WEBVTT 00:00:00.630 --> 00:00:03.858 So raise your hand if you know someone 00:00:03.858 --> 00:00:06.505 in your immediate family or circle of friends 00:00:06.505 --> 00:00:09.993 who suffers from some form of mental illness. 00:00:09.993 --> 00:00:12.777 Yeah. I thought so. Not surprised. NOTE Paragraph 00:00:12.777 --> 00:00:15.072 And raise your hand if you think that 00:00:15.072 --> 00:00:17.897 basic research on fruit flies has anything to do 00:00:17.897 --> 00:00:22.359 with understanding mental illness in humans. 00:00:22.359 --> 00:00:25.152 Yeah. I thought so. I'm also not surprised. 00:00:25.152 --> 00:00:28.472 I can see I've got my work cut out for me here. NOTE Paragraph 00:00:28.472 --> 00:00:31.060 As we heard from Dr. Insel this morning, 00:00:31.060 --> 00:00:35.273 psychiatric disorders like autism, depression and schizophrenia 00:00:35.273 --> 00:00:38.148 take a terrible toll on human suffering. 00:00:38.148 --> 00:00:41.361 We know much less about their treatment 00:00:41.361 --> 00:00:43.967 and the understanding of their basic mechanisms 00:00:43.967 --> 00:00:46.586 than we do about diseases of the body. 00:00:46.586 --> 00:00:49.229 Think about it: In 2013, 00:00:49.229 --> 00:00:51.184 the second decade of the millennium, 00:00:51.184 --> 00:00:53.549 if you're concerned about a cancer diagnosis 00:00:53.549 --> 00:00:56.068 and you go to your doctor, you get bone scans, 00:00:56.068 --> 00:00:58.996 biopsies and blood tests. 00:00:58.996 --> 00:01:02.861 In 2013, if you're concerned about a depression diagnosis, 00:01:02.861 --> 00:01:04.824 you go to your doctor, and what do you get? 00:01:04.824 --> 00:01:06.811 A questionnaire. 00:01:06.811 --> 00:01:09.240 Now, part of the reason for this is that we have 00:01:09.240 --> 00:01:13.063 an oversimplified and increasingly outmoded view 00:01:13.063 --> 00:01:16.950 of the biological basis of psychiatric disorders. 00:01:16.950 --> 00:01:18.193 We tend to view them -- 00:01:18.193 --> 00:01:21.038 and the popular press aids and abets this view -- 00:01:21.038 --> 00:01:24.054 as chemical imbalances in the brain, 00:01:24.054 --> 00:01:27.738 as if the brain were some kind of bag of chemical soup 00:01:27.738 --> 00:01:31.938 full of dopamine, serotonin and norepinephrine. 00:01:31.938 --> 00:01:34.265 This view is conditioned by the fact 00:01:34.265 --> 00:01:37.671 that many of the drugs that are prescribed to treat these disorders, 00:01:37.671 --> 00:01:42.342 like Prozac, act by globally changing brain chemistry, 00:01:42.342 --> 00:01:46.318 as if the brain were indeed a bag of chemical soup. 00:01:46.318 --> 00:01:48.219 But that can't be the answer, 00:01:48.219 --> 00:01:51.456 because these drugs actually don't work all that well. 00:01:51.456 --> 00:01:54.632 A lot of people won't take them, or stop taking them, 00:01:54.632 --> 00:01:57.289 because of their unpleasant side effects. 00:01:57.289 --> 00:01:59.349 These drugs have so many side effects 00:01:59.349 --> 00:02:03.305 because using them to treat a complex psychiatric disorder 00:02:03.305 --> 00:02:05.994 is a bit like trying to change your engine oil 00:02:05.994 --> 00:02:10.107 by opening a can and pouring it all over the engine block. 00:02:10.107 --> 00:02:12.257 Some of it will dribble into the right place, 00:02:12.257 --> 00:02:15.358 but a lot of it will do more harm than good. NOTE Paragraph 00:02:15.358 --> 00:02:17.596 Now, an emerging view 00:02:17.596 --> 00:02:20.546 that you also heard about from Dr. Insel this morning, 00:02:20.546 --> 00:02:23.116 is that psychiatric disorders are actually 00:02:23.116 --> 00:02:26.590 disturbances of neural circuits that mediate 00:02:26.590 --> 00:02:30.109 emotion, mood and affect. 00:02:30.109 --> 00:02:31.871 When we think about cognition, 00:02:31.871 --> 00:02:35.447 we analogize the brain to a computer. That's no problem. 00:02:35.447 --> 00:02:38.028 Well it turns out that the computer analogy 00:02:38.028 --> 00:02:40.411 is just as valid for emotion. 00:02:40.411 --> 00:02:43.197 It's just that we don't tend to think about it that way. 00:02:43.197 --> 00:02:46.480 But we know much less about the circuit basis 00:02:46.480 --> 00:02:48.379 of psychiatric disorders 00:02:48.379 --> 00:02:50.449 because of the overwhelming dominance 00:02:50.449 --> 00:02:53.801 of this chemical imbalance hypothesis. NOTE Paragraph 00:02:53.801 --> 00:02:57.628 Now, it's not that chemicals are not important 00:02:57.628 --> 00:02:59.165 in psychiatric disorders. 00:02:59.165 --> 00:03:03.137 It's just that they don't bathe the brain like soup. 00:03:03.137 --> 00:03:06.786 Rather, they're released in very specific locations 00:03:06.786 --> 00:03:09.511 and they act on specific synapses 00:03:09.511 --> 00:03:13.199 to change the flow of information in the brain. 00:03:13.199 --> 00:03:15.636 So if we ever really want to understand 00:03:15.636 --> 00:03:18.341 the biological basis of psychiatric disorders, 00:03:18.341 --> 00:03:21.373 we need to pinpoint these locations in the brain 00:03:21.373 --> 00:03:23.107 where these chemicals act. 00:03:23.107 --> 00:03:26.586 Otherwise, we're going to keep pouring oil all over our mental engines 00:03:26.586 --> 00:03:29.543 and suffering the consequences. NOTE Paragraph 00:03:29.543 --> 00:03:32.602 Now to begin to overcome our ignorance 00:03:32.602 --> 00:03:36.136 of the role of brain chemistry in brain circuitry, 00:03:36.136 --> 00:03:38.816 it's helpful to work on what we biologists call 00:03:38.816 --> 00:03:40.395 "model organisms," 00:03:40.395 --> 00:03:43.729 animals like fruit flies and laboratory mice, 00:03:43.729 --> 00:03:47.154 in which we can apply powerful genetic techniques 00:03:47.154 --> 00:03:50.779 to molecularly identify and pinpoint 00:03:50.779 --> 00:03:52.342 specific classes of neurons, 00:03:52.342 --> 00:03:55.245 as you heard about in Allan Jones's talk this morning. 00:03:55.245 --> 00:03:57.706 Moreover, once we can do that, 00:03:57.706 --> 00:04:00.455 we can actually activate specific neurons 00:04:00.455 --> 00:04:04.666 or we can destroy or inhibit the activity of those neurons. 00:04:04.666 --> 00:04:07.380 So if we inhibit a particular type of neuron, 00:04:07.380 --> 00:04:09.845 and we find that a behavior is blocked, 00:04:09.845 --> 00:04:12.059 we can conclude that those neurons 00:04:12.059 --> 00:04:15.023 are necessary for that behavior. 00:04:15.023 --> 00:04:17.405 On the other hand, if we activate a group of neurons 00:04:17.405 --> 00:04:20.219 and we find that that produces the behavior, 00:04:20.219 --> 00:04:24.293 we can conclude that those neurons are sufficient for the behavior. 00:04:24.293 --> 00:04:27.302 So in this way, by doing this kind of test, 00:04:27.302 --> 00:04:30.825 we can draw cause and effect relationships 00:04:30.825 --> 00:04:33.181 between the activity of specific neurons 00:04:33.181 --> 00:04:36.094 in particular circuits and particular behaviors, 00:04:36.094 --> 00:04:38.531 something that is extremely difficult, if not impossible, 00:04:38.531 --> 00:04:43.582 to do right now in humans. NOTE Paragraph 00:04:43.582 --> 00:04:46.419 But can an organism like a fruit fly, which is -- 00:04:46.419 --> 00:04:48.619 it's a great model organism 00:04:48.619 --> 00:04:51.157 because it's got a small brain, 00:04:51.157 --> 00:04:54.944 it's capable of complex and sophisticated behaviors, 00:04:54.944 --> 00:04:58.094 it breeds quickly, and it's cheap. 00:04:58.094 --> 00:04:59.889 But can an organism like this 00:04:59.889 --> 00:05:03.732 teach us anything about emotion-like states? 00:05:03.732 --> 00:05:07.032 Do these organisms even have emotion-like states, 00:05:07.032 --> 00:05:10.395 or are they just little digital robots? NOTE Paragraph 00:05:10.395 --> 00:05:13.595 Charles Darwin believed that insects have emotion 00:05:13.595 --> 00:05:16.145 and express them in their behaviors, as he wrote 00:05:16.145 --> 00:05:21.338 in his 1872 monograph on the expression of the emotions in man and animals. 00:05:21.338 --> 00:05:24.857 And my eponymous colleague, Seymour Benzer, believed it as well. 00:05:24.857 --> 00:05:28.271 Seymour is the man that introduced the use of drosophila 00:05:28.271 --> 00:05:31.794 here at CalTech in the '60s as a model organism 00:05:31.794 --> 00:05:35.391 to study the connection between genes and behavior. 00:05:35.391 --> 00:05:38.998 Seymour recruited me to CalTech in the late 1980s. 00:05:38.998 --> 00:05:43.432 He was my Jedi and my rabbi while he was here, 00:05:43.432 --> 00:05:45.820 and Seymour taught me both to love flies 00:05:45.820 --> 00:05:48.869 and also to play with science. NOTE Paragraph 00:05:48.869 --> 00:05:51.985 So how do we ask this question? 00:05:51.985 --> 00:05:56.045 It's one thing to believe that flies have emotion-like states, 00:05:56.045 --> 00:05:59.208 but how do we actually find out whether that's true or not? 00:05:59.208 --> 00:06:03.158 Now, in humans we often infer emotional states, 00:06:03.158 --> 00:06:07.063 as you'll hear later today, from facial expressions. 00:06:07.063 --> 00:06:10.783 However, it's a little difficult to do that in fruit flies. 00:06:10.783 --> 00:06:14.096 (Laughter) 00:06:14.096 --> 00:06:17.233 It's kind of like landing on Mars 00:06:17.233 --> 00:06:19.938 and looking out the window of your spaceship 00:06:19.938 --> 00:06:22.408 at all the little green men who are surrounding it 00:06:22.408 --> 00:06:24.814 and trying to figure out, "How do I find out 00:06:24.814 --> 00:06:27.169 if they have emotions or not?" 00:06:27.169 --> 00:06:30.712 What can we do? It's not so easy. NOTE Paragraph 00:06:30.712 --> 00:06:32.897 Well, one of the ways that we can start 00:06:32.897 --> 00:06:37.022 is to try to come up with some general characteristics 00:06:37.022 --> 00:06:40.770 or properties of emotion-like states 00:06:40.770 --> 00:06:44.234 such as arousal, and see if we can identify 00:06:44.234 --> 00:06:49.610 any fly behaviors that might exhibit some of those properties. 00:06:49.610 --> 00:06:52.430 So three important ones that I can think of 00:06:52.430 --> 00:06:57.102 are persistence, gradations in intensity, and valence. 00:06:57.102 --> 00:06:59.436 Persistence means long-lasting. 00:06:59.436 --> 00:07:03.397 We all know that the stimulus that triggers an emotion 00:07:03.397 --> 00:07:08.413 causes that emotion to last long after the stimulus is gone. 00:07:08.413 --> 00:07:11.503 Gradations of intensity means what it sounds like. 00:07:11.503 --> 00:07:16.086 You can dial up the intensity or dial down the intensity of an emotion. 00:07:16.086 --> 00:07:18.686 If you're a little bit unhappy, the corners of your mouth 00:07:18.686 --> 00:07:20.373 turn down and you sniffle, 00:07:20.373 --> 00:07:23.511 and if you're very unhappy, tears pour down your face 00:07:23.511 --> 00:07:25.343 and you might sob. 00:07:25.343 --> 00:07:29.722 Valence means good or bad, positive or negative. NOTE Paragraph 00:07:29.722 --> 00:07:34.174 So we decided to see if flies could be provoked into showing 00:07:34.174 --> 00:07:36.625 the kind of behavior that you see 00:07:36.625 --> 00:07:39.435 by the proverbial wasp at the picnic table, 00:07:39.435 --> 00:07:42.120 you know, the one that keeps coming back to your hamburger 00:07:42.120 --> 00:07:44.649 the more vigorously you try to swat it away, 00:07:44.649 --> 00:07:46.933 and it seems to keep getting irritated. 00:07:46.933 --> 00:07:50.580 So we built a device, which we call a puff-o-mat, 00:07:50.580 --> 00:07:54.925 in which we could deliver little brief air puffs to fruit flies 00:07:54.925 --> 00:07:57.701 in these plastic tubes in our laboratory bench 00:07:57.701 --> 00:07:59.426 and blow them away. 00:07:59.426 --> 00:08:02.665 And what we found is that if we gave these flies 00:08:02.665 --> 00:08:05.513 in the puff-o-mat several puffs in a row, 00:08:05.513 --> 00:08:08.202 they became somewhat hyperactive 00:08:08.202 --> 00:08:12.637 and continued to run around for some time after the air puffs actually stopped 00:08:12.637 --> 00:08:15.501 and took a while to calm down. 00:08:15.501 --> 00:08:17.690 So we quantified this behavior 00:08:17.690 --> 00:08:20.702 using custom locomotor tracking software 00:08:20.702 --> 00:08:23.502 developed with my collaborator Pietro Perona, 00:08:23.502 --> 00:08:27.114 who's in the electrical engineering division here at CalTech. 00:08:27.114 --> 00:08:29.928 And what this quantification showed us is that, 00:08:29.928 --> 00:08:33.152 upon experiencing a train of these air puffs, 00:08:33.152 --> 00:08:37.466 the flies appear to enter a kind of state of hyperactivity 00:08:37.466 --> 00:08:40.064 which is persistent, long-lasting, 00:08:40.064 --> 00:08:42.568 and also appears to be graded. 00:08:42.568 --> 00:08:45.427 More puffs, or more intense puffs, 00:08:45.427 --> 00:08:49.340 make the state last for a longer period of time. NOTE Paragraph 00:08:49.340 --> 00:08:51.376 So now we wanted to try to understand something 00:08:51.376 --> 00:08:55.090 about what controls the duration of this state. 00:08:55.090 --> 00:08:57.941 So we decided to use our puff-o-mat 00:08:57.941 --> 00:08:59.996 and our automated tracking software 00:08:59.996 --> 00:09:03.778 to screen through hundreds of lines of mutant fruit flies 00:09:03.778 --> 00:09:08.857 to see if we could find any that showed abnormal responses to the air puffs. 00:09:08.857 --> 00:09:11.204 And this is one of the great things about fruit flies. 00:09:11.204 --> 00:09:13.997 There are repositories where you can just pick up the phone 00:09:13.997 --> 00:09:17.638 and order hundreds of vials of flies of different mutants 00:09:17.638 --> 00:09:19.810 and screen them in your assay and then find out 00:09:19.810 --> 00:09:23.129 what gene is affected in the mutation. 00:09:23.129 --> 00:09:26.641 So doing the screen, we discovered one mutant 00:09:26.641 --> 00:09:30.115 that took much longer than normal to calm down 00:09:30.115 --> 00:09:32.392 after the air puffs, 00:09:32.392 --> 00:09:36.342 and when we examined the gene that was affected in this mutation, 00:09:36.342 --> 00:09:39.947 it turned out to encode a dopamine receptor. 00:09:39.947 --> 00:09:42.958 That's right -- flies, like people, have dopamine, 00:09:42.958 --> 00:09:45.730 and it acts on their brains and on their synapses 00:09:45.730 --> 00:09:48.280 through the same dopamine receptor molecules 00:09:48.280 --> 00:09:50.669 that you and I have. 00:09:50.669 --> 00:09:54.155 Dopamine plays a number of important functions in the brain, 00:09:54.155 --> 00:09:57.268 including in attention, arousal, reward, 00:09:57.268 --> 00:10:00.681 and disorders of the dopamine system have been linked 00:10:00.681 --> 00:10:03.781 to a number of mental disorders including drug abuse, 00:10:03.781 --> 00:10:08.015 Parkinson's disease, and ADHD. NOTE Paragraph 00:10:08.015 --> 00:10:10.805 Now, in genetics, it's a little counterintuitive. 00:10:10.805 --> 00:10:14.065 We tend to infer the normal function of something 00:10:14.065 --> 00:10:17.775 by what doesn't happen when we take it away, 00:10:17.775 --> 00:10:20.778 by the opposite of what we see when we take it away. 00:10:20.778 --> 00:10:23.791 So when we take away the dopamine receptor 00:10:23.791 --> 00:10:26.348 and the flies take longer to calm down, 00:10:26.348 --> 00:10:30.194 from that we infer that the normal function of this receptor and dopamine 00:10:30.194 --> 00:10:34.679 is to cause the flies to calm down faster after the puff. 00:10:34.679 --> 00:10:37.629 And that's a bit reminiscent of ADHD, 00:10:37.629 --> 00:10:41.604 which has been linked to disorders of the dopamine system in humans. 00:10:41.604 --> 00:10:46.210 Indeed, if we increase the levels of dopamine in normal flies 00:10:46.210 --> 00:10:47.920 by feeding them cocaine 00:10:47.920 --> 00:10:50.892 after getting the appropriate DEA license 00:10:50.892 --> 00:10:54.892 — oh my God -- (Laughter) — 00:10:54.892 --> 00:10:58.064 we find indeed that these cocaine-fed flies 00:10:58.064 --> 00:11:01.106 calm down faster than normal flies do, 00:11:01.106 --> 00:11:04.305 and that's also reminiscent of ADHD, 00:11:04.305 --> 00:11:06.350 which is often treated with drugs like Ritalin 00:11:06.350 --> 00:11:09.369 that act similarly to cocaine. 00:11:09.369 --> 00:11:12.518 So slowly I began to realize that what started out 00:11:12.518 --> 00:11:16.167 as a rather playful attempt to try to annoy fruit flies 00:11:16.167 --> 00:11:20.143 might actually have some relevance to a human psychiatric disorder. NOTE Paragraph 00:11:20.143 --> 00:11:22.369 Now, how far does this analogy go? 00:11:22.369 --> 00:11:25.491 As many of you know, individuals afflicted with ADHD 00:11:25.491 --> 00:11:27.828 also have learning disabilities. 00:11:27.828 --> 00:11:31.394 Is that true of our dopamine receptor mutant flies? 00:11:31.394 --> 00:11:34.114 Remarkably, the answer is yes. 00:11:34.114 --> 00:11:36.742 As Seymour showed back in the 1970s, 00:11:36.742 --> 00:11:39.193 flies, like songbirds, as you just heard, 00:11:39.193 --> 00:11:40.926 are capable of learning. 00:11:40.926 --> 00:11:45.369 You can train a fly to avoid an odor, shown here in blue, 00:11:45.369 --> 00:11:47.757 if you pair that odor with a shock. 00:11:47.757 --> 00:11:51.141 Then when you give those trained flies the chance to choose 00:11:51.141 --> 00:11:54.295 between a tube with the shock-paired odor and another odor, 00:11:54.295 --> 00:11:58.495 it avoids the tube containing the blue odor that was paired with shock. 00:11:58.495 --> 00:12:01.997 Well, if you do this test on dopamine receptor mutant flies, 00:12:01.997 --> 00:12:04.462 they don't learn. Their learning score is zero. 00:12:04.462 --> 00:12:08.273 They flunk out of CalTech. NOTE Paragraph 00:12:08.273 --> 00:12:13.021 So that means that these flies have two abnormalities, 00:12:13.021 --> 00:12:16.071 or phenotypes, as we geneticists call them, 00:12:16.071 --> 00:12:21.583 that one finds in ADHD: hyperactivity and learning disability. 00:12:21.583 --> 00:12:25.946 Now what's the causal relationship, if anything, between these phenotypes? 00:12:25.946 --> 00:12:29.859 In ADHD, it's often assumed that the hyperactivity 00:12:29.859 --> 00:12:31.765 causes the learning disability. 00:12:31.765 --> 00:12:35.484 The kids can't sit still long enough to focus, so they don't learn. 00:12:35.484 --> 00:12:38.780 But it could equally be the case that it's the learning disabilities 00:12:38.780 --> 00:12:40.652 that cause the hyperactivity. 00:12:40.652 --> 00:12:45.122 Because the kids can't learn, they look for other things to distract their attention. 00:12:45.122 --> 00:12:48.179 And a final possibility is that there's no relationship at all 00:12:48.179 --> 00:12:50.583 between learning disabilities and hyperactivity, 00:12:50.583 --> 00:12:55.498 but that they are caused by a common underlying mechanism in ADHD. NOTE Paragraph 00:12:55.498 --> 00:12:57.840 Now people have been wondering about this for a long time 00:12:57.840 --> 00:13:01.328 in humans, but in flies we can actually test this. 00:13:01.328 --> 00:13:04.412 And the way that we do this is to delve deeply into the mind 00:13:04.412 --> 00:13:08.678 of the fly and begin to untangle its circuitry using genetics. 00:13:08.678 --> 00:13:11.140 We take our dopamine receptor mutant flies 00:13:11.140 --> 00:13:15.704 and we genetically restore, or cure, the dopamine receptor 00:13:15.704 --> 00:13:18.939 by putting a good copy of the dopamine receptor gene 00:13:18.939 --> 00:13:20.990 back into the fly brain. 00:13:20.990 --> 00:13:24.825 But in each fly, we put it back only into certain neurons 00:13:24.825 --> 00:13:28.539 and not in others, and then we test each of these flies 00:13:28.539 --> 00:13:32.207 for their ability to learn and for hyperactivity. NOTE Paragraph 00:13:32.207 --> 00:13:37.025 Remarkably, we find we can completely dissociate these two abnormalities. 00:13:37.025 --> 00:13:39.688 If we put a good copy of the dopamine receptor back 00:13:39.688 --> 00:13:42.649 in this elliptical structure called the central complex, 00:13:42.649 --> 00:13:46.726 the flies are no longer hyperactive, but they still can't learn. 00:13:46.726 --> 00:13:49.452 On the other hand, if we put the receptor back in a different structure 00:13:49.452 --> 00:13:50.970 called the mushroom body, 00:13:50.970 --> 00:13:54.055 the learning deficit is rescued, the flies learn well, 00:13:54.055 --> 00:13:55.885 but they're still hyperactive. 00:13:55.885 --> 00:13:58.135 What that tells us is that dopamine 00:13:58.135 --> 00:14:01.527 is not bathing the brain of these flies like soup. 00:14:01.527 --> 00:14:04.689 Rather, it's acting to control two different functions 00:14:04.689 --> 00:14:06.323 on two different circuits, 00:14:06.323 --> 00:14:10.227 so the reason there are two things wrong with our dopamine receptor flies 00:14:10.227 --> 00:14:14.402 is that the same receptor is controlling two different functions 00:14:14.402 --> 00:14:17.265 in two different regions of the brain. 00:14:17.265 --> 00:14:20.327 Whether the same thing is true in ADHD in humans 00:14:20.327 --> 00:14:22.703 we don't know, but these kinds of results 00:14:22.703 --> 00:14:26.180 should at least cause us to consider that possibility. NOTE Paragraph 00:14:26.180 --> 00:14:30.153 So these results make me and my colleagues more convinced than ever 00:14:30.153 --> 00:14:33.565 that the brain is not a bag of chemical soup, 00:14:33.565 --> 00:14:37.092 and it's a mistake to try to treat complex psychiatric disorders 00:14:37.092 --> 00:14:39.803 just by changing the flavor of the soup. 00:14:39.803 --> 00:14:44.020 What we need to do is to use our ingenuity and our scientific knowledge 00:14:44.020 --> 00:14:46.728 to try to design a new generation of treatments 00:14:46.728 --> 00:14:51.016 that are targeted to specific neurons and specific regions of the brain 00:14:51.016 --> 00:14:54.354 that are affected in particular psychiatric disorders. 00:14:54.354 --> 00:14:57.554 If we can do that, we may be able to cure these disorders 00:14:57.554 --> 00:14:59.601 without the unpleasant side effects, 00:14:59.601 --> 00:15:02.347 putting the oil back in our mental engines, 00:15:02.347 --> 00:15:05.531 just where it's needed. Thank you very much.