[Script Info]
Title: 
[Events]
Format: Layer, Start, End, Style, Name, MarginL, MarginR, MarginV, Effect, Text
Dialogue: 0,0:00:00.63,0:00:03.86,Default,,0000,0000,0000,,So raise your hand if you know someone
Dialogue: 0,0:00:03.86,0:00:06.50,Default,,0000,0000,0000,,in your immediate family or circle of friends
Dialogue: 0,0:00:06.50,0:00:09.99,Default,,0000,0000,0000,,who suffers from some form of mental illness.
Dialogue: 0,0:00:09.99,0:00:12.78,Default,,0000,0000,0000,,Yeah. I thought so. Not surprised.
Dialogue: 0,0:00:12.78,0:00:15.07,Default,,0000,0000,0000,,And raise your hand if you think that
Dialogue: 0,0:00:15.07,0:00:17.90,Default,,0000,0000,0000,,basic research on fruit flies has anything to do
Dialogue: 0,0:00:17.90,0:00:22.36,Default,,0000,0000,0000,,with understanding mental illness in humans.
Dialogue: 0,0:00:22.36,0:00:25.15,Default,,0000,0000,0000,,Yeah. I thought so. I'm also not surprised.
Dialogue: 0,0:00:25.15,0:00:28.47,Default,,0000,0000,0000,,I can see I've got my work cut out for me here.
Dialogue: 0,0:00:28.47,0:00:31.06,Default,,0000,0000,0000,,As we heard from Dr. Insel this morning,
Dialogue: 0,0:00:31.06,0:00:35.27,Default,,0000,0000,0000,,psychiatric disorders like autism, depression and schizophrenia
Dialogue: 0,0:00:35.27,0:00:38.15,Default,,0000,0000,0000,,take a terrible toll on human suffering.
Dialogue: 0,0:00:38.15,0:00:41.36,Default,,0000,0000,0000,,We know much less about their treatment
Dialogue: 0,0:00:41.36,0:00:43.97,Default,,0000,0000,0000,,and the understanding of their basic mechanisms
Dialogue: 0,0:00:43.97,0:00:46.59,Default,,0000,0000,0000,,than we do about diseases of the body.
Dialogue: 0,0:00:46.59,0:00:49.23,Default,,0000,0000,0000,,Think about it: In 2013,
Dialogue: 0,0:00:49.23,0:00:51.18,Default,,0000,0000,0000,,the second decade of the millennium,
Dialogue: 0,0:00:51.18,0:00:53.55,Default,,0000,0000,0000,,if you're concerned about a cancer diagnosis
Dialogue: 0,0:00:53.55,0:00:56.07,Default,,0000,0000,0000,,and you go to your doctor, you get bone scans,
Dialogue: 0,0:00:56.07,0:00:58.100,Default,,0000,0000,0000,,biopsies and blood tests.
Dialogue: 0,0:00:58.100,0:01:02.86,Default,,0000,0000,0000,,In 2013, if you're concerned about a depression diagnosis,
Dialogue: 0,0:01:02.86,0:01:04.82,Default,,0000,0000,0000,,you go to your doctor, and what do you get?
Dialogue: 0,0:01:04.82,0:01:06.81,Default,,0000,0000,0000,,A questionnaire.
Dialogue: 0,0:01:06.81,0:01:09.24,Default,,0000,0000,0000,,Now, part of the reason for this is that we have
Dialogue: 0,0:01:09.24,0:01:13.06,Default,,0000,0000,0000,,an oversimplified and increasingly outmoded view
Dialogue: 0,0:01:13.06,0:01:16.95,Default,,0000,0000,0000,,of the biological basis of psychiatric disorders.
Dialogue: 0,0:01:16.95,0:01:18.19,Default,,0000,0000,0000,,We tend to view them --
Dialogue: 0,0:01:18.19,0:01:21.04,Default,,0000,0000,0000,,and the popular press aids and abets this view --
Dialogue: 0,0:01:21.04,0:01:24.05,Default,,0000,0000,0000,,as chemical imbalances in the brain,
Dialogue: 0,0:01:24.05,0:01:27.74,Default,,0000,0000,0000,,as if the brain were some kind of bag of chemical soup
Dialogue: 0,0:01:27.74,0:01:31.94,Default,,0000,0000,0000,,full of dopamine, serotonin and norepinephrine.
Dialogue: 0,0:01:31.94,0:01:34.26,Default,,0000,0000,0000,,This view is conditioned by the fact
Dialogue: 0,0:01:34.26,0:01:37.67,Default,,0000,0000,0000,,that many of the drugs that are prescribed to treat these disorders,
Dialogue: 0,0:01:37.67,0:01:42.34,Default,,0000,0000,0000,,like Prozac, act by globally changing brain chemistry,
Dialogue: 0,0:01:42.34,0:01:46.32,Default,,0000,0000,0000,,as if the brain were indeed a bag of chemical soup.
Dialogue: 0,0:01:46.32,0:01:48.22,Default,,0000,0000,0000,,But that can't be the answer,
Dialogue: 0,0:01:48.22,0:01:51.46,Default,,0000,0000,0000,,because these drugs actually don't work all that well.
Dialogue: 0,0:01:51.46,0:01:54.63,Default,,0000,0000,0000,,A lot of people won't take them, or stop taking them,
Dialogue: 0,0:01:54.63,0:01:57.29,Default,,0000,0000,0000,,because of their unpleasant side effects.
Dialogue: 0,0:01:57.29,0:01:59.35,Default,,0000,0000,0000,,These drugs have so many side effects
Dialogue: 0,0:01:59.35,0:02:03.30,Default,,0000,0000,0000,,because using them to treat a complex psychiatric disorder
Dialogue: 0,0:02:03.30,0:02:05.99,Default,,0000,0000,0000,,is a bit like trying to change your engine oil
Dialogue: 0,0:02:05.99,0:02:10.11,Default,,0000,0000,0000,,by opening a can and pouring it all over the engine block.
Dialogue: 0,0:02:10.11,0:02:12.26,Default,,0000,0000,0000,,Some of it will dribble into the right place,
Dialogue: 0,0:02:12.26,0:02:15.36,Default,,0000,0000,0000,,but a lot of it will do more harm than good.
Dialogue: 0,0:02:15.36,0:02:17.60,Default,,0000,0000,0000,,Now, an emerging view
Dialogue: 0,0:02:17.60,0:02:20.55,Default,,0000,0000,0000,,that you also heard about from Dr. Insel this morning,
Dialogue: 0,0:02:20.55,0:02:23.12,Default,,0000,0000,0000,,is that psychiatric disorders are actually
Dialogue: 0,0:02:23.12,0:02:26.59,Default,,0000,0000,0000,,disturbances of neural circuits that mediate
Dialogue: 0,0:02:26.59,0:02:30.11,Default,,0000,0000,0000,,emotion, mood and affect.
Dialogue: 0,0:02:30.11,0:02:31.87,Default,,0000,0000,0000,,When we think about cognition,
Dialogue: 0,0:02:31.87,0:02:35.45,Default,,0000,0000,0000,,we analogize the brain to a computer. That's no problem.
Dialogue: 0,0:02:35.45,0:02:38.03,Default,,0000,0000,0000,,Well it turns out that the computer analogy
Dialogue: 0,0:02:38.03,0:02:40.41,Default,,0000,0000,0000,,is just as valid for emotion.
Dialogue: 0,0:02:40.41,0:02:43.20,Default,,0000,0000,0000,,It's just that we don't tend to think about it that way.
Dialogue: 0,0:02:43.20,0:02:46.48,Default,,0000,0000,0000,,But we know much less about the circuit basis
Dialogue: 0,0:02:46.48,0:02:48.38,Default,,0000,0000,0000,,of psychiatric disorders
Dialogue: 0,0:02:48.38,0:02:50.45,Default,,0000,0000,0000,,because of the overwhelming dominance
Dialogue: 0,0:02:50.45,0:02:53.80,Default,,0000,0000,0000,,of this chemical imbalance hypothesis.
Dialogue: 0,0:02:53.80,0:02:57.63,Default,,0000,0000,0000,,Now, it's not that chemicals are not important
Dialogue: 0,0:02:57.63,0:02:59.16,Default,,0000,0000,0000,,in psychiatric disorders.
Dialogue: 0,0:02:59.16,0:03:03.14,Default,,0000,0000,0000,,It's just that they don't bathe the brain like soup.
Dialogue: 0,0:03:03.14,0:03:06.79,Default,,0000,0000,0000,,Rather, they're released in very specific locations
Dialogue: 0,0:03:06.79,0:03:09.51,Default,,0000,0000,0000,,and they act on specific synapses
Dialogue: 0,0:03:09.51,0:03:13.20,Default,,0000,0000,0000,,to change the flow of information in the brain.
Dialogue: 0,0:03:13.20,0:03:15.64,Default,,0000,0000,0000,,So if we ever really want to understand
Dialogue: 0,0:03:15.64,0:03:18.34,Default,,0000,0000,0000,,the biological basis of psychiatric disorders,
Dialogue: 0,0:03:18.34,0:03:21.37,Default,,0000,0000,0000,,we need to pinpoint these locations in the brain
Dialogue: 0,0:03:21.37,0:03:23.11,Default,,0000,0000,0000,,where these chemicals act.
Dialogue: 0,0:03:23.11,0:03:26.59,Default,,0000,0000,0000,,Otherwise, we're going to keep pouring oil all over our mental engines
Dialogue: 0,0:03:26.59,0:03:29.54,Default,,0000,0000,0000,,and suffering the consequences.
Dialogue: 0,0:03:29.54,0:03:32.60,Default,,0000,0000,0000,,Now to begin to overcome our ignorance
Dialogue: 0,0:03:32.60,0:03:36.14,Default,,0000,0000,0000,,of the role of brain chemistry in brain circuitry,
Dialogue: 0,0:03:36.14,0:03:38.82,Default,,0000,0000,0000,,it's helpful to work on what we biologists call
Dialogue: 0,0:03:38.82,0:03:40.40,Default,,0000,0000,0000,,"model organisms,"
Dialogue: 0,0:03:40.40,0:03:43.73,Default,,0000,0000,0000,,animals like fruit flies and laboratory mice,
Dialogue: 0,0:03:43.73,0:03:47.15,Default,,0000,0000,0000,,in which we can apply powerful genetic techniques
Dialogue: 0,0:03:47.15,0:03:50.78,Default,,0000,0000,0000,,to molecularly identify and pinpoint
Dialogue: 0,0:03:50.78,0:03:52.34,Default,,0000,0000,0000,,specific classes of neurons,
Dialogue: 0,0:03:52.34,0:03:55.24,Default,,0000,0000,0000,,as you heard about in Allan Jones's talk this morning.
Dialogue: 0,0:03:55.24,0:03:57.71,Default,,0000,0000,0000,,Moreover, once we can do that,
Dialogue: 0,0:03:57.71,0:04:00.46,Default,,0000,0000,0000,,we can actually activate specific neurons
Dialogue: 0,0:04:00.46,0:04:04.67,Default,,0000,0000,0000,,or we can destroy or inhibit the activity of those neurons.
Dialogue: 0,0:04:04.67,0:04:07.38,Default,,0000,0000,0000,,So if we inhibit a particular type of neuron,
Dialogue: 0,0:04:07.38,0:04:09.84,Default,,0000,0000,0000,,and we find that a behavior is blocked,
Dialogue: 0,0:04:09.84,0:04:12.06,Default,,0000,0000,0000,,we can conclude that those neurons
Dialogue: 0,0:04:12.06,0:04:15.02,Default,,0000,0000,0000,,are necessary for that behavior.
Dialogue: 0,0:04:15.02,0:04:17.40,Default,,0000,0000,0000,,On the other hand, if we activate a group of neurons
Dialogue: 0,0:04:17.40,0:04:20.22,Default,,0000,0000,0000,,and we find that that produces the behavior,
Dialogue: 0,0:04:20.22,0:04:24.29,Default,,0000,0000,0000,,we can conclude that those neurons are sufficient for the behavior.
Dialogue: 0,0:04:24.29,0:04:27.30,Default,,0000,0000,0000,,So in this way, by doing this kind of test,
Dialogue: 0,0:04:27.30,0:04:30.82,Default,,0000,0000,0000,,we can draw cause and effect relationships
Dialogue: 0,0:04:30.82,0:04:33.18,Default,,0000,0000,0000,,between the activity of specific neurons
Dialogue: 0,0:04:33.18,0:04:36.09,Default,,0000,0000,0000,,in particular circuits and particular behaviors,
Dialogue: 0,0:04:36.09,0:04:38.53,Default,,0000,0000,0000,,something that is extremely difficult, if not impossible,
Dialogue: 0,0:04:38.53,0:04:43.58,Default,,0000,0000,0000,,to do right now in humans.
Dialogue: 0,0:04:43.58,0:04:46.42,Default,,0000,0000,0000,,But can an organism like a fruit fly, which is --
Dialogue: 0,0:04:46.42,0:04:48.62,Default,,0000,0000,0000,,it's a great model organism
Dialogue: 0,0:04:48.62,0:04:51.16,Default,,0000,0000,0000,,because it's got a small brain,
Dialogue: 0,0:04:51.16,0:04:54.94,Default,,0000,0000,0000,,it's capable of complex and sophisticated behaviors,
Dialogue: 0,0:04:54.94,0:04:58.09,Default,,0000,0000,0000,,it breeds quickly, and it's cheap.
Dialogue: 0,0:04:58.09,0:04:59.89,Default,,0000,0000,0000,,But can an organism like this
Dialogue: 0,0:04:59.89,0:05:03.73,Default,,0000,0000,0000,,teach us anything about emotion-like states?
Dialogue: 0,0:05:03.73,0:05:07.03,Default,,0000,0000,0000,,Do these organisms even have emotion-like states,
Dialogue: 0,0:05:07.03,0:05:10.40,Default,,0000,0000,0000,,or are they just little digital robots?
Dialogue: 0,0:05:10.40,0:05:13.60,Default,,0000,0000,0000,,Charles Darwin believed that insects have emotion
Dialogue: 0,0:05:13.60,0:05:16.14,Default,,0000,0000,0000,,and express them in their behaviors, as he wrote
Dialogue: 0,0:05:16.14,0:05:21.34,Default,,0000,0000,0000,,in his 1872 monograph on the expression of the emotions in man and animals.
Dialogue: 0,0:05:21.34,0:05:24.86,Default,,0000,0000,0000,,And my eponymous colleague, Seymour Benzer, believed it as well.
Dialogue: 0,0:05:24.86,0:05:28.27,Default,,0000,0000,0000,,Seymour is the man that introduced the use of drosophila
Dialogue: 0,0:05:28.27,0:05:31.79,Default,,0000,0000,0000,,here at CalTech in the '60s as a model organism
Dialogue: 0,0:05:31.79,0:05:35.39,Default,,0000,0000,0000,,to study the connection between genes and behavior.
Dialogue: 0,0:05:35.39,0:05:38.100,Default,,0000,0000,0000,,Seymour recruited me to CalTech in the late 1980s.
Dialogue: 0,0:05:38.100,0:05:43.43,Default,,0000,0000,0000,,He was my Jedi and my rabbi while he was here,
Dialogue: 0,0:05:43.43,0:05:45.82,Default,,0000,0000,0000,,and Seymour taught me both to love flies
Dialogue: 0,0:05:45.82,0:05:48.87,Default,,0000,0000,0000,,and also to play with science.
Dialogue: 0,0:05:48.87,0:05:51.98,Default,,0000,0000,0000,,So how do we ask this question?
Dialogue: 0,0:05:51.98,0:05:56.04,Default,,0000,0000,0000,,It's one thing to believe that flies have emotion-like states,
Dialogue: 0,0:05:56.04,0:05:59.21,Default,,0000,0000,0000,,but how do we actually find out whether that's true or not?
Dialogue: 0,0:05:59.21,0:06:03.16,Default,,0000,0000,0000,,Now, in humans we often infer emotional states,
Dialogue: 0,0:06:03.16,0:06:07.06,Default,,0000,0000,0000,,as you'll hear later today, from facial expressions.
Dialogue: 0,0:06:07.06,0:06:10.78,Default,,0000,0000,0000,,However, it's a little difficult to do that in fruit flies.
Dialogue: 0,0:06:10.78,0:06:14.10,Default,,0000,0000,0000,,(Laughter)
Dialogue: 0,0:06:14.10,0:06:17.23,Default,,0000,0000,0000,,It's kind of like landing on Mars
Dialogue: 0,0:06:17.23,0:06:19.94,Default,,0000,0000,0000,,and looking out the window of your spaceship
Dialogue: 0,0:06:19.94,0:06:22.41,Default,,0000,0000,0000,,at all the little green men who are surrounding it
Dialogue: 0,0:06:22.41,0:06:24.81,Default,,0000,0000,0000,,and trying to figure out, "How do I find out
Dialogue: 0,0:06:24.81,0:06:27.17,Default,,0000,0000,0000,,if they have emotions or not?"
Dialogue: 0,0:06:27.17,0:06:30.71,Default,,0000,0000,0000,,What can we do? It's not so easy.
Dialogue: 0,0:06:30.71,0:06:32.90,Default,,0000,0000,0000,,Well, one of the ways that we can start
Dialogue: 0,0:06:32.90,0:06:37.02,Default,,0000,0000,0000,,is to try to come up with some general characteristics
Dialogue: 0,0:06:37.02,0:06:40.77,Default,,0000,0000,0000,,or properties of emotion-like states
Dialogue: 0,0:06:40.77,0:06:44.23,Default,,0000,0000,0000,,such as arousal, and see if we can identify
Dialogue: 0,0:06:44.23,0:06:49.61,Default,,0000,0000,0000,,any fly behaviors that might exhibit some of those properties.
Dialogue: 0,0:06:49.61,0:06:52.43,Default,,0000,0000,0000,,So three important ones that I can think of
Dialogue: 0,0:06:52.43,0:06:57.10,Default,,0000,0000,0000,,are persistence, gradations in intensity, and valence.
Dialogue: 0,0:06:57.10,0:06:59.44,Default,,0000,0000,0000,,Persistence means long-lasting.
Dialogue: 0,0:06:59.44,0:07:03.40,Default,,0000,0000,0000,,We all know that the stimulus that triggers an emotion
Dialogue: 0,0:07:03.40,0:07:08.41,Default,,0000,0000,0000,,causes that emotion to last long after the stimulus is gone.
Dialogue: 0,0:07:08.41,0:07:11.50,Default,,0000,0000,0000,,Gradations of intensity means what it sounds like.
Dialogue: 0,0:07:11.50,0:07:16.09,Default,,0000,0000,0000,,You can dial up the intensity or dial down the intensity of an emotion.
Dialogue: 0,0:07:16.09,0:07:18.69,Default,,0000,0000,0000,,If you're a little bit unhappy, the corners of your mouth
Dialogue: 0,0:07:18.69,0:07:20.37,Default,,0000,0000,0000,,turn down and you sniffle,
Dialogue: 0,0:07:20.37,0:07:23.51,Default,,0000,0000,0000,,and if you're very unhappy, tears pour down your face
Dialogue: 0,0:07:23.51,0:07:25.34,Default,,0000,0000,0000,,and you might sob.
Dialogue: 0,0:07:25.34,0:07:29.72,Default,,0000,0000,0000,,Valence means good or bad, positive or negative.
Dialogue: 0,0:07:29.72,0:07:34.17,Default,,0000,0000,0000,,So we decided to see if flies could be provoked into showing
Dialogue: 0,0:07:34.17,0:07:36.62,Default,,0000,0000,0000,,the kind of behavior that you see
Dialogue: 0,0:07:36.62,0:07:39.44,Default,,0000,0000,0000,,by the proverbial wasp at the picnic table,
Dialogue: 0,0:07:39.44,0:07:42.12,Default,,0000,0000,0000,,you know, the one that keeps coming back to your hamburger
Dialogue: 0,0:07:42.12,0:07:44.65,Default,,0000,0000,0000,,the more vigorously you try to swat it away,
Dialogue: 0,0:07:44.65,0:07:46.93,Default,,0000,0000,0000,,and it seems to keep getting irritated.
Dialogue: 0,0:07:46.93,0:07:50.58,Default,,0000,0000,0000,,So we built a device, which we call a puff-o-mat,
Dialogue: 0,0:07:50.58,0:07:54.92,Default,,0000,0000,0000,,in which we could deliver little brief air puffs to fruit flies
Dialogue: 0,0:07:54.92,0:07:57.70,Default,,0000,0000,0000,,in these plastic tubes in our laboratory bench
Dialogue: 0,0:07:57.70,0:07:59.43,Default,,0000,0000,0000,,and blow them away.
Dialogue: 0,0:07:59.43,0:08:02.66,Default,,0000,0000,0000,,And what we found is that if we gave these flies
Dialogue: 0,0:08:02.66,0:08:05.51,Default,,0000,0000,0000,,in the puff-o-mat several puffs in a row,
Dialogue: 0,0:08:05.51,0:08:08.20,Default,,0000,0000,0000,,they became somewhat hyperactive
Dialogue: 0,0:08:08.20,0:08:12.64,Default,,0000,0000,0000,,and continued to run around for some time after the air puffs actually stopped
Dialogue: 0,0:08:12.64,0:08:15.50,Default,,0000,0000,0000,,and took a while to calm down.
Dialogue: 0,0:08:15.50,0:08:17.69,Default,,0000,0000,0000,,So we quantified this behavior
Dialogue: 0,0:08:17.69,0:08:20.70,Default,,0000,0000,0000,,using custom locomotor tracking software
Dialogue: 0,0:08:20.70,0:08:23.50,Default,,0000,0000,0000,,developed with my collaborator Pietro Perona,
Dialogue: 0,0:08:23.50,0:08:27.11,Default,,0000,0000,0000,,who's in the electrical engineering division here at CalTech.
Dialogue: 0,0:08:27.11,0:08:29.93,Default,,0000,0000,0000,,And what this quantification showed us is that,
Dialogue: 0,0:08:29.93,0:08:33.15,Default,,0000,0000,0000,,upon experiencing a train of these air puffs,
Dialogue: 0,0:08:33.15,0:08:37.47,Default,,0000,0000,0000,,the flies appear to enter a kind of state of hyperactivity
Dialogue: 0,0:08:37.47,0:08:40.06,Default,,0000,0000,0000,,which is persistent, long-lasting,
Dialogue: 0,0:08:40.06,0:08:42.57,Default,,0000,0000,0000,,and also appears to be graded.
Dialogue: 0,0:08:42.57,0:08:45.43,Default,,0000,0000,0000,,More puffs, or more intense puffs,
Dialogue: 0,0:08:45.43,0:08:49.34,Default,,0000,0000,0000,,make the state last for a longer period of time.
Dialogue: 0,0:08:49.34,0:08:51.38,Default,,0000,0000,0000,,So now we wanted to try to understand something
Dialogue: 0,0:08:51.38,0:08:55.09,Default,,0000,0000,0000,,about what controls the duration of this state.
Dialogue: 0,0:08:55.09,0:08:57.94,Default,,0000,0000,0000,,So we decided to use our puff-o-mat
Dialogue: 0,0:08:57.94,0:08:59.100,Default,,0000,0000,0000,,and our automated tracking software
Dialogue: 0,0:08:59.100,0:09:03.78,Default,,0000,0000,0000,,to screen through hundreds of lines of mutant fruit flies
Dialogue: 0,0:09:03.78,0:09:08.86,Default,,0000,0000,0000,,to see if we could find any that showed abnormal responses to the air puffs.
Dialogue: 0,0:09:08.86,0:09:11.20,Default,,0000,0000,0000,,And this is one of the great things about fruit flies.
Dialogue: 0,0:09:11.20,0:09:13.100,Default,,0000,0000,0000,,There are repositories where you can just pick up the phone
Dialogue: 0,0:09:13.100,0:09:17.64,Default,,0000,0000,0000,,and order hundreds of vials of flies of different mutants
Dialogue: 0,0:09:17.64,0:09:19.81,Default,,0000,0000,0000,,and screen them in your assay and then find out
Dialogue: 0,0:09:19.81,0:09:23.13,Default,,0000,0000,0000,,what gene is affected in the mutation.
Dialogue: 0,0:09:23.13,0:09:26.64,Default,,0000,0000,0000,,So doing the screen, we discovered one mutant
Dialogue: 0,0:09:26.64,0:09:30.12,Default,,0000,0000,0000,,that took much longer than normal to calm down
Dialogue: 0,0:09:30.12,0:09:32.39,Default,,0000,0000,0000,,after the air puffs,
Dialogue: 0,0:09:32.39,0:09:36.34,Default,,0000,0000,0000,,and when we examined the gene that was affected in this mutation,
Dialogue: 0,0:09:36.34,0:09:39.95,Default,,0000,0000,0000,,it turned out to encode a dopamine receptor.
Dialogue: 0,0:09:39.95,0:09:42.96,Default,,0000,0000,0000,,That's right -- flies, like people, have dopamine,
Dialogue: 0,0:09:42.96,0:09:45.73,Default,,0000,0000,0000,,and it acts on their brains and on their synapses
Dialogue: 0,0:09:45.73,0:09:48.28,Default,,0000,0000,0000,,through the same dopamine receptor molecules
Dialogue: 0,0:09:48.28,0:09:50.67,Default,,0000,0000,0000,,that you and I have.
Dialogue: 0,0:09:50.67,0:09:54.16,Default,,0000,0000,0000,,Dopamine plays a number of important functions in the brain,
Dialogue: 0,0:09:54.16,0:09:57.27,Default,,0000,0000,0000,,including in attention, arousal, reward,
Dialogue: 0,0:09:57.27,0:10:00.68,Default,,0000,0000,0000,,and disorders of the dopamine system have been linked
Dialogue: 0,0:10:00.68,0:10:03.78,Default,,0000,0000,0000,,to a number of mental disorders including drug abuse,
Dialogue: 0,0:10:03.78,0:10:08.02,Default,,0000,0000,0000,,Parkinson's disease, and ADHD.
Dialogue: 0,0:10:08.02,0:10:10.80,Default,,0000,0000,0000,,Now, in genetics, it's a little counterintuitive.
Dialogue: 0,0:10:10.80,0:10:14.06,Default,,0000,0000,0000,,We tend to infer the normal function of something
Dialogue: 0,0:10:14.06,0:10:17.78,Default,,0000,0000,0000,,by what doesn't happen when we take it away,
Dialogue: 0,0:10:17.78,0:10:20.78,Default,,0000,0000,0000,,by the opposite of what we see when we take it away.
Dialogue: 0,0:10:20.78,0:10:23.79,Default,,0000,0000,0000,,So when we take away the dopamine receptor
Dialogue: 0,0:10:23.79,0:10:26.35,Default,,0000,0000,0000,,and the flies take longer to calm down,
Dialogue: 0,0:10:26.35,0:10:30.19,Default,,0000,0000,0000,,from that we infer that the normal function of this receptor and dopamine
Dialogue: 0,0:10:30.19,0:10:34.68,Default,,0000,0000,0000,,is to cause the flies to calm down faster after the puff.
Dialogue: 0,0:10:34.68,0:10:37.63,Default,,0000,0000,0000,,And that's a bit reminiscent of ADHD,
Dialogue: 0,0:10:37.63,0:10:41.60,Default,,0000,0000,0000,,which has been linked to disorders of the dopamine system in humans.
Dialogue: 0,0:10:41.60,0:10:46.21,Default,,0000,0000,0000,,Indeed, if we increase the levels of dopamine in normal flies
Dialogue: 0,0:10:46.21,0:10:47.92,Default,,0000,0000,0000,,by feeding them cocaine
Dialogue: 0,0:10:47.92,0:10:50.89,Default,,0000,0000,0000,,after getting the appropriate DEA license
Dialogue: 0,0:10:50.89,0:10:54.89,Default,,0000,0000,0000,,— oh my God -- (Laughter) —
Dialogue: 0,0:10:54.89,0:10:58.06,Default,,0000,0000,0000,,we find indeed that these cocaine-fed flies
Dialogue: 0,0:10:58.06,0:11:01.11,Default,,0000,0000,0000,,calm down faster than normal flies do,
Dialogue: 0,0:11:01.11,0:11:04.30,Default,,0000,0000,0000,,and that's also reminiscent of ADHD,
Dialogue: 0,0:11:04.30,0:11:06.35,Default,,0000,0000,0000,,which is often treated with drugs like Ritalin
Dialogue: 0,0:11:06.35,0:11:09.37,Default,,0000,0000,0000,,that act similarly to cocaine.
Dialogue: 0,0:11:09.37,0:11:12.52,Default,,0000,0000,0000,,So slowly I began to realize that what started out
Dialogue: 0,0:11:12.52,0:11:16.17,Default,,0000,0000,0000,,as a rather playful attempt to try to annoy fruit flies
Dialogue: 0,0:11:16.17,0:11:20.14,Default,,0000,0000,0000,,might actually have some relevance to a human psychiatric disorder.
Dialogue: 0,0:11:20.14,0:11:22.37,Default,,0000,0000,0000,,Now, how far does this analogy go?
Dialogue: 0,0:11:22.37,0:11:25.49,Default,,0000,0000,0000,,As many of you know, individuals afflicted with ADHD
Dialogue: 0,0:11:25.49,0:11:27.83,Default,,0000,0000,0000,,also have learning disabilities.
Dialogue: 0,0:11:27.83,0:11:31.39,Default,,0000,0000,0000,,Is that true of our dopamine receptor mutant flies?
Dialogue: 0,0:11:31.39,0:11:34.11,Default,,0000,0000,0000,,Remarkably, the answer is yes.
Dialogue: 0,0:11:34.11,0:11:36.74,Default,,0000,0000,0000,,As Seymour showed back in the 1970s,
Dialogue: 0,0:11:36.74,0:11:39.19,Default,,0000,0000,0000,,flies, like songbirds, as you just heard,
Dialogue: 0,0:11:39.19,0:11:40.93,Default,,0000,0000,0000,,are capable of learning.
Dialogue: 0,0:11:40.93,0:11:45.37,Default,,0000,0000,0000,,You can train a fly to avoid an odor, shown here in blue,
Dialogue: 0,0:11:45.37,0:11:47.76,Default,,0000,0000,0000,,if you pair that odor with a shock.
Dialogue: 0,0:11:47.76,0:11:51.14,Default,,0000,0000,0000,,Then when you give those trained flies the chance to choose
Dialogue: 0,0:11:51.14,0:11:54.30,Default,,0000,0000,0000,,between a tube with the shock-paired odor and another odor,
Dialogue: 0,0:11:54.30,0:11:58.50,Default,,0000,0000,0000,,it avoids the tube containing the blue odor that was paired with shock.
Dialogue: 0,0:11:58.50,0:12:01.100,Default,,0000,0000,0000,,Well, if you do this test on dopamine receptor mutant flies,
Dialogue: 0,0:12:01.100,0:12:04.46,Default,,0000,0000,0000,,they don't learn. Their learning score is zero.
Dialogue: 0,0:12:04.46,0:12:08.27,Default,,0000,0000,0000,,They flunk out of CalTech.
Dialogue: 0,0:12:08.27,0:12:13.02,Default,,0000,0000,0000,,So that means that these flies have two abnormalities,
Dialogue: 0,0:12:13.02,0:12:16.07,Default,,0000,0000,0000,,or phenotypes, as we geneticists call them,
Dialogue: 0,0:12:16.07,0:12:21.58,Default,,0000,0000,0000,,that one finds in ADHD: hyperactivity and learning disability.
Dialogue: 0,0:12:21.58,0:12:25.95,Default,,0000,0000,0000,,Now what's the causal relationship, if anything, between these phenotypes?
Dialogue: 0,0:12:25.95,0:12:29.86,Default,,0000,0000,0000,,In ADHD, it's often assumed that the hyperactivity
Dialogue: 0,0:12:29.86,0:12:31.76,Default,,0000,0000,0000,,causes the learning disability.
Dialogue: 0,0:12:31.76,0:12:35.48,Default,,0000,0000,0000,,The kids can't sit still long enough to focus, so they don't learn.
Dialogue: 0,0:12:35.48,0:12:38.78,Default,,0000,0000,0000,,But it could equally be the case that it's the learning disabilities
Dialogue: 0,0:12:38.78,0:12:40.65,Default,,0000,0000,0000,,that cause the hyperactivity.
Dialogue: 0,0:12:40.65,0:12:45.12,Default,,0000,0000,0000,,Because the kids can't learn, they look for other things to distract their attention.
Dialogue: 0,0:12:45.12,0:12:48.18,Default,,0000,0000,0000,,And a final possibility is that there's no relationship at all
Dialogue: 0,0:12:48.18,0:12:50.58,Default,,0000,0000,0000,,between learning disabilities and hyperactivity,
Dialogue: 0,0:12:50.58,0:12:55.50,Default,,0000,0000,0000,,but that they are caused by a common underlying mechanism in ADHD.
Dialogue: 0,0:12:55.50,0:12:57.84,Default,,0000,0000,0000,,Now people have been wondering about this for a long time
Dialogue: 0,0:12:57.84,0:13:01.33,Default,,0000,0000,0000,,in humans, but in flies we can actually test this.
Dialogue: 0,0:13:01.33,0:13:04.41,Default,,0000,0000,0000,,And the way that we do this is to delve deeply into the mind
Dialogue: 0,0:13:04.41,0:13:08.68,Default,,0000,0000,0000,,of the fly and begin to untangle its circuitry using genetics.
Dialogue: 0,0:13:08.68,0:13:11.14,Default,,0000,0000,0000,,We take our dopamine receptor mutant flies
Dialogue: 0,0:13:11.14,0:13:15.70,Default,,0000,0000,0000,,and we genetically restore, or cure, the dopamine receptor
Dialogue: 0,0:13:15.70,0:13:18.94,Default,,0000,0000,0000,,by putting a good copy of the dopamine receptor gene
Dialogue: 0,0:13:18.94,0:13:20.99,Default,,0000,0000,0000,,back into the fly brain.
Dialogue: 0,0:13:20.99,0:13:24.82,Default,,0000,0000,0000,,But in each fly, we put it back only into certain neurons
Dialogue: 0,0:13:24.82,0:13:28.54,Default,,0000,0000,0000,,and not in others, and then we test each of these flies
Dialogue: 0,0:13:28.54,0:13:32.21,Default,,0000,0000,0000,,for their ability to learn and for hyperactivity.
Dialogue: 0,0:13:32.21,0:13:37.02,Default,,0000,0000,0000,,Remarkably, we find we can completely dissociate these two abnormalities.
Dialogue: 0,0:13:37.02,0:13:39.69,Default,,0000,0000,0000,,If we put a good copy of the dopamine receptor back
Dialogue: 0,0:13:39.69,0:13:42.65,Default,,0000,0000,0000,,in this elliptical structure called the central complex,
Dialogue: 0,0:13:42.65,0:13:46.73,Default,,0000,0000,0000,,the flies are no longer hyperactive, but they still can't learn.
Dialogue: 0,0:13:46.73,0:13:49.45,Default,,0000,0000,0000,,On the other hand, if we put the receptor back in a different structure
Dialogue: 0,0:13:49.45,0:13:50.97,Default,,0000,0000,0000,,called the mushroom body,
Dialogue: 0,0:13:50.97,0:13:54.06,Default,,0000,0000,0000,,the learning deficit is rescued, the flies learn well,
Dialogue: 0,0:13:54.06,0:13:55.88,Default,,0000,0000,0000,,but they're still hyperactive.
Dialogue: 0,0:13:55.88,0:13:58.14,Default,,0000,0000,0000,,What that tells us is that dopamine
Dialogue: 0,0:13:58.14,0:14:01.53,Default,,0000,0000,0000,,is not bathing the brain of these flies like soup.
Dialogue: 0,0:14:01.53,0:14:04.69,Default,,0000,0000,0000,,Rather, it's acting to control two different functions
Dialogue: 0,0:14:04.69,0:14:06.32,Default,,0000,0000,0000,,on two different circuits,
Dialogue: 0,0:14:06.32,0:14:10.23,Default,,0000,0000,0000,,so the reason there are two things wrong with our dopamine receptor flies
Dialogue: 0,0:14:10.23,0:14:14.40,Default,,0000,0000,0000,,is that the same receptor is controlling two different functions
Dialogue: 0,0:14:14.40,0:14:17.26,Default,,0000,0000,0000,,in two different regions of the brain.
Dialogue: 0,0:14:17.26,0:14:20.33,Default,,0000,0000,0000,,Whether the same thing is true in ADHD in humans
Dialogue: 0,0:14:20.33,0:14:22.70,Default,,0000,0000,0000,,we don't know, but these kinds of results
Dialogue: 0,0:14:22.70,0:14:26.18,Default,,0000,0000,0000,,should at least cause us to consider that possibility.
Dialogue: 0,0:14:26.18,0:14:30.15,Default,,0000,0000,0000,,So these results make me and my colleagues more convinced than ever
Dialogue: 0,0:14:30.15,0:14:33.56,Default,,0000,0000,0000,,that the brain is not a bag of chemical soup,
Dialogue: 0,0:14:33.56,0:14:37.09,Default,,0000,0000,0000,,and it's a mistake to try to treat complex psychiatric disorders
Dialogue: 0,0:14:37.09,0:14:39.80,Default,,0000,0000,0000,,just by changing the flavor of the soup.
Dialogue: 0,0:14:39.80,0:14:44.02,Default,,0000,0000,0000,,What we need to do is to use our ingenuity and our scientific knowledge
Dialogue: 0,0:14:44.02,0:14:46.73,Default,,0000,0000,0000,,to try to design a new generation of treatments
Dialogue: 0,0:14:46.73,0:14:51.02,Default,,0000,0000,0000,,that are targeted to specific neurons and specific regions of the brain
Dialogue: 0,0:14:51.02,0:14:54.35,Default,,0000,0000,0000,,that are affected in particular psychiatric disorders.
Dialogue: 0,0:14:54.35,0:14:57.55,Default,,0000,0000,0000,,If we can do that, we may be able to cure these disorders
Dialogue: 0,0:14:57.55,0:14:59.60,Default,,0000,0000,0000,,without the unpleasant side effects,
Dialogue: 0,0:14:59.60,0:15:02.35,Default,,0000,0000,0000,,putting the oil back in our mental engines,
Dialogue: 0,0:15:02.35,0:15:05.53,Default,,0000,0000,0000,,just where it's needed. Thank you very much.