01:01:27,450 And the mGluR1 and 2 is the neurotransmitter receptor site 1111 01:01:27,450 --> 01:01:30,710 for the OFF bipolar cells. 1112 01:01:30,710 --> 01:01:33,500 Now APB-- can important to remember 1113 01:01:33,500 --> 01:01:35,880 this-- is that glutamate analog. 1114 01:01:35,880 --> 01:01:38,980 A lot of people make a mistake and think it's an antagonist. 1115 01:01:38,980 --> 01:01:40,900 It's a glutamate analog. 1116 01:01:40,900 --> 01:01:44,515 So what happens is that it blocks the ON bipolar. 1117 01:01:44,515 --> 01:01:47,850 Now let me say just a couple more words about this. 1118 01:01:51,060 --> 01:01:54,960 We move our eyes about three times a second. 1119 01:01:54,960 --> 01:02:02,560 Every time you move your eye some mechanisms in the retina 1120 01:02:02,560 --> 01:02:05,690 wipe the slate clean, so to speak, 1121 01:02:05,690 --> 01:02:09,339 because if it didn't, then the image that 1122 01:02:09,339 --> 01:02:11,380 would fall on the retina after you moved your eye 1123 01:02:11,380 --> 01:02:13,530 would interfere with the image that 1124 01:02:13,530 --> 01:02:15,510 had fallen on the eye beforehand. 1125 01:02:15,510 --> 01:02:18,010 So there's an incredibly rapid system 1126 01:02:18,010 --> 01:02:21,530 that breaks down the molecular arrangement 1127 01:02:21,530 --> 01:02:27,910 of glutamate and many other transmitters in the retina 1128 01:02:27,910 --> 01:02:30,880 so that with each movement of the eye, 1129 01:02:30,880 --> 01:02:32,620 you can see things clearly. 1130 01:02:32,620 --> 01:02:34,830 Now there is an exception to that, of course, 1131 01:02:34,830 --> 01:02:36,720 under extreme conditions. 1132 01:02:36,720 --> 01:02:39,390 We have what is called "after images," 1133 01:02:39,390 --> 01:02:41,450 like when you look at the sun for a while. 1134 01:02:41,450 --> 01:02:45,996 Then you will see an after image lingering on in your eye. 1135 01:02:45,996 --> 01:02:49,690 But under normal illumination conditions, 1136 01:02:49,690 --> 01:02:53,910 the slate is wiped clean with every shift in the eye. 1137 01:02:54,920 --> 01:02:56,290 Quite amazing. 1138 01:02:56,290 --> 01:02:56,790 All right. 1139 01:02:56,790 --> 01:03:00,300 Then APB blocks the ON response of retinal ganglion cells. 1140 01:03:00,300 --> 01:03:02,970 The OFF response and center-surround antagonism 1141 01:03:02,970 --> 01:03:03,990 are unaffected. 1142 01:03:05,430 --> 01:03:08,630 APB blocks lighted responses in the cortex, 1143 01:03:08,630 --> 01:03:11,540 but has no effect on orientation, direction, 1144 01:03:11,540 --> 01:03:13,385 and spatial frequency selectivity. 1145 01:03:15,500 --> 01:03:19,400 APB reduces the sensitivity for light increment, 1146 01:03:19,400 --> 01:03:24,520 and the ON and OFF channels for rods arise in the inner retina. 1147 01:03:24,520 --> 01:03:25,970 And I should add here that there's 1148 01:03:25,970 --> 01:03:31,140 only one kind of rod bipolar, which is the ON-type. 1149 01:03:31,140 --> 01:03:33,070 There are no OFF-type rod biopolars. 1150 01:03:34,080 --> 01:03:41,650 Then in most primates there are only ON rod bipolars. 1151 01:03:41,650 --> 01:03:44,170 The rod ON and OFF channels are created 1152 01:03:44,170 --> 01:03:46,700 in the inner retina by the amacrine cells, 1153 01:03:46,700 --> 01:03:49,750 predominately by the so-called A2 amacrine cell, 1154 01:03:49,750 --> 01:03:50,970 as I told you. 1155 01:03:50,970 --> 01:03:54,090 Lastly, excitatory signals are generated 1156 01:03:54,090 --> 01:03:56,820 for both light increment and for light decrement 1157 01:03:56,820 --> 01:04:00,280 by virtue of the ON and OFF channels. 1158 01:04:00,280 --> 01:04:02,600 So those are the major conclusions 1159 01:04:02,600 --> 01:04:10,380 that we need to make about this remarkable achievement of how 1160 01:04:10,380 --> 01:04:13,780 the visual system works, by virtue of having created 1161 01:04:13,780 --> 01:04:18,820 the ON and the OFF channels, by virtue of having then 1162 01:04:18,820 --> 01:04:23,020 done this, by virtue of creating from a single-ended system 1163 01:04:23,020 --> 01:04:26,050 of the photoreceptors, a double-ended system 1164 01:04:26,050 --> 01:04:28,030 at the level of the bipolar cells. 1165 01:04:28,030 --> 01:04:31,285 So that then is-- sorry how complicated 1166 01:04:31,285 --> 01:04:35,830 it is-- the basic layout of the retina and the ON and OFF 1167 01:04:35,830 --> 01:04:37,030 channels. 1168 01:04:37,030 --> 01:04:42,790 Next time we are going to talk about yet another subdivision 1169 01:04:42,790 --> 01:04:46,260 in retinal ganglion cells-- the so-called midget and parasol 1170 01:04:46,260 --> 01:04:46,840 cells. 1171 01:04:46,840 --> 01:04:49,240 I think I've mentioned to you before that we 1172 01:04:49,240 --> 01:04:53,290 have several different classes of retinal ganglion cells-- 1173 01:04:53,290 --> 01:04:54,320 not just ON and OFF. 1174 01:04:56,030 --> 01:04:59,210 And the so-called midget and parasol cells 1175 01:04:59,210 --> 01:05:01,257 have ON and OFF subdivisions. 1176 01:05:01,257 --> 01:05:02,840 And then there are several other cells 1177 01:05:02,840 --> 01:05:04,256 that do all kinds of other things. 1178 01:05:04,256 --> 01:05:05,950 We will talk about some of those. 1179 01:05:05,950 --> 01:05:09,410 But the overwhelming, largest number of cells in the retina 1180 01:05:09,410 --> 01:05:12,120 are the midget and the parasol, and so they 1181 01:05:12,120 --> 01:05:14,970 deserve the greatest scrutiny as to why 1182 01:05:14,970 --> 01:05:17,040 we have those two systems. 1183 01:05:17,040 --> 01:05:20,140 And that's we are going to discuss the next time. 1184 01:05:20,140 --> 01:05:25,880 So that pretty well finishes what I had to cover today, 1185 01:05:25,880 --> 01:05:28,060 and so if any of you have any questions, 1186 01:05:28,060 --> 01:05:31,680 I will be happy to try to answer them for you, as long as it 1187 01:05:31,680 --> 01:05:34,500 pertains, of course, to the ON and OFF channels. 1188 01:05:34,500 --> 01:05:38,170 Anybody not clear on the rules of how 1189 01:05:38,170 --> 01:05:42,890 APB works-- that it's an analog, that it fills the receptor 1190 01:05:42,890 --> 01:05:46,690 sites of the ON bipolar cells, rendering 1191 01:05:46,690 --> 01:05:50,795 them insensitive to subsequent light stimulation? 1192 01:05:50,795 --> 01:05:53,230 Now I should add maybe one more thing here 1193 01:05:53,230 --> 01:05:57,730 is that unlike the glutamate, which is broken down 1194 01:05:57,730 --> 01:06:02,630 in milliseconds, this artificial substance-- APB-- 1195 01:06:02,630 --> 01:06:05,260 there's no natural optic mechanism for it. 1196 01:06:05,260 --> 01:06:10,810 And so it lingers on, and that's why it is so effective. 1197 01:06:12,310 --> 01:06:15,260 And it has to be washed out of the eye-- you typically 1198 01:06:15,260 --> 01:06:21,330 have to wait 10-- 15 minutes for the eye to return to normal 1199 01:06:21,330 --> 01:06:25,950 because there's no rapid optic mechanism for the APB, 1200 01:06:25,950 --> 01:06:27,765 in contrast to the glutamate. 1201 01:06:33,220 --> 01:06:35,390 Well it sounds like I was reasonably clear. 1202 01:06:36,540 --> 01:06:41,020 I hope you can absorb this and marvel 1203 01:06:41,020 --> 01:06:45,980 at the inventiveness, if you will, of evolution 1204 01:06:45,980 --> 01:06:48,960 to have created this incredible mechanisms that we 1205 01:06:48,960 --> 01:06:49,815 see in the retina. 1206 01:06:49,815 --> 01:06:52,300 It's just dumb-founding. 1207 01:06:52,300 --> 01:06:53,500 Yes, it's just incredible. 1208 01:06:55,500 --> 01:07:01,390 So that then is what we going to finish with today. 1209 01:07:01,390 --> 01:07:03,360 And so I will see you Wednesday, and we 1210 01:07:03,360 --> 01:07:06,600 talk about the midget and parasol systems, which 1211 01:07:06,600 --> 01:07:08,610 is also very interesting, by the way. 1212 01:07:08,610 --> 01:07:10,160 And I hope you've enjoyed hearing 1213 01:07:10,160 --> 01:07:13,560 about what those two systems are for.