1 00:00:00,250 --> 00:00:01,800 The following content is provided 2 00:00:01,800 --> 00:00:04,040 under a Creative Commons license. 3 00:00:04,040 --> 00:00:06,890 Your support will help MIT OpenCourseWare continue 4 00:00:06,890 --> 00:00:10,740 to offer high quality educational resources for free. 5 00:00:10,740 --> 00:00:13,360 To make a donation or view additional materials 6 00:00:13,360 --> 00:00:17,241 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,241 --> 00:00:17,866 at ocw.mit.edu. 8 00:00:23,350 --> 00:00:26,910 PROFESSOR: Just a little bit from last time. 9 00:00:26,910 --> 00:00:31,340 I won't say too much about the Polyakoff work on cortex, 10 00:00:31,340 --> 00:00:33,605 but you'll notice that like Mesulam, he 11 00:00:33,605 --> 00:00:39,600 has three kinds of cortex, except his third kind, which 12 00:00:39,600 --> 00:00:44,650 he says is the most advanced area of cognitive functions, 13 00:00:44,650 --> 00:00:48,711 he includes a lot more in this area, 14 00:00:48,711 --> 00:00:54,240 in human-- would include a lot of Mesulam uni-modal visual 15 00:00:54,240 --> 00:00:56,330 association cortex. 16 00:00:56,330 --> 00:00:57,510 That's the major difference. 17 00:00:57,510 --> 00:01:02,700 The other thing to note is just like most other people, 18 00:01:02,700 --> 00:01:05,670 they indicate that that most advanced cortex doesn't 19 00:01:05,670 --> 00:01:12,440 exist in rats and hedgehogs and similar animals. 20 00:01:12,440 --> 00:01:16,650 It's very little even in the dog. 21 00:01:16,650 --> 00:01:23,770 But remember what we said-- the area where our highest 22 00:01:23,770 --> 00:01:32,010 functions are localized, they are the multimodal association 23 00:01:32,010 --> 00:01:36,700 areas, which we postulated that multimodal cortex is 24 00:01:36,700 --> 00:01:38,870 the most primitive cortex. 25 00:01:38,870 --> 00:01:45,250 But it's the area that has expanded the most. 26 00:01:45,250 --> 00:01:47,860 The brain becomes far more compartmentalized and 27 00:01:47,860 --> 00:01:49,580 specialized with evolution. 28 00:01:49,580 --> 00:01:52,650 Human brains are probably the most compartmentalized, 29 00:01:52,650 --> 00:01:54,652 most specialized of all the animals. 30 00:02:00,210 --> 00:02:02,780 A little bit more about these that comes out 31 00:02:02,780 --> 00:02:07,240 of that Moscow work and some other topics. 32 00:02:07,240 --> 00:02:11,520 First of all, postnatal growth of different territories. 33 00:02:11,520 --> 00:02:15,890 He shows the amount of postnatal growth on the ordinate here, 34 00:02:15,890 --> 00:02:19,720 and he's just studied that, made measures 35 00:02:19,720 --> 00:02:22,060 for different regions of cortex. 36 00:02:22,060 --> 00:02:25,030 Just note here the first four bars 37 00:02:25,030 --> 00:02:29,360 are all multimodal association areas. 38 00:02:29,360 --> 00:02:32,610 F means-- he says frontal areas, but he 39 00:02:32,610 --> 00:02:37,390 means the prefrontal cortex-- middle, temple, 40 00:02:37,390 --> 00:02:41,350 inferior parietal, and the temporal parietal occipital 41 00:02:41,350 --> 00:02:45,419 area that's an area in between this multimodal cortex 42 00:02:45,419 --> 00:02:46,460 and the area [INAUDIBLE]. 43 00:02:51,690 --> 00:02:53,675 The second thing, then, is myelin genesis. 44 00:02:57,140 --> 00:03:03,105 This is a picture from Cecil and Oscar Vogt, who studied that. 45 00:03:03,105 --> 00:03:05,690 The areas to get their myelin first start 46 00:03:05,690 --> 00:03:08,890 in the heavy dots and the lights are the areas 47 00:03:08,890 --> 00:03:10,465 to acquire myelin last. 48 00:03:10,465 --> 00:03:14,330 You see that the multimodal association areas 49 00:03:14,330 --> 00:03:20,460 tend to be the areas that have expanded the most postnatally. 50 00:03:20,460 --> 00:03:24,080 The areas where we've been localizing the highest 51 00:03:24,080 --> 00:03:29,800 functions in humans tend to myelinate late. 52 00:03:29,800 --> 00:03:34,370 There are some exceptions in the limbic areas. 53 00:03:34,370 --> 00:03:38,580 This is from the work of Paul Flechsig. 54 00:03:38,580 --> 00:03:41,390 The numbers here in his pictures don't 55 00:03:41,390 --> 00:03:43,550 represent broadening areas. 56 00:03:43,550 --> 00:03:47,230 The numbers represent the order of appearance. 57 00:03:47,230 --> 00:03:51,110 Number one is the first place he saw myelin appearing. 58 00:03:51,110 --> 00:03:55,000 Number 45 is the last place. 59 00:03:55,000 --> 00:03:59,481 45 here in the lateral prefrontal area in humans. 60 00:04:02,130 --> 00:04:05,430 You see the early numbers in the primary visual area, 61 00:04:05,430 --> 00:04:07,625 primary sensory and motor areas. 62 00:04:11,390 --> 00:04:13,900 Primary auditory areas, they all myelinate very early, 63 00:04:13,900 --> 00:04:16,092 and you saw pictures of that way back when 64 00:04:16,092 --> 00:04:20,130 we were doing chapter six when I showed 65 00:04:20,130 --> 00:04:23,420 a picture from the work of Flechsig, 66 00:04:23,420 --> 00:04:27,130 a photograph of one of his sections of the human brain, 67 00:04:27,130 --> 00:04:29,780 a horizontal section. 68 00:04:29,780 --> 00:04:34,490 This is just the growth of the thickness of the association 69 00:04:34,490 --> 00:04:39,730 layers-- layer three. 70 00:04:39,730 --> 00:04:45,790 Here's prenatal growth of these five different areas, 71 00:04:45,790 --> 00:04:49,000 and I pointed out what they are from y fields, 72 00:04:49,000 --> 00:04:51,730 prefrontal cortex, and the Broca's area. 73 00:04:54,630 --> 00:04:57,650 They're all in the frontal lobe. 74 00:04:57,650 --> 00:05:02,030 Note here that these areas are still 75 00:05:02,030 --> 00:05:06,860 becoming thicker after age 15. 76 00:05:06,860 --> 00:05:10,120 He just has 15 and then the put the rest of them 77 00:05:10,120 --> 00:05:12,450 into the adult category. 78 00:05:12,450 --> 00:05:21,800 They're not completely finished growing even in the mid-teens. 79 00:05:21,800 --> 00:05:26,140 I said 15, but it's 12 years. 80 00:05:26,140 --> 00:05:28,570 I just want to mention Larry Benowitz' studies 81 00:05:28,570 --> 00:05:32,290 of these areas, like layers two and three. 82 00:05:32,290 --> 00:05:36,530 That's where he found the protein that is often 83 00:05:36,530 --> 00:05:38,870 referred to as the growth-associated protein 84 00:05:38,870 --> 00:05:42,630 because it's present in axons during early development. 85 00:05:42,630 --> 00:05:46,520 Fallout zones have a lot of growth-associated proteins. 86 00:05:46,520 --> 00:05:49,620 It seems to be correlated with periods when processes 87 00:05:49,620 --> 00:05:51,470 have these filopodia extending. 88 00:05:51,470 --> 00:05:54,740 Growing axons always have those. 89 00:05:54,740 --> 00:05:59,770 I studied it with Larry Benowitz in the hamster optic track, 90 00:05:59,770 --> 00:06:02,040 for example. 91 00:06:02,040 --> 00:06:05,770 We found that it's located all along the axon very early, 92 00:06:05,770 --> 00:06:09,510 and then when the arborization is occurring 93 00:06:09,510 --> 00:06:11,840 in the tectum and geniculate body. 94 00:06:11,840 --> 00:06:16,520 The gap 43 becomes localized to the terminal region 95 00:06:16,520 --> 00:06:22,230 and then declines after the maturation of the axons. 96 00:06:22,230 --> 00:06:27,170 But even in adult humans, Larry finds that protein 97 00:06:27,170 --> 00:06:30,500 localized in these associational areas, 98 00:06:30,500 --> 00:06:33,860 and those are the very areas that 99 00:06:33,860 --> 00:06:36,160 have been found by [? Ellie, ?] and now other people 100 00:06:36,160 --> 00:06:40,610 are confirming that-- that throughout the cortex, 101 00:06:40,610 --> 00:06:45,270 they look with modern imaging techniques and image cells 102 00:06:45,270 --> 00:06:46,740 over an extended period of time. 103 00:06:46,740 --> 00:06:51,410 They see remodeling happening, a lot of changes. 104 00:06:51,410 --> 00:06:57,570 We think that those many small neurons, many interneurons, 105 00:06:57,570 --> 00:06:59,210 mostly gabaeric interneurons. 106 00:06:59,210 --> 00:07:01,280 Whenever they've tried to localize the cell part, 107 00:07:01,280 --> 00:07:06,020 they find that there are these GABA-containing interneurons, 108 00:07:06,020 --> 00:07:11,840 the very neurons most of which don't originate in neocortex, 109 00:07:11,840 --> 00:07:14,710 in the neocortical ventricular layer-- they originate 110 00:07:14,710 --> 00:07:15,435 in other areas. 111 00:07:17,940 --> 00:07:21,547 OK, we don't have time to talk about dominant and non-dominant 112 00:07:21,547 --> 00:07:22,980 hemispheres. 113 00:07:22,980 --> 00:07:25,376 I just want to point out that they are anatomically 114 00:07:25,376 --> 00:07:27,520 a little bit different. 115 00:07:27,520 --> 00:07:29,560 Sometimes, the differences are rather large, 116 00:07:29,560 --> 00:07:34,430 like in the area around the auditory cortex, areas related 117 00:07:34,430 --> 00:07:40,540 to understanding and speech and production of speech. 118 00:07:40,540 --> 00:07:44,076 That work was done right here in Boston 119 00:07:44,076 --> 00:07:47,960 when Norman Geschwind, the famous behavioral neurologist, 120 00:07:47,960 --> 00:07:50,325 was still alive and his associate, 121 00:07:50,325 --> 00:07:53,400 Al Galaburda did those studies, and he's still 122 00:07:53,400 --> 00:07:55,640 working at the Beth Israel Hospital. 123 00:08:00,810 --> 00:08:04,250 The ideas on thalamic evolution, I'm just going to let you read. 124 00:08:04,250 --> 00:08:06,470 I've gone over them before. 125 00:08:06,470 --> 00:08:12,130 I just summarized them in these two slides. 126 00:08:12,130 --> 00:08:18,662 I want to go on and talk about development and plasticity 127 00:08:18,662 --> 00:08:21,360 in the neocortex. 128 00:08:21,360 --> 00:08:25,180 One thing first, very relevant to this topic-- this just 129 00:08:25,180 --> 00:08:28,250 came out fairly recently in the February 20th issue 130 00:08:28,250 --> 00:08:31,680 of Cell-- neurogenesis in the striatum 131 00:08:31,680 --> 00:08:33,100 of the adult human brain. 132 00:08:33,100 --> 00:08:34,210 Here's what they did. 133 00:08:34,210 --> 00:08:39,150 They used carbon-14-- natural labelling of humans exposed 134 00:08:39,150 --> 00:08:42,919 to carbon-14 due to atomic testing. 135 00:08:42,919 --> 00:08:45,940 They're eating foods and so forth. 136 00:08:45,940 --> 00:08:49,240 Some newly-generated neurons end up 137 00:08:49,240 --> 00:08:50,930 being labeled with carbon-14. 138 00:08:50,930 --> 00:08:55,810 If some sensitive measures define them, 139 00:08:55,810 --> 00:08:58,270 they can get measures of neurogenesis. 140 00:08:58,270 --> 00:09:01,340 They can see that rostral migratory stream 141 00:09:01,340 --> 00:09:05,810 that we know from studies of rodents migrates 142 00:09:05,810 --> 00:09:08,660 into the olfactory bulbs and that's 143 00:09:08,660 --> 00:09:12,586 why you get turnover of the small granule cells, the most 144 00:09:12,586 --> 00:09:16,540 numerous cell type in the olfactory bulb. 145 00:09:16,540 --> 00:09:21,113 I think it's around 40-day period there. 146 00:09:21,113 --> 00:09:23,860 They could turnover completely. 147 00:09:23,860 --> 00:09:25,780 There's a lot of generation. 148 00:09:25,780 --> 00:09:29,820 This study says that in humans, those cells 149 00:09:29,820 --> 00:09:34,780 get diverted into the striatum. 150 00:09:34,780 --> 00:09:38,145 In the rodent, they go right past the striatum, 151 00:09:38,145 --> 00:09:40,870 they're generated in the lateral ventricle-- 152 00:09:40,870 --> 00:09:45,850 the ventricular layer there around the lateral ventricle. 153 00:09:45,850 --> 00:09:48,480 But these don't continue into the olfactory bulb. 154 00:09:48,480 --> 00:09:50,270 It wasn't clear to me. 155 00:09:50,270 --> 00:09:54,274 I haven't even completely read every detail of the article. 156 00:09:54,274 --> 00:09:55,690 It's not clear whether any of them 157 00:09:55,690 --> 00:09:58,452 get into the olfactory bulb in humans. 158 00:09:58,452 --> 00:10:00,410 That would be a big surprise if that were true, 159 00:10:00,410 --> 00:10:04,610 but it's a fascinating finding if it 160 00:10:04,610 --> 00:10:08,200 can be confirmed in other labs because it would indicate that 161 00:10:08,200 --> 00:10:10,970 in each of the two major forebrain systems 162 00:10:10,970 --> 00:10:13,360 for learning that we talked about in this class-- 163 00:10:13,360 --> 00:10:19,550 the hippocampus and the corpus striatum, 164 00:10:19,550 --> 00:10:24,140 and that includes for learning both dorsal and ventral 165 00:10:24,140 --> 00:10:26,670 striatum. 166 00:10:26,670 --> 00:10:28,990 He talks as if the new neurons are all 167 00:10:28,990 --> 00:10:30,500 going into dorsal striatum. 168 00:10:30,500 --> 00:10:34,360 I'm not sure that that will turn out to be true. 169 00:10:34,360 --> 00:10:37,540 The point is, new neurons are going right into the striatum 170 00:10:37,540 --> 00:10:41,080 in humans. 171 00:10:41,080 --> 00:10:43,090 Of course, now we have to look carefully 172 00:10:43,090 --> 00:10:45,030 to see if there's none of them going 173 00:10:45,030 --> 00:10:46,710 to the striatum in other animals. 174 00:10:46,710 --> 00:10:50,780 I would suspect in other very large animals 175 00:10:50,780 --> 00:10:53,540 that they probably do, but so far, we only 176 00:10:53,540 --> 00:10:57,730 know about human because the studies just 177 00:10:57,730 --> 00:10:59,432 haven't been done yet. 178 00:10:59,432 --> 00:11:00,650 AUDIENCE: [INAUDIBLE]? 179 00:11:00,650 --> 00:11:01,430 PROFESSOR: Sorry? 180 00:11:01,430 --> 00:11:02,346 AUDIENCE: [INAUDIBLE]? 181 00:11:06,520 --> 00:11:08,400 PROFESSOR: The carbon-14 data dating 182 00:11:08,400 --> 00:11:10,580 was done they were alive, naturally, 183 00:11:10,580 --> 00:11:16,020 because they were exposed to-- the fallout contains carbon-14. 184 00:11:16,020 --> 00:11:18,680 A natural experiment. 185 00:11:18,680 --> 00:11:22,819 Unnatural, actually, but it's atomic tested, yes. 186 00:11:22,819 --> 00:11:23,737 AUDIENCE: [INAUDIBLE]? 187 00:11:26,950 --> 00:11:30,080 PROFESSOR: Very, very interesting question. 188 00:11:30,080 --> 00:11:33,100 Could be exposure to radioactivity 189 00:11:33,100 --> 00:11:35,790 itself caused some abnormalities. 190 00:11:35,790 --> 00:11:39,930 We don't think so because the levels are very low. 191 00:11:39,930 --> 00:11:41,560 But it's still an interesting question, 192 00:11:41,560 --> 00:11:45,830 and I hope it leads to a lot more work 193 00:11:45,830 --> 00:11:49,930 because we've only recently seen a lot of work 194 00:11:49,930 --> 00:11:54,920 on hippocampal turnover and its relationship to learning. 195 00:11:54,920 --> 00:11:57,310 We know that animals are learning a lot 196 00:11:57,310 --> 00:11:59,110 and, exposed to enriching environments, 197 00:11:59,110 --> 00:12:02,150 do generate more cells. 198 00:12:02,150 --> 00:12:04,900 We know the stress reduces cell turnover. 199 00:12:08,690 --> 00:12:10,090 When we talked about development, 200 00:12:10,090 --> 00:12:14,966 we had these four major events-- neurolation 201 00:12:14,966 --> 00:12:17,575 and the formation of the neural tube. 202 00:12:17,575 --> 00:12:20,965 That is formation of the neural plate and then the neural tube. 203 00:12:20,965 --> 00:12:26,180 And then proliferation of cells, and then migration, 204 00:12:26,180 --> 00:12:29,140 and finally, the growth of axons and the dendrites 205 00:12:29,140 --> 00:12:32,680 that we call the differentiation of the cell, the adult cell. 206 00:12:37,690 --> 00:12:39,210 These are questions here. 207 00:12:39,210 --> 00:12:42,335 First of all, what is the subpia granularly? 208 00:12:42,335 --> 00:12:46,120 When we talked about proliferation, 209 00:12:46,120 --> 00:12:54,200 we talked about cells dividing in the cell cycle. 210 00:12:54,200 --> 00:12:57,730 You see them synthesizing DNA here and then 211 00:12:57,730 --> 00:13:01,465 splitting into two, and they split in one of two ways, 212 00:13:01,465 --> 00:13:03,670 either symmetrically or asymmetrically, 213 00:13:03,670 --> 00:13:05,380 and that had different consequences 214 00:13:05,380 --> 00:13:09,610 because proteins are not distributed 215 00:13:09,610 --> 00:13:13,890 the same throughout the cell. 216 00:13:13,890 --> 00:13:17,791 Proteins tend to be distributed differently 217 00:13:17,791 --> 00:13:20,040 and nearer the ventricle than away from the ventricle. 218 00:13:20,040 --> 00:13:22,700 If they split asymmetrically, they 219 00:13:22,700 --> 00:13:26,420 tend to have much more of that protein 220 00:13:26,420 --> 00:13:29,350 in just part of the cell. 221 00:13:29,350 --> 00:13:33,490 The ones that are further from the ventricle 222 00:13:33,490 --> 00:13:36,030 become post-mitotic. 223 00:13:36,030 --> 00:13:39,300 They migrate towards their adult locations 224 00:13:39,300 --> 00:13:44,944 and the others stay mitotic until the end 225 00:13:44,944 --> 00:13:46,235 of the period of proliferation. 226 00:13:48,880 --> 00:13:53,640 OK, but what is the subpia granular there? 227 00:13:53,640 --> 00:13:55,560 You could say these are granule cells. 228 00:13:55,560 --> 00:13:58,085 They're the generating cells of the ventricle. 229 00:13:58,085 --> 00:13:59,535 They're very small cells. 230 00:13:59,535 --> 00:14:01,770 That's why we call them granular. 231 00:14:01,770 --> 00:14:04,770 The subpial granular layer, you may know, 232 00:14:04,770 --> 00:14:08,330 exists in the cerebellum in all the animals 233 00:14:08,330 --> 00:14:11,310 that have been studied. 234 00:14:11,310 --> 00:14:14,186 Cells migrate from the rhombic lip area 235 00:14:14,186 --> 00:14:16,310 of the hindbrain, the other plate of the hindbrain, 236 00:14:16,310 --> 00:14:19,440 and migrate up into the cerebellar cortex. 237 00:14:19,440 --> 00:14:23,020 But then they keep dividing right under the pia 238 00:14:23,020 --> 00:14:25,060 and the cells that are generated in the pia 239 00:14:25,060 --> 00:14:29,050 then migrate down into the cerebellar cortex 240 00:14:29,050 --> 00:14:32,430 and form the granule cells for the cerebellar cortex. 241 00:14:32,430 --> 00:14:37,855 Apparently, in larger-brained animals-- animals 242 00:14:37,855 --> 00:14:42,930 that have a lot more cortext-- again, 243 00:14:42,930 --> 00:14:47,520 there's really numerous small cells, granular cells, 244 00:14:47,520 --> 00:14:49,310 in the cortex. 245 00:14:49,310 --> 00:14:52,960 The larger the brain, the more of them there are. 246 00:14:52,960 --> 00:14:56,680 They develop this transient, generative layer 247 00:14:56,680 --> 00:15:00,280 below the pia in certain parts of the brain. 248 00:15:00,280 --> 00:15:02,340 That's the subpial granular layer. 249 00:15:02,340 --> 00:15:04,460 It's not present in the lab animals 250 00:15:04,460 --> 00:15:07,219 which are normally used. 251 00:15:07,219 --> 00:15:09,510 It's not present in the mice and the rats and hamsters. 252 00:15:19,680 --> 00:15:24,260 Now, these two types of cell division 253 00:15:24,260 --> 00:15:27,665 were related by Rakic, Pashko Rakic. 254 00:15:27,665 --> 00:15:29,710 This just says what I talked about. 255 00:15:29,710 --> 00:15:32,823 This is one of Rakic's illustrations, 256 00:15:32,823 --> 00:15:38,000 but he pointed out that the period of symmetric and also 257 00:15:38,000 --> 00:15:43,870 of asymmetric cell division in the monkey 258 00:15:43,870 --> 00:15:49,140 is-- the periods are shorter than in humans. 259 00:15:49,140 --> 00:15:54,940 He said that even one additional symmetrical cell division 260 00:15:54,940 --> 00:15:58,655 should result in a considerably larger cortex. 261 00:15:58,655 --> 00:16:02,150 The human, just by continuing several more days, 262 00:16:02,150 --> 00:16:04,830 is going to end up with a much larger cortex. 263 00:16:04,830 --> 00:16:08,480 We know this is under genetic control. 264 00:16:08,480 --> 00:16:11,270 What about asymmetric cell division? 265 00:16:11,270 --> 00:16:12,510 What should happen then? 266 00:16:15,900 --> 00:16:23,940 Well, what should happen is you look at his picture here. 267 00:16:23,940 --> 00:16:27,310 Here's the ventricle down here. 268 00:16:27,310 --> 00:16:29,410 Here it is in the cells chain. 269 00:16:29,410 --> 00:16:31,730 The cells are generated in ventricular 270 00:16:31,730 --> 00:16:33,430 and then also the subventricular layer. 271 00:16:37,170 --> 00:16:41,570 The ones that are migrating due to asymmetric cell division as 272 00:16:41,570 --> 00:16:45,710 more continue to be generated by the stem cells down here, 273 00:16:45,710 --> 00:16:49,570 you can have many cells moving, as he shows here-- many cells 274 00:16:49,570 --> 00:16:53,980 moving along the same radial glial cell up 275 00:16:53,980 --> 00:16:56,300 into the cortical plate. 276 00:16:56,300 --> 00:16:58,150 The more asymmetric cell division 277 00:16:58,150 --> 00:17:01,090 there is, the thicker the cortex should become. 278 00:17:01,090 --> 00:17:05,677 The human cortex is considerably thicker than the monkey. 279 00:17:05,677 --> 00:17:08,010 We have a longer period of his asymmetric cell division. 280 00:17:11,079 --> 00:17:14,823 This just illustrates these periods, 281 00:17:14,823 --> 00:17:19,040 and I summarize it here. 282 00:17:19,040 --> 00:17:25,060 He wrote about that back in '95, Trends in Science. 283 00:17:25,060 --> 00:17:29,990 I show pictures, one from Rakic, the monkey-- only the earlier 284 00:17:29,990 --> 00:17:33,710 periods where you see these different layers designated-- 285 00:17:33,710 --> 00:17:37,230 ventricular and subventricular zones where the mitoses are 286 00:17:37,230 --> 00:17:41,540 occurring, and then an intermediate zone, where there 287 00:17:41,540 --> 00:17:45,170 are migrating cells but they don't stay there. 288 00:17:45,170 --> 00:17:48,680 That becomes the layer of the white matter. 289 00:17:48,680 --> 00:17:54,230 Then there's a subplate layer and a cortical plate. 290 00:17:54,230 --> 00:17:57,710 The cortical plate is where the cells collect. 291 00:17:57,710 --> 00:18:02,080 We normally call it the cortical plate in the period 292 00:18:02,080 --> 00:18:05,710 when you can't differentiate different layers. 293 00:18:05,710 --> 00:18:09,880 He shows some of them beginning to differentiate here 294 00:18:09,880 --> 00:18:12,110 and many of them not differentiating. 295 00:18:12,110 --> 00:18:17,630 At the top, mostly process-- just a few neurons. 296 00:18:17,630 --> 00:18:19,300 Call that the marginal zone. 297 00:18:19,300 --> 00:18:22,000 And then he's got in parenthesis here 298 00:18:22,000 --> 00:18:25,950 the subpial granular layer-- that's what SG is. 299 00:18:25,950 --> 00:18:28,690 This is from our work, work I did 300 00:18:28,690 --> 00:18:32,460 with Janice Naegele in her Ph.D. work 301 00:18:32,460 --> 00:18:36,480 where we're showing postnatal day one, postnatal day 302 00:18:36,480 --> 00:18:44,440 five in an adult hamster and labeling those same things, 303 00:18:44,440 --> 00:18:46,350 except there's no obvious subventricular 304 00:18:46,350 --> 00:18:48,050 layer in the hamster. 305 00:18:48,050 --> 00:18:52,380 Animals with a larger cortex tend to develop that. 306 00:18:52,380 --> 00:18:55,250 Notice here at postnatal day five, 307 00:18:55,250 --> 00:18:57,627 there's a layer five and six that 308 00:18:57,627 --> 00:19:00,870 have differentiated so you can identify them. 309 00:19:00,870 --> 00:19:04,080 But above that, we just call it the cortical plate 310 00:19:04,080 --> 00:19:08,730 because you can't see separate layers two, three, and four. 311 00:19:08,730 --> 00:19:09,490 Here's the adult. 312 00:19:09,490 --> 00:19:10,615 You can see all the layers. 313 00:19:18,860 --> 00:19:22,380 We looked at that picture of migration. 314 00:19:22,380 --> 00:19:28,180 What do we mean by the inside out pattern of migration? 315 00:19:28,180 --> 00:19:36,290 It has to do with when cells undergo their final mitosis 316 00:19:36,290 --> 00:19:38,180 and migrate. 317 00:19:38,180 --> 00:19:40,790 That's the birthday of the cell. 318 00:19:40,790 --> 00:19:43,890 We don't say they're born yet when they're just generating. 319 00:19:43,890 --> 00:19:47,730 It's only when they become post-mitotic and they migrate. 320 00:19:47,730 --> 00:19:50,115 You say that's the birth date, when they finish mitosis. 321 00:19:55,640 --> 00:20:00,250 The inside out pattern, this is the picture we were looking at. 322 00:20:00,250 --> 00:20:03,540 This is from the study at Harvard 323 00:20:03,540 --> 00:20:07,420 when Pashko Rakic was at Harvard. 324 00:20:07,420 --> 00:20:09,825 He had a very good technician that 325 00:20:09,825 --> 00:20:13,760 had come here from Vietnam, a Vietnamese couple 326 00:20:13,760 --> 00:20:17,410 that I helped in getting settled here, 327 00:20:17,410 --> 00:20:22,320 and then I found her a job with Pashko Rakic. 328 00:20:22,320 --> 00:20:25,960 She did this fantastic work with him 329 00:20:25,960 --> 00:20:28,760 where they labeled cells in the monkey 330 00:20:28,760 --> 00:20:37,490 by injecting the uterus of the mother at various stages. 331 00:20:37,490 --> 00:20:42,930 Here, you see this is e40, so this is about e45. 332 00:20:42,930 --> 00:20:47,500 When they injected the tritiated thymidine at e45 333 00:20:47,500 --> 00:20:53,120 and then waited until the animal's cortex differentiated, 334 00:20:53,120 --> 00:20:55,400 they found the labeled cells here 335 00:20:55,400 --> 00:20:58,530 at the bottom of layer six. 336 00:20:58,530 --> 00:21:06,330 If they waited much longer here to embryonic day 90, 337 00:21:06,330 --> 00:21:08,380 all of the cells that were labeled 338 00:21:08,380 --> 00:21:12,180 are up here in layers two and three. 339 00:21:12,180 --> 00:21:18,200 In between, you have this pattern-- earliest 340 00:21:18,200 --> 00:21:20,780 born cells end up at the bottom. 341 00:21:20,780 --> 00:21:27,170 The later born cells then have to migrate past the others. 342 00:21:27,170 --> 00:21:33,080 They're generated from-- this is inside, near the ventricle. 343 00:21:33,080 --> 00:21:37,200 This is outside, near the pia. 344 00:21:37,200 --> 00:21:38,620 That's the inside out pattern. 345 00:21:38,620 --> 00:21:40,520 That's all we mean by it. 346 00:21:40,520 --> 00:21:42,100 The same thing has been discovered 347 00:21:42,100 --> 00:21:45,050 and was known earlier from the rodent work 348 00:21:45,050 --> 00:21:47,345 where they use other methods of labeling initially. 349 00:21:50,480 --> 00:21:54,960 It's also been done with tritiated thymidine 350 00:21:54,960 --> 00:22:00,400 for labeling the cells at their last birthday. 351 00:22:00,400 --> 00:22:02,710 There's other methods of labeling, too, 352 00:22:02,710 --> 00:22:03,555 that you can use. 353 00:22:06,830 --> 00:22:10,430 What are the other proliferative zones 354 00:22:10,430 --> 00:22:12,380 other than the ventricular zone? 355 00:22:12,380 --> 00:22:14,460 We've mentioned them before. 356 00:22:14,460 --> 00:22:16,210 We talked about it mainly way back 357 00:22:16,210 --> 00:22:20,450 in chapter 12, where there's some illustrations-- 358 00:22:20,450 --> 00:22:23,730 two illustrations there towards the end of chapter. 359 00:22:23,730 --> 00:22:28,470 One of them is from Rakic, where he summarizes the primate 360 00:22:28,470 --> 00:22:29,580 compared with the rodent. 361 00:22:32,210 --> 00:22:34,230 The other picture is another summary 362 00:22:34,230 --> 00:22:38,060 from work on cells that aren't born in the ventricular 363 00:22:38,060 --> 00:22:42,700 layer in the rodent. 364 00:22:42,700 --> 00:22:46,500 Remember where they come from? 365 00:22:46,500 --> 00:22:49,972 We had just been talking about Harvey Karten's hypothesis 366 00:22:49,972 --> 00:22:54,300 that the dorsal ventricular ridge cells migrate 367 00:22:54,300 --> 00:23:00,796 very differently in mammals and in birds-- 368 00:23:00,796 --> 00:23:06,270 a hypothesis that has been largely supported. 369 00:23:09,650 --> 00:23:14,570 But basically, the small gabaergic interneurons 370 00:23:14,570 --> 00:23:19,260 of the cortex come mainly from the striatal area, 371 00:23:19,260 --> 00:23:22,730 the area that is in the position of the striatum. 372 00:23:22,730 --> 00:23:27,060 It's called ganglionic eminence in humans. 373 00:23:27,060 --> 00:23:30,530 In rodents, there's a very clear medial ganglionic 374 00:23:30,530 --> 00:23:33,760 eminence and lottal ganglionic eminence. 375 00:23:33,760 --> 00:23:35,357 Most of them come from the medial one, 376 00:23:35,357 --> 00:23:37,065 but they come from the lateral one, also. 377 00:23:39,980 --> 00:23:42,770 For the posterior parts of the hemisphere, 378 00:23:42,770 --> 00:23:45,310 it's just one ganglionic eminence, 379 00:23:45,310 --> 00:23:48,200 so they call it the caudal ganglionic eminence. 380 00:23:50,985 --> 00:23:53,840 The ganglionic eminence region gives rise 381 00:23:53,840 --> 00:23:55,800 to most of these interneurons. 382 00:23:58,610 --> 00:24:01,000 These are the chapter 12 pages. 383 00:24:06,260 --> 00:24:10,380 I want you to be a little bit familiar with the Finlay 384 00:24:10,380 --> 00:24:16,480 and Darlington publication of how structures change 385 00:24:16,480 --> 00:24:23,000 in size in different species largely 386 00:24:23,000 --> 00:24:25,250 as a function of the total brain size. 387 00:24:25,250 --> 00:24:29,840 In other words, the degree of concerted evolution, 388 00:24:29,840 --> 00:24:32,125 rather than mosaic evolution, is considerable. 389 00:24:35,450 --> 00:24:38,850 I asked you how they actually do their plots-- just 390 00:24:38,850 --> 00:24:39,895 look at that. 391 00:24:39,895 --> 00:24:42,870 The question, really, is how much does the neocortex 392 00:24:42,870 --> 00:24:45,890 grow with regard to the whole brain 393 00:24:45,890 --> 00:24:49,160 in various mammalian species? 394 00:24:49,160 --> 00:24:52,890 You can ask, does the rest of the brain grow proportionally? 395 00:24:52,890 --> 00:25:00,030 Basically, it seems to-- in these plots on the ordinate, 396 00:25:00,030 --> 00:25:05,940 they take the logarithm of the size, the volume of a structure 397 00:25:05,940 --> 00:25:10,990 like neocortex or striatum. 398 00:25:10,990 --> 00:25:14,100 Or the hippocampus down there, here's the medulla oblongata. 399 00:25:16,760 --> 00:25:19,632 There's the paleo cortex. 400 00:25:19,632 --> 00:25:22,370 There's the septal area. 401 00:25:22,370 --> 00:25:27,370 They plot it against a logarithm of the size 402 00:25:27,370 --> 00:25:28,350 of the entire brain. 403 00:25:31,160 --> 00:25:32,997 Remember, these are logarithmic plots 404 00:25:32,997 --> 00:25:35,910 and they're taking, like for neocortex, 405 00:25:35,910 --> 00:25:39,060 the entire neocortex. 406 00:25:39,060 --> 00:25:42,210 They see the degree of concerted evolution-- 407 00:25:42,210 --> 00:25:44,225 as the brain grows in size, so do 408 00:25:44,225 --> 00:25:46,430 all these structures grow in size. 409 00:25:46,430 --> 00:25:49,470 Note that neocortex is growing more, 410 00:25:49,470 --> 00:25:53,070 and if you plotted on a linear scale and look at the left 411 00:25:53,070 --> 00:25:54,900 here. 412 00:25:54,900 --> 00:26:00,750 This is still the log plot on the [INAUDIBLE] 413 00:26:00,750 --> 00:26:03,690 here on the ordinate in this 3D picture. 414 00:26:03,690 --> 00:26:06,300 You can see the huge amount of increase 415 00:26:06,300 --> 00:26:08,881 in size of the neocortext. 416 00:26:08,881 --> 00:26:10,256 That can sometimes be missed when 417 00:26:10,256 --> 00:26:12,886 you look at a picture like this. 418 00:26:12,886 --> 00:26:15,070 This is very, very large compared 419 00:26:15,070 --> 00:26:19,620 to this because of the logarithmic scale. 420 00:26:19,620 --> 00:26:23,980 But notice also that the different colors 421 00:26:23,980 --> 00:26:25,170 are for different groups. 422 00:26:25,170 --> 00:26:28,875 Note here for the insectivores-- the size of neocortex, 423 00:26:28,875 --> 00:26:35,640 the relative size, falls below the curve for other groups. 424 00:26:35,640 --> 00:26:38,550 For insectivorous again, for the paleo cortex-- 425 00:26:38,550 --> 00:26:42,530 known as the olfactory cortex-- is actually 426 00:26:42,530 --> 00:26:47,520 larger in relative terms, compared to other animals. 427 00:26:47,520 --> 00:26:49,140 But still you have to say there's 428 00:26:49,140 --> 00:26:51,850 considerable concerted evolution. 429 00:26:51,850 --> 00:26:56,250 But remember that when you deal with the neocortex-- 430 00:26:56,250 --> 00:26:58,080 the different parts of the neocortex-- 431 00:26:58,080 --> 00:27:01,720 this says nothing about it because there's 432 00:27:01,720 --> 00:27:04,360 tremendous variation in relative size 433 00:27:04,360 --> 00:27:05,804 of different parts of the cortext. 434 00:27:08,410 --> 00:27:13,150 This would say nothing at all about that. 435 00:27:13,150 --> 00:27:16,940 The other part of their analysis was an interesting one. 436 00:27:16,940 --> 00:27:21,180 They did factor analysis to look at what 437 00:27:21,180 --> 00:27:26,330 correlates with these differences in size 438 00:27:26,330 --> 00:27:28,380 of these different structures? 439 00:27:28,380 --> 00:27:31,750 They found that two factors-- one represented 440 00:27:31,750 --> 00:27:35,940 by the blue bars, one represented by the orange bars, 441 00:27:35,940 --> 00:27:40,555 and you're looking at the amount of the variance explained. 442 00:27:40,555 --> 00:27:44,230 That's what factor analysis does. 443 00:27:44,230 --> 00:27:45,710 This is the summary here. 444 00:27:45,710 --> 00:27:50,360 The blue bars here indicate that one factor accounts 445 00:27:50,360 --> 00:27:54,570 for over 96% of the total variance. 446 00:27:54,570 --> 00:27:59,590 It's highly correlated with neocortical size, least 447 00:27:59,590 --> 00:28:02,330 correlated with olfactory bulb size. 448 00:28:02,330 --> 00:28:09,410 A second factor accounts for 3%, leaving only 1%. 449 00:28:09,410 --> 00:28:11,675 It's most highly correlated with the olfactory bulbs 450 00:28:11,675 --> 00:28:14,970 and next with limbic system structures, 451 00:28:14,970 --> 00:28:19,330 not correlated with neocortex size. 452 00:28:19,330 --> 00:28:23,070 There appears then to have been much more mosaic evolution 453 00:28:23,070 --> 00:28:26,740 in the olfactory and limbic system structures. 454 00:28:26,740 --> 00:28:29,137 We already know how relatively huge 455 00:28:29,137 --> 00:28:32,950 the olfactory bulbs are in rodents compared with primates. 456 00:28:35,600 --> 00:28:37,060 That's just one example of this. 457 00:28:43,000 --> 00:28:44,890 A little bit about nature and nurture 458 00:28:44,890 --> 00:28:47,370 in the formation cortex. 459 00:28:47,370 --> 00:28:49,040 We want to know how the cortex gets 460 00:28:49,040 --> 00:28:51,145 specified into its different areas. 461 00:28:53,970 --> 00:28:57,430 Before there was very much genetic work. 462 00:28:57,430 --> 00:29:01,020 There was a lot of arguing about whether there 463 00:29:01,020 --> 00:29:05,190 was genetic determination of the different areas. 464 00:29:05,190 --> 00:29:08,702 It took a long time to get enough data because there were 465 00:29:08,702 --> 00:29:13,590 no possible explanations, just a pattern of axon connections 466 00:29:13,590 --> 00:29:15,270 could explain a lot. 467 00:29:15,270 --> 00:29:19,260 Actions come in the thalamus in an organized way 468 00:29:19,260 --> 00:29:21,680 and they distribute according to the way 469 00:29:21,680 --> 00:29:23,455 they're organized in the internal capsule. 470 00:29:26,030 --> 00:29:29,416 If their terminations then resulted in differentiation 471 00:29:29,416 --> 00:29:31,010 through the cortex-- differently, 472 00:29:31,010 --> 00:29:32,470 depending on what inputs they were 473 00:29:32,470 --> 00:29:36,580 getting-- that could account for quite a bit. 474 00:29:36,580 --> 00:29:43,590 But the evidence for a genetically-determined map 475 00:29:43,590 --> 00:29:45,500 has been the most supported. 476 00:29:48,120 --> 00:29:51,260 But as we know, in every nature nurture issue, 477 00:29:51,260 --> 00:29:53,380 it's almost always moot. 478 00:29:53,380 --> 00:29:55,970 There's a lot of evidence for the effects 479 00:29:55,970 --> 00:30:01,640 of an experience of various sorts, as well. 480 00:30:01,640 --> 00:30:05,390 But basically, for more and more cortical areas, 481 00:30:05,390 --> 00:30:07,230 we do have specific genes that are 482 00:30:07,230 --> 00:30:11,000 active during our development. 483 00:30:11,000 --> 00:30:15,165 The first one was work by [INAUDIBLE] 484 00:30:15,165 --> 00:30:18,330 that we discovered this limbic-associated membrane 485 00:30:18,330 --> 00:30:18,830 protein. 486 00:30:22,620 --> 00:30:26,810 Then there's been interesting studies of using transplants-- 487 00:30:26,810 --> 00:30:32,010 like if they took some limbic cortex that had this protein 488 00:30:32,010 --> 00:30:35,092 and they transplanted it to somatosensory cortext, 489 00:30:35,092 --> 00:30:38,180 the fate was it didn't become some other sensory cortex. 490 00:30:38,180 --> 00:30:42,400 It stayed limbic cortex. 491 00:30:42,400 --> 00:30:44,800 But the result depends on the age. 492 00:30:44,800 --> 00:30:46,350 If you do it before embryonic day 493 00:30:46,350 --> 00:30:51,870 12, before these proteins start to be expressed, 494 00:30:51,870 --> 00:30:55,860 before that gene is expressed and that protein is formed, 495 00:30:55,860 --> 00:30:59,240 then it just becomes somatosensory cortex. 496 00:30:59,240 --> 00:31:03,300 Similar work was done in the rat between visual area 497 00:31:03,300 --> 00:31:04,790 and somatosensory areas. 498 00:31:04,790 --> 00:31:06,840 You take a little bit of visual cortex 499 00:31:06,840 --> 00:31:10,380 and put it in somatosensory cortex. 500 00:31:10,380 --> 00:31:13,150 It becomes somatosensory cortex if you do it real early, 501 00:31:13,150 --> 00:31:18,220 but if you do it too late, it doesn't 502 00:31:18,220 --> 00:31:19,962 become somatosensory cortex. 503 00:31:19,962 --> 00:31:20,920 It keeps its specifity. 504 00:31:24,300 --> 00:31:27,290 What about the epigenetic factors, like activity? 505 00:31:32,240 --> 00:31:35,090 The visual system's been used for a lot of this, 506 00:31:35,090 --> 00:31:42,040 and I want to know here about an example of how 507 00:31:42,040 --> 00:31:44,730 abnormal activity can affect the development of axon 508 00:31:44,730 --> 00:31:48,315 connections, even when the activity is prenatal. 509 00:31:48,315 --> 00:31:50,880 We think that vision must start after birth, right? 510 00:31:55,690 --> 00:31:58,680 What can an embryo in the womb see? 511 00:31:58,680 --> 00:32:01,290 Well, it's making a big assumption 512 00:32:01,290 --> 00:32:07,100 that activity always depends on open eyes, 513 00:32:07,100 --> 00:32:12,150 and that, in fact, was found out to be true in Carla Shatz' lab. 514 00:32:12,150 --> 00:32:13,910 She gave a talk here just recently. 515 00:32:13,910 --> 00:32:17,690 She's continued to work on these issues. 516 00:32:17,690 --> 00:32:20,850 With her work with Meister, Wong, and Baylor, 517 00:32:20,850 --> 00:32:23,310 they discovered these waves of activity. 518 00:32:23,310 --> 00:32:25,085 This is a little schematic of the retina 519 00:32:25,085 --> 00:32:30,410 that she's repeated, showing it at different times. 520 00:32:30,410 --> 00:32:33,410 She's plotted the time here. 521 00:32:33,410 --> 00:32:35,340 You see the activity beginning here, 522 00:32:35,340 --> 00:32:38,730 and then it moves right across the retina to the other side. 523 00:32:38,730 --> 00:32:43,760 This is happening well before birth. 524 00:32:43,760 --> 00:32:50,230 She found that in fact, activity plays an important role 525 00:32:50,230 --> 00:32:55,460 in the formation of precise topographic and organized 526 00:32:55,460 --> 00:32:56,450 connections. 527 00:32:56,450 --> 00:33:00,660 Topography isn't determined by this activity. 528 00:33:00,660 --> 00:33:05,868 How precisely the axons are terminating is affected by it. 529 00:33:08,880 --> 00:33:10,940 That was the first discovery of this. 530 00:33:15,940 --> 00:33:17,880 If pecks of activity had been worked 531 00:33:17,880 --> 00:33:22,636 on for some time in the lab where Carla was, Hubel's lab-- 532 00:33:22,636 --> 00:33:25,340 she was David Hubel's graduate student. 533 00:33:28,320 --> 00:33:30,370 The study of binocular connections. 534 00:33:30,370 --> 00:33:32,340 We've talked about the ocular dominance 535 00:33:32,340 --> 00:33:34,030 stripes in the cortex. 536 00:33:34,030 --> 00:33:39,470 These are just plots of relative response of single neurons 537 00:33:39,470 --> 00:33:42,520 to input from one eye versus the other eye. 538 00:33:42,520 --> 00:33:45,500 One eye in one side, the other eye in the other side, 539 00:33:45,500 --> 00:33:49,780 and then many neurons get input from both eyes. 540 00:33:49,780 --> 00:33:52,350 You see how the neonate is different, 541 00:33:52,350 --> 00:33:56,560 and if you monocularly deprive the animal-- this is usually 542 00:33:56,560 --> 00:34:00,720 done with cats-- the the occluded eye, 543 00:34:00,720 --> 00:34:02,470 you end up with very few cells. 544 00:34:02,470 --> 00:34:04,830 When you open the eye and stimulate it, 545 00:34:04,830 --> 00:34:06,890 there are very few cells. 546 00:34:06,890 --> 00:34:11,760 Now, it can't respond at all to the occluded eye, 547 00:34:11,760 --> 00:34:14,569 whereas the open eye, most of the cells are responding. 548 00:34:14,569 --> 00:34:16,949 The connections must be changing. 549 00:34:16,949 --> 00:34:19,755 This is basically a picture to summarize 550 00:34:19,755 --> 00:34:24,460 that where you see the diagram here just illustrating 551 00:34:24,460 --> 00:34:29,409 two layers, rather than all the layers, just to indicate 552 00:34:29,409 --> 00:34:31,883 the layers that respond to one eye versus the layers 553 00:34:31,883 --> 00:34:33,909 that respond to the other eye, and you 554 00:34:33,909 --> 00:34:35,989 see how early in development they just 555 00:34:35,989 --> 00:34:37,760 overlap in the cortex. 556 00:34:37,760 --> 00:34:40,600 They go to the right place topographically, 557 00:34:40,600 --> 00:34:43,489 but they just overlap with each other, right eye and left eye. 558 00:34:47,389 --> 00:34:49,480 They end up then segregating over time. 559 00:34:53,130 --> 00:34:57,890 If you block activity, they don't segregate. 560 00:34:57,890 --> 00:35:00,440 You can completely block activity simply 561 00:35:00,440 --> 00:35:04,080 by blocking action potentials [INAUDIBLE]. 562 00:35:06,890 --> 00:35:09,840 They stay completely overlapped. 563 00:35:09,840 --> 00:35:13,733 If you get unequal activity in the two eyes, 564 00:35:13,733 --> 00:35:17,220 like patch one eye, then you end up 565 00:35:17,220 --> 00:35:20,870 with wider stripes for stimulated eye 566 00:35:20,870 --> 00:35:23,030 and narrower stripes for the other eye. 567 00:35:25,650 --> 00:35:27,705 It happens in strabismic individuals. 568 00:35:31,230 --> 00:35:35,187 They can end up using one eye much more than the other eye, 569 00:35:35,187 --> 00:35:37,020 and the eye that they're not using very much 570 00:35:37,020 --> 00:35:39,820 will have much lower acuity. 571 00:35:39,820 --> 00:35:42,660 Acuity depends on the amount of cortex 572 00:35:42,660 --> 00:35:46,280 devoted to the sensory surface. 573 00:35:46,280 --> 00:35:49,340 This shows you what's happening to the axons. 574 00:35:49,340 --> 00:35:53,300 These are in kittens. 575 00:35:53,300 --> 00:35:57,400 This is in layer four, so this is presumably 576 00:35:57,400 --> 00:35:59,430 a thalamocortical axon. 577 00:35:59,430 --> 00:36:02,220 It has all the characteristics of thalamocortical axon 578 00:36:02,220 --> 00:36:06,490 terminating in layer four, bottom of three. 579 00:36:06,490 --> 00:36:11,480 You see a very dense, widespread terminal arbor, 580 00:36:11,480 --> 00:36:16,670 but if you look in adults, this is one axon terminating 581 00:36:16,670 --> 00:36:19,456 in two different ocular dominance stripes. 582 00:36:23,810 --> 00:36:27,025 That's what happens with the activity of development 583 00:36:27,025 --> 00:36:31,300 in a normal adult cat. 584 00:36:31,300 --> 00:36:33,080 Here's the effects of deprivation. 585 00:36:33,080 --> 00:36:36,780 This happens after just a few weeks. 586 00:36:36,780 --> 00:36:40,880 Here, you have the non-deprived eye, 587 00:36:40,880 --> 00:36:43,690 axons representing the non-deprived eye. 588 00:36:43,690 --> 00:36:46,247 Here's the deprived eye where the axons just 589 00:36:46,247 --> 00:36:47,080 don't have symmetry. 590 00:36:51,220 --> 00:36:53,220 That's long term. 591 00:36:53,220 --> 00:37:00,310 Short term, and I think here, they got down to around week. 592 00:37:00,310 --> 00:37:01,920 Maybe it was up to 2 weeks. 593 00:37:01,920 --> 00:37:05,040 These are all up to months. 594 00:37:05,040 --> 00:37:07,497 I said weeks, but these were longer than that. 595 00:37:07,497 --> 00:37:09,080 These are the short-term ones, but you 596 00:37:09,080 --> 00:37:10,940 see they're getting the same effects, even 597 00:37:10,940 --> 00:37:11,990 after the shorter time. 598 00:37:11,990 --> 00:37:13,365 So it's happening pretty rapidly. 599 00:37:20,160 --> 00:37:24,320 We think that the connections made 600 00:37:24,320 --> 00:37:28,510 by these axons are consolidated by the activity they generate 601 00:37:28,510 --> 00:37:33,113 and their ability to fire action potentials themselves. 602 00:37:33,113 --> 00:37:37,585 I think that Hebb's rule cells that are firing together. 603 00:37:37,585 --> 00:37:40,780 They're wired together. 604 00:37:40,780 --> 00:37:43,210 Seems to explain a lot of what's going on 605 00:37:43,210 --> 00:37:45,455 and we know there are many molecular studies of this 606 00:37:45,455 --> 00:37:47,860 in recent years. 607 00:37:47,860 --> 00:37:52,890 There's other paradigms that have been used to study this. 608 00:37:52,890 --> 00:37:59,410 One is alter the wiring diagram by early brain lesions. 609 00:37:59,410 --> 00:38:02,220 I was able to do that pretty early using hamsters, 610 00:38:02,220 --> 00:38:04,170 but the hamsters are more difficult to do 611 00:38:04,170 --> 00:38:06,480 the physiological studies. 612 00:38:06,480 --> 00:38:11,370 So then it started being done on ferrets and other animals. 613 00:38:11,370 --> 00:38:13,340 The ferret was particularly good because it's 614 00:38:13,340 --> 00:38:18,407 born in a pretty immature state before the retinal projections 615 00:38:18,407 --> 00:38:19,115 are fully mature. 616 00:38:22,340 --> 00:38:26,690 This was done by Mriganka Sur and his students. 617 00:38:26,690 --> 00:38:29,880 Here, he shows what happens if you just 618 00:38:29,880 --> 00:38:35,020 remove the inferior colliculus and superior colliculus. 619 00:38:35,020 --> 00:38:37,590 The axons are pruned and they're deprived-- 620 00:38:37,590 --> 00:38:41,960 the thalamus is deprived of its normal large auditory 621 00:38:41,960 --> 00:38:44,460 projection from the inferior colliculus. 622 00:38:44,460 --> 00:38:49,630 What happens is axons of the optic tract that 623 00:38:49,630 --> 00:38:52,030 are passing over the medial geniculate 624 00:38:52,030 --> 00:38:55,730 will grow into the medial geniculate and terminate. 625 00:38:55,730 --> 00:39:00,764 That means you would expect a visually responsive area 626 00:39:00,764 --> 00:39:02,180 in the auditory cortex, and that's 627 00:39:02,180 --> 00:39:05,170 what they found by recording. 628 00:39:05,170 --> 00:39:07,260 They mapped it. 629 00:39:07,260 --> 00:39:09,310 Here's the auditory area. 630 00:39:09,310 --> 00:39:12,510 The visual area would be way up here. 631 00:39:12,510 --> 00:39:17,945 The auditory cortex now has a topographic map 632 00:39:17,945 --> 00:39:22,240 of the visual field that's not quite as precise as normal, 633 00:39:22,240 --> 00:39:23,880 but it's there. 634 00:39:23,880 --> 00:39:28,230 And then when they looked at unit properties, 635 00:39:28,230 --> 00:39:31,060 the selective response to contours 636 00:39:31,060 --> 00:39:32,730 of different orientation. 637 00:39:32,730 --> 00:39:34,330 They found that that existed, too. 638 00:39:34,330 --> 00:39:36,630 Again, it was a little more sloppy, the tuning, 639 00:39:36,630 --> 00:39:37,880 but it could have been normal. 640 00:39:37,880 --> 00:39:41,530 But it was pretty good tuning. 641 00:39:41,530 --> 00:39:44,270 We also know that the brain changes after blinding. 642 00:39:44,270 --> 00:39:49,240 This is from a study of the short-tail possum. 643 00:39:49,240 --> 00:39:53,730 This is the normal where you see the visual areas here, 644 00:39:53,730 --> 00:39:56,310 auditory areas and smell sensory areas 645 00:39:56,310 --> 00:40:02,550 getting mostly unimodal input with some multimodal areas 646 00:40:02,550 --> 00:40:04,790 here in between. 647 00:40:04,790 --> 00:40:08,330 Remember, they're saying the unimodal, and most likely, 648 00:40:08,330 --> 00:40:11,310 there's some multimodal input. 649 00:40:11,310 --> 00:40:13,390 But look what happens if you blind them early. 650 00:40:16,160 --> 00:40:20,210 You get throughout the visual and areas 651 00:40:20,210 --> 00:40:23,070 around auditory and somatosensory. 652 00:40:23,070 --> 00:40:25,490 It's all multimodal. 653 00:40:25,490 --> 00:40:28,660 They were looking at the remaining somatosensory 654 00:40:28,660 --> 00:40:33,870 and auditory modalities and they were getting cells responding 655 00:40:33,870 --> 00:40:36,770 to both modalities in all of its cortex. 656 00:40:36,770 --> 00:40:39,150 Even in the primary auditory cortex, 657 00:40:39,150 --> 00:40:42,230 they were getting somatosensory units now. 658 00:40:42,230 --> 00:40:43,887 Within somatosensory cortex, they 659 00:40:43,887 --> 00:40:45,815 were getting some auditory responses, too. 660 00:40:48,480 --> 00:40:52,100 It's an amazing change. 661 00:40:52,100 --> 00:40:54,880 There is other data on humans as well as 662 00:40:54,880 --> 00:41:01,070 on rats indicating that visual cortex takes on other functions 663 00:41:01,070 --> 00:41:03,325 after blinding. 664 00:41:03,325 --> 00:41:07,270 It's used by rats, for example, in solving mazes. 665 00:41:07,270 --> 00:41:12,510 They're using visual cortex to help them solve mazes. 666 00:41:12,510 --> 00:41:16,500 This kind of data indicates that that's not 667 00:41:16,500 --> 00:41:18,765 surprising considering what's happened. 668 00:41:23,300 --> 00:41:26,470 A possible explanation is that normally, there 669 00:41:26,470 --> 00:41:31,810 are very precise connections, as I've argued before, 670 00:41:31,810 --> 00:41:33,660 that are multimodal. 671 00:41:33,660 --> 00:41:38,240 They're sparse, and they might be too sparse to actually drive 672 00:41:38,240 --> 00:41:41,430 the cells to trigger action potentials. 673 00:41:41,430 --> 00:41:46,760 But when they increase-- when the neural input is gone-- 674 00:41:46,760 --> 00:41:49,590 they could increase in strength. 675 00:41:49,590 --> 00:41:52,096 We call that the silent synapse hypothesis 676 00:41:52,096 --> 00:41:55,860 where once silence synapses suddenly become active, 677 00:41:55,860 --> 00:41:57,360 probably because they're sprouting-- 678 00:41:57,360 --> 00:41:59,300 they're increasing in their strength. 679 00:42:02,280 --> 00:42:04,735 There are experiments now with mature monkeys 680 00:42:04,735 --> 00:42:07,915 that indicate something similar, just 681 00:42:07,915 --> 00:42:12,740 to help you make sure you're understanding that paradigm. 682 00:42:12,740 --> 00:42:16,260 First, look at the receptive fields in the hand. 683 00:42:16,260 --> 00:42:18,980 They're normally limited to one digit. 684 00:42:18,980 --> 00:42:22,030 We have good acuity in our fingers 685 00:42:22,030 --> 00:42:24,500 and monkey has the same. 686 00:42:24,500 --> 00:42:27,570 When you record from units in the hand area of the cortex, 687 00:42:27,570 --> 00:42:30,800 you normally get responses just on one digit. 688 00:42:30,800 --> 00:42:34,120 But if you train them in a task where repeatedly, they 689 00:42:34,120 --> 00:42:39,280 have to grasp a bar and move the bar, 690 00:42:39,280 --> 00:42:42,940 they have to grasp it in a certain way like this. 691 00:42:42,940 --> 00:42:47,480 Multiple digits are touching the bar-- both the distal part 692 00:42:47,480 --> 00:42:49,830 of the hand and the more proximal part of the hand 693 00:42:49,830 --> 00:42:51,640 when they grasp the bar. 694 00:42:51,640 --> 00:42:55,390 They're trained-- not just for many trials a day, 695 00:42:55,390 --> 00:42:57,500 but over many days. 696 00:42:57,500 --> 00:42:59,860 When they do that for a long time, 697 00:42:59,860 --> 00:43:03,401 then they get many cells with these multidigit receptive 698 00:43:03,401 --> 00:43:03,900 fields. 699 00:43:03,900 --> 00:43:05,780 Those kinds of cells weren't there before. 700 00:43:09,300 --> 00:43:10,590 Has there been rewiring? 701 00:43:10,590 --> 00:43:13,480 Has it been sprouting? 702 00:43:13,480 --> 00:43:16,620 This shows a map. 703 00:43:16,620 --> 00:43:19,090 I think this one I put in the book. 704 00:43:19,090 --> 00:43:23,940 The multidigit receptive fields in the distal part of fingers 705 00:43:23,940 --> 00:43:26,040 and the more proximal part of the fingers 706 00:43:26,040 --> 00:43:28,220 are represented by the red and the blue colors. 707 00:43:32,870 --> 00:43:36,125 If you look at a normal, there's almost none of that. 708 00:43:36,125 --> 00:43:38,890 But in these trained animals, the cortex 709 00:43:38,890 --> 00:43:41,601 changes considerably in the nature of those receptive 710 00:43:41,601 --> 00:43:42,100 fields. 711 00:43:47,000 --> 00:43:52,925 You could argue that it's quite possible that such connections 712 00:43:52,925 --> 00:43:58,100 did exist but then they're increasing a lot in strength, 713 00:43:58,100 --> 00:44:00,400 so now we can record their effects. 714 00:44:04,161 --> 00:44:05,660 Other people have thought that there 715 00:44:05,660 --> 00:44:08,090 might be anatomical changes, but it's 716 00:44:08,090 --> 00:44:10,800 been difficult to get any real evidence that that's happening. 717 00:44:14,180 --> 00:44:20,120 OK, now these are just additional questions 718 00:44:20,120 --> 00:44:22,050 that you should be able to think about 719 00:44:22,050 --> 00:44:26,340 from what we've talked about and what you've read about. 720 00:44:26,340 --> 00:44:28,790 We've already mentioned today about changes 721 00:44:28,790 --> 00:44:33,690 going on in those superficial layers two and three. 722 00:44:33,690 --> 00:44:35,650 We think that the input to the hippocampus, 723 00:44:35,650 --> 00:44:37,780 it provides the hippocampus information 724 00:44:37,780 --> 00:44:44,680 about local environments, it remembers. 725 00:44:44,680 --> 00:44:50,962 The hippocampus forms long-term memories to be retained. 726 00:44:50,962 --> 00:44:52,420 They can't stay in the hippocampus. 727 00:44:55,515 --> 00:44:56,890 We think most of that's happening 728 00:44:56,890 --> 00:45:02,860 in the parietal associational areas, the multimodal areas, 729 00:45:02,860 --> 00:45:05,380 and we think the changes are likely now, 730 00:45:05,380 --> 00:45:08,890 from the recent work, to be in those superficials areas. 731 00:45:08,890 --> 00:45:12,020 So far, there's not been studies of just how stable 732 00:45:12,020 --> 00:45:14,860 those changes are that they observe in layers two 733 00:45:14,860 --> 00:45:16,670 and three. 734 00:45:16,670 --> 00:45:21,000 When you just look at them, they seem to be changing a lot, 735 00:45:21,000 --> 00:45:23,480 but when you get a long-term memory forming, 736 00:45:23,480 --> 00:45:27,520 we know these memories might change some 737 00:45:27,520 --> 00:45:30,450 and they may change a little bit when you're sleeping. 738 00:45:30,450 --> 00:45:33,250 In fact, you retain something very, 739 00:45:33,250 --> 00:45:34,750 very well over a very long term. 740 00:45:34,750 --> 00:45:38,680 We don't understand exactly how that's happening 741 00:45:38,680 --> 00:45:41,640 and why some things are more transient even 742 00:45:41,640 --> 00:45:45,910 in the neocortex and some are not. 743 00:45:45,910 --> 00:45:48,040 I just talk a little bit about other areas 744 00:45:48,040 --> 00:45:54,020 of plasticity and especially here. 745 00:45:54,020 --> 00:45:56,530 We talked about it embedded in the corpus striatum, 746 00:45:56,530 --> 00:46:01,130 and that includes not just the ventral striatum, 747 00:46:01,130 --> 00:46:03,740 but the versal striatum. 748 00:46:03,740 --> 00:46:07,550 Both of them involve the dopamine projections. 749 00:46:07,550 --> 00:46:11,110 It happens in the cerebellum. 750 00:46:11,110 --> 00:46:15,580 It leaves shorter-term memories in the hippocampus. 751 00:46:15,580 --> 00:46:17,730 In the brain stem, even in the colliculus, 752 00:46:17,730 --> 00:46:21,390 you're going to [INAUDIBLE] habituation, sensitization, 753 00:46:21,390 --> 00:46:24,047 those are a type of memory. 754 00:46:24,047 --> 00:46:25,505 You have it in all sensory systems. 755 00:46:29,250 --> 00:46:31,700 We know working memory, which is also transient. 756 00:46:31,700 --> 00:46:34,650 It happens in your frontal context, 757 00:46:34,650 --> 00:46:37,600 but it also now happens-- there's recent data here 758 00:46:37,600 --> 00:46:43,080 at MIT, Andrew Bolton's thesis work, that communicates what's 759 00:46:43,080 --> 00:46:45,872 happening in the midbrain tectum, as well. 760 00:46:48,600 --> 00:46:51,920 It's only in recent years that these kinds of learning 761 00:46:51,920 --> 00:46:54,870 have been found to be associated with anatomical changes, 762 00:46:54,870 --> 00:46:57,370 as well. 763 00:46:57,370 --> 00:46:59,510 I'm not going to go through. 764 00:46:59,510 --> 00:47:02,420 Just remember, everything is not plastic. 765 00:47:02,420 --> 00:47:05,250 The basic pattern we talked about in this class 766 00:47:05,250 --> 00:47:10,490 is pretty much the same in all members of a species. 767 00:47:10,490 --> 00:47:13,700 Maybe in humans, if you look at the details, 768 00:47:13,700 --> 00:47:15,790 you're always going to find differences. 769 00:47:15,790 --> 00:47:17,750 Some of those differences are genetic. 770 00:47:17,750 --> 00:47:18,700 They run in families. 771 00:47:18,700 --> 00:47:22,970 That's another finding out of the Moscow group. 772 00:47:22,970 --> 00:47:27,776 Like the ipsilateral pyramidal tract-- some families have it, 773 00:47:27,776 --> 00:47:29,660 some families don't. 774 00:47:29,660 --> 00:47:32,190 The massive intermediate, same thing. 775 00:47:32,190 --> 00:47:36,420 Some families have it crossing the midline there 776 00:47:36,420 --> 00:47:40,640 and another ventricles found there. 777 00:47:40,640 --> 00:47:42,260 These are differences. 778 00:47:42,260 --> 00:47:46,740 There are sex differences, as well. 779 00:47:46,740 --> 00:47:49,350 A lot of that develops postnatally 780 00:47:49,350 --> 00:47:51,774 and some of it's genetic, some of it 781 00:47:51,774 --> 00:47:53,690 is due to the hormonal effects on development, 782 00:47:53,690 --> 00:47:55,030 as we talked about. 783 00:47:59,630 --> 00:48:06,410 Anyway, I talk a little bit about my conclusions 784 00:48:06,410 --> 00:48:25,680 about the cortex and the important role of ability 785 00:48:25,680 --> 00:48:28,690 we have to anticipate and to plan 786 00:48:28,690 --> 00:48:31,835 the major innovation of the neocortex. 787 00:48:31,835 --> 00:48:34,710 It's sometimes neglected. 788 00:48:34,710 --> 00:48:37,400 We have acuity, fine acuity, fine motor control, 789 00:48:37,400 --> 00:48:39,220 that's very important, too. 790 00:48:39,220 --> 00:48:42,260 But it's what came later-- the development of the ability 791 00:48:42,260 --> 00:48:47,000 to plan those movements and to use that sensory information 792 00:48:47,000 --> 00:48:52,700 for anticipating events-- that's the major innovation. 793 00:48:52,700 --> 00:48:57,010 That involves subcortical structures, too, especially 794 00:48:57,010 --> 00:49:00,570 structures like the hippocampal formation, 795 00:49:00,570 --> 00:49:01,750 as we've talked about. 796 00:49:05,790 --> 00:49:08,400 Then I talk about some other things 797 00:49:08,400 --> 00:49:13,070 that I think we need a lot more work on a lot of this, 798 00:49:13,070 --> 00:49:15,540 as I've pointed out. 799 00:49:20,610 --> 00:49:25,726 I hope you are finishing that last chapter, 800 00:49:25,726 --> 00:49:30,000 and I hope the class and the book 801 00:49:30,000 --> 00:49:34,220 help you get at least an outline of the whole central nervous 802 00:49:34,220 --> 00:49:36,020 system in your minds. 803 00:49:36,020 --> 00:49:41,400 In the future, if you encounter more, add to that outline. 804 00:49:41,400 --> 00:49:43,940 If you don't have the outline, it's very difficult 805 00:49:43,940 --> 00:49:48,250 even to retain what you're learning about the brain. 806 00:49:48,250 --> 00:49:51,110 I found that when I studied with [INAUDIBLE], 807 00:49:51,110 --> 00:49:54,010 and I never lost that picture of the brain 808 00:49:54,010 --> 00:49:57,310 I developed at that time-- a picture I did not really 809 00:49:57,310 --> 00:50:00,900 have at all, or it was a very distorted one before 810 00:50:00,900 --> 00:50:03,100 studied it more formally. 811 00:50:03,100 --> 00:50:04,650 That's basically what I was trying 812 00:50:04,650 --> 00:50:06,810 to do in this book-- to help a lot more 813 00:50:06,810 --> 00:50:11,310 people other than my class at MIT do that. 814 00:50:11,310 --> 00:50:13,020 Anyway, you're my keepers. 815 00:50:13,020 --> 00:50:15,970 I'm really thankful that you stayed with it. 816 00:50:19,130 --> 00:50:21,650 I hope you all do really well on the exam. 817 00:50:21,650 --> 00:50:25,310 I'll be happy if you all get As. 818 00:50:25,310 --> 00:50:27,820 I posted the review. 819 00:50:27,820 --> 00:50:30,770 I know it's a lot of questions. 820 00:50:30,770 --> 00:50:34,030 If some of it seems foreign to you or your can't find it, 821 00:50:34,030 --> 00:50:34,600 just ask. 822 00:50:38,990 --> 00:50:43,950 I will check that forum frequently if any of you 823 00:50:43,950 --> 00:50:46,200 actually decide to use it. 824 00:50:46,200 --> 00:50:47,620 It actually works. 825 00:50:47,620 --> 00:50:52,220 Some years, I get a lot of exchange with students. 826 00:50:52,220 --> 00:50:54,410 But what I will do now-- I do want 827 00:50:54,410 --> 00:50:56,210 you to review your mid-term exam, 828 00:50:56,210 --> 00:50:59,360 but I'm not going to post any more questions based 829 00:50:59,360 --> 00:51:05,110 on the pre-midterm classes. 830 00:51:05,110 --> 00:51:07,895 Only the things that occurred after the midterm. 831 00:51:07,895 --> 00:51:10,060 But do look at the midterm itself. 832 00:51:13,240 --> 00:51:16,010 All I do is I take that review sheet. 833 00:51:16,010 --> 00:51:18,460 I don't always repeat the question exactly 834 00:51:18,460 --> 00:51:21,210 because sometimes I think it's a little too vague or something, 835 00:51:21,210 --> 00:51:24,390 and I've highlighted words in there 836 00:51:24,390 --> 00:51:28,320 that I might ask you to define, just 837 00:51:28,320 --> 00:51:31,380 to help you figure out what words might he ask. 838 00:51:31,380 --> 00:51:33,740 I've highlighted them there. 839 00:51:33,740 --> 00:51:37,180 There could be other words that are involved in the figures, 840 00:51:37,180 --> 00:51:38,750 and I've shown you figures I want 841 00:51:38,750 --> 00:51:41,660 you to pay special attention to. 842 00:51:41,660 --> 00:51:45,340 I do that because I might put a figure on the exam, 843 00:51:45,340 --> 00:51:46,890 like I did for the midterm, and you 844 00:51:46,890 --> 00:51:50,460 indicate a few of the labels. 845 00:51:50,460 --> 00:51:53,680 You all did well on the midterm, so this exam 846 00:51:53,680 --> 00:51:55,530 will be very similar.