WEBVTT 00:00:03.617 --> 00:00:06.517 This is the Convergent Science Network podcast. 00:00:08.517 --> 00:00:13.057 Leading researchers in the domain of neuroscience, brain theory and technology 00:00:13.057 --> 00:00:16.797 are interviewed by Paul Verschoor and Tony Prescott. 00:00:19.597 --> 00:00:22.797 This is Paul Verschoor with the Convergent Science Network podcast. 00:00:23.377 --> 00:00:28.717 And in this episode, that's also part of our CSN Barcelona Cognition Brain Technology 00:00:28.717 --> 00:00:31.177 Summer School. I'm talking with Donald Pruf. 00:00:32.297 --> 00:00:41.297 And Donald, you were giving a very elaborate talk, in some sense, focusing very much on, 00:00:41.457 --> 00:00:46.877 let's say, how the arousal system is really very much, let's say, 00:00:46.917 --> 00:00:50.237 a core engine of brain, mind, and behavior. 00:00:53.277 --> 00:00:57.237 Because in some sense also in the psychological literature, arousal is often 00:00:57.237 --> 00:01:02.837 seen as some sort of non-specific, an input to a steam engine and we don't think about it too much. 00:01:03.077 --> 00:01:08.777 So why do you believe that arousal is such a core ingredient of what makes us what we are? 00:01:09.077 --> 00:01:15.277 It used to be thought that the word non-specific is the worst possible word 00:01:15.277 --> 00:01:16.637 in behavioral neuroscience. science. 00:01:16.717 --> 00:01:22.137 And I've tried to turn this coin over and look on the other side and say that 00:01:22.137 --> 00:01:28.917 beneath every act, beneath every cognitive ability, beneath every emotional state is a primitive. 00:01:29.657 --> 00:01:32.417 Impetus, which is essential and powerful. 00:01:32.637 --> 00:01:37.017 It's necessary for any motivated behavior, and it's the place to begin. 00:01:37.197 --> 00:01:38.297 It's like starting at zero. 00:01:39.017 --> 00:01:43.857 Instead of studying the brain, if we were getting together to study the planet, 00:01:44.077 --> 00:01:48.137 the Earth, we would say, what's in there? What's making the whole thing work? 00:01:48.277 --> 00:01:51.637 And it's the magma of the Earth. It's deep, it's complicated, and it's unknown. 00:01:51.997 --> 00:01:57.637 And those things appeal to me. It especially appeals to me because it's been 00:01:57.637 --> 00:02:01.177 discarded, this subject, for about 60 years. 00:02:01.457 --> 00:02:07.397 The great Italian neurophysiologist Marozzi, working together with the American Horace Magoon, 00:02:07.961 --> 00:02:10.761 in the 1940s, really began to break the subject open. 00:02:11.421 --> 00:02:15.801 But then we lost our way, partly because we were interested in, 00:02:15.821 --> 00:02:17.221 quotes, more specific abilities, 00:02:17.541 --> 00:02:22.261 especially in the visual system, close quotes, and also because the tools of 00:02:22.261 --> 00:02:27.201 neuroscience became so detailed that we could indeed study the third dendrite 00:02:27.201 --> 00:02:31.761 from the left or the second nucleotide of DNA from the right, 00:02:31.761 --> 00:02:33.661 and therefore we thought we should. 00:02:33.861 --> 00:02:40.401 And in doing so, I think that we lost the ground substance of the nervous system. 00:02:40.681 --> 00:02:46.341 The substance, the reticular formation, which in any vertebrate nervous system, 00:02:46.401 --> 00:02:50.921 from the fish to the philosopher, is necessary for all motivated behaviors. 00:02:51.601 --> 00:02:55.561 I like the universal aspect of it, and that's why I'm studying it so hard. 00:02:55.781 --> 00:03:01.221 Right. But now, so you started with saying that That both when we talk about, 00:03:01.281 --> 00:03:07.361 let's say, emotional aspects of the brain or cognitive aspects, 00:03:07.761 --> 00:03:11.441 it's all sort of predicated on a basic arousal system. 00:03:11.721 --> 00:03:15.601 It starts out with arousal. Right. So how should I interpret that? 00:03:15.861 --> 00:03:20.441 Well, arousal is necessary but not sufficient, as we were saying a few minutes ago. 00:03:20.721 --> 00:03:25.821 What's necessary, what's sufficient. And in the case of cognitive abilities, 00:03:26.141 --> 00:03:29.781 we know that arousal is necessary for alertness and attention, 00:03:30.021 --> 00:03:31.941 which in turn are necessary for everything else. 00:03:32.141 --> 00:03:35.161 And so it starts with arousal, and it's good to begin at the beginning. 00:03:35.161 --> 00:03:40.461 With respect to emotional function, whether we are talking about temperament, 00:03:40.501 --> 00:03:44.061 whether we're talking about feelings or the emotion of the moment, 00:03:44.361 --> 00:03:48.761 the arousal is necessary for the strength of the behavior. 00:03:49.081 --> 00:03:53.581 And so it could be that we're just mildly annoyed or it could be that we're enraged. 00:03:53.621 --> 00:04:00.941 And the difference between those two is the great arousal necessary for an enraged act. 00:04:00.941 --> 00:04:06.201 But now, so you distinguish different layers of organization, 00:04:06.321 --> 00:04:11.261 both for emotional processing and cognition, each predicated on the preceding layers. 00:04:12.281 --> 00:04:16.421 And at the bottom of that, we then have an arousal system, right? 00:04:16.581 --> 00:04:20.801 But that's still, also earlier I alluded to sort of steam engine metaphor. 00:04:21.221 --> 00:04:26.421 I could look, okay, arousal could be the steam that you pump into this vat. 00:04:26.421 --> 00:04:31.461 But it still doesn't tell you a thing about what you're actually driving with that steam engine. 00:04:31.581 --> 00:04:35.821 So how do I get to a specific insight about what brains are up to? 00:04:36.001 --> 00:04:39.881 Well, in the first place, you're absolutely right. And so we may have one track 00:04:39.881 --> 00:04:43.381 of things which we're going toward cognition and another track of phenomena 00:04:43.381 --> 00:04:44.521 which we're going toward emotion. 00:04:44.941 --> 00:04:50.661 But we both know that I was giving, and now I'm talking about a minimalist description, 00:04:50.821 --> 00:04:53.541 and things are infinitely more complicated than that. 00:04:53.681 --> 00:04:55.901 That's what keeps neuroscientists fully employed. 00:04:56.421 --> 00:04:58.941 All over the world. Right. And so... 00:05:01.795 --> 00:05:04.855 How shall I say, how do we get to those specific abilities? 00:05:05.515 --> 00:05:11.115 I think the proper answer is, it's difficult. And let's talk about learning 00:05:11.115 --> 00:05:14.095 ability, depending on what kind of learning we're talking about. 00:05:14.195 --> 00:05:16.775 Are we talking about the hippocampus? Are we talking about the cortex? 00:05:17.055 --> 00:05:20.395 Are we talking about the frontal lobes of the cortex? It could be all of the 00:05:20.395 --> 00:05:22.195 above. of with respect to emotion. 00:05:22.555 --> 00:05:25.555 Are we talking about the emotional history of the individual? 00:05:25.875 --> 00:05:28.515 Are we talking about the drugs that the person is taking at the moment? 00:05:28.715 --> 00:05:32.375 The person's state of need with respect to hunger, thirst, and so forth? 00:05:32.875 --> 00:05:37.135 All of those will come into play, and it's as complicated as the human mind. 00:05:37.395 --> 00:05:44.875 And so I would never pretend to be able to chart for you on September 7th of 2012. 12. 00:05:46.395 --> 00:05:52.695 Among human abilities, I would not pretend to be able to chart for you any fully 00:05:52.695 --> 00:05:57.775 described task from my primitive arousal, my powerful and essential arousal 00:05:57.775 --> 00:06:00.155 function on the one hand, to the end game, 00:06:00.335 --> 00:06:03.075 that is, the finished behavioral act on the other. 00:06:03.355 --> 00:06:07.175 I would say even in Aplysia, the great Eric Kandel, 00:06:07.455 --> 00:06:11.155 Nobel Prize winner for the work on the Gill withdrawal reflex of Aplysia, 00:06:11.155 --> 00:06:15.815 who mapped out a minimalist circuit, but other people who study aplysia say 00:06:15.815 --> 00:06:18.695 that that minimalist circuit is not really the only way to do things. 00:06:18.755 --> 00:06:20.155 It's much more complicated than that. 00:06:20.375 --> 00:06:25.215 Now, I don't know how long since you've seen an aplysia, but they're stupid. Oh, really? 00:06:28.975 --> 00:06:32.695 And even there, things are more complicated than they seem. 00:06:33.035 --> 00:06:37.255 And so I think the task of neuroscience these days is to keep one's mind wide 00:06:37.255 --> 00:06:43.275 open as opposed to those minimalist descriptions of the mechanisms that go into 00:06:43.275 --> 00:06:46.355 every cognitive ability or every emotional expression, 00:06:46.775 --> 00:06:51.395 there are always likely to be mechanisms available to us that haven't been discussed yet. 00:06:51.735 --> 00:06:56.455 But you and I have been working in this field long enough that we remember the 00:06:56.455 --> 00:06:58.375 neuron-centric idea of the brain. 00:06:58.535 --> 00:07:03.355 But now, functioning in 2012, we know full well that the glial cells are doing 00:07:03.355 --> 00:07:06.655 very complicated things, especially with respect to glutamatergic action. 00:07:07.435 --> 00:07:11.655 That the brain is protected by the blood-brain barrier, We know that there are 00:07:11.655 --> 00:07:13.035 immune cells in the brain. 00:07:13.215 --> 00:07:18.235 When we were little, when you and I were kids, we could talk about the microglia 00:07:18.235 --> 00:07:19.615 in the brain, which are immune cells. 00:07:19.855 --> 00:07:23.835 But now we can talk about dendritic cells and we can talk about mast cells in 00:07:23.835 --> 00:07:27.915 the brain, accounting probably for neuroimmune phenomena, including depression, 00:07:28.275 --> 00:07:30.775 maybe the fatigue states like chronic fatigue syndrome. 00:07:30.975 --> 00:07:38.555 So things can be seen as infinitely complicated when we talk about the end goals 00:07:38.555 --> 00:07:39.855 that you were asking me for. 00:07:39.855 --> 00:07:43.095 I'm trying to start at the beginning I'm also 00:07:43.095 --> 00:07:47.395 following the dictate of Albert Einstein Albert Einstein said that every scientific 00:07:47.395 --> 00:07:52.275 theory should be as simple as possible but not simpler and that's why I'm starting 00:07:52.275 --> 00:08:00.815 at the beginning right so now we've wandered into this pretty complex jungle of around arousal. 00:08:01.561 --> 00:08:08.021 And things are getting indeed hairy. But on the other hand, you have sort of, 00:08:08.021 --> 00:08:11.761 if you want, compensated for that jump into the deep end. Yes. 00:08:11.861 --> 00:08:16.721 With also developing a highly specific, high-throughput behavioral essay for this. 00:08:16.881 --> 00:08:21.861 Yes. Right? So how does such a behavioral essay now help me to get the handle 00:08:21.861 --> 00:08:24.501 on this very complex notion of arousal? So here's what we needed. 00:08:24.581 --> 00:08:28.381 We needed a concept, which we've been talking about. out. We needed a precise 00:08:28.381 --> 00:08:29.581 operational definition, 00:08:29.841 --> 00:08:35.921 which would be that any animal or any human being is more aroused if he or she 00:08:35.921 --> 00:08:40.461 is more alert to sensory stimuli, more motoric activity. 00:08:41.201 --> 00:08:43.161 And more emotionally reactive. 00:08:43.621 --> 00:08:47.941 And you and I both know people who are off the scales at one end or the other. 00:08:48.341 --> 00:08:52.841 Consider the hyperthyroid individual, the person has too much thyroid hormone. 00:08:52.841 --> 00:08:57.821 He or she is responding alertly to every sensory stimulus. 00:08:57.961 --> 00:09:01.181 He or she is twitchy, can't stand still. 00:09:01.341 --> 00:09:05.401 My daughter-in-law is like that. You sit in her kitchen, she is never standing still. 00:09:05.681 --> 00:09:12.141 And he or she is very reactive emotionally, able to weep or able to laugh readily. 00:09:12.561 --> 00:09:17.081 At the other end, let's consider the hypothyroid individual. 00:09:17.261 --> 00:09:22.221 The person clinically does not have enough thyroid hormone. that person will 00:09:22.221 --> 00:09:26.901 be not reactive to sensory stimuli, sluggish, not moving around very much, 00:09:26.981 --> 00:09:30.861 the ultimate couch potato, and also flat emotionally. 00:09:31.061 --> 00:09:33.021 We know folks who are flat emotionally. 00:09:33.441 --> 00:09:38.621 So there's the operational definition and human examples. But I work on animal 00:09:38.621 --> 00:09:44.041 brains, and so we have this assay where the mice are closed off from the world. 00:09:44.101 --> 00:09:49.861 They're on their own little world, about one meter long and one meter wide and one meter tall. 00:09:50.161 --> 00:09:53.521 And we present to them sensory stimuli by computer. 00:09:53.741 --> 00:09:59.661 We measure their motion 50 times per second, 24 hours per day, 00:09:59.801 --> 00:10:03.101 seven days per week. And we measure their fear responses. 00:10:03.261 --> 00:10:05.141 That's what stands in for an emotional response. 00:10:05.501 --> 00:10:09.761 So it gives us an objective measurement, the way a physicist would want, 00:10:09.901 --> 00:10:13.961 of this global behavioral concept arousal. 00:10:14.481 --> 00:10:20.021 So we have the concept and the assay, and now we want to study the neuronal mechanisms. 00:10:20.261 --> 00:10:24.961 Right, exactly. So now that we have this assay and you have this high-resolution 00:10:24.961 --> 00:10:29.921 measurement, first is what are now, for this mouse, for this setup, 00:10:30.081 --> 00:10:33.401 what are the operational definitions for arousal? 00:10:34.281 --> 00:10:40.301 Greater response to olfactory stimuli, greater response to a very gentle touch 00:10:40.301 --> 00:10:46.481 stimulus, a tactile stimulus, and a greater response to a vestibular stimulus which would be shaking. 00:10:46.621 --> 00:10:49.841 The animal standing on something which is shaking. 00:10:50.621 --> 00:10:55.621 Also the animal's moving more. Also the animal, when presented with a conditioned 00:10:55.621 --> 00:10:57.601 stimulus for fear, for the shock, 00:10:58.185 --> 00:11:02.325 The animal will freeze. The animal will stand still. That's moving less. 00:11:02.625 --> 00:11:06.305 And moving less in response to the conditional stimulus for fear. 00:11:06.605 --> 00:11:11.705 That might be contradictory because moving more was the operational definition of high arousal. 00:11:11.905 --> 00:11:15.385 It's opposite but not contradictory because it's under very specific conditions. 00:11:15.645 --> 00:11:18.765 The conditioned stimulus for fear. Then the animal has to move less. 00:11:19.025 --> 00:11:22.085 The animal behaviorist would call it risk assessment. 00:11:22.625 --> 00:11:27.065 The mouse, which almost everything can eat a mouse, and the mouse is freezing, 00:11:27.145 --> 00:11:30.705 trying to be invisible against its environment, saying, oh my god, 00:11:30.865 --> 00:11:33.445 what is happening here? I'm not going to move. 00:11:33.685 --> 00:11:36.365 Yeah. But then that would mean the better definition might be just, 00:11:36.465 --> 00:11:40.645 let's say, the intensity with which the response is executed. 00:11:40.905 --> 00:11:45.025 Otherwise, we would have a potential inconsistency between the freezing behavior 00:11:45.025 --> 00:11:48.385 and exploratory behavior. The intensity and the situational dependence. 00:11:48.805 --> 00:11:52.185 When the animal is just wandering around, it's more activity. but 00:11:52.185 --> 00:11:55.765 when the animal has been given the condition stimulus for fear it's 00:11:55.765 --> 00:11:58.765 saying whoa let's stop let's let's let's 00:11:58.765 --> 00:12:02.325 not do anything until we find out what's going on sure yeah or the cat might 00:12:02.325 --> 00:12:09.705 get me yes so now or the hawk or or the hawk or or don himself yeah right and 00:12:09.705 --> 00:12:16.285 it's not healthy for a mouse to be in my laboratory right but then um so what you said is that. 00:12:16.937 --> 00:12:22.917 You could account for 30% of the behavior in this essay from this perspective of arousal. 00:12:23.137 --> 00:12:26.577 So how should I interpret that? What does that really mean? It means that the 00:12:26.577 --> 00:12:30.517 animal's behavior is varying, is changing all over the place. 00:12:30.857 --> 00:12:35.237 And when you put the animal in a large number of tests, all of which have something 00:12:35.237 --> 00:12:39.377 to do with arousal, you then find out what's correlated with what. 00:12:39.737 --> 00:12:43.597 The fancy word would be that it's a covariance matrix. tricks. 00:12:43.797 --> 00:12:50.297 What that really means is, is the animal who is the most aroused in this test 00:12:50.297 --> 00:12:54.597 also most aroused in test number two, most aroused in test number three, 00:12:54.597 --> 00:12:55.937 and so forth, and so forth, and so forth. 00:12:56.257 --> 00:13:00.617 When you do that for a large number of tests and a large number of mice, 00:13:00.777 --> 00:13:05.617 you can say, aha, there are certain forces beneath all of these tests that are 00:13:05.617 --> 00:13:09.397 regulating the animal's behavior, And these arousal-related tests. 00:13:09.597 --> 00:13:15.457 How much can I account for by one big, massive, let's call it generalized arousal? 00:13:15.477 --> 00:13:20.417 And the answer was about 30%. Now, our colleagues this morning in our meeting 00:13:20.417 --> 00:13:24.357 pointed out that there must be many other determinants of behavior in addition 00:13:24.357 --> 00:13:25.577 to generalized arousal. 00:13:25.577 --> 00:13:31.797 And so when the animal is responding to any individual reason for getting excited, 00:13:32.077 --> 00:13:36.837 let's say it's fear, let's say it's food, it's hunger, it's sex, 00:13:37.097 --> 00:13:39.857 anything that arouses a human being. 00:13:39.897 --> 00:13:42.617 For you and me, it could be a scientific exam. 00:13:42.917 --> 00:13:45.937 I find them very arousing. I always did too. 00:13:47.077 --> 00:13:54.757 Then we say, what percentage roughly of our overall excitement is due to this generalized arousal? 00:13:54.757 --> 00:14:00.417 Maybe 30% but then the other 70% are due to all the other complex causes of 00:14:00.417 --> 00:14:05.337 behavior specific causes to one situation or another but would you be willing 00:14:05.337 --> 00:14:08.237 to consider let's say as a second source a, 00:14:08.691 --> 00:14:13.551 two nonspecific arousal specific forms of arousal. Absolutely. Okay. 00:14:13.911 --> 00:14:18.031 And so we could talk about the arousal of the male approaching the female. 00:14:18.351 --> 00:14:25.851 We could talk about the arousal of an animal or a human being which has woken up because he is hungry. 00:14:26.191 --> 00:14:31.911 And so the orexin neurons in the hypothalamus are receiving the input that the 00:14:31.911 --> 00:14:36.291 animal is hungry, causing the animal to wake up or the human being to wake up. 00:14:36.311 --> 00:14:38.691 I wake up in the middle of the night and I head for the refrigerator. 00:14:40.551 --> 00:14:45.651 And then one reduces the hunger drive by eating and then one can go back to sleep. 00:14:45.931 --> 00:14:51.131 Right. Yeah. Okay. Yeah. But then, so how much would that add to the 30% if 00:14:51.131 --> 00:14:54.231 we take specific arousal into account as well? I don't know. 00:14:54.531 --> 00:14:57.211 Okay. What would be your bet? If you just have to bet. Think of the, okay. 00:14:57.551 --> 00:15:00.911 Think of the, is the prize a good glass of wine perhaps? 00:15:01.131 --> 00:15:06.791 If you want, sure, no problem. Okay. So let's say that every behavior is like an equation. 00:15:07.531 --> 00:15:11.171 If we neuroscientists are trying to go away from philosophy, 00:15:11.471 --> 00:15:18.831 we as young people knew that very smart guys and women, going all the way back 00:15:18.831 --> 00:15:21.351 to the Greeks, were talking about the causation of behavior. 00:15:21.611 --> 00:15:25.431 And they could elaborate very great philosophical theories about behavior. 00:15:25.651 --> 00:15:28.791 And we read about these century after century after century. 00:15:29.451 --> 00:15:33.251 How can we go away from that and turn this behavior into a science? 00:15:33.251 --> 00:15:37.891 And the way we do it is to have precise definitions and to think of behavior 00:15:37.891 --> 00:15:39.211 as quantitative equations. 00:15:39.951 --> 00:15:44.011 Now, for the equation of the rat who was hungry, or the human being, 00:15:44.031 --> 00:15:47.631 the guy who's hungry in the middle of the night, let's say on the left side 00:15:47.631 --> 00:15:52.091 of the equation is the behavioral result, getting up and going to the refrigerator. 00:15:52.391 --> 00:15:55.211 On the right side of the equation are many terms. 00:15:55.611 --> 00:15:58.651 The generalized arousal term is just one of them. 00:15:59.071 --> 00:16:03.011 Now, you're asking me, what about the rest? What about the other 70%? 00:16:03.605 --> 00:16:10.105 For that glass of wine, I'm going to bet for the simple act of eating that maybe 00:16:10.105 --> 00:16:13.305 the hunger drive accounts for another 50% perhaps. 00:16:13.565 --> 00:16:17.785 And so now we're up to 80%. And now you're going to ask me, what about the other 20%? 00:16:18.425 --> 00:16:23.645 And I'm going to say that there are other facts about the person's personality 00:16:23.645 --> 00:16:26.845 which make him either, maybe he feels sorry for himself. 00:16:27.105 --> 00:16:32.765 And that accounts for another 19%. Now, in a way, you could say, 00:16:32.845 --> 00:16:36.045 well, this is pretty good, because if we're right about this as scientists, 00:16:36.265 --> 00:16:38.625 we're accounting for a motivated behavior. 00:16:39.285 --> 00:16:44.565 On the other hand, I'm certainly going to have, at least as I explain in this 00:16:44.565 --> 00:16:49.425 fictitious manner, at least 1% to 5% due to slop. 00:16:49.645 --> 00:16:52.745 I'm not going to know. No. And you, as a realistic scientist, 00:16:52.885 --> 00:16:55.465 are going to say to me, yes, we're going to give Don one to five percent. 00:16:56.045 --> 00:17:00.125 But this is embarrassing in a way as a scientist, and especially a scientist 00:17:00.125 --> 00:17:02.305 who wants to achieve the precision of physics. And here's why. 00:17:02.965 --> 00:17:07.665 Suppose you were a judge, and you were deciding about an American judge, 00:17:07.845 --> 00:17:09.425 where there is a capital punishment. 00:17:09.525 --> 00:17:14.145 A person can be put to death, let's say, by lethal injection for murdering somebody. 00:17:14.785 --> 00:17:18.945 And you're a judge who's deciding about capital punishment. Do you want to have 00:17:18.945 --> 00:17:20.245 a five percent chance of error? 00:17:20.545 --> 00:17:25.825 That as a mature judge out of every 100 individuals whom you sentence to death, 00:17:26.345 --> 00:17:29.725 did you sentence five of them to death by accident? I don't think so. 00:17:29.985 --> 00:17:35.965 And so we're really still striving hard. 00:17:36.065 --> 00:17:38.305 We're trying hard to reduce that error. 00:17:38.505 --> 00:17:42.925 But it's clear that you want to go for the full bottle of wine and one glass is not sufficient. 00:17:43.005 --> 00:17:49.145 I want to go for 100%. Right. But on September 7th of 2012, I'm sure about the 30%. 00:17:49.325 --> 00:17:52.965 Percent and i'm guessing pretty well about the 50 percent and 00:17:52.965 --> 00:17:55.785 i'm pretending uh that we're just 00:17:55.785 --> 00:17:58.585 guessing about the other 20 right but now but now there's 00:17:58.585 --> 00:18:02.485 there are historical examples where people try to develop let's say a physics 00:18:02.485 --> 00:18:05.745 of behavior yes right in a comparable i'm thinking about clark hall for instance 00:18:05.745 --> 00:18:10.565 with the most elaborate theory of this kind absolutely yeah which in some sense 00:18:10.565 --> 00:18:15.005 also collapse under its own weight right and then he had to he had to as soon 00:18:15.005 --> 00:18:16.865 as a new paradigm was discovered, 00:18:17.045 --> 00:18:19.365 let's say eye blink conditioning was one of his difficult cases, 00:18:19.545 --> 00:18:22.865 he had to start to add ad hoc parameters to keep the whole thing afloat, 00:18:22.865 --> 00:18:24.085 and so on. I'll tell you a secret. 00:18:24.305 --> 00:18:28.445 The secret is that he started too complicated. 00:18:29.305 --> 00:18:34.485 As an ambitious and arrogant scientist, he and other people said, 00:18:34.605 --> 00:18:36.205 we're going to explain learning. 00:18:37.005 --> 00:18:41.125 We're going to take the behaviorism of B.F. Skinner and we're going to make 00:18:41.125 --> 00:18:44.965 it into an elaborate theory, not like B.F. Skinner, and explain learning. 00:18:45.725 --> 00:18:51.385 The secret is to start much simpler. Start with behaviors that the animals don't have to learn. 00:18:51.905 --> 00:18:57.525 Start with behaviors that have the simplest possible sensory determinants. 00:18:58.195 --> 00:19:03.615 The simplest possible motor outputs, and the simplest possible regulatory elements. 00:19:03.935 --> 00:19:08.875 And so that's what I did. I started this a long time ago, an embarrassing number of years ago. 00:19:09.275 --> 00:19:16.395 And as a chemistry student, I had figured out that these steroids are actually 00:19:16.395 --> 00:19:18.835 hormones, and they're very simple chemicals. 00:19:18.935 --> 00:19:24.835 A steroid hormone is a rigid, flat piece of carbon atoms, which you can draw 00:19:24.835 --> 00:19:28.635 on a piece of paper. If we were doing this in video, I could draw a steroid 00:19:28.635 --> 00:19:30.315 hormone for you in about 30 seconds. 00:19:30.915 --> 00:19:35.415 And it turns out that these steroid hormones regulate simple behaviors, 00:19:35.595 --> 00:19:40.255 not learned behaviors necessarily, but simple behaviors. And the simplest of all is sex. 00:19:40.555 --> 00:19:46.295 And among the simplest sex behaviors are behavior where the animal doesn't even have to locomote. 00:19:47.115 --> 00:19:52.335 Locomotion is pretty hard, actually. But before we go to the sex behavior, 00:19:52.515 --> 00:19:57.115 I think there's a step in between, right? Because I think there's another really 00:19:57.115 --> 00:20:00.915 important difference between what you're doing and what Clark Hull is doing. 00:20:00.975 --> 00:20:07.235 Because by simplifying the behavior you explain, you do not necessarily insure 00:20:07.235 --> 00:20:08.575 yourself against failure. 00:20:08.775 --> 00:20:13.175 The complexity can still be too high to come to a physics of behavior. 00:20:13.275 --> 00:20:16.015 Oh, yes. It's easy to fail. Exactly. There's no certainty. 00:20:16.375 --> 00:20:21.135 Yeah. But you, I think, have added a new ingredient in this equation, 00:20:21.315 --> 00:20:23.635 which is a neuroscientific one. 00:20:23.775 --> 00:20:27.675 Yes. Right? You have been mapping this functional interpretation of behavior 00:20:27.675 --> 00:20:30.055 and arousal also back onto the brain. 00:20:30.115 --> 00:20:33.875 And now things start to become, I think, it becomes a very different game and 00:20:33.875 --> 00:20:36.795 a game that Hull couldn't play because now we have new constraints. 00:20:37.035 --> 00:20:41.415 Yes. Now we have the neural substrate. Yes. So I think that really distinguishes 00:20:41.415 --> 00:20:43.295 what you're doing from these more traditional approaches. 00:20:43.335 --> 00:20:45.735 So how has this helped you to look at the substrate? 00:20:45.915 --> 00:20:49.055 What are the insights? Well, first, let's talk about the tools that compared 00:20:49.055 --> 00:20:53.535 to the behavioral neuroscientists, or shall we say the behavioral scientists 00:20:53.535 --> 00:20:55.695 of 60 years ago or 50 years ago. 00:20:56.015 --> 00:21:00.355 On the neuroanatomical side, we know so much more about nerve cells connected 00:21:00.355 --> 00:21:03.215 to other nerve cells than people did 50 years ago. 00:21:04.195 --> 00:21:09.455 Techniques that map cell-to-cell connectivity and discriminate individual cell 00:21:09.455 --> 00:21:12.215 types and say, where do these cell types go? 00:21:12.355 --> 00:21:16.295 This is available to us now. Now, in terms of the physiology, 00:21:16.475 --> 00:21:20.275 the function of neurons, we have electrical recording techniques that we didn't used to have. 00:21:20.495 --> 00:21:24.995 We can record from single nerve cells, whereas people couldn't do that so well 60 years ago. 00:21:25.195 --> 00:21:29.675 We can also not only record the cortical electroencephalogram, 00:21:29.895 --> 00:21:33.835 EEG, with precision, but we can analyze it with mathematical detail. 00:21:34.815 --> 00:21:39.495 We can get nerve cells into the dish. And instead of having it mixed up with 00:21:39.495 --> 00:21:42.815 all the other nerve cells in the brain, And I did this on Tuesday. 00:21:42.915 --> 00:21:43.975 We're now talking on Friday. 00:21:44.115 --> 00:21:49.175 On Tuesday, I was looking at individual nerve cells and a so-called nerve cell line. 00:21:49.395 --> 00:21:54.575 And I could bring my pipette in, a tiny pipette, which has a tip of one micron, 00:21:54.775 --> 00:21:56.915 which would be one millionth of a meter. 00:21:57.538 --> 00:22:00.718 And bring that next to the nerve cell and record the nerve cell's activity. 00:22:01.038 --> 00:22:04.538 So on the physiological electrical side, we have tools. 00:22:04.858 --> 00:22:09.238 Let's talk about the chemistry. We have the chemistry of neurotransmitters now 00:22:09.238 --> 00:22:10.818 that weren't so much known then. 00:22:11.018 --> 00:22:14.698 And we now know that there are these neuromodulators called neuropeptides, 00:22:14.798 --> 00:22:19.118 which are tiny pieces of proteins, which are now not fully described necessarily, 00:22:19.278 --> 00:22:24.238 but compared to 60 years ago, I mean, we're in heaven compared to 60 years. We're in nirvana. 00:22:24.558 --> 00:22:28.978 And now we have molecular biology. The genes expressed in the nervous system 00:22:28.978 --> 00:22:32.238 and the regulations of those genes by transcription factors. 00:22:32.838 --> 00:22:37.398 Clark Hull didn't know about DNA and he didn't know about transcription factors, 00:22:37.578 --> 00:22:39.338 but now we know these things. Sure, exactly. 00:23:08.698 --> 00:23:14.978 About the other 349 degrees or in some cases we collaborate with guys and teams 00:23:14.978 --> 00:23:20.798 who know about the other 349 in order to make a story and sometimes we succeed and sometimes we don't. 00:23:21.018 --> 00:23:25.138 You choose your problem right if you're surrounded by people who are smarter 00:23:25.138 --> 00:23:28.338 than you are and work long enough then you can succeed. 00:23:28.578 --> 00:23:33.998 Right yeah that's very good but now of all these possibilities you have have 00:23:33.998 --> 00:23:40.318 in the arsenal, you highlighted two in particular. So on the one end, it was to map, 00:23:40.992 --> 00:23:44.832 a functional notion of arousal to neuromodulation, right? And the other one 00:23:44.832 --> 00:23:48.752 then to map it to very specific ascending, descending neurons in the brainstem. 00:23:48.852 --> 00:23:50.192 So let's first look at neuromodulation. 00:23:50.852 --> 00:23:57.792 So how does a neuromodulation view on arousal help us to sort of get a better 00:23:57.792 --> 00:24:00.672 grasp on this functional notion? 00:24:00.932 --> 00:24:03.972 Well, we're starting with the more complex part of it, but let's talk about it. 00:24:05.272 --> 00:24:10.772 Neuromodulators are typically hormones or small pieces of proteins. 00:24:11.312 --> 00:24:17.852 And so if we think about neuromodulation of the animal alerting because there's 00:24:17.852 --> 00:24:18.832 danger in the environment, 00:24:19.192 --> 00:24:25.492 chances are we're talking about a little piece of a peptide called CRF, 00:24:25.672 --> 00:24:28.072 corticotropin releasing factor. 00:24:28.412 --> 00:24:32.352 The guy that discovered that died just about six years ago, I mean six months 00:24:32.352 --> 00:24:34.352 ago, and his name was Wiley Vail. 00:24:34.692 --> 00:24:40.832 And many years ago, maybe 20 years ago, he described these, it's about 40 amino 00:24:40.832 --> 00:24:45.332 acids in a row, which is CRF operating through three types of receptors. 00:24:45.732 --> 00:24:52.172 And the neurons, which are most essential for turning on the rest of the brain, have CRF receptors. 00:24:52.432 --> 00:24:58.112 And so that would be one way in which a neuromodulation could tell the individual, 00:24:58.352 --> 00:25:01.832 oops, you are in a situation where something bad has happened. 00:25:01.832 --> 00:25:07.432 You're in a part of town where you were robbed, or you're in a situation with 00:25:07.432 --> 00:25:09.992 your girlfriend where she's going to get angry at you. 00:25:10.112 --> 00:25:15.052 In these cases, you're made alert in order to not do the wrong thing, 00:25:15.072 --> 00:25:20.412 in the wrong part of town to avoid getting killed, with your girlfriend to avoid 00:25:20.412 --> 00:25:23.892 losing her, or boyfriend to avoid losing him. 00:25:23.892 --> 00:25:29.232 And so there's an example of how a specific chemical could set up the arousal 00:25:29.232 --> 00:25:32.512 system to say, whoops, let's be careful about this. 00:25:33.072 --> 00:25:36.532 Now, what about the pathways that are being acted upon? 00:25:39.052 --> 00:25:46.252 The neuroscientists will quickly start talking about pathways that go from lower 00:25:46.252 --> 00:25:49.712 parts of the brain, like the brain stem above the spinal cord, 00:25:49.912 --> 00:25:55.292 to upper parts of the brain, like the forebrain, the cerebral cortex in a human being. 00:25:56.009 --> 00:25:58.969 And those pathways, their chemistry is known. 00:25:59.849 --> 00:26:04.589 Norepinephrine and dopamine, anybody that's used cocaine or methamphetamine 00:26:04.589 --> 00:26:09.489 is operating on norepinephrine and dopamine systems, probably with disastrous complications. 00:26:10.649 --> 00:26:16.769 Serotonin, anybody who's taken his antidepressant today, selective serotonin 00:26:16.769 --> 00:26:21.589 reuptake inhibitor, SSRI, has been manipulating the serotonin system. 00:26:22.429 --> 00:26:29.429 Histamine, well, if you took your allergy medicine today, and if it was an old 00:26:29.429 --> 00:26:31.249 type of allergy medicine, it made you sleepy. 00:26:31.449 --> 00:26:34.769 And the reason it made you sleepy was because it blocked histamine receptors. 00:26:35.329 --> 00:26:40.489 And acetylcholine, if we're talking now about, let's say, an 85-year-old person 00:26:40.489 --> 00:26:41.989 who's succumbing to Alzheimer's disease, 00:26:42.349 --> 00:26:49.809 his doctor is giving him a drug which will slow the breakdown of acetylcholine 00:26:49.809 --> 00:26:54.969 so that the acetylcholine can come to that guy's cerebral cortex and try to 00:26:54.969 --> 00:26:58.729 keep him functioning a little bit longer. So those are five ascending systems. 00:26:59.129 --> 00:27:02.769 But it also turns out there are systems going from the upper part of the brain 00:27:02.769 --> 00:27:06.809 to the lower part of the brain. And those are more complicated to talk about. 00:27:07.109 --> 00:27:11.949 But I think rather than talking about their chemistry, what I'd like to say 00:27:11.949 --> 00:27:15.089 is that part of arousal is the autonomic nervous system. 00:27:15.089 --> 00:27:20.249 You and I know that the James Lange theory of emotion was that a person gets 00:27:20.249 --> 00:27:24.809 a sense of fear partly because his guts and his heart and his breathing are 00:27:24.809 --> 00:27:25.789 telling him that he's afraid. 00:27:26.009 --> 00:27:29.349 Well, what about those controls? The autonomic nervous system controls. 00:27:30.169 --> 00:27:34.049 Sympathetic nervous system and parasympathetic nervous system are controlled 00:27:34.049 --> 00:27:38.269 by systems going from the upper part of the brain to the lower part of the brain. 00:27:38.569 --> 00:27:42.649 And of course, I'm especially excited about nerve cells that could contribute to both. 00:27:42.769 --> 00:27:45.229 Right, exactly. Exactly. And we're going to get to those, right? 00:27:45.269 --> 00:27:49.209 Because in some sense, if we look at this neuromodulatory view, 00:27:49.649 --> 00:27:52.869 you can talk about, let's say, what you also call the high and the low road 00:27:52.869 --> 00:27:55.009 towards controlling arousal. 00:27:55.049 --> 00:27:57.849 So how should I think about that with respect to these neuromodulatory systems? 00:27:59.289 --> 00:28:04.429 Well, let's consider the evolution of the brain from the simplest vertebrate 00:28:04.429 --> 00:28:08.049 animal, which would be a fish or even a simple fish like a lamprey, 00:28:08.675 --> 00:28:13.295 I don't know what the Latin word for lamprey is, up to the most complicated 00:28:13.295 --> 00:28:15.735 individuals, which I would still think would be human beings. 00:28:17.075 --> 00:28:20.475 In the simplest individuals, we have the low road to arousal, 00:28:20.495 --> 00:28:26.135 and that would be the systems that go from the spinal cord through the lower 00:28:26.135 --> 00:28:28.395 part of the brainstem, down where our neck is, 00:28:28.575 --> 00:28:33.075 along the roof of our mouth, which would be through the hypothalamus, 00:28:33.095 --> 00:28:35.655 to the basal forebrain, which is quite primitive, 00:28:35.855 --> 00:28:38.415 and that's what we call the low road to arousal. 00:28:38.435 --> 00:28:44.275 And in fact, some cholinergic neurons are at the target of that low road of arousal. 00:28:44.375 --> 00:28:49.415 But as we move into higher forms of vertebrates, even mammals, 00:28:49.655 --> 00:28:52.315 we're developing that thalamocortical system. 00:28:52.535 --> 00:28:58.335 So that would mean that perched on top of the brainstem is something called the thalamus. 00:28:58.535 --> 00:29:03.175 And the thalamus is the Greek word for antechamber. And the reason it's called 00:29:03.175 --> 00:29:07.975 the antechamber, the thalamus, is because it is the doorway to the cerebral cortex. 00:29:08.315 --> 00:29:14.095 All of these high roads to arousal go through the antechamber to the crowning 00:29:14.095 --> 00:29:17.235 glory of the mammalian brain, the cerebral cortex. 00:29:17.555 --> 00:29:22.035 So, the high road would go from the lower brainstem into this thing called the 00:29:22.035 --> 00:29:27.455 thalamus, and then certain thalamocortical pathways would wake up. 00:29:27.715 --> 00:29:32.195 And when we're lucky, both of them are working, the high road and the low road. 00:29:32.195 --> 00:29:37.935 But all the neuromodulatory systems you alluded to earlier would completely bypass the thalamus. 00:29:38.035 --> 00:29:40.075 They are directly tapping into the neocortex. 00:29:40.415 --> 00:29:43.955 I think they do, yes. I would agree with that. 00:29:44.155 --> 00:29:47.495 So then this high road seems to be more based on, let's say, 00:29:47.615 --> 00:29:53.975 glutamatergic transduction, probably conveying signals from the periphery, memory, etc. 00:29:54.295 --> 00:29:57.975 Into neocortex. Is this really the distinction you would agree with? 00:29:57.975 --> 00:30:02.395 You have to be correct in the sense that one of the important inputs to the 00:30:02.395 --> 00:30:07.835 medial part of the thalamus is a glutamatergic input from the midbrain reticular 00:30:07.835 --> 00:30:10.775 formation, also called mesencephalic reticular formation. 00:30:10.775 --> 00:30:17.495 So, when the neurologist Nicholas Schiff, S-C-H-I-F-F, stimulated the brain 00:30:17.495 --> 00:30:22.915 of a vegetative state patient in the central thalamus, and he woke up that patient 00:30:22.915 --> 00:30:24.295 so that patient could be conscious. 00:30:25.075 --> 00:30:31.415 He lays the success of his electrical stimulation to the fact that he was stimulating 00:30:31.415 --> 00:30:34.995 glutamatergic inputs to the medial thalamus. Right, exactly. 00:30:35.535 --> 00:30:39.295 Okay, so now, so we have this high and low road. And then what you also mentioned 00:30:39.295 --> 00:30:42.595 earlier, in some sense, of course, we can now start to think about, 00:30:42.655 --> 00:30:46.775 okay, but how could these systems possibly be coupled in some way, right? 00:30:46.875 --> 00:30:52.955 And what you were talking about, there was a very, very unique category of cells 00:30:52.955 --> 00:30:57.215 that you found in the brainstem that might be, let's say, some sort of mediators 00:30:57.215 --> 00:31:00.515 between this high and low road of arousal, possibly. 00:31:00.715 --> 00:31:05.295 Okay, this is my interpretation right now. So what makes these cells so special? 00:31:05.939 --> 00:31:12.359 Their size and their location. You and I both know that the name of the game 00:31:12.359 --> 00:31:19.379 in neuroanatomy and in the brain research is just like real estate in New York City. 00:31:19.879 --> 00:31:24.979 Location, location, location. Probably real estate in Barcelona as well. I think so. 00:31:25.179 --> 00:31:29.439 I think so, yeah. And so these cells have the right connections, so to speak. 00:31:30.059 --> 00:31:35.939 If you're a politician and you talk to your sister, you may not be too influential. 00:31:36.259 --> 00:31:39.199 But if you talk to William Clinton, the former president of the United States, 00:31:39.419 --> 00:31:42.399 and he talks to everybody, well, then you're going to be influential. 00:31:43.219 --> 00:31:47.439 Talking to these nerve cells, which are called nucleus gigantocellularis, 00:31:47.439 --> 00:31:48.519 these nerve cells, they're huge. 00:31:49.059 --> 00:31:52.359 Let's call them giant nerve cells, nucleus gigantocellularis. 00:31:52.699 --> 00:31:55.259 Talking with them is a little bit like talking with Bill Clinton, 00:31:55.399 --> 00:31:57.959 because they talk in turn, 00:31:58.139 --> 00:32:04.819 not only to systems ascending the nervous system up in the midbrain, for example, 00:32:05.159 --> 00:32:06.979 but also down in the spinal cord. 00:32:07.199 --> 00:32:09.699 And so I believe that they have a unique role. 00:32:09.999 --> 00:32:15.199 Okay, but now, so what makes them gigantic? So in terms of, if you would compare 00:32:15.199 --> 00:32:19.239 them to your standard, let's say, layer five pyramidal cell in terms of their, 00:32:19.299 --> 00:32:21.979 let's say, cell body, their dendrites, their axons, how are they, 00:32:22.019 --> 00:32:24.679 why are they gigantic compared to those? Honestly, the answer is I don't know. 00:32:24.839 --> 00:32:28.539 Within the past six months, I've gone to people smarter than me. 00:32:28.599 --> 00:32:33.339 James Darnell, the great cell biologist who's a molecular biologist at Rockefeller 00:32:33.339 --> 00:32:37.979 University, and several other people like him, and said, what about these huge cells? 00:32:38.179 --> 00:32:42.339 Is there something about their gene expression which is likely to be unique, 00:32:42.539 --> 00:32:48.099 which automatically would know that I'm dealing with nucleus gigantocellularis 00:32:48.099 --> 00:32:50.799 neuron because it expresses the X factor? 00:32:51.959 --> 00:32:57.799 And all we can think of is, no, there is no X factor. It's simply more of the same. 00:32:58.379 --> 00:33:01.099 Now, if you were to say to me, why is there more of the same? 00:33:01.579 --> 00:33:05.039 I would have to get very nervous and say, I just don't know the answer to that. 00:33:05.239 --> 00:33:09.939 I want to find that out. And within, I would say within the next six months, 00:33:10.159 --> 00:33:14.199 we'll be doing molecular biological experiments attempting to answer your question. Right, exactly. 00:33:14.399 --> 00:33:16.819 But now, okay, let's try to understand this a little bit better, 00:33:16.859 --> 00:33:21.339 right? So if we talk about how they're organized in the reticular formation, 00:33:21.499 --> 00:33:22.979 the brainstem, how distributed are they? 00:33:23.039 --> 00:33:28.119 Are they very clumpy and clustered or is it sort of diffuse in the structure? They tend to be diffuse. 00:33:28.319 --> 00:33:32.279 And first I'll be literal and then I'll reflect on our state of knowledge in 00:33:32.279 --> 00:33:34.519 neuroscience at the moment. Okay. 00:33:35.169 --> 00:33:38.689 Uh, the reticular formation comes from the word for reticule. 00:33:39.149 --> 00:33:43.069 And a reticule is like a grid. And so if we were to look, let's say, 00:33:43.089 --> 00:33:46.829 through a microscope, and we see a bunch of vertical lines crossing and a bunch 00:33:46.829 --> 00:33:50.909 of horizontal lines crossing them, then we're talking about a reticule. 00:33:51.229 --> 00:33:54.089 When you look at a cross-section of the reticular formation, 00:33:54.449 --> 00:33:55.589 that's what it looks like. 00:33:55.709 --> 00:33:59.169 You see these cell bodies in their separate little boxes, so to speak, 00:33:59.309 --> 00:34:03.069 but you see these fibers zooming back and forth, vertically and horizontally, 00:34:03.449 --> 00:34:05.649 and that's why it was called the reticular formation. 00:34:06.229 --> 00:34:12.169 And so going all the way from the brain just above the spinal cord up into, 00:34:12.289 --> 00:34:16.389 but not including the thalamus, we have this kind of pattern. 00:34:16.769 --> 00:34:20.929 Now I might say that a couple of the questions that you're asking are touching 00:34:20.929 --> 00:34:22.469 on the very frontiers of neuroscience. 00:34:23.069 --> 00:34:28.049 And you and I hope that many people, not just our friends, our colleagues, 00:34:28.149 --> 00:34:32.109 our students, who are already in the know, so to speak, we'll listen to this 00:34:32.109 --> 00:34:35.549 but we also hope that many many people in many different countries. 00:34:36.649 --> 00:34:38.589 Who don't exactly know what this 00:34:38.589 --> 00:34:41.949 neuroscience is all about are going to listen to all of your podcasts. 00:34:42.049 --> 00:34:45.149 How many did you say you have at the moment? Well we should have about 50 by now or so. 00:34:45.229 --> 00:34:50.089 Yeah 50 and going right? 50 and growing. Do I hear 51? Do I hear 52? 00:34:50.269 --> 00:34:54.869 Oh yeah you will So and by one year from now you'll probably have 60 and so 00:34:54.869 --> 00:34:59.669 we hope that large numbers of people one, people who are deciding what to study And two, 00:34:59.809 --> 00:35:05.149 citizens who are paying for this, because we both know that good neuroscience 00:35:05.149 --> 00:35:08.169 and good science of any sort is dependent upon good economy. 00:35:08.329 --> 00:35:13.269 And good economy is dependent on governments collecting taxes and knowing that 00:35:13.269 --> 00:35:15.589 the scientists are doing the best possible thing with the money, 00:35:15.689 --> 00:35:20.629 either to push back the envelope and push back the frontiers of knowledge with 00:35:20.629 --> 00:35:22.089 respect to what we know about ourselves, 00:35:22.349 --> 00:35:24.309 or for that matter, what we know about the universe. 00:35:24.309 --> 00:35:30.429 So in that spirit, what I'd like to do is to say that there will be free in 00:35:30.429 --> 00:35:33.649 economically developing countries coming from the publisher Springer. 00:35:33.749 --> 00:35:37.549 So this would be the formerly German medical publisher. 00:35:37.629 --> 00:35:39.749 It used to be called Springer Verlag, but now it's just Springer. 00:35:39.749 --> 00:35:44.089 They worked at cost, and all of the editors and the authors worked for free, 00:35:44.169 --> 00:35:48.589 to produce an online text called Neuroscience in the 21st Century. 00:35:48.769 --> 00:35:53.089 And while it will be sold as a regular electronic text to universities in developed 00:35:53.089 --> 00:35:55.389 countries like Germany or the States or Japan. 00:35:56.229 --> 00:35:59.569 In large numbers of economically developing countries, 00:35:59.649 --> 00:36:03.449 which are identified by low gross domestic product per capita, 00:36:03.449 --> 00:36:09.349 and there's a specific list of 78 of these countries and another 28 where they 00:36:09.349 --> 00:36:12.249 get this list of Springer things for a very, very small amount of money. 00:36:12.869 --> 00:36:16.129 This electronic text will be published and we hope that people will make use 00:36:16.129 --> 00:36:19.749 of it. Besides our talking on this Friday afternoon... 00:36:20.244 --> 00:36:25.504 There are two organized ways of getting this out, and one would be the International 00:36:25.504 --> 00:36:27.084 Brain Research Organization. 00:36:27.344 --> 00:36:31.024 You and I call it Ebro, International Brain Research Organization, 00:36:31.224 --> 00:36:33.524 headquartered in Switzerland. 00:36:33.844 --> 00:36:38.844 And the other would be the Human Frontiers Science Program, headed in Strasbourg, 00:36:38.904 --> 00:36:43.184 France. And both of these organizations are devoted to the neuroscience as an 00:36:43.184 --> 00:36:44.704 international enterprise. 00:36:45.264 --> 00:36:50.084 And so all the university librarian in Zimbabwe, let's say, or in Sierra Leone 00:36:50.084 --> 00:36:54.984 or in Sri Lanka, the university librarian just has to tell Springer what the 00:36:54.984 --> 00:36:57.324 IP number of their computer is. 00:36:57.324 --> 00:37:00.304 And then automatically they not only get this text that 00:37:00.304 --> 00:37:03.764 i've done neuroscience in the 21st century 106 chapters 00:37:03.764 --> 00:37:06.444 including a chapter about how to set up a 00:37:06.444 --> 00:37:11.204 neuroscience program in a developing country the great canadian uh richard brown 00:37:11.204 --> 00:37:16.244 great sense of humor uh i wrote that chapter how to send how to set up a neuroscience 00:37:16.244 --> 00:37:19.684 program in a developing country with the order of things to do the problems 00:37:19.684 --> 00:37:25.544 you're going to have and so forth 106 chapters and the university librarian will get Get that text, 00:37:25.664 --> 00:37:27.784 and then everybody associated with the university, 00:37:28.064 --> 00:37:30.304 the students and faculty, get it for free. 00:37:30.464 --> 00:37:34.584 So we hope that this effort, which we're doing with podcasts here in Barcelona. 00:37:34.904 --> 00:37:41.764 Will be supplemented by Ebro's efforts and by Human Frontier's science program 00:37:41.764 --> 00:37:43.764 efforts. Well, that will be excellent. 00:37:44.084 --> 00:37:49.804 And I say that because now your questions, although we'll maybe not continue 00:37:49.804 --> 00:37:53.064 in that vein, are touching on the frontiers of neuroscience. 00:37:53.064 --> 00:37:55.904 Neuroscience what makes that large cell the 00:37:55.904 --> 00:38:01.404 way it is don uh nucleus gigantosalers how did it get to be that way and the 00:38:01.404 --> 00:38:04.964 answer is i hope to start studying that within six months right that's very 00:38:04.964 --> 00:38:09.144 good and so now this is an excellent initiative and then we definitely support 00:38:09.144 --> 00:38:14.084 that um but in some sense i would i would still i would like to go back to the 00:38:14.084 --> 00:38:14.844 frontier of neuroscience. 00:38:15.524 --> 00:38:19.704 And think a little bit more and discuss a bit more about about these these cells 00:38:19.704 --> 00:38:25.044 Because you said you estimate there might be around a thousand of them, 00:38:25.084 --> 00:38:26.304 let's say, more or less. Good guess. 00:38:26.364 --> 00:38:30.064 So they're embedded in this sort of matrix structure of the particular formation. 00:38:31.224 --> 00:38:35.204 They have both ascending and descending projections. Precisely. 00:38:36.204 --> 00:38:39.924 That extend over millimeters, I assume, because they have to touch… Depending 00:38:39.924 --> 00:38:41.744 on the size of the brain. Right, exactly. 00:38:42.024 --> 00:38:47.524 And you called them then the first responders. A fashion model with a long neck, 00:38:47.644 --> 00:38:51.764 a supermodel may have a long axon. Right, exactly. 00:38:53.444 --> 00:38:57.104 So now the question becomes, what are they really responding to? 00:38:57.244 --> 00:38:59.504 So you showed some physiology of these neurons, right? 00:39:01.463 --> 00:39:05.823 What do these guys like? What do they respond to? Well, your question during 00:39:05.823 --> 00:39:07.803 our discussions this morning was right on. 00:39:08.083 --> 00:39:11.823 And that is that these cells have dendrites. 00:39:12.443 --> 00:39:17.003 Dendrite comes from the Greek word for tree branch, which are very unusual. 00:39:17.543 --> 00:39:21.523 If we take the first segment of the dendrite as it emerges from the cell body, 00:39:21.743 --> 00:39:23.483 it has a certain length. Let's call it L. 00:39:23.903 --> 00:39:27.763 The next segment after that branching point will be longer than L. 00:39:27.883 --> 00:39:32.343 It'll be LL. And the next segment after that, going farther away from the cell 00:39:32.343 --> 00:39:34.183 body, will be longer than that, LLL. 00:39:34.483 --> 00:39:38.923 And you can picture, therefore, that these birds have very big wings. 00:39:39.023 --> 00:39:41.383 These nerve cells have a very large spread. 00:39:41.663 --> 00:39:46.683 And therefore, they're beautifully attuned to be able to pick up large numbers 00:39:46.683 --> 00:39:49.263 of signals from sensory neurons, sensory stimuli. 00:39:49.543 --> 00:39:53.223 And we know that they're capable of responding to every sensory stimulus we 00:39:53.223 --> 00:39:55.403 could give them. Right. Vision might be the worst. 00:39:55.803 --> 00:39:59.983 But since these are on the hindbrain, it was rather surprising that they responded 00:39:59.983 --> 00:40:03.863 as well as they did to olfactory stimuli, because the olfactory stimuli come in the nose. 00:40:04.203 --> 00:40:09.823 But they did respond to olfactory stimuli. So even though these are not sensory, 00:40:09.963 --> 00:40:14.263 these cells we're talking about are not out in the skin, or they're not in the 00:40:14.263 --> 00:40:15.683 eye, or they're not in the nose, 00:40:15.943 --> 00:40:20.563 they seem to be central for telling the rest of the central nervous system that 00:40:20.563 --> 00:40:21.683 something just happened. 00:40:21.843 --> 00:40:24.823 Right. Right, but now, what are their ascending targets? 00:40:25.843 --> 00:40:30.583 Ascending targets in, I'm not going to name all of them, because I might make 00:40:30.583 --> 00:40:34.003 somebody ill, and I probably would forget some. 00:40:34.163 --> 00:40:41.003 But they're going forward in the brainstem to the higher up parts of the particular formation. 00:40:41.363 --> 00:40:45.583 They're going to the hypothalamus, and they're going to the central thalamus, 00:40:45.583 --> 00:40:48.443 where you can stimulate in order to wake up the individual. 00:40:48.483 --> 00:40:51.603 Right, exactly. Are they also targeting structures like this periaqueductal 00:40:51.603 --> 00:40:52.543 gray, for instance? Yes. 00:40:53.003 --> 00:40:56.043 That's an incredibly important target. Yes, absolutely. Because there you would 00:40:56.043 --> 00:40:57.903 have more behavioral output, right? Oh, yeah. 00:40:58.043 --> 00:41:01.483 Because if you want to make an animal attack another animal, 00:41:01.623 --> 00:41:04.063 I mean, it's quite sad, actually, and quite vicious. 00:41:04.763 --> 00:41:09.243 Then stimulating the periaqueductal gray, that's called the central gray because 00:41:09.243 --> 00:41:10.863 it's right in the middle of the midbrain. 00:41:11.263 --> 00:41:15.143 And remember that the aqueduct is filled full of cerebrospinal fluid. 00:41:15.143 --> 00:41:20.123 It. It's like a land locked lake, uh, which is in the middle of the brain and 00:41:20.123 --> 00:41:22.103 people don't exactly know what it's doing. 00:41:22.163 --> 00:41:26.003 Is it, is it, is it just a pressure absorber to protect the brain from a, 00:41:26.003 --> 00:41:29.083 from a traumatic injury or is it a vehicle of communication? 00:41:29.603 --> 00:41:33.043 I think that many people would say that it's a vehicle of communication. 00:41:33.143 --> 00:41:36.403 They would speculate that the nervous system has a Navy, uh, 00:41:36.543 --> 00:41:42.083 and, and that signals can go up and down and it's people are just working that out now. 00:41:42.732 --> 00:41:45.752 But again, that's on the frontiers of neuroscience. Sure. Yeah. 00:41:45.932 --> 00:41:49.832 But on top of that, you found that, interestingly enough, some of these neurons 00:41:49.832 --> 00:41:56.032 are coupled rather directly, both to the circulatory system and to each other. 00:41:56.612 --> 00:41:58.172 Yes, to each other for sure. 00:41:58.972 --> 00:42:01.792 We don't know how quantitatively important that is. 00:42:01.792 --> 00:42:05.052 If we were to say, if this is an important part of the brain, 00:42:05.152 --> 00:42:08.592 this reticular formation, and its output is a certain amount, 00:42:08.772 --> 00:42:15.572 let's call it 100, what portion of that 100 units of output is due to them talking with each other? 00:42:16.092 --> 00:42:20.612 We're not sure. We're sure that it would make signaling faster, but how much faster? 00:42:21.272 --> 00:42:24.692 We think that some of these neurons can pick up signals from the blood, 00:42:24.732 --> 00:42:29.692 and we're excited about that because we know that some mental illnesses have 00:42:29.692 --> 00:42:31.192 something to do with the immune system. 00:42:31.192 --> 00:42:34.652 And if these nerve cells are picking up proteins in the blood, 00:42:34.752 --> 00:42:38.052 if they're receptive to proteins in the blood which reflect infections, 00:42:38.152 --> 00:42:42.472 for example, or even HIV, AIDS, then that would be very important. 00:42:42.732 --> 00:42:44.472 But right now we're in the realm of speculation. 00:42:45.212 --> 00:42:48.992 Although you did show in the morning that you have data that shows that these 00:42:48.992 --> 00:42:53.132 neurons can actually absorb substances that float around in the blood, right? It is possible. 00:42:53.292 --> 00:42:55.792 It is possible. But is it a small story or a big story? Sure. 00:42:55.852 --> 00:42:58.952 Shall we spend this weekend in the laboratory trying to find out? 00:42:59.032 --> 00:43:03.812 That's a good idea. But then, what's the transmitter they use? 00:43:05.812 --> 00:43:12.272 Glutamate. Glutamate. Some of them use GABA, and I can't figure out why. Okay. This is a puzzle. 00:43:13.192 --> 00:43:16.352 Glutamate is what we were expecting, and many of them do use glutamate. 00:43:16.592 --> 00:43:21.852 Some of them use GABA. And as you pointed out, and as Nick pointed out in our 00:43:21.852 --> 00:43:22.812 discussions this morning, 00:43:23.092 --> 00:43:27.832 even as it is important to figure out what makes these nerve cells fire their signals, 00:43:27.832 --> 00:43:30.912 their action potentials it's equally important to 00:43:30.912 --> 00:43:33.712 understand how to keep them quiet when nothing is happening right 00:43:33.712 --> 00:43:37.032 exactly because their their output would be meaningless if 00:43:37.032 --> 00:43:40.172 they're chattering away all the time sure it's like you when certain 00:43:40.172 --> 00:43:43.832 people can't stop talking you stop listening to them whereas another person 00:43:43.832 --> 00:43:48.672 he hardly says anything but when he says it we all listen right uh so how do 00:43:48.672 --> 00:43:52.912 we keep them quiet and it was pointed out in the morning uh discussion that 00:43:52.912 --> 00:43:59.812 That small nerve cells nearby the giant nerve cells might use the transmitter GABA, 00:43:59.872 --> 00:44:01.812 gamma-aminobutyric acid, 00:44:02.032 --> 00:44:06.932 in order to keep these cells shut up and quiet when there's nothing important to say. 00:44:07.252 --> 00:44:11.092 Yes. Very good. So then, what is their descending target? 00:44:12.915 --> 00:44:17.275 The entire spinal cord is the safest thing to say. Right. Both motor neurons 00:44:17.275 --> 00:44:19.755 directly and interneurons indirectly. 00:44:20.255 --> 00:44:24.515 And are there any specific patterns to these terminations they have in spinal 00:44:24.515 --> 00:44:26.275 cord? Not really. Not that I know of. 00:44:26.975 --> 00:44:32.875 The best way to study about this would be to study the work of the really accomplished 00:44:32.875 --> 00:44:37.475 Dutch neuroanatomist, Geert Holstege, who's in Groningen. 00:44:37.595 --> 00:44:41.495 Would you say? Groningen, yeah. Oh, there you are. and then in the United States 00:44:41.495 --> 00:44:45.155 there's a wonderful physiologist by the name of Barry Peterson with an S-O-N 00:44:45.155 --> 00:44:50.835 Peterson and you put his neurophysiology together with Herod's neuroanatomy 00:44:50.835 --> 00:44:53.755 and you have a picture of a whopping massive. 00:44:54.915 --> 00:45:00.015 Signal to the spinal cord but it's hard to figure out any specificity so here 00:45:00.015 --> 00:45:05.395 we have these neurons fairly clusters of them, they're coupled through these 00:45:05.395 --> 00:45:07.635 inhibitory local neurons, 00:45:07.855 --> 00:45:11.055 having both these ascending and descending projections, 00:45:11.435 --> 00:45:15.615 if you want, regulating lots of subsystems in the brain, right? 00:45:15.715 --> 00:45:22.375 And in some sense, you started to look at these as these neurons after you had 00:45:22.375 --> 00:45:27.615 been trying to dissect also these subsystems in a more complete way. 00:45:27.775 --> 00:45:30.795 So you were describing how you took very specific sexual behaviors, 00:45:30.895 --> 00:45:36.995 for instance, to try to understand how, let's say, this kind of behavior regulation could take place. 00:45:37.175 --> 00:45:40.795 And these first responders we just talked about, these large neurons in the 00:45:40.795 --> 00:45:42.935 brainstem, could be like a substrate 00:45:42.935 --> 00:45:45.455 that helps with this kind of behavior regulation. Yes, I think so. 00:45:45.655 --> 00:45:51.315 So to understand on the other side of that story, so how should I think about 00:45:51.315 --> 00:45:54.435 the regulation of a very basic behavioral pattern? 00:45:54.955 --> 00:45:59.095 So I think that so many neuroscientists are interested in how the body informs 00:45:59.095 --> 00:46:00.935 the brain of what needs to be done. 00:46:01.335 --> 00:46:04.535 After all, I think it was the talk…. 00:46:05.922 --> 00:46:11.542 Nick's talk yesterday had the quotation from Theodosius Dobzhansky, 00:46:11.682 --> 00:46:15.102 a geneticist who incidentally worked on my campus at Rockefeller University, 00:46:15.442 --> 00:46:20.042 who was quoted as saying, nothing makes sense except in the light of evolution. 00:46:20.522 --> 00:46:25.502 And therefore, we have to say that the brain, and Ernhard Holstege would say 00:46:25.502 --> 00:46:31.622 the same thing, really has two functions, to keep the individual alive and to prolong the species. 00:46:32.042 --> 00:46:38.722 And so all of these motivated behaviors, which are meant to make life longer and more worthwhile, 00:46:38.942 --> 00:46:42.942 so to speak, longer in the case of a laboratory rat and perhaps more worthwhile 00:46:42.942 --> 00:46:47.662 in the case of a citizen of Spain or the citizen of the United States and so forth. 00:46:48.002 --> 00:46:51.142 And among those things would be the hunger and the thirst motivations, 00:46:51.242 --> 00:46:52.582 the fear to avoid danger. 00:46:52.782 --> 00:46:59.022 But what I chose to study was a very simple system, which is triggered and modulated 00:46:59.022 --> 00:47:01.782 by a hormone whose chemistry is very, very well known. 00:47:02.182 --> 00:47:05.922 These steroid hormones, the same kinds of steroids that athletes are not supposed 00:47:05.922 --> 00:47:09.282 to use, are simple, flat molecules. 00:47:09.802 --> 00:47:14.282 And it turns out that sex behavior in these lower animals absolutely depends upon them. 00:47:15.102 --> 00:47:18.462 Estrogens in the female and androgens in the male. 00:47:18.582 --> 00:47:24.042 So androgens would mean from the Greek, what is it that makes a male? The androgen. 00:47:24.382 --> 00:47:26.882 And estrogen, what is it that makes a female? 00:47:27.362 --> 00:47:32.442 And the estrogens and the androgens circulate in the blood from the ovaries 00:47:32.442 --> 00:47:33.762 and the testes, respectively. 00:47:34.202 --> 00:47:39.622 And because the brain is looking for lipid molecules, like the hormones, 00:47:39.902 --> 00:47:42.842 these hormones go right into the brain and they flood the entire brain, 00:47:43.002 --> 00:47:44.302 estrogens and androgens. 00:47:44.302 --> 00:47:50.182 But in certain parts of the brain, there are proteins and certain neurons that 00:47:50.182 --> 00:47:53.802 soak up these steroid hormones, and they're called hormone receptors. 00:47:54.762 --> 00:47:58.282 So an estrogen would bind to a protein called an estrogen receptor. 00:47:58.502 --> 00:48:02.322 A testosterone, an androgen, would bind to an androgen receptor. 00:48:02.582 --> 00:48:03.882 Let's stick with the estrogens. 00:48:04.362 --> 00:48:09.342 It turns out that this protein, which is called estrogen receptor alpha. 00:48:10.415 --> 00:48:14.615 Is manufactured by nerve cells in the primitive part of the forebrain, 00:48:14.655 --> 00:48:18.375 which is called the limbic system, the amygdala, the hippocampus, 00:48:18.375 --> 00:48:21.755 the septum, and so forth, and also in the hypothalamus. 00:48:21.795 --> 00:48:24.775 So it is a limbic hypothalamic system. 00:48:25.055 --> 00:48:29.595 And again, from the fish to the philosopher, the limbic hypothalamic system 00:48:29.595 --> 00:48:34.235 is well and thriving, working to receive hormones and to regulate behavior. 00:48:34.815 --> 00:48:39.535 So that was the first step of making a big advance and explaining how sex behavior 00:48:39.535 --> 00:48:41.575 happens is to know where the receptors are. 00:48:42.755 --> 00:48:47.595 Secondly, the receptors are at the top of a behavior-regulating loop. 00:48:47.975 --> 00:48:51.515 Now, let's think of the loop from the sensory stimulus, which would be being 00:48:51.515 --> 00:48:56.275 touched by the male on the flanks of the animal, and the signals go into the spinal cord, 00:48:56.435 --> 00:49:01.415 up the spinal cord, to the nucleus gigantocellularis, and also to the midbrain 00:49:01.415 --> 00:49:03.635 central gray, which you mentioned, the periaqueductal gray. 00:49:04.135 --> 00:49:09.795 And there, if the animal's ready to mate, If the estrogens are circulating and 00:49:09.795 --> 00:49:14.115 have turned on the estrogen receptor alpha, which in turn turned on certain genes, 00:49:14.375 --> 00:49:19.775 then a signal will come from the hypothalamus to tell that midbrain periaqueductal gray, 00:49:20.035 --> 00:49:22.915 yes, this is a go. 00:49:23.115 --> 00:49:27.635 This is ready. We are ready to mate. and then the descending side of the circuit 00:49:27.635 --> 00:49:32.515 goes back down through nucleus gigante cellularis back down to the spinal cord 00:49:32.515 --> 00:49:38.455 and it says to the spinal cord when you are touched on your flanks by the male the male. 00:49:39.168 --> 00:49:45.768 If dorsiflex, your spinal cord, that would mean lift your rump so that the male can fertilize. 00:49:46.208 --> 00:49:50.928 If and only if the female quadruped, the female with four feet, 00:49:51.048 --> 00:49:55.008 does that, then fertilization will occur and mating will occur. 00:49:55.308 --> 00:49:59.868 So we have the entire circuit. And by the way, if I can pat my colleagues on 00:49:59.868 --> 00:50:02.488 the back, it was the first circuit for any mammalian behavior, 00:50:02.808 --> 00:50:06.388 any vertebrate behavior for that matter. Now, at that point, 00:50:06.408 --> 00:50:07.368 as you know, we got lucky. 00:50:07.848 --> 00:50:12.628 Because when I started this work, the phrase transcription factor was not even 00:50:12.628 --> 00:50:14.848 a phrase. Nobody had that idea. 00:50:15.228 --> 00:50:20.848 But a transcription factor is a protein that tells a gene either to turn on 00:50:20.848 --> 00:50:22.568 or to turn off. It can work either way. 00:50:22.928 --> 00:50:27.608 And it turns out that the estrogen receptors that we had discovered are transcription 00:50:27.608 --> 00:50:29.628 factors which are regulated by the hormone. 00:50:29.628 --> 00:50:36.288 So if and only if the hormone like estradiol in a female comes from the blood 00:50:36.288 --> 00:50:41.008 and touches that estrogen receptor and binds to it, if and only if that happens, 00:50:41.208 --> 00:50:45.188 the estrogen receptor will bind to DNA, 00:50:45.408 --> 00:50:50.508 to a specific sequence of nucleotide bases on the DNA, and will turn on genes. 00:50:50.508 --> 00:50:52.288 Genes, and we know what several of those genes are. 00:50:52.648 --> 00:50:57.288 And then that affects the activity of that cell, it gives an estrogen-dependent 00:50:57.288 --> 00:50:59.928 signal back to the midbrain, and the behavior occurs. 00:51:00.608 --> 00:51:03.728 So at this point, we know the neuroanatomy of this behavior, 00:51:03.948 --> 00:51:09.228 simple behavior, we know the electrophysiology, and we know some of the functional 00:51:09.228 --> 00:51:10.808 genomics of the behavior. 00:51:11.568 --> 00:51:15.968 Right, so this is a really very complete description of a very specific behavioral. 00:51:18.268 --> 00:51:23.948 But the question that it raises is that, so do you believe this generalizes 00:51:23.948 --> 00:51:26.228 to any type of behavioral subsystem? 00:51:26.328 --> 00:51:32.588 Like the philosopher might not only engage in reproductive behaviors, 00:51:32.668 --> 00:51:33.648 they might also read a book. 00:51:33.768 --> 00:51:37.828 Yes. And reading a book might be on less hormonal control than reproductive behavior. 00:51:38.048 --> 00:51:41.748 So will it generalize to the ability of philosophers to read a book? 00:51:42.148 --> 00:51:43.848 The answer is I don't know. No. 00:51:44.368 --> 00:51:50.268 Probably, we talked about ripple analogies in one of the talks in this meeting. 00:51:50.508 --> 00:51:54.688 And what's probably going to happen is that my behavioral system, 00:51:54.788 --> 00:51:57.768 which we've explained, is like throwing the rock into the water. 00:51:57.868 --> 00:52:03.228 And it shows how to explain a simple man behavior, and the ripples will spread. 00:52:03.448 --> 00:52:08.568 And so from this example, we'll learn how to study other simple motivated behaviors, 00:52:08.568 --> 00:52:12.028 And we'll start approaching even more complex behaviors, 00:52:12.188 --> 00:52:17.008 like let's say the philosopher is a graduate student in philosophy and he would 00:52:17.008 --> 00:52:19.528 like to pass his test in order to get his PhD. 00:52:19.808 --> 00:52:24.168 And we could call that mastery motivation. What's the word? 00:52:24.868 --> 00:52:28.848 It's a motivation for accomplishment. And it used to be studied by something 00:52:28.848 --> 00:52:30.668 called a thematic apperception test. 00:52:32.908 --> 00:52:34.188 Mastery, there's a word... 00:52:35.198 --> 00:52:38.958 I'm not a native speaker, so I have an excuse. There's probably a good Dutch word for it. 00:52:39.498 --> 00:52:43.978 I know all the Dutch words for it. And probably the Dutch words are better than the American words. 00:52:45.458 --> 00:52:51.738 But you could measure people's motivation to do complicated things. 00:52:52.018 --> 00:52:56.438 And this philosophy graduate student, this fictitious student whom we're talking 00:52:56.438 --> 00:52:58.978 about, is going to have that kind of motivation. 00:52:59.678 --> 00:53:04.898 Now, will that sort of behavioral regulation follow the same kind of simple pattern? 00:53:05.258 --> 00:53:10.398 I would not bet on it. But for instance, to make it easier, would you believe 00:53:10.398 --> 00:53:13.278 that even in that behavior, also in that behavior, the hypothalamus would be 00:53:13.278 --> 00:53:16.518 playing a coordinating role as it does in the sexual behavior? 00:53:16.838 --> 00:53:20.098 I suspect that the hypothalamus will be down at the core of it, 00:53:20.138 --> 00:53:22.618 even as the magma is down at the core of the earth. 00:53:23.398 --> 00:53:26.778 But the magma doesn't explain everything about the earth. There are many things 00:53:26.778 --> 00:53:32.698 about the mountains and the oceans and the caves of the earth and the weather 00:53:32.698 --> 00:53:34.438 of the earth that the magna cannot explain. 00:53:34.718 --> 00:53:39.158 This is very important, right? Because you are saying whatever behaviors we 00:53:39.158 --> 00:53:41.638 observe, they're all driven by motivation. 00:53:41.818 --> 00:53:46.318 There's a motivational driver of this, which comes back to your arousal system in some form. 00:53:46.458 --> 00:53:50.578 Yes. And the core structure that is setting it up is hypothalamus. 00:53:50.578 --> 00:53:53.178 So in some sense, I would imply without hypothalamus, you will have no motivated 00:53:53.178 --> 00:53:56.938 behavior, whether they're abstract reading of books or the reproductive behaviors 00:53:56.938 --> 00:53:58.718 that occurred just before it. I think that's right. 00:53:58.838 --> 00:54:03.258 And so I think you and I are very interested in striving forward into forms 00:54:03.258 --> 00:54:08.098 of behavioral regulation, notably social behaviors, which are not likely to 00:54:08.098 --> 00:54:13.098 subsume, to be subject to this very simple model that I've worked out for sex behavior. 00:54:14.218 --> 00:54:17.698 They're likely to have equations that are of a different sort. 00:54:17.698 --> 00:54:21.818 I would make the analogy of the difference between arithmetic and calculus, 00:54:22.018 --> 00:54:29.818 or perhaps the difference between arithmetic and fractal geometry, 00:54:30.138 --> 00:54:32.878 maybe nonlinear equations. 00:54:33.938 --> 00:54:38.598 And they're both mathematics, but understanding arithmetic may be necessary 00:54:38.598 --> 00:54:41.838 for understanding more complicated forms of mathematics, but not sufficient. 00:54:41.998 --> 00:54:43.718 Right. But aren't you a little bit…. 00:54:44.255 --> 00:54:47.175 Let's say, holding back too much here, because in some sense, 00:54:47.315 --> 00:54:50.955 if we would just pursue this line of reasoning, if you place, 00:54:50.975 --> 00:54:54.875 let's say, the hypothalamus always at the center of this, or these neurons, 00:54:55.255 --> 00:54:57.115 these gigantic neurons in the brainstem. 00:54:57.575 --> 00:55:01.355 You could say this is an invariant substrate of any motivated behavior. 00:55:01.415 --> 00:55:05.495 These guys always have to be involved, and if they're doing arithmetic, 00:55:05.915 --> 00:55:08.135 there's always arithmetic playing a role here. 00:55:08.155 --> 00:55:10.455 And they will, I agree with you, they absolutely will be involved, 00:55:10.715 --> 00:55:12.595 but it's going to be a lot more complicated than that. 00:55:12.595 --> 00:55:17.055 And so as we strive forward, I think on the one hand, the reason I'm being so 00:55:17.055 --> 00:55:20.015 shy about it is I don't want to be presumptuous and say, oh, 00:55:20.235 --> 00:55:23.495 what we discovered is going to be the Bauplan for pretty much everything there 00:55:23.495 --> 00:55:25.415 is. Well, that would just be silly of me to say that. 00:55:25.615 --> 00:55:29.755 On the other hand, as scientists, we have to be optimists and we have to be proactive. 00:55:30.195 --> 00:55:34.075 We have to say, yes, there is a reality out there. There are sequences of behavior 00:55:34.075 --> 00:55:39.075 that we want to explain, and we have the faith that they are explainable. 00:55:39.075 --> 00:55:43.455 And so you have robots downstairs and you already know how to regulate some 00:55:43.455 --> 00:55:48.315 of their behaviors and you're about to study their ability to regulate social behaviors. 00:55:48.535 --> 00:55:53.055 And so even though you don't know all the formula yet by which the social behaviors 00:55:53.055 --> 00:55:56.875 will be regulated, you have the faith that sooner or later you're going to be 00:55:56.875 --> 00:55:58.735 able to figure it out. Am I right? Sure, absolutely. 00:55:58.995 --> 00:56:01.895 But at least in my case, the robots will have to do something. 00:56:02.115 --> 00:56:06.095 So it's an easy test. But now, in case of the rat, 00:56:06.275 --> 00:56:13.915 let's say, how many of these behavioral subsystems do you think are implemented 00:56:13.915 --> 00:56:18.515 in these circuits and would this map onto these clusters of gigantic cells? else. 00:56:18.595 --> 00:56:22.395 It's easier to state an inequality than it is to guess an exact number. 00:56:22.635 --> 00:56:27.055 And so, for example, if we were in a guessing game and you were the great neuroscientist 00:56:27.055 --> 00:56:30.735 in the sky who knew the exact answer, you could say, how many of these systems 00:56:30.735 --> 00:56:32.595 are involved? And I would say seven. 00:56:32.895 --> 00:56:35.975 And you would say, wrong, you do not win the trip to Las Vegas. 00:56:36.075 --> 00:56:37.275 So you do not win the trip to. 00:56:39.415 --> 00:56:43.735 Monaco. But it's easier to say it's greater than. 00:56:43.955 --> 00:56:49.035 And so if I, as a person who's a sophisticated and well-educated and well-read 00:56:49.035 --> 00:56:52.915 neuroscientist at the moment, I would say that there's probably greater than 10. 00:56:53.215 --> 00:56:56.535 Greater than 10. How much greater than 10? I'm not going to say. 00:56:56.715 --> 00:57:01.875 Right. Okay. Very good. No, because what I, so my contention would be also, 00:57:01.975 --> 00:57:06.615 so having taken on to these kinds of concepts of behavior regulation, right? 00:57:08.534 --> 00:57:11.994 If you now start to generalize this towards more complex behaviors like social 00:57:11.994 --> 00:57:15.834 interaction, you very quickly see actually you have to even decompose those 00:57:15.834 --> 00:57:20.074 overall behavioral systems in all sorts of subsystems. 00:57:20.094 --> 00:57:25.574 And it's very difficult to get away with, let's say, getting to plausible social 00:57:25.574 --> 00:57:29.394 interaction just relying on a single kind of arousal-based drive. 00:57:29.694 --> 00:57:33.034 So I think it will start to fragment very rapidly. 00:57:33.214 --> 00:57:36.114 This will be an interesting problem to address in the future. 00:57:36.274 --> 00:57:37.914 I think so too. So it's dynamic. 00:57:38.534 --> 00:57:41.514 In the sense that everything that you're going to be studying, 00:57:41.574 --> 00:57:44.754 that I study with animals and are also interested in human beings, 00:57:44.834 --> 00:57:51.614 studying autistic children, it's dynamic in the sense that it's a flow of behavior through time. 00:57:51.954 --> 00:57:57.654 And on the other hand, it's things working in parallel, one system, 00:57:57.754 --> 00:58:01.154 a second system, a third system, all working in parallel in order to govern the behavior. 00:58:01.334 --> 00:58:05.314 Maybe sensory systems, motor systems, regulatory systems, all working at the same time. 00:58:05.454 --> 00:58:10.394 And so the equations are not going to be simple. The great British physiologist, 00:58:10.554 --> 00:58:15.234 Sir Charles Sherrington, he not only was maybe the best of the 20th century, 00:58:15.314 --> 00:58:17.634 but he trained the great Australian physiologist, 00:58:17.854 --> 00:58:21.934 Sir John Eccles, both Nobel Prize winners, and then they trained other guys. 00:58:22.954 --> 00:58:27.274 And Sir Charles Sherrington said that the job of the neuroscientist is to explain 00:58:27.274 --> 00:58:29.874 the flow of behavior through time. 00:58:30.054 --> 00:58:35.754 And so it's not just the individual reflex, the cat taking its paw away from 00:58:35.754 --> 00:58:37.394 the source of the damaging heat. 00:58:37.674 --> 00:58:42.474 But it's the sequence of behaviors, whether we're talking about simple behaviors 00:58:42.474 --> 00:58:46.494 like avoidance reflexes or complicated behaviors like social interactions. 00:58:47.694 --> 00:58:52.394 Okay, so Don, after this exploration of, let's say, arousal systems and behavior, 00:58:53.354 --> 00:58:55.914 two questions to finish up. 00:58:56.014 --> 00:59:00.794 So you've been around the blog quite a while in this business, right? 00:59:01.814 --> 00:59:06.774 Over 50 years. Right. And also now you've produced this marvelous book, 00:59:07.054 --> 00:59:12.734 Neuroscience for the 21st Century, that I hope will find many readers in your target audience. 00:59:14.874 --> 00:59:18.134 You've also taken a very, let's say, you're trying to develop this physics of 00:59:18.134 --> 00:59:20.494 behavior, but using modern neuroscience tools. 00:59:21.114 --> 00:59:26.094 So if you would have to give us the law, Don's law, the law we should adhere 00:59:26.094 --> 00:59:28.794 to in trying to understand brain and behavior, what would that law be? 00:59:30.074 --> 00:59:33.014 Don't be shy about it, okay? The law would be to say, don't say a law. 00:59:33.254 --> 00:59:42.154 And the reason is that even as we strain to accomplish the explanation of behavioral 00:59:42.154 --> 00:59:44.334 regulation in the simplest possible way, 00:59:44.454 --> 00:59:49.074 and again, we shared the idea that Einstein said every theory should be as simple 00:59:49.074 --> 00:59:50.234 as possible, but not simpler, 00:59:50.374 --> 00:59:59.514 that the temptation to do the shortcut is something that we should avoid. And so... 01:00:01.071 --> 01:00:09.811 I would never say that any substantial fraction of human behavior is going to 01:00:09.811 --> 01:00:12.791 be encompassed by a very simple lawful statement. 01:00:12.871 --> 01:00:16.951 It's going to be encompassed by large numbers of complex lawful statements, 01:00:17.191 --> 01:00:22.851 which I have the faith that neuroscientists will indeed explain over a period of time. 01:00:22.851 --> 01:00:29.031 But on this particular Friday afternoon, it would not only be false to try to state the law, 01:00:29.131 --> 01:00:33.211 but it would be discouraging because we hope that many people listening to this 01:00:33.211 --> 01:00:36.891 podcast will be people who are about to become neuroscientists, 01:00:36.931 --> 01:00:38.951 who are thinking about becoming neuroscientists. 01:00:38.951 --> 01:00:43.231 And if they think that it's already done, that's what I thought about physics 01:00:43.231 --> 01:00:46.751 when I was, therefore I went into the neurobiology. 01:00:46.911 --> 01:00:52.491 We want people who hear this podcast to get some sense that neuroscience is 01:00:52.491 --> 01:00:58.911 alive and kicking and that we're now, we're about to enter the golden age of neuroscience. 01:00:58.911 --> 01:01:03.911 And so if I had a law, it would be to say that we are entering the golden age 01:01:03.911 --> 01:01:05.591 of neuroscience. And why do I say that? 01:01:06.091 --> 01:01:11.431 It's because our science of how behavior is regulated has reached a stage of 01:01:11.431 --> 01:01:17.051 detail and sophistication, such that on the one hand, we can make use of the 01:01:17.051 --> 01:01:19.471 tools of physics and chemistry and mathematics, 01:01:19.831 --> 01:01:24.991 as you and I have talked about, to try to bring it to the service of behavioral explanation. 01:01:24.991 --> 01:01:29.231 Maybe simple behaviors, but we're getting there step by step by step. 01:01:29.451 --> 01:01:34.031 Thousands of neuroscientists across the world are getting there step by step by step. 01:01:34.331 --> 01:01:39.171 On the other hand, as sophisticated individuals and scientists, 01:01:39.331 --> 01:01:41.591 we know that as well as coming from bottom up, 01:01:42.077 --> 01:01:46.737 that every form of complicated human behavior is also governed by the lawfulness 01:01:46.737 --> 01:01:52.017 of society, that there are well-described social laws that we're all conforming 01:01:52.017 --> 01:01:53.297 to as civilized individuals. 01:01:53.657 --> 01:01:57.257 Let's call that from the collective on down to the individual. 01:01:57.537 --> 01:02:02.657 And so I believe that social scientists are getting more sophisticated than 01:02:02.657 --> 01:02:07.957 ever, and therefore we who are trying to study individual animal behavior, human behavior, 01:02:08.137 --> 01:02:13.517 robot behavior, can take advantage on the low side of the physical sciences 01:02:13.517 --> 01:02:16.197 and on the high side of the social sciences. 01:02:16.437 --> 01:02:23.217 And I think we're going to be doing that big time, all 216 countries and territories. 01:02:23.457 --> 01:02:25.977 How do I summarize that law now? What's Don's law? 01:02:26.737 --> 01:02:31.297 It's make use of all the tools of the physical sciences, all the tools of the 01:02:31.297 --> 01:02:36.237 social sciences, and that will keep you busy for 50 years. Like be inclusive and take the challenge. 01:02:36.497 --> 01:02:40.497 When I think of all the places this could be going on, the reason I said 216 01:02:40.497 --> 01:02:45.037 is because that's the numbers of countries and territories that took part in 01:02:45.037 --> 01:02:47.097 the Olympics in London in 2012. 01:02:47.577 --> 01:02:50.797 If you look at the UN right now, I think it's 196. 01:02:51.677 --> 01:02:57.617 And out of those 196, about half of them are in miserable economic shape. 01:02:57.617 --> 01:03:02.197 And so we really want the brilliant people in those countries to go to Springer 01:03:02.197 --> 01:03:05.597 and through perhaps Ebro, International Brain Research Organization, 01:03:05.957 --> 01:03:10.437 or perhaps through the Human Frontier Science Program and look for this text 01:03:10.437 --> 01:03:12.337 called Neuroscience in the 21st Century. 01:03:12.497 --> 01:03:16.717 Because we've got great scientists from all over the world. How many different 01:03:16.717 --> 01:03:17.897 countries contributed to that? 01:03:18.824 --> 01:03:22.444 Oh, I would guess inequality again. 01:03:22.684 --> 01:03:26.124 Certainly greater than 20 countries. Right. Greater than 20 countries. 01:03:26.144 --> 01:03:29.704 And they worked their hearts out to produce great stuff. Right. 01:03:29.984 --> 01:03:32.944 For neuroscience students all over the world. Excellent. Now, 01:03:32.964 --> 01:03:33.424 I'm looking forward to it. 01:03:33.484 --> 01:03:37.444 So, the last question then is, so five years from now, I'm going to go find 01:03:37.444 --> 01:03:39.244 you there at the campus of Rockefeller University. 01:03:39.564 --> 01:03:42.784 Yes, I'll be there. And I'm going to ask you, like, look, listen, 01:03:42.844 --> 01:03:44.564 Don, five years back you made this prediction. 01:03:44.804 --> 01:03:49.924 Yeah. And today it's pay up time, you know. You're going to lose your wine or you're going to gain it. 01:03:50.464 --> 01:03:53.744 What is one prediction you feel most strongly about today? 01:03:54.184 --> 01:03:58.284 I'd like to know what are the rules by which these giant neurons, 01:03:58.524 --> 01:04:02.384 nucleus giganticellularis, neurons in the reticular formation just above the 01:04:02.384 --> 01:04:05.884 spinal cord, what are the rules by which they operate? 01:04:06.244 --> 01:04:11.364 And the answer is going to come in two parts. One will be, what are the internal rules of governance? 01:04:11.744 --> 01:04:16.984 Is there something special about them? Is there really a factor X that we haven't conceived yet? 01:04:17.144 --> 01:04:20.244 Or is there a new channel? Or is there a different protein expressed? 01:04:20.464 --> 01:04:24.384 Or is there a different kind of mitochondrion, a fundamentally different kind 01:04:24.384 --> 01:04:27.904 of mitochondrion to use energy by those neurons that makes them great? 01:04:28.864 --> 01:04:32.584 And I would like to be able to tell you, if there is a factor X, 01:04:32.724 --> 01:04:34.904 and if so, what is that factor X? Right. 01:04:35.124 --> 01:04:38.404 Especially if there's not a factor X, then I'd like to go to the second part 01:04:38.404 --> 01:04:41.504 of the equation, which is to say, how are they managing their inputs? 01:04:42.004 --> 01:04:49.244 As you pointed out, there are many sensory surfaces that have started to receive 01:04:49.244 --> 01:04:53.044 these signals, somatosensory signals, olfactory signals, you name it, 01:04:53.044 --> 01:04:55.804 auditory signals, coming onto these dendrites. 01:04:55.964 --> 01:05:00.704 How exactly does that happen? If I could tell you that, then I would be able 01:05:00.704 --> 01:05:05.304 to tell you what is the rules of operation of these nerve cells, 01:05:05.504 --> 01:05:10.124 which are at the center of arousal, which I believe is at the beginning of the 01:05:10.124 --> 01:05:12.324 execution of every behavioral response. 01:05:12.764 --> 01:05:16.144 Right. So what's the specific prediction, the specific one? 01:05:16.544 --> 01:05:19.704 The specific prediction is going to be that there is no factor X. 01:05:19.784 --> 01:05:23.084 I hate to say this. I really hate to say this. This is no fun. 01:05:24.164 --> 01:05:26.924 That there is no factor x it's more of the 01:05:26.924 --> 01:05:29.904 same okay more of the same a bigger cell body more 01:05:29.904 --> 01:05:32.844 mitochondria more dendrites and therefore 01:05:32.844 --> 01:05:36.344 a greater integrative capacity and that they 01:05:36.344 --> 01:05:41.444 operate in groups in a fish they operated one by one but in some way i want 01:05:41.444 --> 01:05:45.124 to know how they operate in groups we're dealing with teamwork here exactly 01:05:45.124 --> 01:05:48.824 excellent well donald prof thank you very much for this conversation this is 01:05:48.824 --> 01:05:54.144 a great series of podcasts i hope that uh people People will listen to all 100. Very good. Thank you. 01:05:58.264 --> 01:06:03.984 The CSN podcast was produced by the Convergent Science Network of Biometrics 01:06:03.984 --> 01:06:10.364 and Biohybrid Systems, a project funded by the European Sevens Research Framework Program. 01:06:10.960 --> 01:06:38.693 Music.