0:00:00.630,0:00:03.858 So raise your hand if you know someone 0:00:03.858,0:00:06.505 in your immediate family or circle of friends 0:00:06.505,0:00:09.993 who suffers from some form of mental illness. 0:00:09.993,0:00:12.777 Yeah. I thought so. Not surprised. 0:00:12.777,0:00:15.072 And raise your hand if you think that 0:00:15.072,0:00:17.897 basic research on fruit flies has anything to do 0:00:17.897,0:00:22.359 with understanding mental illness in humans. 0:00:22.359,0:00:25.152 Yeah. I thought so. I'm also not surprised. 0:00:25.152,0:00:28.472 I can see I've got my work cut out for me here. 0:00:28.472,0:00:31.060 As we heard from Dr. Insel this morning, 0:00:31.060,0:00:35.273 psychiatric disorders like autism, depression and schizophrenia 0:00:35.273,0:00:38.148 take a terrible toll on human suffering. 0:00:38.148,0:00:41.361 We know much less about their treatment 0:00:41.361,0:00:43.967 and the understanding of their basic mechanisms 0:00:43.967,0:00:46.586 than we do about diseases of the body. 0:00:46.586,0:00:49.229 Think about it: In 2013, 0:00:49.229,0:00:51.184 the second decade of the millennium, 0:00:51.184,0:00:53.549 if you're concerned about a cancer diagnosis 0:00:53.549,0:00:56.068 and you go to your doctor, you get bone scans, 0:00:56.068,0:00:58.996 biopsies and blood tests. 0:00:58.996,0:01:02.861 In 2013, if you're concerned about a depression diagnosis, 0:01:02.861,0:01:04.824 you go to your doctor, and what do you get? 0:01:04.824,0:01:06.811 A questionnaire. 0:01:06.811,0:01:09.240 Now, part of the reason for this is that we have 0:01:09.240,0:01:13.063 an oversimplified and increasingly outmoded view 0:01:13.063,0:01:16.950 of the biological basis of psychiatric disorders. 0:01:16.950,0:01:18.193 We tend to view them -- 0:01:18.193,0:01:21.038 and the popular press aids and abets this view -- 0:01:21.038,0:01:24.054 as chemical imbalances in the brain, 0:01:24.054,0:01:27.738 as if the brain were some kind of bag of chemical soup 0:01:27.738,0:01:31.938 full of dopamine, serotonin and norepinephrine. 0:01:31.938,0:01:34.265 This view is conditioned by the fact 0:01:34.265,0:01:37.671 that many of the drugs that are prescribed to treat these disorders, 0:01:37.671,0:01:42.342 like Prozac, act by globally changing brain chemistry, 0:01:42.342,0:01:46.318 as if the brain were indeed a bag of chemical soup. 0:01:46.318,0:01:48.219 But that can't be the answer, 0:01:48.219,0:01:51.456 because these drugs actually don't work all that well. 0:01:51.456,0:01:54.632 A lot of people won't take them, or stop taking them, 0:01:54.632,0:01:57.289 because of their unpleasant side effects. 0:01:57.289,0:01:59.349 These drugs have so many side effects 0:01:59.349,0:02:03.305 because using them to treat a complex psychiatric disorder 0:02:03.305,0:02:05.994 is a bit like trying to change your engine oil 0:02:05.994,0:02:10.107 by opening a can and pouring it all over the engine block. 0:02:10.107,0:02:12.257 Some of it will dribble into the right place, 0:02:12.257,0:02:15.358 but a lot of it will do more harm than good. 0:02:15.358,0:02:17.596 Now, an emerging view 0:02:17.596,0:02:20.546 that you also heard about from Dr. Insel this morning, 0:02:20.546,0:02:23.116 is that psychiatric disorders are actually 0:02:23.116,0:02:26.590 disturbances of neural circuits that mediate 0:02:26.590,0:02:30.109 emotion, mood and affect. 0:02:30.109,0:02:31.871 When we think about cognition, 0:02:31.871,0:02:35.447 we analogize the brain to a computer. That's no problem. 0:02:35.447,0:02:38.028 Well it turns out that the computer analogy 0:02:38.028,0:02:40.411 is just as valid for emotion. 0:02:40.411,0:02:43.197 It's just that we don't tend to think about it that way. 0:02:43.197,0:02:46.480 But we know much less about the circuit basis 0:02:46.480,0:02:48.379 of psychiatric disorders 0:02:48.379,0:02:50.449 because of the overwhelming dominance 0:02:50.449,0:02:53.801 of this chemical imbalance hypothesis. 0:02:53.801,0:02:57.628 Now, it's not that chemicals are not important 0:02:57.628,0:02:59.165 in psychiatric disorders. 0:02:59.165,0:03:03.137 It's just that they don't bathe the brain like soup. 0:03:03.137,0:03:06.786 Rather, they're released in very specific locations 0:03:06.786,0:03:09.511 and they act on specific synapses 0:03:09.511,0:03:13.199 to change the flow of information in the brain. 0:03:13.199,0:03:15.636 So if we ever really want to understand 0:03:15.636,0:03:18.341 the biological basis of psychiatric disorders, 0:03:18.341,0:03:21.373 we need to pinpoint these locations in the brain 0:03:21.373,0:03:23.107 where these chemicals act. 0:03:23.107,0:03:26.586 Otherwise, we're going to keep pouring oil all over our mental engines 0:03:26.586,0:03:29.543 and suffering the consequences. 0:03:29.543,0:03:32.602 Now to begin to overcome our ignorance 0:03:32.602,0:03:36.136 of the role of brain chemistry in brain circuitry, 0:03:36.136,0:03:38.816 it's helpful to work on what we biologists call 0:03:38.816,0:03:40.395 "model organisms," 0:03:40.395,0:03:43.729 animals like fruit flies and laboratory mice, 0:03:43.729,0:03:47.154 in which we can apply powerful genetic techniques 0:03:47.154,0:03:50.779 to molecularly identify and pinpoint 0:03:50.779,0:03:52.342 specific classes of neurons, 0:03:52.342,0:03:55.245 as you heard about in Allan Jones's talk this morning. 0:03:55.245,0:03:57.706 Moreover, once we can do that, 0:03:57.706,0:04:00.455 we can actually activate specific neurons 0:04:00.455,0:04:04.666 or we can destroy or inhibit the activity of those neurons. 0:04:04.666,0:04:07.380 So if we inhibit a particular type of neuron, 0:04:07.380,0:04:09.845 and we find that a behavior is blocked, 0:04:09.845,0:04:12.059 we can conclude that those neurons 0:04:12.059,0:04:15.023 are necessary for that behavior. 0:04:15.023,0:04:17.405 On the other hand, if we activate a group of neurons 0:04:17.405,0:04:20.219 and we find that that produces the behavior, 0:04:20.219,0:04:24.293 we can conclude that those neurons are sufficient for the behavior. 0:04:24.293,0:04:27.302 So in this way, by doing this kind of test, 0:04:27.302,0:04:30.825 we can draw cause and effect relationships 0:04:30.825,0:04:33.181 between the activity of specific neurons 0:04:33.181,0:04:36.094 in particular circuits and particular behaviors, 0:04:36.094,0:04:38.531 something that is extremely difficult, if not impossible, 0:04:38.531,0:04:43.582 to do right now in humans. 0:04:43.582,0:04:46.419 But can an organism like a fruit fly, which is -- 0:04:46.419,0:04:48.619 it's a great model organism 0:04:48.619,0:04:51.157 because it's got a small brain, 0:04:51.157,0:04:54.944 it's capable of complex and sophisticated behaviors, 0:04:54.944,0:04:58.094 it breeds quickly, and it's cheap. 0:04:58.094,0:04:59.889 But can an organism like this 0:04:59.889,0:05:03.732 teach us anything about emotion-like states? 0:05:03.732,0:05:07.032 Do these organisms even have emotion-like states, 0:05:07.032,0:05:10.395 or are they just little digital robots? 0:05:10.395,0:05:13.595 Charles Darwin believed that insects have emotion 0:05:13.595,0:05:16.145 and express them in their behaviors, as he wrote 0:05:16.145,0:05:21.338 in his 1872 monograph on the expression of the emotions in man and animals. 0:05:21.338,0:05:24.857 And my eponymous colleague, Seymour Benzer, believed it as well. 0:05:24.857,0:05:28.271 Seymour is the man that introduced the use of drosophila 0:05:28.271,0:05:31.794 here at CalTech in the '60s as a model organism 0:05:31.794,0:05:35.391 to study the connection between genes and behavior. 0:05:35.391,0:05:38.998 Seymour recruited me to CalTech in the late 1980s. 0:05:38.998,0:05:43.432 He was my Jedi and my rabbi while he was here, 0:05:43.432,0:05:45.820 and Seymour taught me both to love flies 0:05:45.820,0:05:48.869 and also to play with science. 0:05:48.869,0:05:51.985 So how do we ask this question? 0:05:51.985,0:05:56.045 It's one thing to believe that flies have emotion-like states, 0:05:56.045,0:05:59.208 but how do we actually find out whether that's true or not? 0:05:59.208,0:06:03.158 Now, in humans we often infer emotional states, 0:06:03.158,0:06:07.063 as you'll hear later today, from facial expressions. 0:06:07.063,0:06:10.783 However, it's a little difficult to do that in fruit flies. 0:06:10.783,0:06:14.096 (Laughter) 0:06:14.096,0:06:17.233 It's kind of like landing on Mars 0:06:17.233,0:06:19.938 and looking out the window of your spaceship 0:06:19.938,0:06:22.408 at all the little green men who are surrounding it 0:06:22.408,0:06:24.814 and trying to figure out, "How do I find out 0:06:24.814,0:06:27.169 if they have emotions or not?" 0:06:27.169,0:06:30.712 What can we do? It's not so easy. 0:06:30.712,0:06:32.897 Well, one of the ways that we can start 0:06:32.897,0:06:37.022 is to try to come up with some general characteristics 0:06:37.022,0:06:40.770 or properties of emotion-like states 0:06:40.770,0:06:44.234 such as arousal, and see if we can identify 0:06:44.234,0:06:49.610 any fly behaviors that might exhibit some of those properties. 0:06:49.610,0:06:52.430 So three important ones that I can think of 0:06:52.430,0:06:57.102 are persistence, gradations in intensity, and valence. 0:06:57.102,0:06:59.436 Persistence means long-lasting. 0:06:59.436,0:07:03.397 We all know that the stimulus that triggers an emotion 0:07:03.397,0:07:08.413 causes that emotion to last long after the stimulus is gone. 0:07:08.413,0:07:11.503 Gradations of intensity means what it sounds like. 0:07:11.503,0:07:16.086 You can dial up the intensity or dial down the intensity of an emotion. 0:07:16.086,0:07:18.686 If you're a little bit unhappy, the corners of your mouth 0:07:18.686,0:07:20.373 turn down and you sniffle, 0:07:20.373,0:07:23.511 and if you're very unhappy, tears pour down your face 0:07:23.511,0:07:25.343 and you might sob. 0:07:25.343,0:07:29.722 Valence means good or bad, positive or negative. 0:07:29.722,0:07:34.174 So we decided to see if flies could be provoked into showing 0:07:34.174,0:07:36.625 the kind of behavior that you see 0:07:36.625,0:07:39.435 by the proverbial wasp at the picnic table, 0:07:39.435,0:07:42.120 you know, the one that keeps coming back to your hamburger 0:07:42.120,0:07:44.649 the more vigorously you try to swat it away, 0:07:44.649,0:07:46.933 and it seems to keep getting irritated. 0:07:46.933,0:07:50.580 So we built a device, which we call a puff-o-mat, 0:07:50.580,0:07:54.925 in which we could deliver little brief air puffs to fruit flies 0:07:54.925,0:07:57.701 in these plastic tubes in our laboratory bench 0:07:57.701,0:07:59.426 and blow them away. 0:07:59.426,0:08:02.665 And what we found is that if we gave these flies 0:08:02.665,0:08:05.513 in the puff-o-mat several puffs in a row, 0:08:05.513,0:08:08.202 they became somewhat hyperactive 0:08:08.202,0:08:12.637 and continued to run around for some time after the air puffs actually stopped 0:08:12.637,0:08:15.501 and took a while to calm down. 0:08:15.501,0:08:17.690 So we quantified this behavior 0:08:17.690,0:08:20.702 using custom locomotor tracking software 0:08:20.702,0:08:23.502 developed with my collaborator Pietro Perona, 0:08:23.502,0:08:27.114 who's in the electrical engineering division here at CalTech. 0:08:27.114,0:08:29.928 And what this quantification showed us is that, 0:08:29.928,0:08:33.152 upon experiencing a train of these air puffs, 0:08:33.152,0:08:37.466 the flies appear to enter a kind of state of hyperactivity 0:08:37.466,0:08:40.064 which is persistent, long-lasting, 0:08:40.064,0:08:42.568 and also appears to be graded. 0:08:42.568,0:08:45.427 More puffs, or more intense puffs, 0:08:45.427,0:08:49.340 make the state last for a longer period of time. 0:08:49.340,0:08:51.376 So now we wanted to try to understand something 0:08:51.376,0:08:55.090 about what controls the duration of this state. 0:08:55.090,0:08:57.941 So we decided to use our puff-o-mat 0:08:57.941,0:08:59.996 and our automated tracking software 0:08:59.996,0:09:03.778 to screen through hundreds of lines of mutant fruit flies 0:09:03.778,0:09:08.857 to see if we could find any that showed abnormal responses to the air puffs. 0:09:08.857,0:09:11.204 And this is one of the great things about fruit flies. 0:09:11.204,0:09:13.997 There are repositories where you can just pick up the phone 0:09:13.997,0:09:17.638 and order hundreds of vials of flies of different mutants 0:09:17.638,0:09:19.810 and screen them in your assay and then find out 0:09:19.810,0:09:23.129 what gene is affected in the mutation. 0:09:23.129,0:09:26.641 So doing the screen, we discovered one mutant 0:09:26.641,0:09:30.115 that took much longer than normal to calm down 0:09:30.115,0:09:32.392 after the air puffs, 0:09:32.392,0:09:36.342 and when we examined the gene that was affected in this mutation, 0:09:36.342,0:09:39.947 it turned out to encode a dopamine receptor. 0:09:39.947,0:09:42.958 That's right -- flies, like people, have dopamine, 0:09:42.958,0:09:45.730 and it acts on their brains and on their synapses 0:09:45.730,0:09:48.280 through the same dopamine receptor molecules 0:09:48.280,0:09:50.669 that you and I have. 0:09:50.669,0:09:54.155 Dopamine plays a number of important functions in the brain, 0:09:54.155,0:09:57.268 including in attention, arousal, reward, 0:09:57.268,0:10:00.681 and disorders of the dopamine system have been linked 0:10:00.681,0:10:03.781 to a number of mental disorders including drug abuse, 0:10:03.781,0:10:08.015 Parkinson's disease, and ADHD. 0:10:08.015,0:10:10.805 Now, in genetics, it's a little counterintuitive. 0:10:10.805,0:10:14.065 We tend to infer the normal function of something 0:10:14.065,0:10:17.775 by what doesn't happen when we take it away, 0:10:17.775,0:10:20.778 by the opposite of what we see when we take it away. 0:10:20.778,0:10:23.791 So when we take away the dopamine receptor 0:10:23.791,0:10:26.348 and the flies take longer to calm down, 0:10:26.348,0:10:30.194 from that we infer that the normal function of this receptor and dopamine 0:10:30.194,0:10:34.679 is to cause the flies to calm down faster after the puff. 0:10:34.679,0:10:37.629 And that's a bit reminiscent of ADHD, 0:10:37.629,0:10:41.604 which has been linked to disorders of the dopamine system in humans. 0:10:41.604,0:10:46.210 Indeed, if we increase the levels of dopamine in normal flies 0:10:46.210,0:10:47.920 by feeding them cocaine 0:10:47.920,0:10:50.892 after getting the appropriate DEA license 0:10:50.892,0:10:54.892 — oh my God -- (Laughter) — 0:10:54.892,0:10:58.064 we find indeed that these cocaine-fed flies 0:10:58.064,0:11:01.106 calm down faster than normal flies do, 0:11:01.106,0:11:04.305 and that's also reminiscent of ADHD, 0:11:04.305,0:11:06.350 which is often treated with drugs like Ritalin 0:11:06.350,0:11:09.369 that act similarly to cocaine. 0:11:09.369,0:11:12.518 So slowly I began to realize that what started out 0:11:12.518,0:11:16.167 as a rather playful attempt to try to annoy fruit flies 0:11:16.167,0:11:20.143 might actually have some relevance to a human psychiatric disorder. 0:11:20.143,0:11:22.369 Now, how far does this analogy go? 0:11:22.369,0:11:25.491 As many of you know, individuals afflicted with ADHD 0:11:25.491,0:11:27.828 also have learning disabilities. 0:11:27.828,0:11:31.394 Is that true of our dopamine receptor mutant flies? 0:11:31.394,0:11:34.114 Remarkably, the answer is yes. 0:11:34.114,0:11:36.742 As Seymour showed back in the 1970s, 0:11:36.742,0:11:39.193 flies, like songbirds, as you just heard, 0:11:39.193,0:11:40.926 are capable of learning. 0:11:40.926,0:11:45.369 You can train a fly to avoid an odor, shown here in blue, 0:11:45.369,0:11:47.757 if you pair that odor with a shock. 0:11:47.757,0:11:51.141 Then when you give those trained flies the chance to choose 0:11:51.141,0:11:54.295 between a tube with the shock-paired odor and another odor, 0:11:54.295,0:11:58.495 it avoids the tube containing the blue odor that was paired with shock. 0:11:58.495,0:12:01.997 Well, if you do this test on dopamine receptor mutant flies, 0:12:01.997,0:12:04.462 they don't learn. Their learning score is zero. 0:12:04.462,0:12:08.273 They flunk out of CalTech. 0:12:08.273,0:12:13.021 So that means that these flies have two abnormalities, 0:12:13.021,0:12:16.071 or phenotypes, as we geneticists call them, 0:12:16.071,0:12:21.583 that one finds in ADHD: hyperactivity and learning disability. 0:12:21.583,0:12:25.946 Now what's the causal relationship, if anything, between these phenotypes? 0:12:25.946,0:12:29.859 In ADHD, it's often assumed that the hyperactivity 0:12:29.859,0:12:31.765 causes the learning disability. 0:12:31.765,0:12:35.484 The kids can't sit still long enough to focus, so they don't learn. 0:12:35.484,0:12:38.780 But it could equally be the case that it's the learning disabilities 0:12:38.780,0:12:40.652 that cause the hyperactivity. 0:12:40.652,0:12:45.122 Because the kids can't learn, they look for other things to distract their attention. 0:12:45.122,0:12:48.179 And a final possibility is that there's no relationship at all 0:12:48.179,0:12:50.583 between learning disabilities and hyperactivity, 0:12:50.583,0:12:55.498 but that they are caused by a common underlying mechanism in ADHD. 0:12:55.498,0:12:57.840 Now people have been wondering about this for a long time 0:12:57.840,0:13:01.328 in humans, but in flies we can actually test this. 0:13:01.328,0:13:04.412 And the way that we do this is to delve deeply into the mind 0:13:04.412,0:13:08.678 of the fly and begin to untangle its circuitry using genetics. 0:13:08.678,0:13:11.140 We take our dopamine receptor mutant flies 0:13:11.140,0:13:15.704 and we genetically restore, or cure, the dopamine receptor 0:13:15.704,0:13:18.939 by putting a good copy of the dopamine receptor gene 0:13:18.939,0:13:20.990 back into the fly brain. 0:13:20.990,0:13:24.825 But in each fly, we put it back only into certain neurons 0:13:24.825,0:13:28.539 and not in others, and then we test each of these flies 0:13:28.539,0:13:32.207 for their ability to learn and for hyperactivity. 0:13:32.207,0:13:37.025 Remarkably, we find we can completely dissociate these two abnormalities. 0:13:37.025,0:13:39.688 If we put a good copy of the dopamine receptor back 0:13:39.688,0:13:42.649 in this elliptical structure called the central complex, 0:13:42.649,0:13:46.726 the flies are no longer hyperactive, but they still can't learn. 0:13:46.726,0:13:49.452 On the other hand, if we put the receptor back in a different structure 0:13:49.452,0:13:50.970 called the mushroom body, 0:13:50.970,0:13:54.055 the learning deficit is rescued, the flies learn well, 0:13:54.055,0:13:55.885 but they're still hyperactive. 0:13:55.885,0:13:58.135 What that tells us is that dopamine 0:13:58.135,0:14:01.527 is not bathing the brain of these flies like soup. 0:14:01.527,0:14:04.689 Rather, it's acting to control two different functions 0:14:04.689,0:14:06.323 on two different circuits, 0:14:06.323,0:14:10.227 so the reason there are two things wrong with our dopamine receptor flies 0:14:10.227,0:14:14.402 is that the same receptor is controlling two different functions 0:14:14.402,0:14:17.265 in two different regions of the brain. 0:14:17.265,0:14:20.327 Whether the same thing is true in ADHD in humans 0:14:20.327,0:14:22.703 we don't know, but these kinds of results 0:14:22.703,0:14:26.180 should at least cause us to consider that possibility. 0:14:26.180,0:14:30.153 So these results make me and my colleagues more convinced than ever 0:14:30.153,0:14:33.565 that the brain is not a bag of chemical soup, 0:14:33.565,0:14:37.092 and it's a mistake to try to treat complex psychiatric disorders 0:14:37.092,0:14:39.803 just by changing the flavor of the soup. 0:14:39.803,0:14:44.020 What we need to do is to use our ingenuity and our scientific knowledge 0:14:44.020,0:14:46.728 to try to design a new generation of treatments 0:14:46.728,0:14:51.016 that are targeted to specific neurons and specific regions of the brain 0:14:51.016,0:14:54.354 that are affected in particular psychiatric disorders. 0:14:54.354,0:14:57.554 If we can do that, we may be able to cure these disorders 0:14:57.554,0:14:59.601 without the unpleasant side effects, 0:14:59.601,0:15:02.347 putting the oil back in our mental engines, 0:15:02.347,0:15:05.531 just where it's needed. Thank you very much.