WEBVTT 00:00:03.537 --> 00:00:10.497 This is the Convergent Science Network podcast. Leading researchers in the domain 00:00:10.497 --> 00:00:16.777 of neuroscience, brain theory and technology are interviewed by Paul Verschoor and Tony Prescott. 00:00:25.617 --> 00:00:29.977 This is Paul Verschoor with the Convergent Science Network And I'm here with 00:00:29.977 --> 00:00:32.397 Tony Prescott and our guest, Stan Grillner. 00:00:33.537 --> 00:00:38.777 Stan is a neurophysiologist, and Stan was speaking this morning about the control 00:00:38.777 --> 00:00:42.537 of motor behavior of action, in particular in the lamprey. 00:00:42.537 --> 00:00:51.237 And Stan, the starting point of your presentation was the observation that there 00:00:51.237 --> 00:00:56.317 are lots of similarities in how motor patterns are organized across different species, 00:00:56.557 --> 00:00:58.377 right, from fish to humans. 00:00:58.537 --> 00:01:06.977 So what's really the invariance there that you see? I mean, the invariance is in the control systems. 00:01:07.317 --> 00:01:13.717 From the brainstem, you have command centers that activate spinal locomotor circuits. 00:01:13.937 --> 00:01:23.637 Of course, you have then different species, of course, of different forms of locomotion. 00:01:23.817 --> 00:01:29.077 And fish locomotion and human locomotion is not identical, but it's built up 00:01:29.077 --> 00:01:33.937 in the same way with central networks, with sensory control on these networks. 00:01:35.757 --> 00:01:40.977 And so there is, with the control structure, it's very clear similarities. 00:01:41.517 --> 00:01:45.677 Okay, but that runs across the whole nervous system? 00:01:45.857 --> 00:01:49.097 Or are they adding divergent patterns there? 00:01:49.157 --> 00:01:52.597 Or for you, that really goes from, let's say, spinal cord, where you directly 00:01:52.597 --> 00:01:55.197 interface the periphery all the way to frontal areas? 00:01:57.957 --> 00:02:05.597 Essentially, we have the execution of different behaviors like locomotion, 00:02:05.717 --> 00:02:08.037 posture, control, eye movements, etc. 00:02:08.397 --> 00:02:13.117 Is controlled at the brainstem, spinal cord level. 00:02:13.417 --> 00:02:21.457 But then in addition, you have control circuits in the forebrain that decide 00:02:21.457 --> 00:02:28.717 or helps to decide when a given motor program should be turned on or turned off. 00:02:30.070 --> 00:02:37.330 Okay. But now, you very early on, so we're talking quite some decades now ago, 00:02:37.690 --> 00:02:43.590 decided to really focus on one species in particular, which is the lamprey, 00:02:43.690 --> 00:02:49.990 which you believe is really, let's say, the prototypical brain of all vertebrates. 00:02:50.850 --> 00:02:55.570 So, what's the power of this lamprey model? Why did you zoom in on that one so strongly? 00:02:55.570 --> 00:03:01.590 Well, I mean, the history before that is that we were interested in the mammals, 00:03:01.830 --> 00:03:05.990 in the basic design of the locomotor control system. 00:03:06.190 --> 00:03:14.210 And there we showed that you can activate the spinal cord motor centers from 00:03:14.210 --> 00:03:17.810 the brainstem in a well-conserved command center. 00:03:17.810 --> 00:03:22.350 Center in the spinal cord, we have the networks that coordinate the different 00:03:22.350 --> 00:03:28.830 movements, and they can do so without any sensory input. 00:03:29.070 --> 00:03:33.170 On the other hand, we show that when the sensory input is present, 00:03:33.450 --> 00:03:39.970 it can help regulate the locomotor movement in a very good way. 00:03:40.550 --> 00:03:47.210 So that was the starting point when I like to go further and understand not 00:03:47.210 --> 00:03:49.290 only that that we have a network in the spinal cord, 00:03:49.430 --> 00:03:56.690 but the intrinsic mechanism that is responsible for this. 00:03:57.090 --> 00:04:05.950 And I did not think that was reachable in the mammal at the time, 00:04:06.070 --> 00:04:12.610 so that's why I selected to go to as simple a vertebrate as possible, 00:04:12.850 --> 00:04:17.710 but still a vertebrate with the same basic design of the nervous system. 00:04:18.170 --> 00:04:22.070 So that's when we opted for the lamprey for several reasons. 00:04:22.550 --> 00:04:24.770 What other options did you have at the time? 00:04:25.530 --> 00:04:29.070 I was thinking about the amphioxus as one possibility. 00:04:29.510 --> 00:04:35.070 I actually started and we did some work on elasmobranchs, the dogfish, 00:04:35.270 --> 00:04:42.750 and showed that you have sensory generation there and you have sensory feedback and so forth. 00:04:43.730 --> 00:04:48.570 But also the elastomer branch spinal cord was not very useful, 00:04:48.750 --> 00:04:52.910 so that's why we opted for the lamprey. 00:04:53.030 --> 00:04:58.750 I looked on the amphioxus also, but the amphioxus is, 00:04:59.830 --> 00:05:04.530 the spinal cord is only 50 microns in dimension, And at the time, 00:05:04.530 --> 00:05:09.850 I didn't think this was possible to use experimentally. 00:05:10.490 --> 00:05:15.950 Would you consider going back to Amphioxus now and seeing how many of the conserved 00:05:15.950 --> 00:05:18.490 traits that you see in the jawless fish are also present? 00:05:19.880 --> 00:05:24.640 Are there techniques there now to do that? Well, in my next life, I would like to do that. 00:05:26.460 --> 00:05:31.220 But now, did you ever regret that early choice for Lamprey? Did you ever think, 00:05:31.300 --> 00:05:33.060 oh no, this was actually a mistake? 00:05:33.480 --> 00:05:38.220 No, I have always thought it was a very good choice at the time. 00:05:38.460 --> 00:05:45.680 If I would have had to do it today with all the tools that there are in the 00:05:45.680 --> 00:05:49.300 zebrafish, I mean, the zebrafish would have been... 00:05:50.360 --> 00:05:53.180 Been probably a choice to make because 00:05:53.180 --> 00:05:56.140 i mean you have all the different tools with the 00:05:56.140 --> 00:06:01.660 gdf marked subtypes on neurons etc on the other hand the zebrafish brain is 00:06:01.660 --> 00:06:05.880 much much smaller i'm not sure that we would have done been able to do the things 00:06:05.880 --> 00:06:13.300 that we did have done in the lamprey so right so the lamprey uh appears in evolution 00:06:13.300 --> 00:06:15.860 about 560 million years ago, 00:06:17.220 --> 00:06:20.060 so at the beginning of the Cambrian explosion. 00:06:20.760 --> 00:06:25.700 So how firm is that understanding of the lamprey really, let's say, 00:06:25.720 --> 00:06:30.260 anchoring this phylogenetic expansion of vertebrate? 00:06:30.440 --> 00:06:34.140 Well, it's the jawless fish, really, isn't it? So we don't know exactly what 00:06:34.140 --> 00:06:36.260 the ancestral jawless fish would have been like. 00:06:36.320 --> 00:06:38.980 Well, that's really what I'm fishing for, right? Yeah, yeah, yeah. 00:06:39.600 --> 00:06:46.900 I mean, one has fossil records, And the claim is that it is quite conserved, 00:06:46.900 --> 00:06:52.280 but of course, over 560 million years, a few things may have happened. 00:06:53.800 --> 00:06:57.080 So now we have the lamprey, and then in some sense, 00:06:57.240 --> 00:07:02.420 a significant amount of time you really spend on understanding how the spinal 00:07:02.420 --> 00:07:07.900 cord of this fish works, and how the physiology of that spinal cord and also 00:07:07.900 --> 00:07:11.380 its anatomy in the end translate into locomotion. 00:07:11.380 --> 00:07:16.780 So, what are now the basic design principles of that spinal cord of the lamprey? 00:07:18.740 --> 00:07:25.160 The original goal of taking up the lamprey was to understand a CPG, 00:07:25.240 --> 00:07:27.440 a central path generator network. 00:07:28.020 --> 00:07:38.280 And I think what is the basic tenet is that we have excitatory premotor interneurons 00:07:38.280 --> 00:07:40.080 that are also interacting. 00:07:40.080 --> 00:07:45.940 Interacting and together as a collective generating the burst pattern. 00:07:46.220 --> 00:07:52.180 And then in addition, we have inhibitory interneurons that coordinate the different burst generators. 00:07:52.580 --> 00:07:56.720 So, I mean, that's, so essentially, membrane properties are critical, 00:07:56.820 --> 00:08:01.720 synaptic interaction is critical, and the types of synaptic interaction that you have. 00:08:03.980 --> 00:08:11.020 But which key parameters of, at a cellular level? are really key here. 00:08:12.616 --> 00:08:17.016 With regard to the membrane properties, 00:08:17.736 --> 00:08:24.256 the calcium NMDA receptors, voltage-dependent calcium channels, 00:08:24.576 --> 00:08:32.116 low-voltage activated calcium channels are quite important for regulating the 00:08:32.116 --> 00:08:35.876 calcium levels in the neurons. 00:08:35.876 --> 00:08:44.836 And then we have the related calcium-activated potassium channels and also at 00:08:44.836 --> 00:08:45.756 higher level of activity, 00:08:45.936 --> 00:08:51.516 sodium-activated potassium channels that pull the membrane potential down and 00:08:51.516 --> 00:08:57.456 helps to terminate the burst and then also to close the voltage-dependent NMDA receptors. 00:08:57.456 --> 00:09:02.776 So function basically means you need a bursting unit that is asymmetrically 00:09:02.776 --> 00:09:07.876 coupled to an opponent bursting unit, so you have your oscillation. 00:09:08.136 --> 00:09:14.396 Yeah, but I mean even without the reciprocal coupling, you still have oscillation. Of course. Yeah. 00:09:14.656 --> 00:09:19.736 But you need opponent coupling if you want to translate this into movement. Yeah, yeah, sure. Okay. 00:09:20.996 --> 00:09:26.096 So, but now what you also showed is that basic central pattern generator network 00:09:26.096 --> 00:09:33.476 about which which we have about 100 making up the spinal cord of a lamprey, if I'm correct, 00:09:33.716 --> 00:09:38.756 is also, again, under a lot of additional control, descending control, 00:09:38.956 --> 00:09:41.576 coming out of higher brain areas, right? 00:09:41.656 --> 00:09:45.676 So what are the key features of that kind of control? 00:09:46.976 --> 00:09:54.056 The key features and what can drive the network is a tonic drive from the brainstem. 00:09:54.056 --> 00:10:02.196 Them, and the Locomotor Command Centers in turn can activate the reticulus behind the new wounds. 00:10:03.551 --> 00:10:09.531 So that is sufficient. So you elevate the excitability of the spinal cord via 00:10:09.531 --> 00:10:15.611 rather unspecific activation of excitatory and inhibitory interneurons. 00:10:15.671 --> 00:10:19.971 The same reticulospinal can activate both excitatory and inhibitory and motor 00:10:19.971 --> 00:10:22.931 neurons, but the overall excitation increases. 00:10:24.451 --> 00:10:31.251 So that's answer one. Answer two is that in addition, 00:10:31.471 --> 00:10:38.811 we actually have a feedback from the head wards, the segments that are rather 00:10:38.811 --> 00:10:42.571 close to the head, which feeds into the reticulospinal neurons. 00:10:43.651 --> 00:10:49.211 So they are actually, even though they may be tonically activated from command 00:10:49.211 --> 00:10:52.371 centers, they get rhythmically active. 00:10:52.371 --> 00:10:57.291 And it turns out that the fact that the reticulospinins are rhythmically active 00:10:57.291 --> 00:11:05.131 provides a stronger excitation of the more rostral segments and more tonic of 00:11:05.131 --> 00:11:08.431 the remaining, but it also provides, 00:11:09.251 --> 00:11:14.291 gating signals, so that if you have steering signals from the, 00:11:14.451 --> 00:11:24.171 for instance, tectum or or spherical iclos-like, then these signals need not be very precise. 00:11:24.691 --> 00:11:32.611 The command signal that lasts for one cycle will then be gated by the reticulospinal actin. 00:11:32.911 --> 00:11:37.111 So that's an added feature that I didn't speak about. Right. 00:11:37.891 --> 00:11:42.431 Another added feature that you did speak about, though, is also the role of, 00:11:42.451 --> 00:11:45.631 if you want the embodiment itself of the spinal cord, right? 00:11:45.631 --> 00:11:49.971 There's also a dense coupling with the periphery through the stretch receptors 00:11:49.971 --> 00:11:52.531 in the body of the spinal, of the lamprey. 00:11:52.711 --> 00:12:00.811 So how does that body itself contribute to, in the end, the very smooth sinusoidal 00:12:00.811 --> 00:12:03.771 movements that you have to generate to get swimming? 00:12:04.831 --> 00:12:14.671 Yeah, and you can have well-coordinated swimming movements without any sensory feedback. 00:12:15.631 --> 00:12:18.631 But with the sensory feedback you get a 00:12:18.631 --> 00:12:24.871 compensation for any perturbation 00:12:24.871 --> 00:12:34.971 which helps then the animal to handle unexpected perturbations like when swimming 00:12:34.971 --> 00:12:38.751 in a brook and being moved in different directions. 00:12:40.311 --> 00:12:48.171 There are also additional, actually, the mid-cells have somewhat different power 00:12:48.171 --> 00:12:49.871 in different parts of the body. 00:12:50.071 --> 00:12:55.431 But if you would take a spinal cord out of the body and you would activate it, would it also swim? 00:12:59.197 --> 00:13:05.557 Only the spinal cord. I mean, the spinal cord would generate rhythmic activity. 00:13:05.757 --> 00:13:07.837 The spinal cord itself would not swim. 00:13:08.197 --> 00:13:12.197 Right, but what are the minimum components of the muscles that you have to retain 00:13:12.197 --> 00:13:15.157 to get swimming movement of this body? 00:13:15.757 --> 00:13:27.177 Okay, so you're asking how much muscle should be retained in order to have movement. I don't know. 00:13:27.317 --> 00:13:35.757 I mean, essentially, I cannot answer that directly, but I can say that during 00:13:35.757 --> 00:13:41.357 slow swimming, you have primarily the slow motor units activated, 00:13:41.697 --> 00:13:46.857 and that's sufficient to activate the locomotive movement. 00:13:47.357 --> 00:13:52.637 Okay. Now, what is interesting is that, for instance, if you look at the modeling of behavior, 00:13:53.137 --> 00:13:58.437 there's quite a discussion now on the very intricate coupling of nervous system 00:13:58.437 --> 00:14:02.397 control and the specific biomechanics that are effectuating. 00:14:02.737 --> 00:14:07.657 And that's also, if you take the body of this lamprey, it's not that this spinal 00:14:07.657 --> 00:14:12.097 cord is really deciding exactly on the positions of different body segments. 00:14:12.677 --> 00:14:17.577 It just depends, again, on the bending and the forces that this body is exposed 00:14:17.577 --> 00:14:20.377 to generate the movement. Sure. 00:14:20.697 --> 00:14:25.117 It was for that reason I was asking about a more decomposed lamprey and how 00:14:25.117 --> 00:14:26.317 well that would still function. 00:14:27.877 --> 00:14:33.717 So, Stan, you mentioned slow swimming, and I guess the lamprey can swim at different speeds. 00:14:33.937 --> 00:14:40.917 Can it locomote in different modes, or is everything a variant on the basic pattern? 00:14:41.977 --> 00:14:48.377 I mean, when it swims forward, it's essentially the same pattern. 00:14:48.377 --> 00:14:58.057 But the frequency of oscillations, the burst frequency, can go from 0.3, 0.4 Hz up to 10 Hz. 00:15:00.937 --> 00:15:07.337 It's a considerable range. And what happens then is that you recruit more and 00:15:07.337 --> 00:15:11.697 more motor neurons in order to achieve these alternating movements. 00:15:11.697 --> 00:15:18.437 So in terms of vertebrate locomotion pattern generation, it's almost the simplest 00:15:18.437 --> 00:15:21.217 kind because whereas land mammals will have different gates, 00:15:21.717 --> 00:15:28.037 the lamprey will have a basic swimming pattern and then it can do that at different 00:15:28.037 --> 00:15:30.957 speeds and I guess it can turn by different amounts. 00:15:31.317 --> 00:15:34.497 It can turn and it can swim backwards. Right, okay. 00:15:35.057 --> 00:15:37.237 Can it roll? Would it do that? 00:15:39.407 --> 00:15:45.167 Yes, it is rolling, particularly if you leach in one vestibular apparatus. Okay. 00:15:47.107 --> 00:15:52.067 But I mean, what is interesting, I mean, we haven't talked at all about the 00:15:52.067 --> 00:15:53.867 control of body orientation, 00:15:54.287 --> 00:16:01.687 but we've done an experiment quite some time ago where we, I mean, 00:16:01.747 --> 00:16:07.647 the The lamprey corrects itself, and we have looked in detail on that connectivity, 00:16:07.967 --> 00:16:11.907 but then you have the different reticulospinal nuclei, 00:16:12.667 --> 00:16:14.827 the anterior, the middle, and the posterior, 00:16:15.967 --> 00:16:23.987 and the mesencephalic, and they are activated, maximally activated at different 00:16:23.987 --> 00:16:28.047 angles, one one at 45 degree, another at 90 degree. 00:16:28.227 --> 00:16:36.367 The anterior rhombocephalic reticular nucleus is activated maximally when the lamprey is upside down. 00:16:36.587 --> 00:16:42.107 So, I mean, there's a selective control of body orientation. 00:16:43.567 --> 00:16:53.687 And you also have that bias under conditions when the lamprey likes to orient 00:16:53.687 --> 00:16:56.207 itself towards the light, 00:16:57.027 --> 00:17:00.467 when the light is coming in from the side. 00:17:00.867 --> 00:17:05.387 Right. So now you've analyzed in great detail the spinal cord, 00:17:05.547 --> 00:17:07.847 and now we know roughly how this animal can swim. 00:17:08.127 --> 00:17:10.687 And it's a very robust system. 00:17:11.767 --> 00:17:16.047 And now in order to validate your understanding, you also build a very detailed 00:17:16.047 --> 00:17:17.907 model of this lamprey spinal cord. 00:17:18.167 --> 00:17:24.387 Yeah. Right, so was it really like a one-to-one copy of a biological spinal cord? 00:17:25.547 --> 00:17:32.027 I mean, what we have done, probably not a one-to-one copy, but we have simulated 00:17:32.027 --> 00:17:35.147 in this later large simulation from 2009, 00:17:36.127 --> 00:17:43.487 we have simulated the excitatory interneurons with the variability in cellular 00:17:43.487 --> 00:17:46.107 properties and size that you have. 00:17:46.107 --> 00:17:50.687 So in each segment we have that variability introduced. 00:17:52.107 --> 00:17:55.107 So I mean it's a fairly close copy. 00:17:56.566 --> 00:18:02.406 And the ambition is that each group, each population of cells should be as close 00:18:02.406 --> 00:18:04.866 as possible to the natural counterpart. 00:18:05.406 --> 00:18:15.826 And it turns out that it's very important that we have the variability in each pool of interneurons, 00:18:15.826 --> 00:18:21.606 because that makes for a much more stable motor pattern. 00:18:26.026 --> 00:18:34.186 Because with a different sensitivity of the neurons, some neurons in the population 00:18:34.186 --> 00:18:40.066 are recruited first, and then you have a progressive recruitment and a progressive de-recruitment. 00:18:40.366 --> 00:18:45.546 And that makes for a much more stable activity. So, the variability is not an 00:18:45.546 --> 00:18:47.306 accident, it's built into the system. 00:18:47.486 --> 00:18:52.286 So, in what properties, what cellular properties do you find this variability? 00:18:53.126 --> 00:19:02.206 I mean, it's overall size, so the input resistance, but it is also the size of the, 00:19:03.386 --> 00:19:10.686 sort of the calcium dependent potassium channels, we also vary different cellular 00:19:10.686 --> 00:19:13.446 properties it is plus or minus 15% or so. 00:19:13.726 --> 00:19:16.226 So that is roughly the range in which you will find this variability. 00:19:16.626 --> 00:19:21.626 And you identified it first in these simulations, or you already had seen that 00:19:21.626 --> 00:19:23.486 in your biological preparation? 00:19:23.846 --> 00:19:26.526 In that case, we had seen that in the biological preparation, 00:19:26.686 --> 00:19:31.006 and we introduced that, but we could also then show that without that, 00:19:31.266 --> 00:19:33.306 the system didn't perform well. 00:19:33.426 --> 00:19:39.886 With a variability, you have a much more stable matter activity. Okay. 00:19:40.026 --> 00:19:44.646 So then what were the main lessons that you extracted from the system level 00:19:44.646 --> 00:19:48.766 model and this highly detailed and then constraint model? 00:19:50.291 --> 00:19:57.251 One thing was clear, the variability, and we could also explore things that if we modified. 00:19:59.411 --> 00:20:02.911 Particularly the spike frequency adaptations through calcium-dependent potassium 00:20:02.911 --> 00:20:04.691 channels, it's important. 00:20:04.971 --> 00:20:10.071 We could also simulate the effect of FADGT on the network. 00:20:16.131 --> 00:20:21.511 But it seems that the model sort of like confirmed your understanding of the 00:20:21.511 --> 00:20:26.091 system, but it didn't necessarily generate a new insight, did it? 00:20:26.551 --> 00:20:30.331 I think, I mean, the simulations, 00:20:30.611 --> 00:20:35.951 the segmental simulations that we did quite a quite a long time ago, 00:20:36.111 --> 00:20:42.791 that certainly gave a lot of insights to new experiments and so forth. 00:20:43.071 --> 00:20:46.131 So, I mean, there we had a close interaction. 00:20:47.911 --> 00:20:54.451 The insights that we got with these larger system simulations were also related 00:20:54.451 --> 00:20:57.251 to the control and forward and backward. 00:20:57.391 --> 00:21:01.891 I spoke a little bit about that. The fact that if you have this huge network 00:21:01.891 --> 00:21:04.631 with 10,000 neurons, and it's 00:21:04.631 --> 00:21:09.331 sufficient that you tinker a little bit with about 5-10% of the network, 00:21:09.591 --> 00:21:14.011 and then you can modify the pattern of activity entirely in the entire network, 00:21:14.171 --> 00:21:15.811 it was something that we had not predicted. 00:21:16.471 --> 00:21:22.391 Right. So now here we have, so you've done, I mean, how many years did it take 00:21:22.391 --> 00:21:26.051 you to sort of work your way through the spinal cord, finish the simulations? 00:21:26.051 --> 00:21:28.531 You could say, okay, now we understand really how this thing works. 00:21:28.691 --> 00:21:30.351 How many years of work is that? 00:21:34.871 --> 00:21:36.031 Well, too many. 00:21:41.351 --> 00:21:44.091 But would 20 years be a reasonable guess? 00:21:45.655 --> 00:21:51.615 I mean, of course, during this period, we have, I mean, the first was that you 00:21:51.615 --> 00:21:57.115 had rhythmic activity and then the definition of the local excitatory interneurons, 00:21:57.255 --> 00:21:59.255 and we could approximately understand that. 00:22:00.275 --> 00:22:06.835 And then we had the intersegmental and in parallel, we have had the work on 00:22:06.835 --> 00:22:09.395 the brainstem and the control of body orientation. 00:22:10.395 --> 00:22:15.955 So, we have added on things that we did not think about before. 00:22:16.075 --> 00:22:23.275 If you take the basics of the first question that I had, 00:22:23.975 --> 00:22:30.835 what in the hell, I mean, how does a birth generation occur in the spinal cord, 00:22:31.095 --> 00:22:38.175 which was the reason why I went from from mammals to the lamprey. 00:22:38.275 --> 00:22:41.375 That took probably five years or something like that. 00:22:42.335 --> 00:22:45.875 Since we had a reasonable understanding on that, we have perfected on that. 00:22:46.795 --> 00:22:52.815 But then you have the intersegmental, forward-backward sensory control, 00:22:52.975 --> 00:22:59.955 how that is integrated in the posterior control at the brainstem level and now 00:22:59.955 --> 00:23:04.795 with the basic anglia addition and tactile and eye movement. 00:23:04.795 --> 00:23:07.775 And it keeps on going right yeah there's 00:23:07.775 --> 00:23:10.855 a few things left to do yeah so having got 00:23:10.855 --> 00:23:14.535 this detailed understanding of lamprey spinal cord can 00:23:14.535 --> 00:23:18.015 you now look across the other vertebrate groups 00:23:18.015 --> 00:23:23.235 and say something about how spinal cord has evolved because when people talk 00:23:23.235 --> 00:23:27.975 about brain evolution they often say spinal cord is is pretty much conserved 00:23:27.975 --> 00:23:31.555 but there must be important things that have changed and what what would you 00:23:31.555 --> 00:23:36.695 say are the are the main ones and what does that say about about neural evolution more generally. 00:23:37.475 --> 00:23:41.095 I mean, essentially, of course, what has happened. 00:23:42.766 --> 00:23:46.186 The lamprey does not have paired fins, so it's essentially the trunk. 00:23:46.906 --> 00:23:52.586 Then you have the evolution of paired fins, first in elasmobranchs, 00:23:52.746 --> 00:23:57.766 where the fins are used mostly for posture control and steering. 00:23:58.406 --> 00:24:07.466 And then you have the further elaboration on the pectoral fins in teleosts, ray-finned fish, 00:24:07.686 --> 00:24:16.006 where the fins can actually be used for positioning the mouse quite accurately and so forth. 00:24:16.366 --> 00:24:22.406 It can also be used for slow locomotion, whereas with fast locomotion the fins are not used. 00:24:23.026 --> 00:24:30.326 So then again, it is trunk movements, and then you have the elaboration of the 00:24:30.326 --> 00:24:39.366 pectoral fins to forelimbs in frogs and other higher vertebrates, 00:24:39.466 --> 00:24:41.286 and there again, 00:24:41.986 --> 00:24:46.546 rather little is known about the exact pattern. 00:24:47.886 --> 00:25:01.426 But in a salamander, it swims in a lamprey-like way, and that has been done simulations also. 00:25:01.606 --> 00:25:08.466 It walks however with the limbs coordinated with the trunk. 00:25:10.066 --> 00:25:19.106 So you have the trunk movements there, but then of course the limb movements take over, 00:25:20.146 --> 00:25:30.706 and we have the, at least for the hind limbs, the foreface movements maybe slightly 00:25:30.706 --> 00:25:33.966 different from the forelegs. 00:25:34.726 --> 00:25:40.426 And what happens during evolution then is that for posterior stability, 00:25:40.806 --> 00:25:44.226 the limbs point out laterally and with a support, 00:25:45.406 --> 00:25:52.826 and then progressively in some lizards and then mammals, the limbs move in under 00:25:52.826 --> 00:25:57.546 the body, which makes for more efficient locomotion, but much greater posture 00:25:57.546 --> 00:26:00.146 problems or balance problems. 00:26:02.544 --> 00:26:08.764 So you have a huge amount of change in the periphery, and does that induce fundamental 00:26:08.764 --> 00:26:14.144 changes in the circuits that generate patterns, or are they really the same circuits, 00:26:14.324 --> 00:26:21.504 but maybe with some new add-ons to cope with these extra appendages like limbs? 00:26:21.504 --> 00:26:29.084 I mean, one knows rather little about the exact relation, but in the tadpole 00:26:29.084 --> 00:26:35.524 and the frog tadpole that then develops limbs, in the period where they just develop limbs, 00:26:35.744 --> 00:26:43.764 work by Combs and Kieselar, then you have a period where you have the rhythmic 00:26:43.764 --> 00:26:49.244 activity of the limbs going in phase with the locomotive movements of the truck. 00:26:49.244 --> 00:26:55.724 And then you get the phase where they sometimes are in phase and sometimes are 00:26:55.724 --> 00:26:58.304 independent, and then they become independent. 00:26:58.744 --> 00:27:05.004 And it has been argued that it's probably a group of interneurons that are gradually 00:27:05.004 --> 00:27:12.564 parceled out to control the limb that are maybe initially part of that. 00:27:12.564 --> 00:27:17.764 And it's also a possibility that you have the dorsal and the ventral part of 00:27:17.764 --> 00:27:20.944 the myotome related to extensors and flexors. 00:27:21.304 --> 00:27:24.424 But Sten, the consequence of this seems to be that you're saying, 00:27:24.524 --> 00:27:28.964 well, the periphery shows many changes, but in this local organization, 00:27:29.264 --> 00:27:33.304 the spinal cord, not many modifications are found. 00:27:33.304 --> 00:27:39.764 No, I mean, if you have new populations that are singled out from the older 00:27:39.764 --> 00:27:44.104 population that become independent, or at least independent. 00:27:44.900 --> 00:27:51.740 Correlated with the other. It tells you possibly that it's the same, well, 00:27:52.080 --> 00:27:57.260 it seems to be the same group of interneuron genetically, the B2A interneurons, 00:27:57.380 --> 00:28:02.940 but that they are singled out. 00:28:03.060 --> 00:28:09.000 So you have a large population and then you single out some that become independent 00:28:09.000 --> 00:28:17.100 and And we have essentially four different patterns of motor activity, at least for the hind. 00:28:17.200 --> 00:28:20.720 But there isn't a qualitative change, right? 00:28:20.760 --> 00:28:27.540 If we go from lamprey, salamander to, let's say, humans, in our case, 00:28:27.620 --> 00:28:29.480 it's much more transient control, right? 00:28:29.540 --> 00:28:34.560 You can change posture and then you fix it. It's static. 00:28:35.080 --> 00:28:39.240 Well, if you're a lamprey, okay, either you do nothing or you're oscillating. 00:28:40.980 --> 00:28:45.720 I mean, you correct body orientation very actively also. Okay, fine. 00:28:46.000 --> 00:28:49.120 But still, everything you do is in oscillatory mode. 00:28:49.420 --> 00:28:54.180 And also, how it transduces to the periphery is in an oscillatory fashion. 00:28:54.540 --> 00:28:57.760 Within our case, we would have an oscillatory substrate, our spinal cord, 00:28:57.960 --> 00:29:00.460 while my movement control is much more transient. 00:29:01.360 --> 00:29:05.640 Right? I have change and then I fix my posture. It would be very annoying if 00:29:05.640 --> 00:29:08.580 I would be oscillating here with my arms around you while we're speaking. 00:29:09.860 --> 00:29:15.040 So wouldn't that suggest that there must be an additional layer of control superimposed 00:29:15.040 --> 00:29:17.720 on that design template of the lamp break? 00:29:20.810 --> 00:29:27.830 I'm not, I mean, as humans, of course, we are walking around, 00:29:28.070 --> 00:29:35.990 we are stopping, and we can stand and we can lie and we can stand on our head. 00:29:36.670 --> 00:29:45.450 So we have a flexibility, and even when standing, we tend to oscillate a little 00:29:45.450 --> 00:29:48.650 bit, actually, and maintain stability. 00:29:51.010 --> 00:29:58.350 I'm not convinced that there is a fundamental difference there. 00:29:58.710 --> 00:30:02.950 Okay. I mean, essentially… Yeah. 00:30:04.750 --> 00:30:09.170 Well, look, as you know, in the literature, people would talk about how a spinal 00:30:09.170 --> 00:30:11.790 cord is organized around force fields, and that in that sense, 00:30:11.850 --> 00:30:15.590 you can get the form of kinematic control because you can now guide limbs to 00:30:15.590 --> 00:30:17.510 defined positions in space. 00:30:17.510 --> 00:30:22.690 Bay exploiting an oscillatory dynamic but it would mean that the whole control 00:30:22.690 --> 00:30:25.410 system itself has sort of changed in character, 00:30:27.270 --> 00:30:30.950 that's a little bit what I'm searching for whether you find any evidence for 00:30:30.950 --> 00:30:34.830 that if you just look at that your understanding of spinal cord to lumbar and 00:30:34.830 --> 00:30:38.930 how it would generalize to other vertebrates and mammals, 00:30:39.990 --> 00:30:45.890 I mean the force field experiments are interesting but they are. 00:30:48.843 --> 00:30:53.423 Um complicated in interpretation okay so 00:30:53.423 --> 00:30:56.843 look so what so we know now 00:30:56.843 --> 00:30:59.643 how the lamprey spinal cord works you've modeled it 00:30:59.643 --> 00:31:02.503 you understand roughly or actually in 00:31:02.503 --> 00:31:06.003 great detail or every segment does its job how the different cells contribute 00:31:06.003 --> 00:31:12.243 to this and now um you want to make a jump forward and say okay let's now see 00:31:12.243 --> 00:31:16.803 how and so you could think about this this is like a piano Because you have 00:31:16.803 --> 00:31:19.743 these central pattern generators that can make you move forward, backwards, 00:31:20.043 --> 00:31:22.103 you can change body orientation, 00:31:22.663 --> 00:31:25.963 you can change speed by pushing discrete buttons, you can push these discrete 00:31:25.963 --> 00:31:31.563 pattern generators, and then you move one step up in the system to say, 00:31:31.603 --> 00:31:32.463 okay, how is now control? 00:31:33.183 --> 00:31:37.343 And with that, you start looking at basal ganglia, right? So how do you see 00:31:37.343 --> 00:31:38.523 these structures really relate? 00:31:38.523 --> 00:31:43.803 The output 00:31:43.803 --> 00:31:47.483 both nigra reticulata and 00:31:47.483 --> 00:31:56.723 globus pallidus project to the brainstem level you have direct projections the 00:31:56.723 --> 00:32:03.623 locomotor command center you have direct projections to tectum superior colliculus 00:32:03.623 --> 00:32:07.303 the output targets directly, 00:32:07.823 --> 00:32:16.723 the efferents of the tectum, and they target the soma level, 00:32:16.943 --> 00:32:25.023 so you have a very powerful inhibition there, whereas the visual input. 00:32:26.257 --> 00:32:33.497 It comes on more peripheral dendrites. So, it seems that the output of the basal ganglia, 00:32:34.017 --> 00:32:40.457 is directly hooked up to neurons that are involved in eye movements, 00:32:40.777 --> 00:32:43.597 orienting movements, locomotion, and so forth. 00:32:44.017 --> 00:32:47.977 And these would be then the neurons, the brainstem neurons, that were nuclei 00:32:47.977 --> 00:32:50.817 that in turn interface to your spinal cord? 00:32:51.057 --> 00:32:54.697 Well, to the reticulospinal neurons and and then the spinal cord. 00:32:55.457 --> 00:32:59.197 So we'd have two layers in between still, two stages, if you want. 00:32:59.377 --> 00:33:04.297 Yeah, yeah. Okay. Is it possible that those brainstem systems which are talking 00:33:04.297 --> 00:33:09.537 down to the spinal cord might have a reorganization to the extent that, 00:33:10.177 --> 00:33:14.097 rather than talking directly to bits of motor plan and, say, 00:33:14.097 --> 00:33:15.357 controlling speed or direction, 00:33:16.137 --> 00:33:21.837 they are organizing elements of behavior so that in the brainstem already you 00:33:21.837 --> 00:33:26.317 might somehow have some integration whereby activation of a brainstem nuclei 00:33:26.317 --> 00:33:29.677 could generate a pattern behavior across the whole body? 00:33:30.057 --> 00:33:36.757 Or would you say that that kind of coordination is going up to the full brain, to the basic energy? 00:33:36.977 --> 00:33:41.017 No, I mean, essentially, the different radiculospinal nuclei. 00:33:42.677 --> 00:33:49.877 Are specialized in that they target different groups of motor neurons or probably 00:33:49.877 --> 00:33:52.437 different groups of interneurons. 00:33:53.277 --> 00:33:58.997 So, I mean, as with the example I just took with the controller body orientation, 00:33:59.077 --> 00:34:05.137 when different reticulospinal neurons are maximally activated at different degree of tilt. 00:34:07.317 --> 00:34:10.577 So, I think it's well possible. 00:34:12.610 --> 00:34:18.930 You elicit locomotion, but you can elicit locomotion with a bias for the dorsal 00:34:18.930 --> 00:34:21.230 part of the myotome, which would mean swimming upwards, 00:34:21.550 --> 00:34:27.570 or with a bias for the motor neurons that swim, the ventral motor neurons that 00:34:27.570 --> 00:34:29.690 will swim towards the side. 00:34:29.930 --> 00:34:35.570 And an asymmetric activation of them, which would not be produced by the locomotor 00:34:35.570 --> 00:34:41.450 command man region but superimposed on that would lead to a turning movement 00:34:41.450 --> 00:34:42.930 in one direction or the other. 00:34:43.350 --> 00:34:48.410 But this distinction is an important one. Certainly if, 00:34:49.190 --> 00:34:55.350 we look at in more detail the overall model that you present of how basal ganglia controls behavior, 00:34:55.590 --> 00:34:58.770 so maybe for now in the discussion, good to really anchor this point, 00:34:58.910 --> 00:35:05.930 right, that anatomically from the nigra and in globus pallidus, 00:35:05.990 --> 00:35:09.270 we have two stages of processing before we hit spinal cord. 00:35:10.490 --> 00:35:16.930 I mean, we have the locomotor command region, and then a massive activation 00:35:16.930 --> 00:35:24.450 on the different reticular spinates, which they do, would probably result in forward locomotion. 00:35:24.610 --> 00:35:28.050 But then you can have other inputs to the reticular spinate from tectum, 00:35:28.110 --> 00:35:31.570 for instance, that would be able to bias the activity. For instance, yes. 00:35:31.810 --> 00:35:35.010 But in a system that I know a bit better, sort of the rat brain, 00:35:35.230 --> 00:35:42.810 you would have areas in the brainstem, the midbrain, places like the periaqueductal gray, 00:35:43.050 --> 00:35:48.950 where you organize intact behaviors or certainly components of intact behavior. 00:35:49.010 --> 00:35:53.590 So, for example, freezing, which would be a whole body activity, 00:35:53.770 --> 00:35:59.350 and you could get that by stimulating an appropriate place in the periaqueductal gray. 00:35:59.870 --> 00:36:04.090 But maybe this is a difference from the lamprey. 00:36:04.530 --> 00:36:10.630 Maybe there is a more direct talking from the lamprey to the basic pattern generator. 00:36:11.610 --> 00:36:15.190 I mean, periaqueductal gray is a very interesting structure. 00:36:15.570 --> 00:36:19.930 I mean, in cats, you can activate different parts of the periaqueductal gray, 00:36:20.070 --> 00:36:25.510 and you get hissing sounds, or you get meowing, whatever that should be, 00:36:25.550 --> 00:36:29.550 one would say that, and maybe also freezing. 00:36:29.750 --> 00:36:34.210 So I mean, and I think in birds you can get warning calls and so forth, 00:36:34.350 --> 00:36:45.650 so you get a mix of different parts of escape freezing behavior from this area. 00:36:46.230 --> 00:36:50.330 In the lamprey we know nothing about that, but the very fact that we have the 00:36:50.330 --> 00:36:55.950 medial habendela projecting to the interpeduncle nucleus that in most other 00:36:55.950 --> 00:36:59.290 species project to the area with the periodontal grade, 00:36:59.450 --> 00:37:03.030 certainly does that in zebrafish, would suggest that. 00:37:04.475 --> 00:37:08.875 But then for the discussion, maybe what's good, I mean, I don't think anyone 00:37:08.875 --> 00:37:10.735 ever observed a lamprey meowing. 00:37:11.155 --> 00:37:15.335 That's what I'm told. But now they're underwater, so that might not help. 00:37:15.975 --> 00:37:21.935 It may be different. Exactly. But the key point being, already if you go to 00:37:21.935 --> 00:37:28.175 rodent or we go to cat, the behavioral repertoire might be actually significantly more extended. 00:37:28.495 --> 00:37:34.335 No, of course. I mean, what we've been saying all along is that the advantage 00:37:34.335 --> 00:37:38.075 of the LAMPRI has been that it has a very limited behavior repertoire. 00:37:38.735 --> 00:37:43.655 And what happens during evolution is that you add more and more sophisticated 00:37:43.655 --> 00:37:46.975 mechanisms to interact. 00:37:47.615 --> 00:37:54.035 The bottom line of your proposal is that, and you spent quite some time explaining 00:37:54.035 --> 00:37:58.715 it in more detail, You see it really as, let's say, a four-layered structure 00:37:58.715 --> 00:38:01.815 with a core modulatory hub, right? 00:38:01.855 --> 00:38:05.855 So the structure would be at the bottom layer of behavior control, 00:38:05.995 --> 00:38:09.895 we have our CPGs driving the spinal cord, right? 00:38:09.935 --> 00:38:15.395 Above that, we have the nigra, reticulata, and the globus pallidus. 00:38:15.875 --> 00:38:20.835 Then that's interfaced to the striatum, and the striatum in turn gets inputs from the cortex. 00:38:20.835 --> 00:38:26.495 And then across these layers, these top three layers, we have the thalamus that 00:38:26.495 --> 00:38:31.235 is on the one presenting excitatory inputs to these top uppermost layers, 00:38:31.435 --> 00:38:36.615 cortex teratum, and receiving an inhibitory input also from the pallidus and the nigra. 00:38:36.895 --> 00:38:42.715 This is roughly the architectural scheme that you present. I mean, you did not. 00:38:43.895 --> 00:38:48.035 I think between the CPDs, of course, you have…, 00:38:49.006 --> 00:38:53.506 in the locomotive command centers and so forth. I didn't think you mentioned them. 00:38:53.706 --> 00:38:57.426 I didn't mention them because I think in your scheme, they don't really perform 00:38:57.426 --> 00:39:01.466 any further transformations because the control, the guiding control signals 00:39:01.466 --> 00:39:04.206 come straight out of the Nigra and the Polydose. 00:39:04.486 --> 00:39:09.086 And there's no further modulation by these motor nuclei. 00:39:09.266 --> 00:39:14.126 They are straight control signals for your CPGs, if I understood it correctly. 00:39:14.126 --> 00:39:24.046 Exactly. Yeah, I mean, MLR is then two of the different reticulospinins that then activate this. 00:39:25.346 --> 00:39:33.546 The thing is, however, that the reticulospinins are not only used for the MLR. 00:39:33.546 --> 00:39:36.546 They are also used in the posture control, 00:39:37.006 --> 00:39:45.326 they are also used by a tectum for the steering signals, orienting signals, 00:39:45.626 --> 00:39:50.906 and perhaps more important, evasive signals that are rather avoid to bumping. 00:39:50.906 --> 00:39:57.126 Okay, but then it's more like a divergence of signaling than that it is transforming anything. 00:39:58.286 --> 00:40:01.946 It's like a hub, right? It sends a collateral to the tectum, 00:40:02.006 --> 00:40:03.146 let's say, as an example. 00:40:03.546 --> 00:40:11.106 Yeah. No, I mean, what you have essentially is then nagra reticulata, 00:40:11.326 --> 00:40:15.666 MLR, reticulospinals, and the CPG. 00:40:15.786 --> 00:40:20.786 At the level of the reticulospinals, you have interference with a number of 00:40:20.786 --> 00:40:24.686 different other control signals that can modulate that signal, 00:40:24.766 --> 00:40:27.426 modify the signal very significantly. Okay. 00:40:28.670 --> 00:40:33.470 Okay. But then what you emphasized, this was not an element you emphasized very 00:40:33.470 --> 00:40:35.050 much this morning, right? 00:40:35.130 --> 00:40:39.610 What we focused on more was this basic ganglia structure and its modulation 00:40:39.610 --> 00:40:42.910 or its control of action. You only gave me 90 minutes. 00:40:43.970 --> 00:40:46.730 Yeah, I know. We were very stingy with that. 00:40:48.070 --> 00:40:51.030 But, you know, you can compensate now. 00:40:51.030 --> 00:40:55.110 But the point is then what you also, actually what you spent quite some time 00:40:55.110 --> 00:41:00.170 on explaining and even more time on investigating in the lab is to show that 00:41:00.170 --> 00:41:05.050 the basal ganglia of the lamprey is again a template of a vertebrate basal ganglia. 00:41:05.910 --> 00:41:12.310 The main pathways, like your direct and indirect, the go-no-go pathways can 00:41:12.310 --> 00:41:14.270 also be found in that structure. 00:41:14.830 --> 00:41:18.310 So why was that so important to establish that? 00:41:18.310 --> 00:41:31.190 I mean, what was the goal of taking up the basic anglia was first to try to 00:41:31.190 --> 00:41:38.190 investigate the mechanism by which the different motor programs in the brainstem are controlled. 00:41:38.630 --> 00:41:43.270 And so then we took up the basic anglia. 00:41:43.270 --> 00:41:51.330 And my expectation as we started this was it would probably be much simpler, 00:41:51.530 --> 00:41:54.230 perhaps something like the direct pathway and so forth. 00:41:55.430 --> 00:41:57.950 But as we explored it and we... 00:41:59.044 --> 00:42:02.964 Then we found that we have absolutely all elements, 00:42:03.244 --> 00:42:10.704 which probably means that this circuit has been proven to be a useful control 00:42:10.704 --> 00:42:17.604 circuit for controlling specific patterns of behavior. 00:42:17.884 --> 00:42:25.544 And this circuit has been so useful so that it has not been modified significantly 00:42:25.544 --> 00:42:28.644 significantly during evolution. 00:42:29.104 --> 00:42:36.424 And what has happened is instead of modifying the circuit, one has created modules 00:42:36.424 --> 00:42:39.684 controlling each pattern of behavior. 00:42:40.064 --> 00:42:46.104 And as our behavior repertoire has become progressively more complex, 00:42:46.384 --> 00:42:48.764 we have added more units. 00:42:49.024 --> 00:42:54.864 Okay. But then... That's our current interpretation. Sure, but how do you interpret 00:42:54.864 --> 00:42:59.284 the functional relevance of a direct and indirect distinction? 00:43:02.104 --> 00:43:13.024 Yeah, and it's still… I mean, a direct pathway would be implied in releasing a behavior. 00:43:13.844 --> 00:43:18.444 And why do we have an indirect pathway? pathway. It has recently been shown 00:43:18.444 --> 00:43:24.864 by Rui Costa, for instance, that you may have activation of the direct-indirect imperative. 00:43:25.564 --> 00:43:29.284 On the other hand, what is equally evident, 00:43:29.704 --> 00:43:36.684 and that's how he interprets it, I understand, is that if you initiate a pattern 00:43:36.684 --> 00:43:41.364 of behavior, you have to see to that the other patterns of behavior do not occur. 00:43:41.684 --> 00:43:44.584 I mean, you cannot not turn right and left at the same time. 00:43:44.984 --> 00:43:48.304 You could think that that could be arranged at the lower level also. 00:43:48.384 --> 00:43:52.624 But I mean, it's, it's, it's very clear that if you initiate something, 00:43:52.844 --> 00:43:57.544 you have to see to that other patterns of behavior are not initiated. Okay. 00:43:58.657 --> 00:44:02.777 Yeah, I think the work that you've done in basal ganglia has been really useful 00:44:02.777 --> 00:44:07.217 for researchers looking at mammalian basal ganglia. 00:44:07.397 --> 00:44:11.537 So since the mid-90s, I've been working with Peter Redgrave developing and Kevin 00:44:11.537 --> 00:44:14.177 Gurney developing models of basal ganglia. 00:44:14.177 --> 00:44:17.557 And certainly when we looked at the evolutionary literature at that point, 00:44:17.677 --> 00:44:19.617 we thought, well, yes, there may have 00:44:19.617 --> 00:44:23.737 been a direct pathway in the first vertebrates, but perhaps that's it. 00:44:23.877 --> 00:44:29.217 And our models were based on the mammalian circuitry, which turns out to be 00:44:29.217 --> 00:44:31.617 not too different from the circuitry that you describe. 00:44:31.617 --> 00:44:35.157 Now in mammals we 00:44:35.157 --> 00:44:37.977 also see a pattern where these circuits like 00:44:37.977 --> 00:44:41.117 you say are repeated and across different domains 00:44:41.117 --> 00:44:46.497 of the basal ganglia as you go from dorsal to ventral there are some significant 00:44:46.497 --> 00:44:51.457 differences and also people have proposed that you might separate those into 00:44:51.457 --> 00:44:56.657 a motor domain an associative domain an limbic domain and people have described 00:44:56.657 --> 00:45:00.157 possibly a spiral going down through these different domains, 00:45:00.437 --> 00:45:04.337 whereby one might be modulating another area. 00:45:04.737 --> 00:45:09.817 Now, I'm wondering, maybe there's no answer for this yet, but is the lamprey 00:45:09.817 --> 00:45:13.897 basal ganglia most similar to the dorsal striatum, i.e. 00:45:13.937 --> 00:45:17.577 The motor domain, or is there any evidence there might be different domains 00:45:17.577 --> 00:45:19.837 that are modulating each other there too? 00:45:21.497 --> 00:45:31.017 Currently, we cannot say to what degree it's more the dorsal and the ventral tritium, 00:45:31.057 --> 00:45:36.837 but one would think at least it's a very clear motor aspect to the control. 00:45:38.177 --> 00:45:44.657 But one knows in rodent that at activation of the ventral tritium can lead to 00:45:44.657 --> 00:45:47.057 locomotion channels through MLR. 00:45:47.257 --> 00:45:52.697 So it's difficult to say, I think. 00:45:54.297 --> 00:45:58.897 But of course from the perspective where you are entering this discussion, 00:45:59.137 --> 00:46:00.637 which is pure motor-oriented, 00:46:01.617 --> 00:46:07.237 in some sense, these more ventral striatal aspects would actually not have a 00:46:07.237 --> 00:46:12.897 function, because what you want to control are in the anti-CPGs driving behavior. 00:46:13.557 --> 00:46:20.037 I mean, it's easy, pity is driving behavior, but then it's what is driving the 00:46:20.037 --> 00:46:21.497 animal to like to locomote. 00:46:22.748 --> 00:46:27.848 It may even be the other way around, that your basal ganglia in LAMFRE is more 00:46:27.848 --> 00:46:32.108 like ventral, because your decision there is stay or go, run, 00:46:32.388 --> 00:46:34.308 eat, these kinds of things. 00:46:34.648 --> 00:46:38.148 And in the mammal, you have so many more effector systems. 00:46:38.548 --> 00:46:42.548 Maybe you need more basal ganglia domains in order to allow you to organize 00:46:42.548 --> 00:46:44.268 movement of different effector systems. 00:46:44.348 --> 00:46:49.148 Whereas in the LAMFRE, you really only have a mouth and a swimming tail. 00:46:49.148 --> 00:46:52.368 Well, indeed, you could speculate that. 00:46:53.288 --> 00:46:57.708 I mean, another argument would be to say, well, basal ganglia co-evolved very 00:46:57.708 --> 00:47:04.028 much with cortex to sort of balance the memory systems of the cortex that are 00:47:04.028 --> 00:47:07.848 very in-selective, right, to become more selective. 00:47:07.848 --> 00:47:11.568 And in that sense, you would have these dual pathways dealing with, 00:47:11.588 --> 00:47:15.388 say, value and action and sensory modalities and so on. 00:47:15.528 --> 00:47:19.528 But from this pure motor perspective, if you look at that structure from a spinal 00:47:19.528 --> 00:47:24.148 cord perspective, these are aspects you actually don't deal with because this 00:47:24.148 --> 00:47:26.128 is not a selection problem for spinal cord. 00:47:26.128 --> 00:47:29.448 So one challenge I see for what Stan is proposing, we could say, 00:47:29.468 --> 00:47:33.508 well, maybe Stan, maybe you're barking up the wrong tree because the spinal 00:47:33.508 --> 00:47:38.248 cord is, if you want, sort of the slave of all these higher systems. 00:47:38.628 --> 00:47:42.508 Well, the function of a higher system like basal ganglia is not so much to do 00:47:42.508 --> 00:47:47.368 that action selection issue at a level that's relevant to a spinal cord, right? 00:47:47.368 --> 00:47:53.008 That selection among CPGs you could solve in a fairly straightforward way without 00:47:53.008 --> 00:47:58.248 having to rely on this really complex machinery of a basal ganglia. Is it so complex? 00:47:59.549 --> 00:48:02.389 Well, if you look at the different transmitter systems used, 00:48:02.689 --> 00:48:06.169 the connectivity, it's not a straightforward system. 00:48:06.609 --> 00:48:12.349 I mean, the spinal cord has more transmitters and more receptors. Yeah. 00:48:14.589 --> 00:48:17.789 But how would you deal with that challenge? You could say, well, 00:48:17.809 --> 00:48:22.809 look, this co-evolved cortex, basal ganglia is part of a sequencing system that 00:48:22.809 --> 00:48:26.089 helps decision-making, that helps to implement behavioral strategies. 00:48:26.089 --> 00:48:32.669 But it doesn't assist you so much in really executing a specific behavioral pattern. 00:48:32.889 --> 00:48:38.309 For that, we have very powerful brainstem systems like the central gray or systems 00:48:38.309 --> 00:48:41.349 you might find in the reticular formation. But I mean, you need coordination 00:48:41.349 --> 00:48:43.549 among the different movements. 00:48:43.849 --> 00:48:51.509 So I think you need a coordinated effort that decides in a given situation which 00:48:51.509 --> 00:48:53.169 motor program should be called upon. 00:48:53.169 --> 00:48:55.969 Home okay i think you can 00:48:55.969 --> 00:48:59.209 push too far that it co-evolve the cortex and it's definitely 00:48:59.209 --> 00:49:02.309 deeply integrated with subcortical structures and it 00:49:02.309 --> 00:49:05.229 scales with cortex but cortex grows 00:49:05.229 --> 00:49:09.889 faster and and the interpretation might just be that more cortex you have the 00:49:09.889 --> 00:49:15.509 more filters you need for the input to the basal ganglia yeah but that's fair 00:49:15.509 --> 00:49:19.609 enough but i do feel that that stan now shifted the argument a little bit because 00:49:19.609 --> 00:49:22.529 in the original proposition, 00:49:22.869 --> 00:49:26.829 we have the central pattern generators, and in order to just select which one 00:49:26.829 --> 00:49:29.069 I'm going to push, I need my Baselganglia. 00:49:29.649 --> 00:49:33.669 But if you now talk about coordination, you talk about behavioral patterns. 00:49:34.109 --> 00:49:39.029 Of course, I mean, the next step, I mean, you need to have the Baselganglia 00:49:39.029 --> 00:49:42.829 to select between the different metaprograms, but the Baselganglia needs to 00:49:42.829 --> 00:49:48.629 have an input that makes it appropriate to select one or the other. 00:49:49.169 --> 00:49:58.009 But a behavioral pattern as such would actually comprise many CPGs being coordinated in some way. 00:49:59.441 --> 00:50:02.201 Okay and that's and that's not so apparent if we only 00:50:02.201 --> 00:50:04.981 look at swimming in the lamprey because then it's 00:50:04.981 --> 00:50:09.021 like okay we swim faster slower or we go backwards right it doesn't seem like 00:50:09.021 --> 00:50:14.741 that and that's why we about six seven years ago took up the tectum and eye 00:50:14.741 --> 00:50:19.781 movement and orienting movement and evasive move right so it uh i mean just 00:50:19.781 --> 00:50:24.341 to have a few other items to right who select from But I mean, 00:50:24.381 --> 00:50:31.621 it is very clear that although it seems that we now have a fair understanding 00:50:31.621 --> 00:50:32.841 about the connectivity, 00:50:33.181 --> 00:50:38.961 and I think we have not touched on the basic angle, we have not touched on the 00:50:38.961 --> 00:50:43.721 benula, the control of the dopamine neurons, reward, evasive. 00:50:48.081 --> 00:50:57.141 So I think that's the circuit for evaluation of the result of a given task, 00:50:57.281 --> 00:51:01.981 I think, is also very critical and needs to be integrated. 00:51:02.501 --> 00:51:05.821 But I mean, I have not talked about... 00:51:06.501 --> 00:51:10.761 We know that there is input from salivacy, we know that there is prominent input 00:51:10.761 --> 00:51:21.021 from on pallium cortex, but we have no information as yet about the pattern of activity, 00:51:21.461 --> 00:51:24.121 the processing taking part in cortex. 00:51:24.421 --> 00:51:30.381 We know that there is a direct animal striatum input, but we have not recorded from these neurons. 00:51:31.101 --> 00:51:37.881 So, I mean, you have a lot of… I mean, clearly, for a stratum to do something 00:51:37.881 --> 00:51:40.781 useful, it needs to have an interesting input. 00:51:41.161 --> 00:51:43.941 And it has to come from your cortex in the end. 00:51:45.201 --> 00:51:51.461 From the atmosphere. And in global pallidus, you've identified a topography 00:51:51.461 --> 00:51:55.001 there, that different parts of the pallidum projecting out to these different 00:51:55.001 --> 00:51:57.641 areas linked with certain CPGs. 00:51:58.861 --> 00:52:04.161 And substantia nigra then has one for eye movements. And I mean, 00:52:04.161 --> 00:52:11.941 it projects also to the DLR, the encephalic locomotor. 00:52:12.721 --> 00:52:18.341 So we have a topography in the lamprey, 00:52:18.481 --> 00:52:26.401 and Takakusaki has shown quite nicely a nigra reticulata in rodents, 00:52:26.441 --> 00:52:35.381 that different parts of nigra reticulata projects to MLR, 00:52:35.581 --> 00:52:38.921 to tectum, to the postural centers, 00:52:39.201 --> 00:52:44.661 and also to swallowing and chewing circuitry. 00:52:44.721 --> 00:52:46.701 So it seems you have. 00:52:47.928 --> 00:52:52.588 You have subpopulations of cells, so you would have the option also in rodents 00:52:52.588 --> 00:52:54.448 to control selectively each one. 00:52:55.268 --> 00:53:01.608 So we earlier talked about the distinction between dorsal-ventral striatum and 00:53:01.608 --> 00:53:06.948 where you would in your ventral striatum have also more evaluation of states. 00:53:08.168 --> 00:53:13.948 But what you emphasized very much for that in your presentation was this habendula, 00:53:13.948 --> 00:53:22.168 which you saw as playing a key role in this lamprey brain, in the valuation of state. 00:53:22.348 --> 00:53:28.428 So why do you bring that now in in this discussion on the architecture of action control? 00:53:28.828 --> 00:53:32.208 I mean, it's not only in the lamprey. 00:53:32.528 --> 00:53:36.068 I mean, Hikosaka and others have identified, have been on that. 00:53:36.068 --> 00:53:43.868 Several years ago, Malenka had a large article in Nature about recording dopamine 00:53:43.868 --> 00:53:48.328 neurons and input from Habenela. 00:53:48.648 --> 00:53:55.788 I mean, we published Habenela in 2011, I think, first, and we have a paper just 00:53:55.788 --> 00:53:57.888 now coming out on that also. 00:53:58.228 --> 00:54:05.688 But what was striking then is that, I mean, you one very important. 00:54:07.436 --> 00:54:14.896 Earlier missing link has been what is controlling the dopamine neurons. 00:54:15.196 --> 00:54:20.656 I mean, Peter Redgrave has worked on that, and you have the pedonclopontine, 00:54:20.696 --> 00:54:27.876 but now the albinula comes in as a very important structure, it seems, 00:54:28.096 --> 00:54:30.896 from work in primates and rodents. 00:54:30.896 --> 00:54:37.936 And then we have shown that we have the same control, 00:54:40.576 --> 00:54:46.596 the same sort of projections. What I did not mention is lateral habanera controls dopamine neurons, 00:54:46.856 --> 00:54:52.636 but there is a separate population within the lateral habanera that projects 00:54:52.636 --> 00:54:57.876 to 5-HT neurons and a separate that projects to histamine neurons. 00:54:57.876 --> 00:55:00.876 Do we have all these three as separate populations? 00:55:01.896 --> 00:55:08.116 And then what we have shown now, I mean, it was… Gosaka showed in primate that 00:55:08.116 --> 00:55:13.636 some of the globus pallidus neurons projected to pallidum. 00:55:13.716 --> 00:55:20.096 What we have shown here is that we have a separate glutamatergic nucleus that projects. 00:55:20.096 --> 00:55:26.636 Moreover, we have one sub-compartment of stratum, the stereosomes, 00:55:26.756 --> 00:55:32.196 that project to this glutamatergic. 00:55:34.616 --> 00:55:43.536 Glupus pallidus abendra-projecting neurons, and the stereosomes are important 00:55:43.536 --> 00:55:46.256 in that they also project to dopamine neurons directly. 00:55:46.256 --> 00:55:55.496 And these neurons are also having input from pallium onto them. 00:55:56.776 --> 00:56:03.796 It's known in primates or rodents 00:56:03.796 --> 00:56:09.676 that pallium or cortex can activate the lateral habendelon neurons. 00:56:09.676 --> 00:56:15.696 But we have shown that this now are prepped and that we have direct projections 00:56:15.696 --> 00:56:24.196 to this globus pallidus, and have been projecting some population. 00:56:24.556 --> 00:56:28.456 So I mean, evaluation of behavior, 00:56:28.956 --> 00:56:34.116 the success of behavior, or threatening things, I mean, I mean, 00:56:34.156 --> 00:56:40.416 this is, I think, the absolutely critical part in any motor system. 00:56:40.676 --> 00:56:44.216 Sure. But would you argue that the Habendel life should be considered an additional 00:56:44.216 --> 00:56:45.696 nucleus of the basal ganglia? 00:56:47.217 --> 00:56:52.057 I don't care. Okay. No, it means more when it's an integrated component. No, no. 00:56:52.157 --> 00:56:56.457 It is definitely an integrated component. 00:56:56.797 --> 00:57:01.737 And I mean, one starts now to understand the different inputs that you have 00:57:01.737 --> 00:57:05.337 to the dopamine neurons. 00:57:05.717 --> 00:57:11.957 And I mean, it's so central for both motor performance and for... 00:57:12.717 --> 00:57:17.937 Okay. But that means in the Lamprey discussion, the key significance was, 00:57:18.097 --> 00:57:23.277 I guess, for you to again show, look, this lamprey basal ganglia extended structure 00:57:23.277 --> 00:57:27.037 is fully consistent with what we find in mammals. 00:57:27.557 --> 00:57:34.457 And I mean, we have some things that have been elaborated, but which has not 00:57:34.457 --> 00:57:35.857 yet been shown in mammals. 00:57:36.217 --> 00:57:39.657 Right, okay. So in mammals, it's 00:57:39.657 --> 00:57:45.257 been strongly argued that the short latency dopamine signal is acting as a prediction 00:57:45.257 --> 00:57:51.257 error signal for learning and is your idea that maybe the in conjunction with 00:57:51.257 --> 00:57:57.137 the Herbannula a similar sort of system is going to exist in the Lanphrey? 00:57:57.917 --> 00:58:02.457 I would think so but... But you're not there yet in terms of being able to confirm that? 00:58:02.637 --> 00:58:06.497 I heard a resound that, 00:58:07.117 --> 00:58:17.397 in a meeting last week where Rue Costa from Lisbon showed that he was recording 00:58:17.397 --> 00:58:21.437 dopamine neurons in the behaving mouse, I think. 00:58:21.737 --> 00:58:33.057 And what he found was very consistently that whenever the mouse started to run, 00:58:33.317 --> 00:58:40.937 there was but a short blip of dopamine-urine activity preceding the onset of locomotion. 00:58:42.337 --> 00:58:49.197 I mean, that probably, I would think, is a signal that interacts together with 00:58:49.197 --> 00:58:53.757 other signals, input to striatum and salamus, 00:58:53.877 --> 00:58:58.757 but I mean, it's still quite interesting. 00:58:58.757 --> 00:59:07.117 And in that context, one may also say that old experiments in rats, 00:59:07.197 --> 00:59:12.597 I think, showed that injection of dopamine into the ventral striatum led to locomotor activity. 00:59:13.477 --> 00:59:19.937 But then following up on the encoding of prediction error in some form by dopamine 00:59:19.937 --> 00:59:25.997 and an effect on plasticity, does it mean lampreys can show operant conditioning? 00:59:28.024 --> 00:59:32.684 I would think so, but it has not been shown. Okay, but that might be a relevant 00:59:32.684 --> 00:59:34.024 experiment to try, I guess. 00:59:35.624 --> 00:59:38.784 Are you going to do that? Someday, probably. 00:59:39.664 --> 00:59:43.764 Okay. Can we quickly touch on the pallium? 00:59:43.824 --> 00:59:45.824 So you mentioned in your talk you 00:59:45.824 --> 00:59:51.604 didn't expound on the possibility of the hyperdirect pathway from cortex. 00:59:51.604 --> 01:00:00.844 I mean, what we have shown, there is a small area on the ventrolateral pallium, 01:00:00.924 --> 01:00:02.884 which can be stimulated. 01:00:03.144 --> 01:00:09.244 And when you stimulate that, you can elicit both movements of the mouse. 01:00:09.504 --> 01:00:16.024 And it's a small area, and we think there's a selectivity between different 01:00:16.024 --> 01:00:17.984 parts, but it's still a work in progress. 01:00:18.244 --> 01:00:24.044 We can elicit locomotor activity, we can elicit orienting behavior. 01:00:24.504 --> 01:00:27.964 So it's a discrete palliative area. 01:00:28.404 --> 01:00:37.484 And when we inject dye into this area, then we have anthragrade fibers in stratum, 01:00:37.624 --> 01:00:41.104 in the subsalamic nucleus, and in tectum. 01:00:41.604 --> 01:00:46.104 So I mean, we have the hyperdirect pathway. way. 01:00:46.344 --> 01:00:51.444 So the important part of our models was to have that projection from cortex, 01:00:51.684 --> 01:00:55.564 not just the striatum, but also to the subclimate nucleus STN, 01:00:55.744 --> 01:00:59.204 so that you can get the balance of excitation and inhibition. 01:00:59.524 --> 01:01:03.544 And so there's evidence that that might be there in the first vertebrates. 01:01:03.704 --> 01:01:10.004 Yeah. No, no, it's not yet published, but very clear evidence. Yes. 01:01:10.564 --> 01:01:16.324 So now to, so at the core of the discussion and sort of the spinal cord, 01:01:16.404 --> 01:01:18.764 this notion of a central pattern generator, rhythmic activity. 01:01:19.404 --> 01:01:24.764 We find rhythmic activity in many parts of the brain, local and global levels. 01:01:25.444 --> 01:01:30.924 So would you think that the central pattern generator that you've studied in 01:01:30.924 --> 01:01:34.464 the spinal cord is also like a building block, 01:01:34.524 --> 01:01:40.544 a fundamental building block of the whole of the brain, higher areas of the brain? 01:01:40.924 --> 01:01:44.064 Or do you see them really as qualitatively different? Yeah. 01:01:45.525 --> 01:01:53.205 I mean, we had many years ago, or some years ago, we had a microcircuit grant 01:01:53.205 --> 01:01:58.845 where we had the spinal cord, 01:01:59.205 --> 01:02:05.365 we had hippocampus, we had cerebellum, and we had neocortex. 01:02:05.665 --> 01:02:11.505 And the intention there was to look at similarities between these circuits. 01:02:11.505 --> 01:02:20.005 And at the end of the grant, we published a TINS issue with, 01:02:20.025 --> 01:02:22.485 I think, five different reviews, 01:02:22.885 --> 01:02:30.565 with essentially claiming that you mix the different building blocks in order 01:02:30.565 --> 01:02:35.345 to make the different microcircuits that suits that particular behavior. Right. 01:02:35.705 --> 01:02:44.085 Okay. So to finish up, Stan, so look, you've been around in neuroscience now for a long time, 01:02:44.225 --> 01:02:49.305 also in different positions that are really very important for the field, 01:02:49.405 --> 01:02:50.705 like now you're leading FENCE. 01:02:52.065 --> 01:02:56.685 So based on your experience, what would be Stan's law that should guide our science? 01:02:58.965 --> 01:03:13.285 I think the most important for any researcher is to try to identify what she 01:03:13.285 --> 01:03:17.705 or he thinks is important and try to do that well. 01:03:17.705 --> 01:03:23.245 Well, that's what you call a cottage science. 01:03:23.425 --> 01:03:33.765 But I think the major progress in neuroscience may often come from small groups that are dedicated. 01:03:35.525 --> 01:03:39.965 And I think it's an advantage if you work in a group where you have people with 01:03:39.965 --> 01:03:42.685 different expertise but interested 01:03:42.685 --> 01:03:46.245 fundamentally in the same problem so they complement each other. 01:03:46.245 --> 01:03:56.545 So focus focus on the on the problem that is important at least important in 01:03:56.545 --> 01:04:01.085 your own mind right exactly and then the last question so, 01:04:02.585 --> 01:04:07.525 five years from now Tony and I will come and visit you in Stockholm and we're 01:04:07.525 --> 01:04:11.905 going to confront you with a prediction you're going to make today so what's 01:04:11.905 --> 01:04:15.865 the key prediction that you would like to put on the table today that you find 01:04:15.865 --> 01:04:20.285 is the most important one that you want to see validated in five years' time. 01:04:24.523 --> 01:04:32.563 I mean, what I think, my prediction is that, 01:04:32.863 --> 01:04:44.123 what I like to see is that we really understand 01:04:44.523 --> 01:04:53.783 much better the role of the basic angle in terms of the control of behavior. 01:04:54.143 --> 01:05:03.943 And this also includes input, and that we also understand the circuit's underlying 01:05:03.943 --> 01:05:05.543 evaluation on behavior. 01:05:06.003 --> 01:05:09.043 So you're saying in five years' time you will understand it? 01:05:10.543 --> 01:05:13.203 Is that a prediction? There is always levels of understanding. 01:05:14.123 --> 01:05:18.343 That's safe. All right, Stan Grillner, thank you very much for this conversation. 01:05:25.203 --> 01:05:30.983 The CSN Podcast was produced by the Convergent Science Network of Biometrics 01:05:30.983 --> 01:05:37.403 and Biohybrid Systems, a project funded by the European Sevens Research Framework Program. 01:05:38.883 --> 01:05:44.243 For more interviews, recorded lectures, or upcoming conferences in the field 01:05:44.243 --> 01:05:50.503 of biometrics and biohybrid systems, go to csnnetwork.eu. 01:05:50.763 --> 01:05:52.663 And thank you for listening. 01:05:51.280 --> 01:05:58.320 Music.