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 00:00:22,610 --> 00:00:26,337 PROFESSOR: I decided against giving you 9 00:00:26,337 --> 00:00:28,670 any kind of quiz today, because I put those questions up 10 00:00:28,670 --> 00:00:30,440 pretty late. 11 00:00:30,440 --> 00:00:35,295 And some of you are studying on a schedule that might not 12 00:00:35,295 --> 00:00:37,560 have fitted my schedule for this week. 13 00:00:40,390 --> 00:00:46,470 But we're working on worksheets that will be full-page things 14 00:00:46,470 --> 00:00:50,830 like this, and where I've-- basically on something like 15 00:00:50,830 --> 00:00:54,760 this, I've taken out the identification, 16 00:00:54,760 --> 00:00:57,040 so you have to fill them in. 17 00:00:57,040 --> 00:00:58,900 Or we might ask you to draw a pathway 18 00:00:58,900 --> 00:01:02,350 on a diagram like this-- these major pathways 19 00:01:02,350 --> 00:01:04,290 that we want you to learn. 20 00:01:04,290 --> 00:01:07,608 So Caitlin and I'll come up with questions. 21 00:01:07,608 --> 00:01:15,050 And we'll do some of that partly homework, I think, 22 00:01:15,050 --> 00:01:19,790 and maybe a quiz, but we'll decide just when. 23 00:01:19,790 --> 00:01:23,030 We want you to have a chance to work with it for a while 24 00:01:23,030 --> 00:01:27,640 before it gets thrown at you in an exam. 25 00:01:27,640 --> 00:01:29,730 And that way, in the exam, it's just 26 00:01:29,730 --> 00:01:32,280 a test to see whether you can remember what you did. 27 00:01:35,300 --> 00:01:39,410 All right, let's finish talking about axonal plasticity. 28 00:01:44,710 --> 00:01:48,450 First of all, we hadn't finished talking about regeneration 29 00:01:48,450 --> 00:01:48,950 at all. 30 00:01:48,950 --> 00:01:53,390 I just introduced it a little bit last time. 31 00:01:53,390 --> 00:01:54,970 So what's the answer to this? 32 00:01:54,970 --> 00:01:59,550 What happens to regeneration of central nervous system axons 33 00:01:59,550 --> 00:02:08,030 in mammals that changes it with development? 34 00:02:08,030 --> 00:02:11,850 Basically, you cut axons early enough 35 00:02:11,850 --> 00:02:14,790 in the developmental period-- at least 36 00:02:14,790 --> 00:02:16,700 in the systems that have been examined, 37 00:02:16,700 --> 00:02:20,120 the optic tract, and the lateral olfactory tract, 38 00:02:20,120 --> 00:02:21,890 and corticospinal tract. 39 00:02:21,890 --> 00:02:24,560 And these systems will all regrow 40 00:02:24,560 --> 00:02:27,940 if you do the lesion early. 41 00:02:27,940 --> 00:02:30,610 And if you're a frog or a fish, it'll 42 00:02:30,610 --> 00:02:34,380 still regrow even when you do it later in life. 43 00:02:34,380 --> 00:02:37,490 But not mammals-- in mammals, there 44 00:02:37,490 --> 00:02:40,940 seems to be a pretty early cut-off. 45 00:02:40,940 --> 00:02:43,170 There are a few exceptions. 46 00:02:43,170 --> 00:02:46,870 There's a few systems that have a lot more growth-- 47 00:02:46,870 --> 00:02:51,420 vigor of growth-- that is retained right into adulthood, 48 00:02:51,420 --> 00:02:55,570 although that doesn't mean they'll cross an actual gap, 49 00:02:55,570 --> 00:02:58,170 but they'll find some way to get around, 50 00:02:58,170 --> 00:02:59,890 like the norepinephrine-containing 51 00:02:59,890 --> 00:03:00,480 axons. 52 00:03:00,480 --> 00:03:06,480 But that's what this slide summarizes. 53 00:03:09,270 --> 00:03:11,960 So I want to talk about methods now 54 00:03:11,960 --> 00:03:16,570 that have been used to get that regeneration later in life. 55 00:03:16,570 --> 00:03:19,000 This is a topic that I've done research 56 00:03:19,000 --> 00:03:20,215 on for a number of years. 57 00:03:23,050 --> 00:03:25,870 And I still collaborate on some of this research 58 00:03:25,870 --> 00:03:31,560 with Rutledge Ellis-Behnke, who comes here in January 59 00:03:31,560 --> 00:03:35,680 to give a little neuroanatomy class in IAP. 60 00:03:35,680 --> 00:03:38,900 So some of you have met him. 61 00:03:38,900 --> 00:03:43,770 All right, so this is what we've been doing. 62 00:03:43,770 --> 00:03:46,300 We've use peripheral nerve bridges. 63 00:03:46,300 --> 00:03:47,485 Why would you do that? 64 00:03:50,270 --> 00:03:53,900 It was discovered a while back-- yeah, you wanted to answer? 65 00:03:53,900 --> 00:04:03,570 AUDIENCE: [INAUDIBLE] actually do regenerate [INAUDIBLE] 66 00:04:07,510 --> 00:04:11,420 PROFESSOR: Exactly, that's exactly right. 67 00:04:11,420 --> 00:04:13,010 The idea was very simple. 68 00:04:13,010 --> 00:04:17,483 You cut a nerve in the arm, and it 69 00:04:17,483 --> 00:04:20,040 will regenerate, or in the leg. 70 00:04:20,040 --> 00:04:20,779 OK? 71 00:04:20,779 --> 00:04:24,250 Unless the axons just get outside their usual track-- 72 00:04:24,250 --> 00:04:26,160 so they have no guidance-- then sometimes, 73 00:04:26,160 --> 00:04:27,860 they just won't find their way back 74 00:04:27,860 --> 00:04:30,860 to their normal termination point. 75 00:04:30,860 --> 00:04:36,370 But the idea was, since axons will grow in peripheral nerves, 76 00:04:36,370 --> 00:04:39,540 but they won't grow in the CNS after a certain age, 77 00:04:39,540 --> 00:04:43,580 maybe if you put some peripheral nerves into the CNS, 78 00:04:43,580 --> 00:04:48,660 maybe the central nervous system axons would grow. 79 00:04:48,660 --> 00:04:53,160 Maybe there's inhibitory factors in the CNS. 80 00:04:53,160 --> 00:04:55,310 And separate investigations of that 81 00:04:55,310 --> 00:04:57,330 have found exactly that-- there's 82 00:04:57,330 --> 00:05:00,310 a lot of factors in the central nervous system, 83 00:05:00,310 --> 00:05:02,070 in the mature central nervous system, that 84 00:05:02,070 --> 00:05:05,420 inhibit axon growth. 85 00:05:05,420 --> 00:05:09,640 So one way to get around it is to use peripheral nerve bridges 86 00:05:09,640 --> 00:05:12,700 over lesions in the CNS. 87 00:05:12,700 --> 00:05:15,540 This has been tried in just a few labs. 88 00:05:15,540 --> 00:05:20,710 It's not easy to do this kind of surgery. 89 00:05:20,710 --> 00:05:24,740 The details make a huge difference. 90 00:05:24,740 --> 00:05:28,150 And after meeting some of the failures that 91 00:05:28,150 --> 00:05:31,730 weren't complete failures-- they were only partial failures-- 92 00:05:31,730 --> 00:05:37,930 I decided to give it a try myself in this at MIT, 93 00:05:37,930 --> 00:05:41,240 working with several students including Rutledge. 94 00:05:41,240 --> 00:05:45,970 And we found that we could get quite a bit of regeneration. 95 00:05:45,970 --> 00:05:49,200 We started with cutting the optic nerve 96 00:05:49,200 --> 00:05:52,400 right behind the eye and connecting 97 00:05:52,400 --> 00:05:56,460 a long piece of peripheral nerve from the leg, 98 00:05:56,460 --> 00:05:58,290 right to that stump. 99 00:05:58,290 --> 00:06:00,870 Now, these are central nervous system axon 100 00:06:00,870 --> 00:06:03,850 coming from the retina. 101 00:06:03,850 --> 00:06:07,930 They had to go 17 millimeters, all the way 102 00:06:07,930 --> 00:06:10,180 to the midbrain tectum. 103 00:06:10,180 --> 00:06:12,000 We wanted to put them there, because we 104 00:06:12,000 --> 00:06:15,260 knew the function of the tectum in controlling orienting 105 00:06:15,260 --> 00:06:18,690 movements, so we could test for the functional return. 106 00:06:21,460 --> 00:06:26,810 The problem with that was it took a really long time 107 00:06:26,810 --> 00:06:28,610 to get the regeneration. 108 00:06:28,610 --> 00:06:31,740 Almost every lab that had tried it gave up 109 00:06:31,740 --> 00:06:33,420 many months before I gave up. 110 00:06:36,110 --> 00:06:41,030 I kept doing other experiments, but returning to these animals 111 00:06:41,030 --> 00:06:42,440 and testing them some more. 112 00:06:42,440 --> 00:06:45,760 And I had about given up when students told me 113 00:06:45,760 --> 00:06:47,710 they just couldn't see anything. 114 00:06:47,710 --> 00:06:49,990 I decided before we get rid of these animals, 115 00:06:49,990 --> 00:06:54,780 I'm going to try it, look myself, and see. 116 00:06:54,780 --> 00:06:58,360 And I saw something really remarkable in an animal 117 00:06:58,360 --> 00:07:02,070 where we had put the nerve in the mid brain. 118 00:07:02,070 --> 00:07:04,000 We had led it from the eye to the midbrain. 119 00:07:04,000 --> 00:07:07,750 But we put it on the wrong side. 120 00:07:07,750 --> 00:07:09,640 So if we got any functional return, 121 00:07:09,640 --> 00:07:11,550 they would turn in the wrong direction. 122 00:07:11,550 --> 00:07:14,290 And I started seeing wrong direction turning. 123 00:07:14,290 --> 00:07:17,280 That was the first animal where we succeeded 124 00:07:17,280 --> 00:07:19,910 in getting a peripheral nerve to work. 125 00:07:19,910 --> 00:07:22,985 I'll show you that animal in a video. 126 00:07:25,530 --> 00:07:27,490 And then how we've used shorter bridges 127 00:07:27,490 --> 00:07:31,460 to improve the percentage of animals 128 00:07:31,460 --> 00:07:34,060 and the speed of return-- percentage of animals 129 00:07:34,060 --> 00:07:37,547 where we get success, and the speed at which it happens. 130 00:07:37,547 --> 00:07:38,630 So I'll show you all that. 131 00:07:38,630 --> 00:07:45,180 And then we'll talk about using new materials that 132 00:07:45,180 --> 00:07:49,010 seem to act like extracellular matrix. 133 00:07:49,010 --> 00:07:54,510 They support axon growth, and let me get to that in a minute. 134 00:07:54,510 --> 00:07:57,420 They also inhibit scar formation. 135 00:07:57,420 --> 00:08:00,380 We've worked with a few other things, 136 00:08:00,380 --> 00:08:02,469 like genetic transfections. 137 00:08:02,469 --> 00:08:04,135 I want to show you the two methods where 138 00:08:04,135 --> 00:08:06,140 we've been most successful. 139 00:08:06,140 --> 00:08:08,660 This is how we start. 140 00:08:08,660 --> 00:08:11,560 We just transect. 141 00:08:11,560 --> 00:08:15,300 On at least one side, we transect the optic tract 142 00:08:15,300 --> 00:08:17,570 as it comes into the midbrain tectum. 143 00:08:17,570 --> 00:08:19,500 If you test such animals behaviorally, 144 00:08:19,500 --> 00:08:23,380 they cannot orient in the opposite side-- 145 00:08:23,380 --> 00:08:25,850 the visual field on the opposite side. 146 00:08:25,850 --> 00:08:30,480 So it's a very good model to look for functional return. 147 00:08:30,480 --> 00:08:33,710 So this is, then, the method of the shorter bridges. 148 00:08:36,812 --> 00:08:38,770 Instead of putting it all the way from the eye, 149 00:08:38,770 --> 00:08:40,470 they don't have so far to grow if we 150 00:08:40,470 --> 00:08:45,800 can get them to grow in on the side towards the retina, 151 00:08:45,800 --> 00:08:47,740 and get them to grow across the lesion 152 00:08:47,740 --> 00:08:51,050 where they've been transected, and grow 153 00:08:51,050 --> 00:08:52,900 into the tectum on the opposite side. 154 00:08:52,900 --> 00:08:53,760 It's very tricky. 155 00:08:53,760 --> 00:08:55,375 I'm happy to discuss the details. 156 00:08:58,460 --> 00:09:01,410 Obviously, for this to be used in neurosurgery, 157 00:09:01,410 --> 00:09:04,610 these details can make a lot of difference. 158 00:09:04,610 --> 00:09:07,340 All right. 159 00:09:07,340 --> 00:09:11,040 I was able to put up to three bridges like this 160 00:09:11,040 --> 00:09:13,640 across a single transection. 161 00:09:13,640 --> 00:09:18,880 This distance here is only about two and a half millimeters-- 162 00:09:18,880 --> 00:09:20,990 the width here. 163 00:09:20,990 --> 00:09:22,050 So it's not very big. 164 00:09:22,050 --> 00:09:24,580 But the pieces of peripheral nerve 165 00:09:24,580 --> 00:09:28,090 proportionately are about the way you see them there. 166 00:09:28,090 --> 00:09:32,070 We take-- these are branches of the sciatic from the leg. 167 00:09:32,070 --> 00:09:33,940 The animal is impaired a little bit 168 00:09:33,940 --> 00:09:37,750 without the nerve we take out, but he gets along pretty well. 169 00:09:37,750 --> 00:09:41,810 There's enough redundancy in the innervation of the periphery 170 00:09:41,810 --> 00:09:43,765 so we don't render them functionless. 171 00:09:46,540 --> 00:09:52,480 All right, so what I'm going to do here, put on the PowerPoint 172 00:09:52,480 --> 00:09:56,405 where I can show you these video clips most easily. 173 00:10:00,300 --> 00:10:04,330 These are the slides we've seen already. 174 00:10:04,330 --> 00:10:07,230 OK, this is, first of all, an animal 175 00:10:07,230 --> 00:10:10,980 leg with that last lesion where made the lesion, 176 00:10:10,980 --> 00:10:15,120 put the little bridges across several of them. 177 00:10:15,120 --> 00:10:15,620 OK. 178 00:10:19,200 --> 00:10:21,880 So here he is. 179 00:10:21,880 --> 00:10:25,750 Just to give you an idea-- a method of testing them. 180 00:10:25,750 --> 00:10:29,290 They can't see much at all of that white wire. 181 00:10:29,290 --> 00:10:31,700 There's a white background surrounding them normally. 182 00:10:31,700 --> 00:10:34,320 You don't see it here, but when we're testing them, 183 00:10:34,320 --> 00:10:36,920 we have them surrounded with a white background. 184 00:10:36,920 --> 00:10:40,940 We can put that wire in over the barrier, 185 00:10:40,940 --> 00:10:45,990 and about all they see is that black ball. 186 00:10:45,990 --> 00:10:49,940 And this animal's fairly old. 187 00:10:49,940 --> 00:10:52,020 He's been kept a long time just to see 188 00:10:52,020 --> 00:10:53,190 how far he would recover. 189 00:10:53,190 --> 00:10:55,922 So he's a little slow when he turns, 190 00:10:55,922 --> 00:11:00,430 but he's obviously able to turn, whereas he 191 00:11:00,430 --> 00:11:03,720 didn't before the regeneration occurred. 192 00:11:03,720 --> 00:11:06,810 Now this one is the very first animal. 193 00:11:06,810 --> 00:11:10,640 We did the surgery when he was 12 weeks old, 194 00:11:10,640 --> 00:11:12,180 cut the nerve behind the eye. 195 00:11:12,180 --> 00:11:16,120 And then we led the implanted peripheral nerve 196 00:11:16,120 --> 00:11:22,570 all the way from behind the eye to the tectum 197 00:11:22,570 --> 00:11:25,760 on the same side-- so it was the wrong side. 198 00:11:25,760 --> 00:11:29,070 And we eliminated the other eye. 199 00:11:29,070 --> 00:11:32,930 So he was blind unless he got-- these 200 00:11:32,930 --> 00:11:36,554 were the first animals we were testing. 201 00:11:36,554 --> 00:11:41,200 Now, I actually put several of the sequences together. 202 00:11:41,200 --> 00:11:43,150 So you see it three times. 203 00:11:43,150 --> 00:11:47,530 Note the stimulus come in, stimulating this right eye. 204 00:11:47,530 --> 00:11:48,910 And see what he does. 205 00:11:48,910 --> 00:11:50,095 He turns to the left. 206 00:11:53,800 --> 00:11:57,030 Every time he catches that stimulus, 207 00:11:57,030 --> 00:11:59,920 he turns in the wrong direction. 208 00:11:59,920 --> 00:12:05,600 And that was the first success with that method we had. 209 00:12:05,600 --> 00:12:08,440 There's no way it can be any other explanation. 210 00:12:08,440 --> 00:12:10,660 There's no auditory cue, olfactory cue. 211 00:12:10,660 --> 00:12:13,010 People will make up all kinds of things 212 00:12:13,010 --> 00:12:14,400 to explain away your behavior. 213 00:12:14,400 --> 00:12:16,160 And I appreciate that from scientists. 214 00:12:16,160 --> 00:12:18,920 They want to make sure you're really 215 00:12:18,920 --> 00:12:20,760 seeing what you're claiming. 216 00:12:20,760 --> 00:12:24,250 So this was a perfect control for that. 217 00:12:24,250 --> 00:12:28,660 OK, this case shows what that-- when you label the axons. 218 00:12:28,660 --> 00:12:31,305 Here's a piece of the peripheral nerve bridge. 219 00:12:31,305 --> 00:12:34,690 It shriveled quite a bit, but axons are growing through it. 220 00:12:34,690 --> 00:12:39,240 And you can see all of these labeled fibers in the tectum 221 00:12:39,240 --> 00:12:40,410 have regenerated. 222 00:12:40,410 --> 00:12:41,960 Because the tectum was completely 223 00:12:41,960 --> 00:12:44,680 denervated before this, the only way to get in 224 00:12:44,680 --> 00:12:47,560 is through those nerve bridges. 225 00:12:47,560 --> 00:12:50,690 And quite a few of them did grow in. 226 00:12:50,690 --> 00:12:56,360 Here's another-- the one that live five and a half months 227 00:12:56,360 --> 00:12:57,500 after the surgery. 228 00:12:57,500 --> 00:12:59,720 And you can see quite a few axons 229 00:12:59,720 --> 00:13:01,970 coming in, and terminating not throughout the tectum, 230 00:13:01,970 --> 00:13:04,730 in this case, but in the tectum right near were 231 00:13:04,730 --> 00:13:07,870 the implant was put in. 232 00:13:07,870 --> 00:13:13,090 OK, the other method uses a self-assembling peptide, 233 00:13:13,090 --> 00:13:17,060 usually a sequence of 16 amino acids that 234 00:13:17,060 --> 00:13:19,615 are-- there's usually only four different amino acids. 235 00:13:19,615 --> 00:13:22,240 But they're put together in a certain sequence 236 00:13:22,240 --> 00:13:26,850 in a good protein lab. 237 00:13:26,850 --> 00:13:29,850 So they're synthesized peptides. 238 00:13:29,850 --> 00:13:32,360 They have unique property that they assemble 239 00:13:32,360 --> 00:13:36,000 into a kind of gel when they contact a salt solution. 240 00:13:36,000 --> 00:13:39,080 So it looks like a little vial of water 241 00:13:39,080 --> 00:13:41,240 when we use it in the surgery. 242 00:13:41,240 --> 00:13:44,670 And we can put it into a pipette. 243 00:13:44,670 --> 00:13:47,200 And we put it right into the gap. 244 00:13:47,200 --> 00:13:49,770 If this is a deep lesion in the middle of the tectum, 245 00:13:49,770 --> 00:13:51,860 that's how we started the experiments. 246 00:13:51,860 --> 00:13:54,690 We put it right in that gap. 247 00:13:54,690 --> 00:13:57,080 OK, now without putting anything in, 248 00:13:57,080 --> 00:14:01,320 this is what you end up with-- just gaps in the tissue. 249 00:14:01,320 --> 00:14:04,970 So the axons are way up here. 250 00:14:04,970 --> 00:14:08,390 They will not grow all the way down and around, 251 00:14:08,390 --> 00:14:12,500 unless it's a baby animal Then they will, but in an adult, 252 00:14:12,500 --> 00:14:14,720 they never do. 253 00:14:14,720 --> 00:14:17,375 So they just come up to that barrier and stop, 254 00:14:17,375 --> 00:14:18,600 if we label them. 255 00:14:18,600 --> 00:14:23,280 But here's what we first noticed about this material-- 256 00:14:23,280 --> 00:14:25,980 the tissue seems to heal itself. 257 00:14:25,980 --> 00:14:27,400 The gap disappears. 258 00:14:27,400 --> 00:14:29,720 This is not the gap over here. 259 00:14:29,720 --> 00:14:33,020 This is a distortion due to the-- after the surgery. 260 00:14:33,020 --> 00:14:34,500 The cut is here. 261 00:14:37,280 --> 00:14:41,520 You can see the bright fluorescence of the red blood 262 00:14:41,520 --> 00:14:44,690 cells there to indicate that. 263 00:14:44,690 --> 00:14:46,200 OK, so this is the model. 264 00:14:46,200 --> 00:14:49,540 This shows the pathway we're testing. 265 00:14:49,540 --> 00:14:53,730 The pathway from the eye crosses at the optic chiasm 266 00:14:53,730 --> 00:14:56,130 and reaches the superior colliculus, which 267 00:14:56,130 --> 00:14:59,190 represents the entire-- on the right, 268 00:14:59,190 --> 00:15:01,350 represents the entire left visual field. 269 00:15:01,350 --> 00:15:05,500 And the crossed pathway from there-- the tectospinal tract 270 00:15:05,500 --> 00:15:07,792 that controls turning movements-- 271 00:15:07,792 --> 00:15:09,740 so it controls turning to the left. 272 00:15:12,980 --> 00:15:15,700 And the same for the other side. 273 00:15:15,700 --> 00:15:21,420 So then what we do is we make the lesion, for example, 274 00:15:21,420 --> 00:15:22,940 like that. 275 00:15:22,940 --> 00:15:25,200 So there's the tectum. 276 00:15:25,200 --> 00:15:26,150 And you can see it. 277 00:15:26,150 --> 00:15:28,705 And during surgery, it looks like this, though, of course 278 00:15:28,705 --> 00:15:30,150 we never get this wide view. 279 00:15:30,150 --> 00:15:32,580 You get the view through a tiny, little window. 280 00:15:32,580 --> 00:15:36,230 But you get so-- if you're a good surgeon, 281 00:15:36,230 --> 00:15:38,710 you learn to recognize all the landmarks. 282 00:15:38,710 --> 00:15:40,400 And you can expose it. 283 00:15:40,400 --> 00:15:41,830 And you can see these landmarks. 284 00:15:41,830 --> 00:15:43,130 We make the cut right there. 285 00:15:43,130 --> 00:15:48,190 And we've been pretty successful at putting it where we want. 286 00:15:48,190 --> 00:15:50,700 And here shows some histology, where 287 00:15:50,700 --> 00:15:53,940 we put a fluorescent label in the axons. 288 00:15:53,940 --> 00:15:56,640 There the red cell-- these are blood cells. 289 00:15:56,640 --> 00:15:58,530 And you can see where the gap was. 290 00:15:58,530 --> 00:16:04,010 And you see quite a few axons-- the green the axons-- in that, 291 00:16:04,010 --> 00:16:06,080 among those red cells. 292 00:16:06,080 --> 00:16:10,440 OK, and if we do a histology with parasagittal sections, 293 00:16:10,440 --> 00:16:11,790 the cut was right here. 294 00:16:11,790 --> 00:16:15,830 And this is pre-tectal termination here. 295 00:16:15,830 --> 00:16:17,196 Here's the superior colliculus. 296 00:16:17,196 --> 00:16:20,330 It's a little thinner than normal here near the lesion, 297 00:16:20,330 --> 00:16:23,900 but you see the axons growing right across 298 00:16:23,900 --> 00:16:29,030 and re-innervating the superior colliculus-- 299 00:16:29,030 --> 00:16:30,660 not at full density. 300 00:16:30,660 --> 00:16:33,160 They don't all regrow, but enough of them 301 00:16:33,160 --> 00:16:36,600 regrow that you can get function. 302 00:16:36,600 --> 00:16:39,330 OK, so I'm going to start here by showing you 303 00:16:39,330 --> 00:16:42,050 an animal that has no right eye. 304 00:16:42,050 --> 00:16:43,800 This is the control. 305 00:16:43,800 --> 00:16:48,350 And you can see it's very simple. 306 00:16:48,350 --> 00:16:50,190 He doesn't respond at all on the right. 307 00:16:50,190 --> 00:16:52,240 We're staying away from the whiskers. 308 00:16:52,240 --> 00:16:54,800 We're basically up above him a little bit. 309 00:16:54,800 --> 00:16:59,570 As soon as we move far enough across the midline, he turns. 310 00:16:59,570 --> 00:17:02,420 This is an animal, now, who's been rewarded many times 311 00:17:02,420 --> 00:17:03,850 for turning. 312 00:17:03,850 --> 00:17:06,359 He simply won't turn unless he sees it, 313 00:17:06,359 --> 00:17:08,359 or you touch the whiskers, either one. 314 00:17:08,359 --> 00:17:10,910 And that's always a control. 315 00:17:10,910 --> 00:17:13,430 Like this animal, we stimulate many times 316 00:17:13,430 --> 00:17:15,880 by stimulating the whiskers on the right side. 317 00:17:15,880 --> 00:17:17,359 Then he does turn right. 318 00:17:17,359 --> 00:17:19,990 So we show that he's perfectly capable of the motor response. 319 00:17:22,770 --> 00:17:26,440 So now here's the one where we had the self-assembling peptide 320 00:17:26,440 --> 00:17:32,145 in the cut that transacted the break 321 00:17:32,145 --> 00:17:33,270 in the superior colliculus. 322 00:17:33,270 --> 00:17:35,700 And then we put that bridge over the break 323 00:17:35,700 --> 00:17:36,850 in the superior colliculus. 324 00:17:42,830 --> 00:17:47,220 And you can see, again he's fairly old. 325 00:17:47,220 --> 00:17:50,740 And he is not making a quick, wide turn, 326 00:17:50,740 --> 00:17:54,060 the way a normal young animal would do. 327 00:17:54,060 --> 00:17:55,350 But he is turning. 328 00:17:58,000 --> 00:18:01,680 And he keeps turning until he gets to the seed. 329 00:18:01,680 --> 00:18:02,180 All right. 330 00:18:16,809 --> 00:18:18,350 AUDIENCE: So the hamster [INAUDIBLE], 331 00:18:18,350 --> 00:18:22,770 it's all in the [INAUDIBLE]? 332 00:18:22,770 --> 00:18:27,330 PROFESSOR: They don't orient without visual input 333 00:18:27,330 --> 00:18:29,290 into the superior colliculus. 334 00:18:29,290 --> 00:18:31,890 Some of it does come from the visual cortex. 335 00:18:31,890 --> 00:18:34,660 But in a hamster, you can take the visual cortex out 336 00:18:34,660 --> 00:18:37,100 completely, and he will still orient, 337 00:18:37,100 --> 00:18:39,430 as long as he's got that retinal projection 338 00:18:39,430 --> 00:18:40,970 to the superior colliculus. 339 00:18:40,970 --> 00:18:44,581 That's what makes it such a nice animal for this. 340 00:18:44,581 --> 00:18:47,530 Animals with a somewhat smaller tectum 341 00:18:47,530 --> 00:18:50,590 depend more on other things. 342 00:18:50,590 --> 00:18:52,980 Did you want to-- oh, sorry. 343 00:18:56,263 --> 00:18:57,763 AUDIENCE: What's the life expectancy 344 00:18:57,763 --> 00:19:00,080 of a laboratory hamster? 345 00:19:00,080 --> 00:19:01,900 PROFESSOR: Yeah, very good question. 346 00:19:01,900 --> 00:19:05,600 They live anywhere from about nine months up 347 00:19:05,600 --> 00:19:07,350 to a year and half. 348 00:19:07,350 --> 00:19:10,290 The oldest I've ever had was about two years 349 00:19:10,290 --> 00:19:11,640 and three months. 350 00:19:11,640 --> 00:19:15,112 No, in fact, I've had one at home live three years. 351 00:19:15,112 --> 00:19:16,570 But in the laboratory, they usually 352 00:19:16,570 --> 00:19:19,850 don't make it much beyond two years. 353 00:19:19,850 --> 00:19:22,280 And even that's unusual. 354 00:19:22,280 --> 00:19:23,870 We don't know why that difference. 355 00:19:23,870 --> 00:19:25,180 Nobody's ever studied it. 356 00:19:25,180 --> 00:19:29,520 But people with pets have often told me 357 00:19:29,520 --> 00:19:31,340 they have hamsters live longer. 358 00:19:31,340 --> 00:19:34,917 I think it's because their parents replace them, 359 00:19:34,917 --> 00:19:39,410 and the kid doesn't know, because they all look alike. 360 00:19:39,410 --> 00:19:42,460 AUDIENCE: Pet rats also live longer than laboratory rats. 361 00:19:42,460 --> 00:19:43,950 PROFESSOR: You think that's true? 362 00:19:43,950 --> 00:19:44,840 See, that's an-- 363 00:19:44,840 --> 00:19:46,756 AUDIENCE: [INAUDIBLE] live a really long time, 364 00:19:46,756 --> 00:19:48,210 turned completely gray. 365 00:19:48,210 --> 00:19:49,610 PROFESSOR: Whoa. 366 00:19:49,610 --> 00:19:51,950 See, it's an interesting thing. 367 00:19:51,950 --> 00:19:55,079 People-- scientists simply haven't paid attention 368 00:19:55,079 --> 00:19:55,870 to that phenomenon. 369 00:19:55,870 --> 00:19:57,610 I think it would be an interesting thing 370 00:19:57,610 --> 00:19:59,133 to try to figure that out. 371 00:19:59,133 --> 00:20:00,508 AUDIENCE: Is there a reason-- I'm 372 00:20:00,508 --> 00:20:05,430 curious-- why you chose a hamster [INAUDIBLE]? 373 00:20:05,430 --> 00:20:09,760 PROFESSOR: Yes, I did because hamsters are cuter. 374 00:20:09,760 --> 00:20:11,596 [LAUGHTER] 375 00:20:11,596 --> 00:20:14,490 No, I did because-- for several reasons. 376 00:20:14,490 --> 00:20:18,220 One is, the behavior is easier to study. 377 00:20:18,220 --> 00:20:20,190 They show all this visually guided behavior. 378 00:20:20,190 --> 00:20:23,720 It's very difficult to see in rats and mice. 379 00:20:23,720 --> 00:20:26,890 I've done it with the rats and mice, but it's harder. 380 00:20:26,890 --> 00:20:30,610 With the hamsters-- and also, hamsters are stupider. 381 00:20:30,610 --> 00:20:32,360 And that is a big advantage. 382 00:20:32,360 --> 00:20:34,520 You don't want them learning all the time. 383 00:20:34,520 --> 00:20:35,270 And you know what? 384 00:20:35,270 --> 00:20:37,330 You want really fixed action patterns. 385 00:20:37,330 --> 00:20:40,080 And that's what the hamster's doing for us. 386 00:20:40,080 --> 00:20:42,790 He's very predictable. 387 00:20:42,790 --> 00:20:43,860 They learn, too. 388 00:20:43,860 --> 00:20:47,330 I've tested their learning, visual discrimination. 389 00:20:47,330 --> 00:20:47,830 Sorry? 390 00:20:47,830 --> 00:20:49,750 AUDIENCE: Are ferrets smarter than hamsters? 391 00:20:49,750 --> 00:20:50,130 PROFESSOR: Oh, yeah. 392 00:20:50,130 --> 00:20:51,755 AUDIENCE: A lot of people like ferrets. 393 00:20:51,755 --> 00:20:53,300 PROFESSOR: Yeah, ferrets are good. 394 00:20:53,300 --> 00:20:56,730 The ferret gives you the advantage of a large cortex. 395 00:20:56,730 --> 00:20:59,910 And the other thing where the ferret fits, 396 00:20:59,910 --> 00:21:05,100 also, is that hamsters are born in a very immature state. 397 00:21:05,100 --> 00:21:10,300 They're born less than 16 days-- they are born on the 16th day 398 00:21:10,300 --> 00:21:13,460 after conception. 399 00:21:13,460 --> 00:21:16,835 You know, the nearest to that among the laboratory animals 400 00:21:16,835 --> 00:21:21,910 is 21 days, or 23 days for mice and rats. 401 00:21:21,910 --> 00:21:26,580 So the hamster is much more immature than those animals. 402 00:21:26,580 --> 00:21:30,060 So the optic tract is just starting 403 00:21:30,060 --> 00:21:32,540 to grow into the tectum when they're born. 404 00:21:32,540 --> 00:21:36,550 And the critical projection to the tectum 405 00:21:36,550 --> 00:21:40,530 appears later-- all postnatal. 406 00:21:40,530 --> 00:21:44,590 So those are some of the advantages. 407 00:21:44,590 --> 00:21:48,380 OK, so you can read this. 408 00:21:48,380 --> 00:21:50,600 Rutledge summarized the whole problem 409 00:21:50,600 --> 00:21:52,260 of getting central nervous system 410 00:21:52,260 --> 00:21:55,640 generation as a series of problems. 411 00:21:55,640 --> 00:21:57,390 Preserve-- keeping cells from dying-- 412 00:21:57,390 --> 00:22:01,180 if they're missing the tips of their axons, 413 00:22:01,180 --> 00:22:04,040 they no longer are innervating their target. 414 00:22:04,040 --> 00:22:08,550 Many cells will just gradually shrivel up and even die. 415 00:22:08,550 --> 00:22:10,709 So you've got to keep them alive. 416 00:22:10,709 --> 00:22:12,750 You've got to give them a permissive environment. 417 00:22:12,750 --> 00:22:17,176 There's a lot of inhibitory factors in adult tissue. 418 00:22:17,176 --> 00:22:19,620 And in some cases, you have to promote their growth. 419 00:22:19,620 --> 00:22:26,590 Sometimes, like I told you, that not all the axons are growing. 420 00:22:26,590 --> 00:22:28,840 We were able to get enough of them to grow to get good 421 00:22:28,840 --> 00:22:30,710 function, but all of them won't. 422 00:22:30,710 --> 00:22:33,470 In some systems, you can get none of them to grow. 423 00:22:33,470 --> 00:22:40,020 You need to use growth factors, and perhaps even 424 00:22:40,020 --> 00:22:42,880 genetic transfections to get them to grow. 425 00:22:42,880 --> 00:22:44,130 AUDIENCE: Do they remyelinate? 426 00:22:44,130 --> 00:22:47,010 PROFESSOR: And then there's-- they do have to myelinate. 427 00:22:47,010 --> 00:22:49,770 That's another problem. 428 00:22:49,770 --> 00:22:55,420 But generally, it takes a long time for all this recovery 429 00:22:55,420 --> 00:22:56,850 to occur. 430 00:22:56,850 --> 00:23:00,620 And even after we can label the regeneration in the tectum, 431 00:23:00,620 --> 00:23:03,470 we don't see function right away. 432 00:23:03,470 --> 00:23:07,420 One of the reasons might be plasticity. 433 00:23:07,420 --> 00:23:11,290 The places they terminate on in the tectum 434 00:23:11,290 --> 00:23:14,180 have been occupied by other axons. 435 00:23:14,180 --> 00:23:16,680 The proper ones, when they come in, 436 00:23:16,680 --> 00:23:20,342 often have to compete for axons that 437 00:23:20,342 --> 00:23:23,380 have taken over the synaptic space. 438 00:23:23,380 --> 00:23:27,650 And in studies of non-mammals, that's been examined, 439 00:23:27,650 --> 00:23:29,790 and they find out that they are able to compete. 440 00:23:29,790 --> 00:23:33,980 They will basically push out the ones that are there. 441 00:23:33,980 --> 00:23:36,990 But in any case, however that's happening in the mammal, 442 00:23:36,990 --> 00:23:39,540 we're getting it to work in the colliculus. 443 00:23:45,290 --> 00:23:50,450 All right, well, I want to get started 444 00:23:50,450 --> 00:23:52,090 talking about the motor system today. 445 00:23:58,870 --> 00:24:04,190 This just summarizes where we are in the class right now. 446 00:24:04,190 --> 00:24:08,540 We've looked at all the levels of the CNS. 447 00:24:08,540 --> 00:24:11,200 I want to go through specific functional systems. 448 00:24:11,200 --> 00:24:13,230 We start with the motor system. 449 00:24:13,230 --> 00:24:15,410 And I'll talk a little bit-- it won't 450 00:24:15,410 --> 00:24:17,830 be very long-- about brain state control 451 00:24:17,830 --> 00:24:21,230 before we get into sensory systems. 452 00:24:21,230 --> 00:24:23,070 And then after sensory systems, we 453 00:24:23,070 --> 00:24:27,480 have quite a bit of study of the limbic system, 454 00:24:27,480 --> 00:24:30,250 the corpus striatum, and finally, the neocortex. 455 00:24:34,890 --> 00:24:39,910 So I start by considering the evolution of motor control, 456 00:24:39,910 --> 00:24:44,665 with these questions that you see-- three major questions. 457 00:24:48,130 --> 00:24:51,430 And to study organization of that system, 458 00:24:51,430 --> 00:24:53,410 I want to begin with the motor neurons. 459 00:24:53,410 --> 00:24:56,489 Because that's what's essential. 460 00:24:56,489 --> 00:24:58,030 If you don't reach the motor neurons, 461 00:24:58,030 --> 00:24:59,599 you don't get any movement at all. 462 00:24:59,599 --> 00:25:01,640 So we'll see how the motor neurons are organized. 463 00:25:01,640 --> 00:25:04,200 And then we'll see what connects to those motor neurons. 464 00:25:04,200 --> 00:25:05,940 We've already done a little bit, just 465 00:25:05,940 --> 00:25:08,505 to talk about the simple reflex function. 466 00:25:14,060 --> 00:25:16,265 So the first questions are simply 467 00:25:16,265 --> 00:25:21,440 a review of things we've talked about before. 468 00:25:21,440 --> 00:25:23,790 The general purpose movements that 469 00:25:23,790 --> 00:25:26,930 are used for many different purposes, 470 00:25:26,930 --> 00:25:29,100 and what are the three types of movements 471 00:25:29,100 --> 00:25:31,420 we talked about already? 472 00:25:31,420 --> 00:25:33,330 We were talking about the midbrain, remember? 473 00:25:33,330 --> 00:25:34,246 Yeah. 474 00:25:34,246 --> 00:25:37,000 AUDIENCE: Locomotion, orienting and [? resting. ?] 475 00:25:37,000 --> 00:25:40,700 PROFESSOR: That's right, locomotion, orienting 476 00:25:40,700 --> 00:25:43,000 movements, which means turning towards the source 477 00:25:43,000 --> 00:25:47,230 of a stimulus, usually, and grasping it. 478 00:25:47,230 --> 00:25:51,540 That can be by mouth or by the limbs. 479 00:25:51,540 --> 00:25:56,150 OK, and then I said before a neocortex evolved, 480 00:25:56,150 --> 00:25:58,050 the midbrain had evolved structures 481 00:25:58,050 --> 00:26:02,620 for controlling those three types of movement. 482 00:26:02,620 --> 00:26:04,190 So can you think of the structure 483 00:26:04,190 --> 00:26:07,820 in the midbrain we talked about for each of them? 484 00:26:07,820 --> 00:26:10,092 First-- 485 00:26:10,092 --> 00:26:11,451 AUDIENCE: [INAUDIBLE] 486 00:26:11,451 --> 00:26:15,590 PROFESSOR: The locomotion, the midbrain locomotor region 487 00:26:15,590 --> 00:26:16,190 or area. 488 00:26:19,280 --> 00:26:21,086 And there are other locomotor areas, 489 00:26:21,086 --> 00:26:22,710 but that's the one in the midbrain that 490 00:26:22,710 --> 00:26:26,290 seems to be almost always involved in locomotion. 491 00:26:26,290 --> 00:26:31,520 OK, now for orienting, we know that the tectum 492 00:26:31,520 --> 00:26:34,170 in the majority of vertebrates is 493 00:26:34,170 --> 00:26:35,940 the dominant structure for orienting. 494 00:26:35,940 --> 00:26:40,010 It doesn't mean it was the first. 495 00:26:40,010 --> 00:26:44,860 And then for grasping, well, it depends 496 00:26:44,860 --> 00:26:47,560 on the kind of grasping, doesn't it? 497 00:26:47,560 --> 00:26:52,940 What animals-- we probably-- earliest vertebrates probably 498 00:26:52,940 --> 00:26:57,300 didn't have limbs at all, so you had to get oral grasping. 499 00:26:57,300 --> 00:26:59,400 How do you get that? 500 00:26:59,400 --> 00:27:02,120 Well, what controls opening of the mouth 501 00:27:02,120 --> 00:27:03,360 and shutting the mouth? 502 00:27:05,940 --> 00:27:08,850 It's the trigeminal system. 503 00:27:08,850 --> 00:27:12,870 And there's a motor component there 504 00:27:12,870 --> 00:27:16,290 that's involved in jaw control. 505 00:27:16,290 --> 00:27:21,970 And there are pathways to that system from the optic tectum, 506 00:27:21,970 --> 00:27:22,820 OK? 507 00:27:22,820 --> 00:27:30,570 But then to get grasping with limbs in tetrapods, 508 00:27:30,570 --> 00:27:33,767 there is a nucleus there in the midbrain. 509 00:27:33,767 --> 00:27:34,850 AUDIENCE: The red nucleus. 510 00:27:34,850 --> 00:27:39,950 PROFESSOR: The red nucleus, or nucleus ruber, in Latin. 511 00:27:39,950 --> 00:27:43,016 There's only one issue there, though, that's 512 00:27:43,016 --> 00:27:44,220 a bit of a problem. 513 00:27:44,220 --> 00:27:47,110 I said tetrapods, animals with limbs. 514 00:27:47,110 --> 00:27:51,810 Then why is it that, at least the more advanced fish 515 00:27:51,810 --> 00:27:54,280 have them, too? 516 00:27:54,280 --> 00:27:57,410 The fact is, we don't fully understand the red nucleus. 517 00:27:57,410 --> 00:28:02,820 It may not have evolved initially for control of limbs. 518 00:28:02,820 --> 00:28:05,840 But then, again, fish have fins, of course. 519 00:28:05,840 --> 00:28:10,240 They can be used, but not really for grasping, 520 00:28:10,240 --> 00:28:12,140 except for the rare fish that use 521 00:28:12,140 --> 00:28:16,885 their tail as a means of-- as a weapon to kill prey 522 00:28:16,885 --> 00:28:19,260 and slap them out of the water and so forth. 523 00:28:19,260 --> 00:28:22,250 There are fish like that. 524 00:28:22,250 --> 00:28:22,800 Yes. 525 00:28:22,800 --> 00:28:29,105 AUDIENCE: [INAUDIBLE] fish that essentially [INAUDIBLE] 526 00:28:36,380 --> 00:28:37,790 PROFESSOR: Well, that's right. 527 00:28:37,790 --> 00:28:41,070 Yeah, you see it moving in that direction. 528 00:28:41,070 --> 00:28:44,470 But then, you'd have to postulate 529 00:28:44,470 --> 00:28:49,750 that all the advanced fish developed the red nucleus, 530 00:28:49,750 --> 00:28:51,960 and then went back to having no limbs later. 531 00:28:51,960 --> 00:28:56,390 And it seems very unlikely that that is true. 532 00:28:56,390 --> 00:29:01,460 So OK, these are what we just talked about. 533 00:29:01,460 --> 00:29:06,190 And these are the specific pathways 534 00:29:06,190 --> 00:29:08,970 involved with those three kinds of movements. 535 00:29:08,970 --> 00:29:11,130 We've talked about all of them. 536 00:29:11,130 --> 00:29:12,890 We know there are descending pathways 537 00:29:12,890 --> 00:29:15,010 from the midbrain locomotor area. 538 00:29:15,010 --> 00:29:18,140 How have they been studied? 539 00:29:18,140 --> 00:29:22,890 It's very difficult to define precisely that area 540 00:29:22,890 --> 00:29:23,850 anatomically. 541 00:29:23,850 --> 00:29:26,488 It involves a number of structures. 542 00:29:26,488 --> 00:29:27,730 AUDIENCE: [INAUDIBLE]. 543 00:29:27,730 --> 00:29:29,520 PROFESSOR: So they use electrophysiology. 544 00:29:29,520 --> 00:29:31,510 They use electrical stimulation, where, 545 00:29:31,510 --> 00:29:33,640 with very low amounts of current, 546 00:29:33,640 --> 00:29:36,720 they can elicit locomotion. 547 00:29:36,720 --> 00:29:39,130 And it's in one region there, the caudal midbrain. 548 00:29:42,110 --> 00:29:44,400 We'll talk about some of those components later. 549 00:29:44,400 --> 00:29:48,250 Some of them have horrendous names like nucleus tegmenti 550 00:29:48,250 --> 00:29:52,470 pedunculopontine pars compacta is a big part of it. 551 00:29:52,470 --> 00:29:57,500 And it gets a direct projection from the striatum. 552 00:29:57,500 --> 00:29:59,350 And then you have the tectospinal tract. 553 00:29:59,350 --> 00:30:01,600 We've talked about that. 554 00:30:01,600 --> 00:30:03,630 It's not the same as that pathway 555 00:30:03,630 --> 00:30:06,030 that controls the skate movements. 556 00:30:06,030 --> 00:30:08,520 Here we're talking about turning movements. 557 00:30:08,520 --> 00:30:12,950 The skate movements are part of the locomotor system. 558 00:30:12,950 --> 00:30:15,900 That ipsolateral pathway from the tectum 559 00:30:15,900 --> 00:30:20,140 goes to the midbrain locomotor area, and other locomotor 560 00:30:20,140 --> 00:30:22,790 areas, too, to control rapid locomotion. 561 00:30:25,420 --> 00:30:27,460 And then you have the rubrospinal tract 562 00:30:27,460 --> 00:30:32,250 from the red nucleus, nucleus ruber, 563 00:30:32,250 --> 00:30:41,570 another crossed pathway for controlling the limbs. 564 00:30:41,570 --> 00:30:45,780 And then I mentioned for oral grasping, the separate pathways 565 00:30:45,780 --> 00:30:47,365 involved in that. 566 00:30:49,740 --> 00:30:51,490 And they, of course, are the main pathways 567 00:30:51,490 --> 00:30:57,240 for grasping in most fish. 568 00:30:57,240 --> 00:30:59,360 So here's that picture of the midbrain, 569 00:30:59,360 --> 00:31:02,300 just to remind you where these pathways are. 570 00:31:02,300 --> 00:31:05,930 There are deep neurons in the superior colliculus that 571 00:31:05,930 --> 00:31:09,950 get input from the more superficial layers. 572 00:31:09,950 --> 00:31:14,170 They get input from what's stimulating 573 00:31:14,170 --> 00:31:17,540 the superficial layers. 574 00:31:17,540 --> 00:31:20,730 These axons are coming from the retina. 575 00:31:20,730 --> 00:31:26,820 What are the other axons coming in there-- non-visual inputs? 576 00:31:26,820 --> 00:31:29,580 AUDIENCE: [INAUDIBLE]. 577 00:31:29,580 --> 00:31:35,460 PROFESSOR: Somatosensory and auditory, right. 578 00:31:35,460 --> 00:31:37,960 And there are actually maps of auditory space, 579 00:31:37,960 --> 00:31:41,290 and somatosensory space, especially 580 00:31:41,290 --> 00:31:44,290 in animals with whiskers. 581 00:31:44,290 --> 00:31:47,120 OK, but anyway, you get a convergence 582 00:31:47,120 --> 00:31:50,315 of input on these deep neurons, the output neurons, 583 00:31:50,315 --> 00:31:55,060 that send an axon down across the midline. 584 00:31:55,060 --> 00:31:56,780 And they descend right near the midline 585 00:31:56,780 --> 00:32:00,080 on the opposite side, the tectospinal tract. 586 00:32:00,080 --> 00:32:01,480 We call it tectospinal. 587 00:32:01,480 --> 00:32:04,020 Like a lot of pathways, we name a pathway 588 00:32:04,020 --> 00:32:06,580 after its longest axons. 589 00:32:06,580 --> 00:32:10,010 The longest ones reach the cervical spinal cord. 590 00:32:10,010 --> 00:32:12,440 The others terminate in hindbrain, 591 00:32:12,440 --> 00:32:17,200 because the pathways for orienting movements 592 00:32:17,200 --> 00:32:19,780 include a lot of postural adjustments. 593 00:32:19,780 --> 00:32:21,970 A lot of that is done in the reticular formation 594 00:32:21,970 --> 00:32:25,140 of the hindbrain and involves various movements 595 00:32:25,140 --> 00:32:28,500 in the spinal cord. 596 00:32:28,500 --> 00:32:29,000 All right. 597 00:32:35,350 --> 00:32:37,440 You remember this statement from before. 598 00:32:37,440 --> 00:32:40,140 I talked about the midbrain being the connecting link 599 00:32:40,140 --> 00:32:43,180 between the forebrain and motor systems, 600 00:32:43,180 --> 00:32:48,700 early on before the neocortex evolved and got so big. 601 00:32:48,700 --> 00:32:50,610 And generally, the bigger a structure is, 602 00:32:50,610 --> 00:32:52,320 the more connected it is. 603 00:32:52,320 --> 00:32:56,710 And the neocortex, when it got large, 604 00:32:56,710 --> 00:33:01,560 bypassed that midbrain for many of its functions. 605 00:33:01,560 --> 00:33:04,777 That's not true in animals without this very large 606 00:33:04,777 --> 00:33:05,276 endbrain. 607 00:33:08,060 --> 00:33:11,110 And then I mentioned the visceral nervous system. 608 00:33:11,110 --> 00:33:13,780 And various motivation states are also 609 00:33:13,780 --> 00:33:17,320 represented in the midbrain, OK? 610 00:33:17,320 --> 00:33:20,800 It's not all done by hypothalamus. 611 00:33:20,800 --> 00:33:23,790 And what are the areas in the midbrain? 612 00:33:23,790 --> 00:33:28,385 That central gray right around the ventricle, and then 613 00:33:28,385 --> 00:33:30,625 more ventrally, the midline areas, 614 00:33:30,625 --> 00:33:38,258 the ventral tegmental area-- site of many dopamine pathways. 615 00:33:38,258 --> 00:33:41,660 And there are studies that show that, even 616 00:33:41,660 --> 00:33:44,530 without the hypothalamus, you can elicit 617 00:33:44,530 --> 00:33:49,210 various actions triggered by motivational states 618 00:33:49,210 --> 00:33:51,740 from that midbrain area, including 619 00:33:51,740 --> 00:33:56,140 sexual behavior, including attack behavior in predators. 620 00:33:56,140 --> 00:33:56,690 All right. 621 00:34:04,120 --> 00:34:06,060 So what sensory systems are evolved? 622 00:34:06,060 --> 00:34:08,290 Well, we've just been mentioning this. 623 00:34:08,290 --> 00:34:11,440 But look at-- this is one of your questions there. 624 00:34:11,440 --> 00:34:15,740 I asked what two sensory modalities most strongly shaped 625 00:34:15,740 --> 00:34:19,889 the evolution of the forebrain, which 626 00:34:19,889 --> 00:34:21,962 then influences the midbrain? 627 00:34:24,620 --> 00:34:30,500 Olfaction, and the second one, vision-- these 628 00:34:30,500 --> 00:34:35,500 are the two forebrain cranial nerves. 629 00:34:35,500 --> 00:34:40,679 Actually there are others, but these are the largest ones. 630 00:34:40,679 --> 00:34:41,720 There's a terminal nerve. 631 00:34:41,720 --> 00:34:43,239 There's an [? epiphyseal ?] nerve, 632 00:34:43,239 --> 00:34:46,980 another where visual input can come in. 633 00:34:46,980 --> 00:34:50,580 But the ones that are prominent in modern mammals 634 00:34:50,580 --> 00:34:57,580 are those two-- olfaction and the retinal projections. 635 00:34:57,580 --> 00:35:05,080 So we talked a little bit about these things-- olfaction 636 00:35:05,080 --> 00:35:08,650 and vision-- and their links to these motor systems 637 00:35:08,650 --> 00:35:10,380 in the midbrain. 638 00:35:10,380 --> 00:35:12,620 And then there are other inputs, too, 639 00:35:12,620 --> 00:35:17,300 that come in there that also affect movement-- gustatory 640 00:35:17,300 --> 00:35:19,765 input, somatosensory, and auditory inputs. 641 00:35:22,940 --> 00:35:25,700 And we know-- I've just mentioned here-- 642 00:35:25,700 --> 00:35:26,845 these are also important. 643 00:35:30,620 --> 00:35:34,570 What is the diencephalic structure 644 00:35:34,570 --> 00:35:40,330 often involved in the initiation of locomotion-- much more 645 00:35:40,330 --> 00:35:41,934 than that midbrain structure? 646 00:35:44,600 --> 00:35:45,852 Can't hear you. 647 00:35:45,852 --> 00:35:47,130 AUDIENCE: The hypothalamus. 648 00:35:47,130 --> 00:35:50,400 PROFESSOR: Hypothalamus is the best answer. 649 00:35:50,400 --> 00:35:52,620 Now, there is a specific area in the hypothalamus. 650 00:35:52,620 --> 00:35:55,625 We've mentioned the hypothalamic locomotor area. 651 00:35:55,625 --> 00:35:58,550 But the hypothalamus in general is the best answer. 652 00:36:01,270 --> 00:36:03,520 What about the gaits of locomotion? 653 00:36:03,520 --> 00:36:04,670 Where's that control? 654 00:36:07,990 --> 00:36:14,900 Where are the organized circuits that control walking, trotting, 655 00:36:14,900 --> 00:36:18,780 rapid running, or galloping, if you're a four-legged animal? 656 00:36:18,780 --> 00:36:21,110 And many more animals are four-legged, of course, 657 00:36:21,110 --> 00:36:22,094 than are two-legged. 658 00:36:22,094 --> 00:36:23,010 AUDIENCE: [INAUDIBLE]. 659 00:36:23,010 --> 00:36:23,810 PROFESSOR: Sorry? 660 00:36:23,810 --> 00:36:25,770 AUDIENCE: The brainstem. 661 00:36:25,770 --> 00:36:28,510 PROFESSOR: The brainstem is, no doubt, involved. 662 00:36:28,510 --> 00:36:33,015 But in fact, the gates are controlled further down 663 00:36:33,015 --> 00:36:35,460 in the spinal cord. 664 00:36:35,460 --> 00:36:40,050 So let's talk a little more about-- I 665 00:36:40,050 --> 00:36:43,230 use Larry Swanson's way to conceptualize it initially. 666 00:36:43,230 --> 00:36:46,020 And then I show how the forebrain [INAUDIBLE]. 667 00:36:46,020 --> 00:36:48,550 This is his hierarchy. 668 00:36:48,550 --> 00:36:51,810 He has, at the bottom here, the pools of motor neurons 669 00:36:51,810 --> 00:36:52,990 in the spinal cord. 670 00:36:52,990 --> 00:36:57,030 And of course, there's some of them in the hindbrain, too-- 671 00:36:57,030 --> 00:36:59,675 just not for locomotion that involves the legs. 672 00:36:59,675 --> 00:37:01,870 So it's mostly spinal. 673 00:37:01,870 --> 00:37:05,670 But many other behaviors are controlled by hindbrain, too. 674 00:37:05,670 --> 00:37:08,210 So the motor neurons at the bottom, 675 00:37:08,210 --> 00:37:10,570 and connected to those motor neurons 676 00:37:10,570 --> 00:37:14,820 are many interneurons of the brain and spinal cord. 677 00:37:14,820 --> 00:37:17,810 We call them the central pattern generators. 678 00:37:17,810 --> 00:37:21,500 Those would be things like the gaits of locomotion. 679 00:37:21,500 --> 00:37:22,790 It's built in. 680 00:37:22,790 --> 00:37:25,530 It's an innate pattern of wiring. 681 00:37:25,530 --> 00:37:27,650 Grooming movements would be something 682 00:37:27,650 --> 00:37:30,800 like that, too, controlled by, mainly, 683 00:37:30,800 --> 00:37:32,590 hindbrain and spinal cord. 684 00:37:32,590 --> 00:37:35,900 Many of them, again, are spinal cord, 685 00:37:35,900 --> 00:37:39,900 generating the innate patterns of movement. 686 00:37:39,900 --> 00:37:43,320 But above them, like in the midbrain, 687 00:37:43,320 --> 00:37:46,300 you have the central pattern initiators-- 688 00:37:46,300 --> 00:37:51,920 in Swanson's terminology-- like the midbrain locomotor area. 689 00:37:51,920 --> 00:37:56,060 And above that, the pattern controllers, the forebrain 690 00:37:56,060 --> 00:37:59,190 levels of control, that are usually involved 691 00:37:59,190 --> 00:38:02,880 in animals initiating these movements, OK? 692 00:38:02,880 --> 00:38:04,170 So this is what I did. 693 00:38:04,170 --> 00:38:06,330 This is in your book. 694 00:38:06,330 --> 00:38:11,680 And here it just shows some of the network generating 695 00:38:11,680 --> 00:38:16,240 these patterns of activation of the flexors and extensors 696 00:38:16,240 --> 00:38:20,210 of the limbs, controlling various movement patterns. 697 00:38:20,210 --> 00:38:25,840 And then this would be midbrain level, 698 00:38:25,840 --> 00:38:28,150 like the midbrain locomotor region, if we're just 699 00:38:28,150 --> 00:38:31,740 talking about locomotor behavior here. 700 00:38:31,740 --> 00:38:34,760 And then this would be hypothalamus. 701 00:38:34,760 --> 00:38:37,366 This is where you get the input from what 702 00:38:37,366 --> 00:38:41,570 we call drive states, the motivational states. 703 00:38:41,570 --> 00:38:44,890 And then I show, with evolution, how 704 00:38:44,890 --> 00:38:48,260 first olfaction as the endbrain began 705 00:38:48,260 --> 00:38:54,920 to expand-- remember, that was how the forebrain began-- how 706 00:38:54,920 --> 00:38:58,640 the endbrain began, anyway, with olfaction, which projected 707 00:38:58,640 --> 00:39:02,980 to the most primitive parts of the corpus striatum, which then 708 00:39:02,980 --> 00:39:06,660 projected right into the hypothalamus. 709 00:39:06,660 --> 00:39:13,560 And also, as it grew, it started projecting directly 710 00:39:13,560 --> 00:39:14,740 to the midbrain as well. 711 00:39:14,740 --> 00:39:16,700 So in all modern mammals now, you 712 00:39:16,700 --> 00:39:20,530 have those two kinds of projections, just 713 00:39:20,530 --> 00:39:22,730 controlling locomotion. 714 00:39:22,730 --> 00:39:25,910 And then second, you other inputs besides olfaction. 715 00:39:25,910 --> 00:39:28,160 Remember, that was the second major factor 716 00:39:28,160 --> 00:39:31,830 involved in the expansion of the endbrain. 717 00:39:31,830 --> 00:39:35,790 Other inputs came into the forebrain 718 00:39:35,790 --> 00:39:40,120 through the diencephalon, through the older parts 719 00:39:40,120 --> 00:39:44,510 of the thalamus, which went to corpus striatum. 720 00:39:44,510 --> 00:39:50,980 Those other inputs then went to cortex as well, 721 00:39:50,980 --> 00:39:54,950 and a newer part of the thalamus evolved. 722 00:39:54,950 --> 00:39:57,160 So I put it third here, because it 723 00:39:57,160 --> 00:39:59,390 was this neocortex that expanded the most. 724 00:40:02,810 --> 00:40:06,770 Which again, projected the corpus striatum, also 725 00:40:06,770 --> 00:40:10,390 to the medial pallium here, involving the two kinds 726 00:40:10,390 --> 00:40:16,650 of learning-- habit formation and learning of place. 727 00:40:16,650 --> 00:40:19,864 But notice the big change here with neocortex 728 00:40:19,864 --> 00:40:21,030 when it comes to locomotion. 729 00:40:23,850 --> 00:40:27,290 Projections to the midbrain locomotor region, yes, 730 00:40:27,290 --> 00:40:30,720 but also projections directly to the spinal cord. 731 00:40:30,720 --> 00:40:35,150 That was a big change with the expansion of the pallium 732 00:40:35,150 --> 00:40:40,920 as the neothalamus and cortex evolved, 733 00:40:40,920 --> 00:40:44,850 and that structure began to enlarge. 734 00:40:44,850 --> 00:40:51,070 All right, so this just discusses 735 00:40:51,070 --> 00:40:53,685 these pattern controllers and initiators 736 00:40:53,685 --> 00:40:57,330 of the midbrain and caudal hypothalamus. 737 00:40:57,330 --> 00:41:01,740 And I should mention here that there's subthalamic locomotor 738 00:41:01,740 --> 00:41:03,080 areas, too. 739 00:41:03,080 --> 00:41:05,380 Some people just lump them together, 740 00:41:05,380 --> 00:41:08,880 but the localization by the physiologists 741 00:41:08,880 --> 00:41:11,990 indicates that they're probably separate. 742 00:41:11,990 --> 00:41:16,120 And the subthalamic structures and their involvement 743 00:41:16,120 --> 00:41:20,660 in these things, including locomotion and even things 744 00:41:20,660 --> 00:41:22,980 like feeding, is less studied. 745 00:41:22,980 --> 00:41:25,800 We usually focus on the hypothalamus. 746 00:41:25,800 --> 00:41:27,520 And yet I think the subthalamus is 747 00:41:27,520 --> 00:41:31,510 very important in brain evolution, too. 748 00:41:31,510 --> 00:41:34,830 But this is just the-- I have a question in there-- discuss 749 00:41:34,830 --> 00:41:38,700 the types of connections that the early forebrain could have 750 00:41:38,700 --> 00:41:41,350 used to influence the general purpose 751 00:41:41,350 --> 00:41:48,410 movements of the midbrain in those first questions. 752 00:41:48,410 --> 00:41:50,720 And so here I show the midbrain locomotor area. 753 00:41:50,720 --> 00:41:54,470 Here I show the hypothalamic locomotor region, 754 00:41:54,470 --> 00:41:58,230 and I show pathways from the olfactory bones. 755 00:41:58,230 --> 00:42:03,230 There are a few more direct connections in many fish. 756 00:42:06,260 --> 00:42:09,424 I show how the polysynaptic pathways were probably 757 00:42:09,424 --> 00:42:10,290 more common. 758 00:42:10,290 --> 00:42:14,900 They came into both of these locomotor regions. 759 00:42:14,900 --> 00:42:18,806 And some of them took a different route 760 00:42:18,806 --> 00:42:23,060 through the epithalamus, which then also projected 761 00:42:23,060 --> 00:42:26,740 into the midbrain. 762 00:42:26,740 --> 00:42:29,160 All right, and these are the-- did 763 00:42:29,160 --> 00:42:33,810 I show you this before-- just the maps of these locomotor 764 00:42:33,810 --> 00:42:35,470 regions by electrophysiologists? 765 00:42:39,000 --> 00:42:44,940 And then we know that locomotion is influenced 766 00:42:44,940 --> 00:42:47,850 by a lot of other kinds of inputs. 767 00:42:47,850 --> 00:42:52,770 Maintaining balance of the body during standing or locomotion 768 00:42:52,770 --> 00:42:55,580 depends on multiple pathways, some of them 769 00:42:55,580 --> 00:42:57,700 from the reticular formation of the hindbrain. 770 00:43:00,610 --> 00:43:03,225 But there's two other really important descending pathways. 771 00:43:03,225 --> 00:43:06,660 Do you know what they are besides reticulospinal? 772 00:43:06,660 --> 00:43:09,440 They're mainly concerned with controlling the body axis 773 00:43:09,440 --> 00:43:14,880 and what we call whole-body movements like locomotion. 774 00:43:14,880 --> 00:43:18,190 Locomotion involves a lot more than legs. 775 00:43:18,190 --> 00:43:21,350 It involves your whole body. 776 00:43:21,350 --> 00:43:22,690 AUDIENCE: Vestibulospinal. 777 00:43:22,690 --> 00:43:27,360 PROFESSOR: Vestibulospinal, exactly-- so reticulospinal, 778 00:43:27,360 --> 00:43:31,210 vestibulospinal, and remember a structure that 779 00:43:31,210 --> 00:43:34,850 coordinates the timing when multiple systems are involved 780 00:43:34,850 --> 00:43:41,230 in controlling the same movement-- cerebellum. 781 00:43:41,230 --> 00:43:45,930 So we usually don't call it the cerebellospinal. 782 00:43:45,930 --> 00:43:48,620 It's OK with me if you want to call it that, 783 00:43:48,620 --> 00:43:52,190 but it gets the name of the structure in the cerebellum 784 00:43:52,190 --> 00:43:55,290 that gives rise to it, the nucleus fastigii. 785 00:43:55,290 --> 00:43:59,020 So we'll just wait and see the pictures of it. 786 00:43:59,020 --> 00:44:02,555 So this just talks about what we just said. 787 00:44:02,555 --> 00:44:05,790 And this is the picture. 788 00:44:05,790 --> 00:44:08,230 Based on pictures of-- this is the picture 789 00:44:08,230 --> 00:44:11,910 of [? Nauta ?] where he shows the position. 790 00:44:11,910 --> 00:44:14,540 I've emphasized it here-- the position 791 00:44:14,540 --> 00:44:17,000 of the vestibular nuclei in the top view 792 00:44:17,000 --> 00:44:20,450 and the side view, the vestibular 793 00:44:20,450 --> 00:44:25,037 nuclei near the dorsal part of the hindbrain 794 00:44:25,037 --> 00:44:32,750 there, at the same level as the cochlear nuclei, 795 00:44:32,750 --> 00:44:35,660 so just hovering near the lateral edge of the cerebellum 796 00:44:35,660 --> 00:44:37,210 here. 797 00:44:37,210 --> 00:44:40,810 You have that vestibular input coming in 798 00:44:40,810 --> 00:44:43,800 through the eighth nerve. 799 00:44:43,800 --> 00:44:51,780 And the cerebellum developed as a vestibular structure, 800 00:44:51,780 --> 00:44:54,370 as far as we can tell. 801 00:44:54,370 --> 00:44:57,670 This is-- I used a different figure in the book, 802 00:44:57,670 --> 00:44:59,040 but it's really very similar. 803 00:44:59,040 --> 00:45:01,750 This one is from [? Rodahl ?]. 804 00:45:01,750 --> 00:45:05,190 The most primitive part of the cerebellum is here, 805 00:45:05,190 --> 00:45:10,610 the floccular nodular lobe-- the flocculus 806 00:45:10,610 --> 00:45:15,230 out here, the nodulus near the midline. 807 00:45:15,230 --> 00:45:17,680 And things near the midline in the cerebellum 808 00:45:17,680 --> 00:45:22,112 control the body axis, as does the vestibular system. 809 00:45:22,112 --> 00:45:25,020 Out in the hemispheres, it's very different. 810 00:45:25,020 --> 00:45:27,050 The hemispheres are mostly concerned 811 00:45:27,050 --> 00:45:29,446 with the distal muscles of the limbs. 812 00:45:33,870 --> 00:45:36,170 And here on a sagittal section, they 813 00:45:36,170 --> 00:45:39,790 show the position of those vestibular structures. 814 00:45:39,790 --> 00:45:46,700 But this one shows that the vestibular system-- 815 00:45:46,700 --> 00:45:49,100 primary sensory neurons of the vestibular system-- 816 00:45:49,100 --> 00:45:51,530 project into the cerebellum. 817 00:45:51,530 --> 00:45:53,360 And they do so an interesting way, 818 00:45:53,360 --> 00:45:55,220 because no other system does this. 819 00:45:55,220 --> 00:45:57,560 They go directly to the cerebellar cortex. 820 00:45:57,560 --> 00:45:59,820 So here's a little diagram. 821 00:45:59,820 --> 00:46:02,150 You see the vestibular nerve. 822 00:46:02,150 --> 00:46:03,630 These are primary sensory neurons 823 00:46:03,630 --> 00:46:05,802 in the vestibular system. 824 00:46:05,802 --> 00:46:07,760 You see them coming into the vestibular nuclei. 825 00:46:07,760 --> 00:46:11,264 But they also go up into the cerebellum. 826 00:46:13,920 --> 00:46:17,750 And the cerebellum normally projects 827 00:46:17,750 --> 00:46:22,962 to these various deep nuclei-- below the cerebellar cortex. 828 00:46:22,962 --> 00:46:24,670 But in the case of the vestibular system, 829 00:46:24,670 --> 00:46:26,880 it projects directly to the vestibular nuclei. 830 00:46:29,890 --> 00:46:34,790 And there you see a very simplified view. 831 00:46:34,790 --> 00:46:37,440 There's actually four different vestibular nuclei. 832 00:46:37,440 --> 00:46:40,440 They don't show that here, but this is, again, 833 00:46:40,440 --> 00:46:42,190 the [? Rodahl ?] book, where he shows 834 00:46:42,190 --> 00:46:45,520 the origin of the vestibulospinal tract. 835 00:46:45,520 --> 00:46:51,060 And there's also another set of axons 836 00:46:51,060 --> 00:46:57,250 going in the opposite direction, connecting to the motor neurons 837 00:46:57,250 --> 00:46:59,030 controlling eye muscles. 838 00:46:59,030 --> 00:47:05,770 There's a very close tie between vestibular system, cerebellum, 839 00:47:05,770 --> 00:47:09,960 and eye movements, and head movements. 840 00:47:09,960 --> 00:47:11,900 And there's a whole group of axons 841 00:47:11,900 --> 00:47:15,660 running between these nuclei interconnected with reticular 842 00:47:15,660 --> 00:47:19,240 formation, vestibular nuclei, and cerebellum, 843 00:47:19,240 --> 00:47:22,600 always coordinating the eye and the head and turning movements. 844 00:47:22,600 --> 00:47:28,400 They're so important for animals to get around. 845 00:47:28,400 --> 00:47:31,210 All right, you don't need to learn this, 846 00:47:31,210 --> 00:47:35,030 but I wanted to emphasize this nucleus. 847 00:47:35,030 --> 00:47:41,740 That's the nucleus that projects directly to the spinal cord. 848 00:47:41,740 --> 00:47:45,100 It's heavily connected with the vestibular system as well. 849 00:47:45,100 --> 00:47:48,490 OK, so we'll come back there next time. 850 00:47:48,490 --> 00:47:50,840 And we'll start by going over orienting 851 00:47:50,840 --> 00:47:55,841 a little more in order to finish this introduction to the motor 852 00:47:55,841 --> 00:47:56,340 system. 853 00:47:56,340 --> 00:47:58,880 I didn't expect to finish this today. 854 00:47:58,880 --> 00:48:02,290 But what follows is a little easier. 855 00:48:02,290 --> 00:48:09,000 So you've got-- I've posted all the things here 856 00:48:09,000 --> 00:48:10,433 for you to read. 857 00:48:10,433 --> 00:48:12,410 So please continue with that reading. 858 00:48:12,410 --> 00:48:16,290 And we'll give you something on Wednesday. 859 00:48:16,290 --> 00:48:18,849 If we're going to give it a little bit as a quiz, 860 00:48:18,849 --> 00:48:19,640 we'll let you know. 861 00:48:19,640 --> 00:48:21,820 I'm not sure we'll do that, but we'll 862 00:48:21,820 --> 00:48:25,227 get that done as soon as we can.