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 00:00:22,290 --> 00:00:24,480 PROFESSOR: We're talking about axon growth, 9 00:00:24,480 --> 00:00:27,670 and I'd like to spend most of the time 10 00:00:27,670 --> 00:00:35,380 today talking about various kinds of neuroplasticity, 11 00:00:35,380 --> 00:00:40,150 how axons respond to damage in the brain, 12 00:00:40,150 --> 00:00:43,520 either by regeneration or various kinds of spotting. 13 00:00:43,520 --> 00:00:53,945 So we were talking about chemicals, effects on growth, 14 00:00:53,945 --> 00:00:57,500 and this is where we ended last time. 15 00:00:57,500 --> 00:01:06,339 And I think this was on your quiz. 16 00:01:06,339 --> 00:01:08,130 Caitlin and I wrote very different courses, 17 00:01:08,130 --> 00:01:12,790 so we're giving Caitlin's today. 18 00:01:12,790 --> 00:01:14,665 We debated about which one's was easier. 19 00:01:26,010 --> 00:01:32,530 Well, it's sometimes hard for me to judge what will be easier. 20 00:01:32,530 --> 00:01:35,770 So we went by her judgment today. 21 00:01:40,100 --> 00:01:45,572 So this was one of your questions, right? 22 00:01:45,572 --> 00:01:46,655 So what is the difference? 23 00:01:50,252 --> 00:01:53,680 It's pretty straightforward. 24 00:01:53,680 --> 00:01:57,970 Tropic always means affecting direction. 25 00:01:57,970 --> 00:02:03,285 So remember we talked about nerve growth factor axons 26 00:02:03,285 --> 00:02:08,770 can throw up a gradient of nerve growth factor. 27 00:02:08,770 --> 00:02:15,710 But trophic always means survival or growth. 28 00:02:15,710 --> 00:02:21,250 So I divided into two types-- survival promoting effects, 29 00:02:21,250 --> 00:02:24,710 many cells that depend on nerve growth factor won't survive. 30 00:02:24,710 --> 00:02:27,550 Their axons don't take it up. 31 00:02:30,870 --> 00:02:35,220 But we know that these neurotrophic factors also 32 00:02:35,220 --> 00:02:37,110 increase the amount of growth. 33 00:02:37,110 --> 00:02:40,620 So you get very little growth without growth factor, 34 00:02:40,620 --> 00:02:43,035 and you get a lot of growth with it. 35 00:02:43,035 --> 00:02:46,070 And they effect just how robust the growth is too. 36 00:02:51,090 --> 00:02:56,620 Now, this question has come up a number of times, 37 00:02:56,620 --> 00:02:59,160 or had come up a number of times in trying 38 00:02:59,160 --> 00:03:02,920 to decide how these growth factors work. 39 00:03:02,920 --> 00:03:06,409 So for example, there's a particular-- 40 00:03:06,409 --> 00:03:07,950 this will come up later in the class, 41 00:03:07,950 --> 00:03:09,450 but we can cover it right now. 42 00:03:09,450 --> 00:03:13,520 The base at the floor plate of the spinal cord, 43 00:03:13,520 --> 00:03:17,100 there are molecules called netrins that are secreted. 44 00:03:17,100 --> 00:03:21,345 And they attract the axons of the spinothalamic tract-- that 45 00:03:21,345 --> 00:03:23,540 is, axons of dorsal horn neurons. 46 00:03:23,540 --> 00:03:27,540 So they grow down to the floor plate. 47 00:03:27,540 --> 00:03:31,160 But then they cross over, and they go up 48 00:03:31,160 --> 00:03:33,550 into the lateral columns on the other side. 49 00:03:33,550 --> 00:03:36,160 Well, if netrins had only one effect, 50 00:03:36,160 --> 00:03:41,260 they attract these axons, why do they grow past the floor plate 51 00:03:41,260 --> 00:03:44,280 at all? 52 00:03:44,280 --> 00:03:47,000 So that raised the question, well, 53 00:03:47,000 --> 00:03:50,560 could the same molecule be critical for both attraction 54 00:03:50,560 --> 00:03:51,320 and repulsion? 55 00:03:54,150 --> 00:03:56,010 How could that be? 56 00:03:56,010 --> 00:03:58,120 And it was Mu-Ming Poo at Stanford 57 00:03:58,120 --> 00:04:06,090 who found a specific mechanism involved in just such a change. 58 00:04:06,090 --> 00:04:11,750 We won't go over the words here, but this is from an experiment. 59 00:04:11,750 --> 00:04:16,519 And this-- you just look at these pictures. 60 00:04:16,519 --> 00:04:18,720 See the growth cone here? 61 00:04:18,720 --> 00:04:22,770 And here's where they put a little pipette that's 62 00:04:22,770 --> 00:04:28,790 oozing the growth factor. 63 00:04:28,790 --> 00:04:33,290 This is semaphorin-3 that they're working. 64 00:04:33,290 --> 00:04:36,850 So it appears to be repelling the axon. 65 00:04:36,850 --> 00:04:40,040 It's turning away. 66 00:04:40,040 --> 00:04:46,100 Then, they add cyclic GMP to the solution. 67 00:04:46,100 --> 00:04:48,350 And see what happens? 68 00:04:48,350 --> 00:04:53,230 It changes and turns towards the source of semaphorin-3, 69 00:04:53,230 --> 00:04:57,510 And he did a number of experiments like that. 70 00:04:57,510 --> 00:05:03,796 And he tried both cyclic GMP and cyclic AMP, very similar 71 00:05:03,796 --> 00:05:05,340 in their actions. 72 00:05:05,340 --> 00:05:10,552 And both of them could have this effect 73 00:05:10,552 --> 00:05:15,790 on the way an axon responded to these semaphorins, which 74 00:05:15,790 --> 00:05:19,050 like netrin, they could affect the growth of axons-- 75 00:05:19,050 --> 00:05:26,740 at a distance, just by diffusing through the intercellular 76 00:05:26,740 --> 00:05:27,240 space. 77 00:05:27,240 --> 00:05:28,156 AUDIENCE: [INAUDIBLE]. 78 00:05:33,880 --> 00:05:34,880 PROFESSOR: That's right. 79 00:05:34,880 --> 00:05:37,090 Yeah, he's a good experimenter. 80 00:05:37,090 --> 00:05:38,300 He did all the controls. 81 00:05:44,170 --> 00:05:47,250 This just shows another way. 82 00:05:47,250 --> 00:05:49,750 The graphs can be a little hard to figure out, 83 00:05:49,750 --> 00:05:52,800 but basically it's always that same thing. 84 00:05:52,800 --> 00:05:58,960 He varies the substance in its concentration 85 00:05:58,960 --> 00:06:04,110 and looks for the directional effects on the axon. 86 00:06:04,110 --> 00:06:09,720 And he finds this dependence not just on the growth factor 87 00:06:09,720 --> 00:06:12,050 but also on the presence of these other molecules. 88 00:06:14,600 --> 00:06:16,620 That doesn't mean we completely understand 89 00:06:16,620 --> 00:06:21,510 what's happening in the floor plate region, OK? 90 00:06:21,510 --> 00:06:25,970 That story has never to my mind been finished. 91 00:06:25,970 --> 00:06:30,230 We know that netrins are important in the attraction 92 00:06:30,230 --> 00:06:32,530 effect. 93 00:06:32,530 --> 00:06:37,340 But whether these energy-supplying molecules, 94 00:06:37,340 --> 00:06:40,120 how they change when they reach the floor plate, 95 00:06:40,120 --> 00:06:41,760 that's not as clear. 96 00:06:41,760 --> 00:06:45,210 You can imagine other things that could be going on. 97 00:06:45,210 --> 00:06:51,720 The axon, as it matures, could change in its metabolism. 98 00:06:51,720 --> 00:06:54,150 So it simply changes in the way it's 99 00:06:54,150 --> 00:06:57,682 responding to various chemicals as it grows. 100 00:06:57,682 --> 00:07:00,370 So a lot of that still remains to be figured out. 101 00:07:06,480 --> 00:07:09,070 This is a summary of some of the work 102 00:07:09,070 --> 00:07:13,520 on this molecule, semaphorin-3. 103 00:07:13,520 --> 00:07:21,080 It's found in the ventral part, the ventral horns 104 00:07:21,080 --> 00:07:22,810 of the spinal cord. 105 00:07:22,810 --> 00:07:25,900 So where you see the darker brown here, 106 00:07:25,900 --> 00:07:27,420 you have some semaphorin-3. 107 00:07:27,420 --> 00:07:31,790 And notice, as is well known from anatomical studies, 108 00:07:31,790 --> 00:07:35,632 these large axons from the muscle stretch receptors, 109 00:07:35,632 --> 00:07:38,486 grow right into the ventral horn. 110 00:07:38,486 --> 00:07:42,370 But the fibers that terminate in the dorsal horn 111 00:07:42,370 --> 00:07:46,770 just won't grow into that ventral horn region. 112 00:07:46,770 --> 00:07:51,380 So the proposal is that it could serve 113 00:07:51,380 --> 00:07:53,310 as a kind of molecular sieve. 114 00:07:53,310 --> 00:07:56,660 It's just sorting the axons. 115 00:07:56,660 --> 00:07:58,415 Only some of them can grow. 116 00:07:58,415 --> 00:07:59,080 See that here. 117 00:08:05,940 --> 00:08:08,735 So this is what we talked about. 118 00:08:08,735 --> 00:08:10,110 Here I've already written answers 119 00:08:10,110 --> 00:08:12,080 because I posted these already, what's 120 00:08:12,080 --> 00:08:14,610 meant by exuberant axonal projections. 121 00:08:14,610 --> 00:08:18,100 This is a well-known phenomenon in axon development. 122 00:08:18,100 --> 00:08:23,050 Many times, axons form a lot of-- they 123 00:08:23,050 --> 00:08:28,280 distribute terminals in areas that they don't later on. 124 00:08:28,280 --> 00:08:30,260 So they disappear. 125 00:08:30,260 --> 00:08:32,409 So we say they have exuberant projections, 126 00:08:32,409 --> 00:08:36,440 but then they regress with maturation. 127 00:08:36,440 --> 00:08:40,539 And that's true for a number of different fiber bundles, 128 00:08:40,539 --> 00:08:43,890 both subcortically-- it was named initially 129 00:08:43,890 --> 00:08:46,810 for transcortical projections by Innocenti 130 00:08:46,810 --> 00:08:50,220 and [INAUDIBLE] who was working with transcortical projections 131 00:08:50,220 --> 00:08:51,300 in the cat. 132 00:08:51,300 --> 00:08:54,075 But it's been discovered in other systems too. 133 00:08:54,075 --> 00:08:56,680 It's been discovered in thalamocortical axons that 134 00:08:56,680 --> 00:08:59,130 branch profusely in the cortex, and then they 135 00:08:59,130 --> 00:09:01,980 regress to sort of prune themselves 136 00:09:01,980 --> 00:09:04,390 back to their adult form. 137 00:09:04,390 --> 00:09:07,640 It happens for optic tract, where they're truly exuberant. 138 00:09:07,640 --> 00:09:10,135 They grow even into the ventral basal nucleus, 139 00:09:10,135 --> 00:09:13,650 it's somatosensory structure and into the medial geniculate 140 00:09:13,650 --> 00:09:14,846 body. 141 00:09:14,846 --> 00:09:20,320 They don't stay there normally. 142 00:09:20,320 --> 00:09:24,670 They do in the case of some early brain damage. 143 00:09:24,670 --> 00:09:28,791 Then you sometimes can get them to stay there. 144 00:09:28,791 --> 00:09:29,290 OK. 145 00:09:29,290 --> 00:09:34,070 And then, I think you were asked about this two modes of growth. 146 00:09:34,070 --> 00:09:38,690 I'll just show you the pictures of that and how they differ. 147 00:09:38,690 --> 00:09:40,155 These are the pictures. 148 00:09:42,770 --> 00:09:46,020 This is one of the figures in the book also. 149 00:09:46,020 --> 00:09:49,100 This is from the work in my lab, where 150 00:09:49,100 --> 00:09:53,310 we were looking at stages in the growth of the optic tract. 151 00:09:53,310 --> 00:09:56,550 We've used a number of different techniques to look at this. 152 00:09:56,550 --> 00:09:58,855 And when you first see the axons-- these aren't Golgi, 153 00:09:58,855 --> 00:10:03,440 but Golgi-stained axons in this early period 154 00:10:03,440 --> 00:10:06,670 look very much like this. 155 00:10:06,670 --> 00:10:11,020 We were normally using other methods to look at them. 156 00:10:11,020 --> 00:10:12,950 And you can use various methods to do it. 157 00:10:12,950 --> 00:10:15,210 But you need a macro that can show 158 00:10:15,210 --> 00:10:22,440 the entire axon and its little swellings and collaterals. 159 00:10:22,440 --> 00:10:25,610 So here, when they're elongating, 160 00:10:25,610 --> 00:10:26,850 they look like this. 161 00:10:26,850 --> 00:10:29,360 They don't really form collaterals. 162 00:10:29,360 --> 00:10:32,370 They do have these little filopodia. 163 00:10:32,370 --> 00:10:36,250 And notice, the filopodia aren't always at the growth column. 164 00:10:36,250 --> 00:10:41,120 You find filopodia along the length of the axon too. 165 00:10:41,120 --> 00:10:43,855 And normally, if they do from a collateral, 166 00:10:43,855 --> 00:10:47,010 it starts at one of these swellings 167 00:10:47,010 --> 00:10:50,300 where filopodia appear and then a growth cone appears, 168 00:10:50,300 --> 00:10:54,130 and a collateral starts to form. 169 00:10:54,130 --> 00:10:57,320 But that's normally not what happens right away. 170 00:10:57,320 --> 00:11:01,780 So when they're elongating, they're growing quite rapidly. 171 00:11:01,780 --> 00:11:03,865 In the optic tract, we measured it. 172 00:11:03,865 --> 00:11:08,370 It's between 60 and 100 microns an hour. 173 00:11:08,370 --> 00:11:12,140 So then here's the next stage. 174 00:11:12,140 --> 00:11:14,060 They start to form branches. 175 00:11:14,060 --> 00:11:17,590 And you'll notice the exuberant projections-- 176 00:11:17,590 --> 00:11:19,910 they're forming branches in many places. 177 00:11:19,910 --> 00:11:25,200 If this, from here to here, is all superior colliculus, 178 00:11:25,200 --> 00:11:28,160 that means they're terminating the whole length 179 00:11:28,160 --> 00:11:31,100 of the colliculus early on. 180 00:11:31,100 --> 00:11:37,110 And that's typical of many of these axons in the optic tract. 181 00:11:37,110 --> 00:11:40,180 And apparently in other places too, similar phenomena 182 00:11:40,180 --> 00:11:42,190 had been seen for the fibers that grow up 183 00:11:42,190 --> 00:11:44,120 into the visual cortex from the thalamus. 184 00:11:44,120 --> 00:11:46,830 That was done by another student that I 185 00:11:46,830 --> 00:11:49,400 worked with in the lab, Jan Naegele, who's 186 00:11:49,400 --> 00:11:54,080 been at Wesleyan University now for some time. 187 00:11:54,080 --> 00:11:57,370 And then, we call this initial focalization-- 188 00:11:57,370 --> 00:12:02,420 when they lose most of these very rudimentary little 189 00:12:02,420 --> 00:12:06,720 branches, they lose most of them, 190 00:12:06,720 --> 00:12:08,550 and they retain one of them. 191 00:12:08,550 --> 00:12:10,440 Here's one that's retaining one here, 192 00:12:10,440 --> 00:12:14,070 but it's still got that trailing axon. 193 00:12:14,070 --> 00:12:19,220 And because we don't see a lot of regeneration occurring, 194 00:12:19,220 --> 00:12:23,090 we assume that that axon is literally pulled back, 195 00:12:23,090 --> 00:12:26,405 retracted, just like we saw in the tissue culture pictures. 196 00:12:26,405 --> 00:12:30,850 We just saw the axon was able to retract some distance. 197 00:12:30,850 --> 00:12:33,570 That's what's happening apparently here. 198 00:12:33,570 --> 00:12:37,190 So they end up forming their arbor in one location. 199 00:12:37,190 --> 00:12:39,020 And they might form more than one arbor. 200 00:12:39,020 --> 00:12:42,350 Like, they might form an arbor here in this colliculus. 201 00:12:42,350 --> 00:12:43,852 They might form another arbor-- I 202 00:12:43,852 --> 00:12:45,560 showed it going in the opposite direction 203 00:12:45,560 --> 00:12:47,720 because this could be in the thalamus, 204 00:12:47,720 --> 00:12:51,610 or they're terminating in one of the geniculate bodies. 205 00:12:51,610 --> 00:12:56,510 And then when they first arborize here, 206 00:12:56,510 --> 00:12:59,150 they tend to arborize throughout the layers 207 00:12:59,150 --> 00:13:02,550 of the geniculate body or the colliculus. 208 00:13:02,550 --> 00:13:04,220 But then they become more focal. 209 00:13:04,220 --> 00:13:06,590 They end up only in the one layer. 210 00:13:06,590 --> 00:13:07,810 So they're maturing now. 211 00:13:07,810 --> 00:13:09,640 They're doing more pruning. 212 00:13:09,640 --> 00:13:12,345 And then, they go through a slower process. 213 00:13:12,345 --> 00:13:17,670 This is even after the eyes open, 214 00:13:17,670 --> 00:13:24,640 is right here, which in the hamster is about 15 days old. 215 00:13:24,640 --> 00:13:29,070 Then they undergo changes, the ending matures, 216 00:13:29,070 --> 00:13:30,922 they form synapses, and so forth. 217 00:13:33,880 --> 00:13:35,940 In these earlier stages, they're not 218 00:13:35,940 --> 00:13:37,220 forming mature synapses yet. 219 00:13:37,220 --> 00:13:39,430 But it doesn't mean they don't form contexts. 220 00:13:39,430 --> 00:13:42,930 There are immature synapses that they do form, and many of them 221 00:13:42,930 --> 00:13:44,962 are not maintained in the adulthood. 222 00:13:44,962 --> 00:13:45,729 Yeah? 223 00:13:45,729 --> 00:13:46,645 AUDIENCE: [INAUDIBLE]. 224 00:13:55,067 --> 00:13:55,650 PROFESSOR: No. 225 00:13:55,650 --> 00:13:56,840 No, good question. 226 00:13:56,840 --> 00:13:59,320 There's no myelin yet in these earlier stages. 227 00:13:59,320 --> 00:14:01,850 The myelinization, the oligodendrocytes 228 00:14:01,850 --> 00:14:05,120 don't appear until the animal is a couple weeks old. 229 00:14:05,120 --> 00:14:07,470 They appear in these later stages. 230 00:14:07,470 --> 00:14:10,020 When we talk about arbor maturation, 231 00:14:10,020 --> 00:14:14,090 that's when you're beginning to get the oligodendrocytes 232 00:14:14,090 --> 00:14:17,240 starting to wrap axons. 233 00:14:17,240 --> 00:14:18,700 Very important point. 234 00:14:18,700 --> 00:14:23,310 The myelin appears after the initial formation 235 00:14:23,310 --> 00:14:26,750 of the axons and its connection. 236 00:14:26,750 --> 00:14:28,415 Thank you for that question. 237 00:14:28,415 --> 00:14:28,915 OK. 238 00:14:32,130 --> 00:14:33,640 So this is just about the rate. 239 00:14:33,640 --> 00:14:38,050 And I point out, we were able to estimate the arborization 240 00:14:38,050 --> 00:14:41,540 rate in the geniculate body especially. 241 00:14:41,540 --> 00:14:43,750 When they start to arborize, how long 242 00:14:43,750 --> 00:14:45,770 does it take for those arbors to form? 243 00:14:45,770 --> 00:14:47,510 And in the geniculate body, they have 244 00:14:47,510 --> 00:14:50,220 to grow from the surface all the way into the deeper 245 00:14:50,220 --> 00:14:51,850 part of the geniculate. 246 00:14:51,850 --> 00:14:56,240 It's about a tenth of the rate of elongation. 247 00:14:56,240 --> 00:14:57,410 So it's much slower. 248 00:14:57,410 --> 00:14:59,210 But remember, they now are supporting 249 00:14:59,210 --> 00:15:05,080 multiple growth cones instead of just that one, or just a few. 250 00:15:05,080 --> 00:15:08,125 And that might be all you need to account 251 00:15:08,125 --> 00:15:11,260 for how much they slow down. 252 00:15:11,260 --> 00:15:13,250 Because remember, in order to grow, 253 00:15:13,250 --> 00:15:15,290 they have to get membrane from the cell body, 254 00:15:15,290 --> 00:15:17,750 and it's transported down the axon 255 00:15:17,750 --> 00:15:20,170 in the form of these little vesicles that then join 256 00:15:20,170 --> 00:15:21,936 to the membrane at the growth cone area. 257 00:15:25,640 --> 00:15:29,000 Oh, and then I also point out arborization, 258 00:15:29,000 --> 00:15:30,640 they never fasciculate. 259 00:15:30,640 --> 00:15:34,130 But the axons, when they're growing, 260 00:15:34,130 --> 00:15:37,090 even though they're not really following each other, 261 00:15:37,090 --> 00:15:39,690 they do become more and more tightly packed. 262 00:15:39,690 --> 00:15:42,140 And they end up in fascicles. 263 00:15:42,140 --> 00:15:44,060 Because when they retract from each other, 264 00:15:44,060 --> 00:15:47,200 they're retracting very short distances. 265 00:15:47,200 --> 00:15:50,790 But in the arborization period, when they retract, 266 00:15:50,790 --> 00:15:53,240 they're retracting much further. 267 00:15:53,240 --> 00:15:54,746 So they tend to stay further apart. 268 00:15:58,860 --> 00:16:01,820 These are other molecules, the ephrins, the ephrin receptors. 269 00:16:01,820 --> 00:16:04,360 Do you have any idea what those do? 270 00:16:07,370 --> 00:16:08,430 Yes? 271 00:16:08,430 --> 00:16:09,346 AUDIENCE: [INAUDIBLE]. 272 00:16:17,391 --> 00:16:18,390 PROFESSOR: That's right. 273 00:16:18,390 --> 00:16:24,650 There are gradients of ephrins in the tectum, 274 00:16:24,650 --> 00:16:31,070 and there are gradients of the receptor for those ligands 275 00:16:31,070 --> 00:16:34,110 in the retinal cells, meaning all down the axon 276 00:16:34,110 --> 00:16:35,120 from the retina. 277 00:16:38,510 --> 00:16:45,520 And this just shows the picture summarizing 278 00:16:45,520 --> 00:16:48,270 the gradients of different ephrins. 279 00:16:48,270 --> 00:16:52,770 Some of them, it's a more gradual gradient. 280 00:16:52,770 --> 00:16:54,500 This is ephrin-A2. 281 00:16:57,700 --> 00:17:02,582 And here's A5 that's not found at all in the more anterior 282 00:17:02,582 --> 00:17:03,415 parts of the tectum. 283 00:17:05,965 --> 00:17:10,910 This is the retina here and the tectum here and these diagrams. 284 00:17:10,910 --> 00:17:14,550 And they know that these play a very particular role 285 00:17:14,550 --> 00:17:19,400 in the formation of the map, at least the nasotemporal map. 286 00:17:19,400 --> 00:17:21,910 But then later, they discover there were often 287 00:17:21,910 --> 00:17:25,670 greater gradients in the other direction too. 288 00:17:25,670 --> 00:17:30,130 So even though the axons are organized when they come in, 289 00:17:30,130 --> 00:17:31,700 there's a greater organization that 290 00:17:31,700 --> 00:17:36,590 results from these ephrins. 291 00:17:36,590 --> 00:17:39,500 So how does it work? 292 00:17:39,500 --> 00:17:44,170 The major mechanism seems to be a selective repulsion. 293 00:17:44,170 --> 00:17:50,370 And it's known from experiments like this where they form-- 294 00:17:50,370 --> 00:17:52,680 they force the axons to grow down 295 00:17:52,680 --> 00:17:55,780 these little channels in culture. 296 00:17:59,280 --> 00:18:03,560 They have axons coming from temporal retina 297 00:18:03,560 --> 00:18:05,900 or from nasal retina. 298 00:18:05,900 --> 00:18:10,680 And they create in these channels 299 00:18:10,680 --> 00:18:14,600 a distribution of tectral membranes 300 00:18:14,600 --> 00:18:18,330 that are drawn from the more rostral tectum 301 00:18:18,330 --> 00:18:21,126 or from the more caudal tectum. 302 00:18:21,126 --> 00:18:23,654 AUDIENCE: [INAUDIBLE]. 303 00:18:23,654 --> 00:18:24,320 PROFESSOR: Yeah. 304 00:18:27,290 --> 00:18:29,615 I guess I didn't name it, but that's what it's called. 305 00:18:32,870 --> 00:18:36,210 And you can see here that if they're axons 306 00:18:36,210 --> 00:18:39,140 coming from temporal retina, they 307 00:18:39,140 --> 00:18:42,130 won't grow when they get to the membranes 308 00:18:42,130 --> 00:18:44,060 from the caudal tectum. 309 00:18:44,060 --> 00:18:44,810 They repel there. 310 00:18:44,810 --> 00:18:47,870 They will only grow over the axons 311 00:18:47,870 --> 00:18:50,920 from the more rostral tectum. 312 00:18:50,920 --> 00:18:55,970 Whereas if they come from the other end of the retina, 313 00:18:55,970 --> 00:19:00,281 from the nasal retina, then they will grow all the way through. 314 00:19:00,281 --> 00:19:03,350 And some of them-- there is a gradient. 315 00:19:03,350 --> 00:19:04,690 Some of them are stopping here. 316 00:19:04,690 --> 00:19:06,290 Some of them are stopping here. 317 00:19:06,290 --> 00:19:09,730 Some of them will go all the way to the back, 318 00:19:09,730 --> 00:19:13,490 just depending on where those members came from. 319 00:19:13,490 --> 00:19:16,540 So that's apparently how the ephrins work. 320 00:19:16,540 --> 00:19:22,000 Depending on where the axons-- the amount of the ephrin 321 00:19:22,000 --> 00:19:25,721 receptor, they can grow various distances into the tectum. 322 00:19:35,170 --> 00:19:40,030 So, that's all about normal development. 323 00:19:40,030 --> 00:19:43,670 Mostly the visual system, where it's been studied most 324 00:19:43,670 --> 00:19:45,550 extensively, but there are good studies 325 00:19:45,550 --> 00:19:48,815 of the growth of the corticospinal tract. 326 00:19:51,930 --> 00:19:54,200 There are other systems that have been studied, 327 00:19:54,200 --> 00:19:56,550 but that retinal tectal system has 328 00:19:56,550 --> 00:20:03,940 been the major model for the study of map formation 329 00:20:03,940 --> 00:20:06,260 and early development of the axons. 330 00:20:10,670 --> 00:20:12,555 I want now to talk about plasticity. 331 00:20:12,555 --> 00:20:15,860 We'll start with plasticity in those maps. 332 00:20:15,860 --> 00:20:20,120 I just described that these chemical gradients 333 00:20:20,120 --> 00:20:24,910 are sort of determining where they're going to end. 334 00:20:24,910 --> 00:20:29,150 Is that a real rigid determination, 335 00:20:29,150 --> 00:20:31,620 or is there some plasticity in it? 336 00:20:31,620 --> 00:20:38,180 We find that there's considerable plasticity. 337 00:20:38,180 --> 00:20:46,188 I just sketched here the tectum. 338 00:20:46,188 --> 00:20:49,750 Let me show you here, you're looking down 339 00:20:49,750 --> 00:20:54,330 on the top of a hamster midbrain. 340 00:20:54,330 --> 00:20:55,920 That's the superior colliculus. 341 00:20:55,920 --> 00:20:57,760 This is inferior colliculus back here, 342 00:20:57,760 --> 00:21:01,800 where those axons don't go. 343 00:21:01,800 --> 00:21:04,380 And here's another picture like that. 344 00:21:04,380 --> 00:21:06,590 And then I show a picture of the retina. 345 00:21:06,590 --> 00:21:09,280 And I've labeled them according to retinal coordinates here. 346 00:21:13,241 --> 00:21:15,390 The coordinates that we use are based 347 00:21:15,390 --> 00:21:17,610 on the attachment of the eye muscles, 348 00:21:17,610 --> 00:21:19,780 because it's always the same. 349 00:21:19,780 --> 00:21:25,520 And if you just go by the position with respect 350 00:21:25,520 --> 00:21:27,980 to the head, then you're dependent on, well, 351 00:21:27,980 --> 00:21:30,397 exactly how were those eyes rotated 352 00:21:30,397 --> 00:21:34,500 when you were measuring in the eye. 353 00:21:34,500 --> 00:21:37,760 And of course, this is often done with physiology, 354 00:21:37,760 --> 00:21:39,340 getting these maps. 355 00:21:39,340 --> 00:21:41,760 But you still don't know the exact position. 356 00:21:41,760 --> 00:21:44,516 But if you go by the eye muscles, then you know. 357 00:21:44,516 --> 00:21:45,480 All right. 358 00:21:45,480 --> 00:21:51,180 So now, let's do this. 359 00:21:51,180 --> 00:21:53,940 Here's the normal map, temporal retina. 360 00:21:53,940 --> 00:21:55,420 Here's the axons. 361 00:21:55,420 --> 00:22:00,610 Let me indicate axons coming in here. 362 00:22:00,610 --> 00:22:01,790 Here's the optic tract. 363 00:22:05,990 --> 00:22:08,572 Just draw a few of the axons. 364 00:22:08,572 --> 00:22:12,140 But that's the course they follow. 365 00:22:12,140 --> 00:22:15,810 The geniculate body would be up here. 366 00:22:15,810 --> 00:22:18,720 They're crossing over the geniculate body. 367 00:22:18,720 --> 00:22:20,465 And of course, most of these axons 368 00:22:20,465 --> 00:22:21,950 have crossed in the optic chiasm. 369 00:22:21,950 --> 00:22:24,001 So most of them are coming from the left eye, 370 00:22:24,001 --> 00:22:26,250 and they're coming into the right superior colliculus. 371 00:22:28,840 --> 00:22:33,060 So now, very early, when these axons are just 372 00:22:33,060 --> 00:22:41,895 starting to grow in, let's just make a lesion. 373 00:22:41,895 --> 00:22:47,310 We'll just eliminate the whole caudal tectum. 374 00:22:47,310 --> 00:22:49,691 What happens? 375 00:22:49,691 --> 00:22:54,150 Do you just get half a map forming? 376 00:22:54,150 --> 00:22:56,000 That certainly was one of the possibilities. 377 00:22:58,790 --> 00:22:59,290 Sorry? 378 00:22:59,290 --> 00:23:00,710 AUDIENCE: [INAUDIBLE]. 379 00:23:00,710 --> 00:23:02,370 PROFESSOR: It does compress. 380 00:23:02,370 --> 00:23:06,140 The temporal retina is still represented there. 381 00:23:06,140 --> 00:23:08,860 But now the nasal retina is represented here. 382 00:23:12,410 --> 00:23:18,100 Upper and lower retina are still upper retina over here, 383 00:23:18,100 --> 00:23:19,830 lower retina over here. 384 00:23:19,830 --> 00:23:21,410 So you get a compression of the map. 385 00:23:21,410 --> 00:23:23,870 It's not totally linear. 386 00:23:23,870 --> 00:23:26,010 There's quite a bit of variability in it. 387 00:23:26,010 --> 00:23:30,940 There's even the stakes made, depending on how nice and neat 388 00:23:30,940 --> 00:23:32,230 your lesion was. 389 00:23:32,230 --> 00:23:35,550 But in general, we've done this both physiologically and 390 00:23:35,550 --> 00:23:36,830 anatomically. 391 00:23:36,830 --> 00:23:39,130 There's a pretty good compression of the map. 392 00:23:39,130 --> 00:23:39,845 Yes? 393 00:23:39,845 --> 00:23:40,761 AUDIENCE: [INAUDIBLE]. 394 00:23:46,420 --> 00:23:50,620 PROFESSOR: Well, these were done on hamsters that don't really 395 00:23:50,620 --> 00:23:54,780 have good color vision at all. 396 00:23:54,780 --> 00:23:57,620 They do recover their behavior, but that 397 00:23:57,620 --> 00:24:02,740 does not mean their orienting movements were totally normal. 398 00:24:02,740 --> 00:24:04,740 What would you expect? 399 00:24:04,740 --> 00:24:09,040 Well, this front of the tectum is normally 400 00:24:09,040 --> 00:24:11,230 controlling movement in the nasal part 401 00:24:11,230 --> 00:24:14,220 of the field, the nasal half of the field, where 402 00:24:14,220 --> 00:24:17,470 the center of their eye is looking 60 degrees out here. 403 00:24:17,470 --> 00:24:20,730 So basically, now, when they turn to a stimulus affecting 404 00:24:20,730 --> 00:24:24,880 that front of the tectum, they never 405 00:24:24,880 --> 00:24:26,180 make these really big turns. 406 00:24:26,180 --> 00:24:29,580 But then, animals normally make their turns 407 00:24:29,580 --> 00:24:32,182 in a series of small jumps anyway. 408 00:24:32,182 --> 00:24:34,820 But no, they can't make a normal rapid turn 409 00:24:34,820 --> 00:24:35,980 to the more caudal field. 410 00:24:35,980 --> 00:24:36,896 AUDIENCE: [INAUDIBLE]. 411 00:24:42,360 --> 00:24:45,120 PROFESSOR: Well, there is some color representation 412 00:24:45,120 --> 00:24:47,720 in the tectum of animals that have good color 413 00:24:47,720 --> 00:24:50,530 vision, like the squirrel, for example. 414 00:24:50,530 --> 00:24:55,170 But people have not studied color very much in the tectum. 415 00:24:55,170 --> 00:24:58,501 It's mostly in the cortex that it's been studied. 416 00:24:58,501 --> 00:24:59,000 OK. 417 00:24:59,000 --> 00:25:04,680 So now, what about map expansion? 418 00:25:04,680 --> 00:25:07,870 Now, the way that has been studied 419 00:25:07,870 --> 00:25:16,550 is very early, we put a little electrode into the eyeball, 420 00:25:16,550 --> 00:25:19,130 through the sclera. 421 00:25:19,130 --> 00:25:23,550 We poke an electrode in, and we make a lesion, usually 422 00:25:23,550 --> 00:25:25,450 with heat or radio frequency. 423 00:25:28,450 --> 00:25:30,930 So let's say we've done that. 424 00:25:30,930 --> 00:25:34,240 We've made a hole. 425 00:25:34,240 --> 00:25:38,770 So what happens in the eye? 426 00:25:38,770 --> 00:25:43,020 Normally, that would correspond to an area like this. 427 00:25:52,910 --> 00:25:59,620 What happens is the axons up here 428 00:25:59,620 --> 00:26:04,180 that would normally terminate here, 429 00:26:04,180 --> 00:26:08,010 where I'm putting the star, will move. 430 00:26:08,010 --> 00:26:10,320 And they will spread into that hole. 431 00:26:10,320 --> 00:26:13,550 So you'll get an expansion of the map there. 432 00:26:16,054 --> 00:26:17,845 It's not part of the retina that's missing. 433 00:26:21,030 --> 00:26:23,220 There are exceptions to this. 434 00:26:23,220 --> 00:26:27,400 If the lesion here resulted in damage throughout the retina so 435 00:26:27,400 --> 00:26:31,330 there was some loss of cells, all the cells where 436 00:26:31,330 --> 00:26:37,125 you see the red color, but just partial loss out 437 00:26:37,125 --> 00:26:38,720 in the rest of the retina. 438 00:26:38,720 --> 00:26:41,070 And then they don't spread so well. 439 00:26:41,070 --> 00:26:44,400 So the density seems to make a big difference. 440 00:26:44,400 --> 00:26:47,500 That was the discovery of Douglas Frost, who is now 441 00:26:47,500 --> 00:26:50,870 at the University of Maryland, at Baltimore. 442 00:26:50,870 --> 00:26:53,090 He's been working for a number of years. 443 00:26:53,090 --> 00:26:57,930 But in his thesis here at MIT, that was his discovery. 444 00:26:57,930 --> 00:26:59,480 And of course, to do that work, we 445 00:26:59,480 --> 00:27:02,700 had to work out all the details of these maps 446 00:27:02,700 --> 00:27:05,952 that we were describing earlier. 447 00:27:05,952 --> 00:27:08,170 All right. 448 00:27:08,170 --> 00:27:14,000 Now I want to talk about collateral sprouting. 449 00:27:16,610 --> 00:27:20,156 We know it occurs after certain adult lesions. 450 00:27:20,156 --> 00:27:24,220 It happens in the periphery, in muscle tissue and in the skin. 451 00:27:27,970 --> 00:27:32,930 If you lose one of the small nerves coming into your hand-- 452 00:27:32,930 --> 00:27:36,670 or let's say you lose 2/3 of the axons 453 00:27:36,670 --> 00:27:39,100 in the nerve coming into your hand. 454 00:27:39,100 --> 00:27:42,300 The remaining normal axons will sprout. 455 00:27:42,300 --> 00:27:47,350 They will sprout collaterals and make up 456 00:27:47,350 --> 00:27:51,680 for a lot of that loss-- very important in clinical neurology 457 00:27:51,680 --> 00:27:57,050 that this happens, because it results in functional recovery. 458 00:27:57,050 --> 00:28:01,800 But let's talk about the factors that 459 00:28:01,800 --> 00:28:04,700 affect that collateral sprouting and what 460 00:28:04,700 --> 00:28:08,030 could modulate that collateral sprouting. 461 00:28:08,030 --> 00:28:10,620 It is described in the chapter, but I'm not 462 00:28:10,620 --> 00:28:13,960 going to press you to do it. 463 00:28:13,960 --> 00:28:19,930 But it is a good question, once you have gone over it. 464 00:28:19,930 --> 00:28:22,790 The collateral sprouting can be so marred, 465 00:28:22,790 --> 00:28:25,820 it can just violate norms rules of development. 466 00:28:25,820 --> 00:28:28,900 For example, the axons of the optic tract 467 00:28:28,900 --> 00:28:32,710 don't terminate in the medial geniculate body. 468 00:28:32,710 --> 00:28:37,830 But they can sprout into the medial geniculate 469 00:28:37,830 --> 00:28:42,710 if you remove the normal innervation there, 470 00:28:42,710 --> 00:28:47,720 and that is promoted by blocking their ability 471 00:28:47,720 --> 00:28:50,170 to terminate in the tectum. 472 00:28:50,170 --> 00:28:52,690 The major factor for that projection 473 00:28:52,690 --> 00:28:59,095 apparently is just getting rid of the normal projections 474 00:28:59,095 --> 00:29:00,970 to the medial geniculate. 475 00:29:00,970 --> 00:29:03,360 The reason is, the axons of the optic tract 476 00:29:03,360 --> 00:29:07,180 cross right over the medial geniculate, the very caudal 477 00:29:07,180 --> 00:29:12,370 part of the tract, representing the lower visual field. 478 00:29:12,370 --> 00:29:16,610 And they do have some capability to terminate there, 479 00:29:16,610 --> 00:29:20,385 but normally the inferior colliculus projections 480 00:29:20,385 --> 00:29:24,390 are already there, and they won't terminate there. 481 00:29:24,390 --> 00:29:27,220 But if you suddenly get rid of all that normal innervation, 482 00:29:27,220 --> 00:29:31,000 then they can show this kind of collateral sprouting. 483 00:29:31,000 --> 00:29:36,690 So these are pictures of the-- these 484 00:29:36,690 --> 00:29:38,575 are side views of the hamster. 485 00:29:38,575 --> 00:29:41,080 We just see the optic chaism here. 486 00:29:41,080 --> 00:29:42,640 It's just the uppermost brain stem. 487 00:29:42,640 --> 00:29:47,400 So here's the diencephalon, hypothalamus down here, 488 00:29:47,400 --> 00:29:48,440 thalamus there. 489 00:29:48,440 --> 00:29:50,170 These are the geniculate bodies where 490 00:29:50,170 --> 00:29:52,600 the retinal axons terminate. 491 00:29:52,600 --> 00:29:55,840 There's the medial geniculate body. 492 00:29:55,840 --> 00:29:59,470 And there's the colliculi, superior and inferior 493 00:29:59,470 --> 00:30:01,660 colliculus. 494 00:30:01,660 --> 00:30:05,940 This is not really a schematic drawing. 495 00:30:05,940 --> 00:30:11,381 It's accurate in that they really are in this arrangement. 496 00:30:11,381 --> 00:30:16,100 I'm basing it on reconstructions of the hamster brain. 497 00:30:16,100 --> 00:30:20,380 And I'm showing one little bundle of optic tract axons 498 00:30:20,380 --> 00:30:25,970 and showing how the axons can sprout collaterals. 499 00:30:25,970 --> 00:30:28,620 This is normally now, not after a legion. 500 00:30:28,620 --> 00:30:33,300 They send collaterals into each of the two geniculate bodies, 501 00:30:33,300 --> 00:30:35,530 ventral and dorsal. 502 00:30:35,530 --> 00:30:38,650 The one we just called the lateral geniculate, 503 00:30:38,650 --> 00:30:40,755 we usually mean the dorsal one, because that's 504 00:30:40,755 --> 00:30:43,610 the one that projects the visual cortex. 505 00:30:43,610 --> 00:30:46,480 But that ventral one which is part of the subthalamus 506 00:30:46,480 --> 00:30:49,950 also gets retinal input. 507 00:30:49,950 --> 00:30:53,370 And then you see them going on and terminating 508 00:30:53,370 --> 00:30:57,430 in their largest terminal area in the superior colliculus. 509 00:30:57,430 --> 00:31:03,460 And then I'm showing that the colliculus neurons, those very 510 00:31:03,460 --> 00:31:06,330 neurons receiving input from the retinal fibers, 511 00:31:06,330 --> 00:31:09,610 they send axons into the thalamus, 512 00:31:09,610 --> 00:31:12,760 into the diencephalon, into this nucleus 513 00:31:12,760 --> 00:31:15,920 next to the lateral geniculate, the LP, the lateral posterior 514 00:31:15,920 --> 00:31:19,846 nucleus, and to that ventral lateral geniculate body. 515 00:31:19,846 --> 00:31:21,595 So that's just all the normal projections. 516 00:31:24,380 --> 00:31:26,410 So now we do this. 517 00:31:26,410 --> 00:31:32,010 We make an early lesion, wiping out the whole normal terminal 518 00:31:32,010 --> 00:31:36,140 region in the midbrain, the superior colliculus. 519 00:31:36,140 --> 00:31:40,190 We can do that with heat, applying it to the-- the bone 520 00:31:40,190 --> 00:31:42,790 is just cartilage at the age where we do this. 521 00:31:42,790 --> 00:31:44,400 Get rid of all that terminal area. 522 00:31:44,400 --> 00:31:45,860 What happens? 523 00:31:45,860 --> 00:31:49,020 Of course, you lose this projection from the colliculus 524 00:31:49,020 --> 00:31:51,240 into the thalamus. 525 00:31:51,240 --> 00:31:55,600 And these axons which are just growing, but many of them 526 00:31:55,600 --> 00:31:59,400 you've destroyed, some of them are still growing in. 527 00:31:59,400 --> 00:32:03,270 They now don't have a place to terminate. 528 00:32:03,270 --> 00:32:04,870 Here's what happens. 529 00:32:04,870 --> 00:32:07,970 Some of them do grow into the deeper layers 530 00:32:07,970 --> 00:32:11,040 of the tectum, where they normally would not terminate. 531 00:32:11,040 --> 00:32:13,260 So they regrow into that area and they 532 00:32:13,260 --> 00:32:15,420 form some abnormal terminations. 533 00:32:15,420 --> 00:32:18,590 But they also sprout into these areas 534 00:32:18,590 --> 00:32:24,370 that have lost their normal input from the colliculus. 535 00:32:24,370 --> 00:32:26,930 That's collateral sprouting. 536 00:32:26,930 --> 00:32:30,310 They sprout abnormal collaterals there and there. 537 00:32:30,310 --> 00:32:36,110 And these are very dense if you do it early in life-- 538 00:32:36,110 --> 00:32:38,970 very dense abnormal projections. 539 00:32:38,970 --> 00:32:46,130 And if in addition to wiping out the colliculus here 540 00:32:46,130 --> 00:32:50,420 you also eliminate all those auditory system fibers 541 00:32:50,420 --> 00:32:53,850 into the medial geniculate, now you 542 00:32:53,850 --> 00:32:56,400 not only get those abnormal projections described 543 00:32:56,400 --> 00:33:00,640 in the previous slide, now you get axons growing right 544 00:33:00,640 --> 00:33:03,900 into the medial geniculate body. 545 00:33:03,900 --> 00:33:07,130 And this has been studied first in the hamster, 546 00:33:07,130 --> 00:33:11,220 but we didn't do the behavioral work on that. 547 00:33:11,220 --> 00:33:13,880 Then [INAUDIBLE] did it on the ferret, 548 00:33:13,880 --> 00:33:15,670 because there he could do physiology. 549 00:33:15,670 --> 00:33:18,170 He could do detailed physiology better 550 00:33:18,170 --> 00:33:20,830 than we could do in the hamster. 551 00:33:20,830 --> 00:33:23,230 And he even did behavior. 552 00:33:23,230 --> 00:33:28,160 He has behavioral evidence for their functionality. 553 00:33:28,160 --> 00:33:32,650 It's like now the auditory cortex becomes a visual cortex, 554 00:33:32,650 --> 00:33:35,820 and he's recorded from it. 555 00:33:35,820 --> 00:33:40,360 We'll come back to that near the end of the class. 556 00:33:40,360 --> 00:33:44,800 And you can record from them here too, 557 00:33:44,800 --> 00:33:47,790 when you find the visual input in the auditory system 558 00:33:47,790 --> 00:33:49,620 structure. 559 00:33:49,620 --> 00:33:51,310 So that's what I mean when I say they 560 00:33:51,310 --> 00:33:53,140 lose their normal specificity. 561 00:33:53,140 --> 00:33:55,630 They can grow into areas that are denervated. 562 00:33:55,630 --> 00:33:57,530 It does not mean they'll grow anywhere. 563 00:34:00,130 --> 00:34:02,830 They grow heavily into the LP, they 564 00:34:02,830 --> 00:34:06,240 grow into the medial hemisphere, also quite densely, 565 00:34:06,240 --> 00:34:07,990 but we've never been able to get them 566 00:34:07,990 --> 00:34:09,935 to sprout like that in the hypothalamus. 567 00:34:12,650 --> 00:34:16,360 So some places are chemically more compatible 568 00:34:16,360 --> 00:34:19,960 where they're at in the [INAUDIBLE] than others. 569 00:34:19,960 --> 00:34:23,139 So when we talk about collateral sprouting, 570 00:34:23,139 --> 00:34:28,270 sometimes it's more of a spreading, as you see here. 571 00:34:28,270 --> 00:34:31,420 Here I'm just showing you the concept. 572 00:34:31,420 --> 00:34:33,099 Here we have two axons terminating 573 00:34:33,099 --> 00:34:37,819 in a cortex-like arrangement, or it could be in the colliculus, 574 00:34:37,819 --> 00:34:40,659 but in a laminar pattern. 575 00:34:40,659 --> 00:34:46,250 If we get rid of one of them, like this, the other one 576 00:34:46,250 --> 00:34:48,820 here doesn't really have to increase 577 00:34:48,820 --> 00:34:50,310 the number of terminals. 578 00:34:50,310 --> 00:34:54,580 It may just spread its terminals over a wider here. 579 00:34:54,580 --> 00:34:57,050 And in the case of the optic tract in the tectum, 580 00:34:57,050 --> 00:34:59,270 that appears to be exactly what happens. 581 00:34:59,270 --> 00:35:02,410 They don't really increase the total number of terminals. 582 00:35:02,410 --> 00:35:05,540 They spread over a wider here. 583 00:35:05,540 --> 00:35:09,410 So they are showing collateral sprouting, 584 00:35:09,410 --> 00:35:12,310 but they're losing some of their terminals elsewhere. 585 00:35:12,310 --> 00:35:14,920 So often, you get a very thin layer 586 00:35:14,920 --> 00:35:17,950 all the way across the tectum if you 587 00:35:17,950 --> 00:35:20,722 eliminate a good part of the retina. 588 00:35:20,722 --> 00:35:28,750 All right, we talk about-- we say 589 00:35:28,750 --> 00:35:32,700 they sprout because axons compete for terminal space. 590 00:35:32,700 --> 00:35:33,770 What does that mean? 591 00:35:33,770 --> 00:35:35,190 What are they competing for? 592 00:35:37,860 --> 00:35:42,500 They're either competing just to get those synaptic sites 593 00:35:42,500 --> 00:35:45,530 that our cells regulate, so they're 594 00:35:45,530 --> 00:35:49,360 fairly fixed in how many of them there are, but they're also 595 00:35:49,360 --> 00:35:52,300 competing for chemical factors that they take up 596 00:35:52,300 --> 00:35:54,580 from their regions where the terminate. 597 00:35:54,580 --> 00:35:56,980 So they're competing for growth factors, 598 00:35:56,980 --> 00:36:00,800 they're competing for synaptic sites. 599 00:36:00,800 --> 00:36:04,410 They also compete in another way, while they're growing. 600 00:36:04,410 --> 00:36:08,520 We know that when they contact each other, they pull pack, 601 00:36:08,520 --> 00:36:14,360 they repel each other, because sometimes we 602 00:36:14,360 --> 00:36:19,980 know that specific molecules are called collapsing molecules, 603 00:36:19,980 --> 00:36:23,510 and in tissue culture, we call that phenomenon a contact 604 00:36:23,510 --> 00:36:25,190 inhibition of extension. 605 00:36:25,190 --> 00:36:27,550 They contact each other, they pull back, 606 00:36:27,550 --> 00:36:30,860 change direction slightly, and then keep growing. 607 00:36:30,860 --> 00:36:33,725 So that's what we think competition is. 608 00:36:33,725 --> 00:36:35,020 It's multiple things. 609 00:36:39,880 --> 00:36:42,050 But there's something else too. 610 00:36:42,050 --> 00:36:49,450 Axons, when they're growing, can vary in how vigorously they're 611 00:36:49,450 --> 00:36:53,760 growing, how vigorously they will form terminals. 612 00:36:53,760 --> 00:36:57,570 We call that the growth vigor of the axon, and that 613 00:36:57,570 --> 00:37:00,360 is something affected by various factors, 614 00:37:00,360 --> 00:37:04,360 including these chemical factors for many axons 615 00:37:04,360 --> 00:37:07,950 NGF, but other neurotrophins as well. 616 00:37:11,290 --> 00:37:12,850 So let's talk about things that can 617 00:37:12,850 --> 00:37:15,360 modulate that collateral sprouting. 618 00:37:15,360 --> 00:37:21,080 The chemical factors that we just mentioned, 619 00:37:21,080 --> 00:37:23,400 but they can be modulated by activity. 620 00:37:23,400 --> 00:37:26,660 There's very good evidence for this in the visual cortex, 621 00:37:26,660 --> 00:37:29,410 because you have axons that represent 622 00:37:29,410 --> 00:37:31,440 the right eye and the left eye terminating 623 00:37:31,440 --> 00:37:34,360 in adjacent columns in the cortex. 624 00:37:34,360 --> 00:37:37,790 But if you reduce the activity of one eye 625 00:37:37,790 --> 00:37:40,220 so only the activity of the other eye 626 00:37:40,220 --> 00:37:43,860 is present in an early developmental period, what 627 00:37:43,860 --> 00:37:47,410 happens is the axons representing 628 00:37:47,410 --> 00:37:49,660 the open eye will spread further. 629 00:37:49,660 --> 00:37:51,720 They'll form larger arbors. 630 00:37:51,720 --> 00:37:54,900 And the ones not getting as much activity 631 00:37:54,900 --> 00:38:00,510 because the input has been bought, they grow much smaller. 632 00:38:00,510 --> 00:38:04,070 So now you get, we call them ocular dominance columns. 633 00:38:04,070 --> 00:38:05,890 The columns representing the closed eye 634 00:38:05,890 --> 00:38:08,110 will be much smaller, much narrower, 635 00:38:08,110 --> 00:38:10,530 than the ones representing the open eye. 636 00:38:10,530 --> 00:38:12,650 But you can manipulate it in other ways 637 00:38:12,650 --> 00:38:15,250 too when animals have damage. 638 00:38:15,250 --> 00:38:20,150 This just shows the effect of NGF on the amount of growth, 639 00:38:20,150 --> 00:38:24,680 really drastically affecting the growth vigor of the dorsal root 640 00:38:24,680 --> 00:38:26,770 ganglion axons. 641 00:38:26,770 --> 00:38:30,110 And here's a diagram of how we conceptualize this. 642 00:38:30,110 --> 00:38:33,970 Here's the axon just starting to arborize. 643 00:38:33,970 --> 00:38:37,910 It has very high growth potency. 644 00:38:37,910 --> 00:38:40,040 Then it forms more and more. 645 00:38:40,040 --> 00:38:42,640 It doesn't maintain its growth potency. 646 00:38:42,640 --> 00:38:46,890 The more terminals it forms, the less that growth 647 00:38:46,890 --> 00:38:49,070 goes down, until it just stops. 648 00:38:49,070 --> 00:38:51,260 It loses its growth potency, even though there's 649 00:38:51,260 --> 00:38:54,740 no other axons competing. 650 00:38:54,740 --> 00:38:57,950 That's because many axon systems can only 651 00:38:57,950 --> 00:38:59,450 grow so many terminals. 652 00:38:59,450 --> 00:39:02,140 This has been measured in some systems 653 00:39:02,140 --> 00:39:07,480 like in the sympathetic ganglia. 654 00:39:07,480 --> 00:39:10,420 This has been measured in England 655 00:39:10,420 --> 00:39:16,660 by Geoff Raisman and Pauline Fields, that he worked with. 656 00:39:16,660 --> 00:39:18,410 They actually used an electron microscope, 657 00:39:18,410 --> 00:39:22,600 and they could estimate the total number of terminals. 658 00:39:22,600 --> 00:39:24,780 They were always regulated. 659 00:39:24,780 --> 00:39:27,300 So if they eliminated some, it would sprout, 660 00:39:27,300 --> 00:39:32,190 but they could only grow so many terminals per axon, 661 00:39:32,190 --> 00:39:34,202 and that's what we think is happening here. 662 00:39:38,220 --> 00:39:40,450 So now let's do something else. 663 00:39:40,450 --> 00:39:41,870 Here's the normal arbor. 664 00:39:41,870 --> 00:39:43,680 It's formed. 665 00:39:43,680 --> 00:39:47,500 Let's just eliminate some of them. 666 00:39:47,500 --> 00:39:49,260 What happens? 667 00:39:49,260 --> 00:39:52,050 Well, now you're below the normal number, 668 00:39:52,050 --> 00:39:54,210 so the growth potency goes way up. 669 00:39:54,210 --> 00:39:55,780 It goes up here, but it will also 670 00:39:55,780 --> 00:39:59,520 go up for a collateral area, say, 671 00:39:59,520 --> 00:40:05,080 back in the thalamus, until it forms 672 00:40:05,080 --> 00:40:08,276 the number that it regulates. 673 00:40:08,276 --> 00:40:09,192 AUDIENCE: [INAUDIBLE]. 674 00:40:12,440 --> 00:40:14,600 PROFESSOR: If we block them here, 675 00:40:14,600 --> 00:40:18,260 we've eliminated the cells they like to terminate on. 676 00:40:18,260 --> 00:40:23,117 And the cells down here that are still there, 677 00:40:23,117 --> 00:40:25,320 they've got their terminals already. 678 00:40:25,320 --> 00:40:27,270 So terminal space is not available. 679 00:40:32,620 --> 00:40:35,020 All these factors have to be taken into account. 680 00:40:35,020 --> 00:40:38,920 You've got to consider what synaptic space is available 681 00:40:38,920 --> 00:40:43,460 and how many terminals these axons can actually form. 682 00:40:43,460 --> 00:40:47,840 And there are differences in different axon systems. 683 00:40:47,840 --> 00:40:50,450 We know, for example, motor neurons 684 00:40:50,450 --> 00:40:53,140 can grow a lot more terminals if you just 685 00:40:53,140 --> 00:40:54,870 give them more muscle tissue. 686 00:40:54,870 --> 00:40:57,390 So you can grow big muscles, and you'll still 687 00:40:57,390 --> 00:41:02,240 get the whole thing innervated, because motor neurons don't 688 00:41:02,240 --> 00:41:04,790 strictly regulate the total number. 689 00:41:04,790 --> 00:41:08,680 They're capable of forming more terminals or fewer terminals. 690 00:41:08,680 --> 00:41:11,760 And that's of the norepinephrine axons and dopamine axons 691 00:41:11,760 --> 00:41:13,160 and so forth. 692 00:41:13,160 --> 00:41:15,410 Although that's not been as well studied, 693 00:41:15,410 --> 00:41:17,930 the phenomena we know about indicate 694 00:41:17,930 --> 00:41:21,290 that that's true, what I'm saying. 695 00:41:21,290 --> 00:41:24,220 So in other words, there's two different kinds 696 00:41:24,220 --> 00:41:27,510 of factors that affect these. 697 00:41:27,510 --> 00:41:30,460 One of them, you could say, is an extrinsic factor 698 00:41:30,460 --> 00:41:35,670 based on the other axons around, competition among axons. 699 00:41:35,670 --> 00:41:37,830 The other is really intrinsic, and I 700 00:41:37,830 --> 00:41:41,910 call that a conservation of terminal quantity. 701 00:41:41,910 --> 00:41:46,930 They tend to conserve the total quantity of axon terminals they 702 00:41:46,930 --> 00:41:49,860 form, or the total amount of arbor. 703 00:41:49,860 --> 00:41:52,850 Sometimes we don't know exactly if it's always 704 00:41:52,850 --> 00:41:55,680 the number of synapses. 705 00:41:55,680 --> 00:41:57,590 It's only been counted in that one system. 706 00:42:00,280 --> 00:42:06,140 But that's why I use the term terminal quantity. 707 00:42:06,140 --> 00:42:07,180 They tend to conserve. 708 00:42:07,180 --> 00:42:10,765 They can only form so many. 709 00:42:10,765 --> 00:42:14,775 Now, I will make some notes on these remaining slides. 710 00:42:14,775 --> 00:42:17,650 They're pretty straightforward, the concepts. 711 00:42:17,650 --> 00:42:20,370 And what I will do in the next class 712 00:42:20,370 --> 00:42:23,645 is we'll start by going through some phenomena of axon 713 00:42:23,645 --> 00:42:24,186 regeneration. 714 00:42:24,186 --> 00:42:27,070 I'm going to show you what happens if you totally 715 00:42:27,070 --> 00:42:31,160 cut the optic tract at various ages. 716 00:42:31,160 --> 00:42:33,510 And I can tell you just in brief summary, 717 00:42:33,510 --> 00:42:35,692 if you cut it when it's really early, 718 00:42:35,692 --> 00:42:37,150 you don't need to do anything else. 719 00:42:37,150 --> 00:42:39,100 They'll just regenerate. 720 00:42:39,100 --> 00:42:41,920 But after a certain age, they won't anymore. 721 00:42:41,920 --> 00:42:44,100 So the question is, what do you do 722 00:42:44,100 --> 00:42:46,670 to get them to regenerate in the adult, 723 00:42:46,670 --> 00:42:48,700 and I will show you two methods that 724 00:42:48,700 --> 00:42:52,180 have worked and allowed us to get vision back in the hamster 725 00:42:52,180 --> 00:42:55,030 after transecting the optic tract.