Your brain is more than a bag of chemicals
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0:01 - 0:04So raise your hand if you know someone
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0:04 - 0:07in your immediate family or circle of friends
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0:07 - 0:10who suffers from some form of mental illness.
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0:10 - 0:13Yeah. I thought so. Not surprised.
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0:13 - 0:15And raise your hand if you think that
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0:15 - 0:18basic research on fruit flies has anything to do
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0:18 - 0:22with understanding mental illness in humans.
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0:22 - 0:25Yeah. I thought so. I'm also not surprised.
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0:25 - 0:28I can see I've got my work cut out for me here.
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0:28 - 0:31As we heard from Dr. Insel this morning,
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0:31 - 0:35psychiatric disorders like autism, depression and schizophrenia
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0:35 - 0:38take a terrible toll on human suffering.
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0:38 - 0:41We know much less about their treatment
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0:41 - 0:44and the understanding of their basic mechanisms
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0:44 - 0:47than we do about diseases of the body.
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0:47 - 0:49Think about it: In 2013,
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0:49 - 0:51the second decade of the millennium,
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0:51 - 0:54if you're concerned about a cancer diagnosis
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0:54 - 0:56and you go to your doctor, you get bone scans,
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0:56 - 0:59biopsies and blood tests.
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0:59 - 1:03In 2013, if you're concerned about a depression diagnosis,
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1:03 - 1:05you go to your doctor, and what do you get?
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1:05 - 1:07A questionnaire.
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1:07 - 1:09Now, part of the reason for this is that we have
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1:09 - 1:13an oversimplified and increasingly outmoded view
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1:13 - 1:17of the biological basis of psychiatric disorders.
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1:17 - 1:18We tend to view them --
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1:18 - 1:21and the popular press aids and abets this view --
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1:21 - 1:24as chemical imbalances in the brain,
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1:24 - 1:28as if the brain were some kind of bag of chemical soup
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1:28 - 1:32full of dopamine, serotonin and norepinephrine.
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1:32 - 1:34This view is conditioned by the fact
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1:34 - 1:38that many of the drugs that are prescribed to treat these disorders,
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1:38 - 1:42like Prozac, act by globally changing brain chemistry,
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1:42 - 1:46as if the brain were indeed a bag of chemical soup.
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1:46 - 1:48But that can't be the answer,
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1:48 - 1:51because these drugs actually don't work all that well.
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1:51 - 1:55A lot of people won't take them, or stop taking them,
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1:55 - 1:57because of their unpleasant side effects.
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1:57 - 1:59These drugs have so many side effects
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1:59 - 2:03because using them to treat a complex psychiatric disorder
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2:03 - 2:06is a bit like trying to change your engine oil
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2:06 - 2:10by opening a can and pouring it all over the engine block.
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2:10 - 2:12Some of it will dribble into the right place,
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2:12 - 2:15but a lot of it will do more harm than good.
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2:15 - 2:18Now, an emerging view
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2:18 - 2:21that you also heard about from Dr. Insel this morning,
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2:21 - 2:23is that psychiatric disorders are actually
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2:23 - 2:27disturbances of neural circuits that mediate
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2:27 - 2:30emotion, mood and affect.
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2:30 - 2:32When we think about cognition,
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2:32 - 2:35we analogize the brain to a computer. That's no problem.
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2:35 - 2:38Well it turns out that the computer analogy
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2:38 - 2:40is just as valid for emotion.
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2:40 - 2:43It's just that we don't tend to think about it that way.
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2:43 - 2:46But we know much less about the circuit basis
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2:46 - 2:48of psychiatric disorders
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2:48 - 2:50because of the overwhelming dominance
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2:50 - 2:54of this chemical imbalance hypothesis.
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2:54 - 2:58Now, it's not that chemicals are not important
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2:58 - 2:59in psychiatric disorders.
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2:59 - 3:03It's just that they don't bathe the brain like soup.
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3:03 - 3:07Rather, they're released in very specific locations
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3:07 - 3:10and they act on specific synapses
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3:10 - 3:13to change the flow of information in the brain.
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3:13 - 3:16So if we ever really want to understand
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3:16 - 3:18the biological basis of psychiatric disorders,
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3:18 - 3:21we need to pinpoint these locations in the brain
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3:21 - 3:23where these chemicals act.
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3:23 - 3:27Otherwise, we're going to keep pouring oil all over our mental engines
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3:27 - 3:30and suffering the consequences.
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3:30 - 3:33Now to begin to overcome our ignorance
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3:33 - 3:36of the role of brain chemistry in brain circuitry,
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3:36 - 3:39it's helpful to work on what we biologists call
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3:39 - 3:40"model organisms,"
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3:40 - 3:44animals like fruit flies and laboratory mice,
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3:44 - 3:47in which we can apply powerful genetic techniques
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3:47 - 3:51to molecularly identify and pinpoint
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3:51 - 3:52specific classes of neurons,
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3:52 - 3:55as you heard about in Allan Jones's talk this morning.
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3:55 - 3:58Moreover, once we can do that,
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3:58 - 4:00we can actually activate specific neurons
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4:00 - 4:05or we can destroy or inhibit the activity of those neurons.
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4:05 - 4:07So if we inhibit a particular type of neuron,
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4:07 - 4:10and we find that a behavior is blocked,
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4:10 - 4:12we can conclude that those neurons
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4:12 - 4:15are necessary for that behavior.
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4:15 - 4:17On the other hand, if we activate a group of neurons
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4:17 - 4:20and we find that that produces the behavior,
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4:20 - 4:24we can conclude that those neurons are sufficient for the behavior.
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4:24 - 4:27So in this way, by doing this kind of test,
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4:27 - 4:31we can draw cause and effect relationships
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4:31 - 4:33between the activity of specific neurons
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4:33 - 4:36in particular circuits and particular behaviors,
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4:36 - 4:39something that is extremely difficult, if not impossible,
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4:39 - 4:44to do right now in humans.
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4:44 - 4:46But can an organism like a fruit fly, which is --
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4:46 - 4:49it's a great model organism
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4:49 - 4:51because it's got a small brain,
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4:51 - 4:55it's capable of complex and sophisticated behaviors,
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4:55 - 4:58it breeds quickly, and it's cheap.
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4:58 - 5:00But can an organism like this
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5:00 - 5:04teach us anything about emotion-like states?
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5:04 - 5:07Do these organisms even have emotion-like states,
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5:07 - 5:10or are they just little digital robots?
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5:10 - 5:14Charles Darwin believed that insects have emotion
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5:14 - 5:16and express them in their behaviors, as he wrote
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5:16 - 5:21in his 1872 monograph on the expression of the emotions in man and animals.
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5:21 - 5:25And my eponymous colleague, Seymour Benzer, believed it as well.
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5:25 - 5:28Seymour is the man that introduced the use of drosophila
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5:28 - 5:32here at CalTech in the '60s as a model organism
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5:32 - 5:35to study the connection between genes and behavior.
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5:35 - 5:39Seymour recruited me to CalTech in the late 1980s.
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5:39 - 5:43He was my Jedi and my rabbi while he was here,
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5:43 - 5:46and Seymour taught me both to love flies
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5:46 - 5:49and also to play with science.
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5:49 - 5:52So how do we ask this question?
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5:52 - 5:56It's one thing to believe that flies have emotion-like states,
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5:56 - 5:59but how do we actually find out whether that's true or not?
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5:59 - 6:03Now, in humans we often infer emotional states,
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6:03 - 6:07as you'll hear later today, from facial expressions.
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6:07 - 6:11However, it's a little difficult to do that in fruit flies.
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6:11 - 6:14(Laughter)
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6:14 - 6:17It's kind of like landing on Mars
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6:17 - 6:20and looking out the window of your spaceship
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6:20 - 6:22at all the little green men who are surrounding it
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6:22 - 6:25and trying to figure out, "How do I find out
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6:25 - 6:27if they have emotions or not?"
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6:27 - 6:31What can we do? It's not so easy.
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6:31 - 6:33Well, one of the ways that we can start
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6:33 - 6:37is to try to come up with some general characteristics
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6:37 - 6:41or properties of emotion-like states
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6:41 - 6:44such as arousal, and see if we can identify
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6:44 - 6:50any fly behaviors that might exhibit some of those properties.
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6:50 - 6:52So three important ones that I can think of
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6:52 - 6:57are persistence, gradations in intensity, and valence.
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6:57 - 6:59Persistence means long-lasting.
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6:59 - 7:03We all know that the stimulus that triggers an emotion
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7:03 - 7:08causes that emotion to last long after the stimulus is gone.
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7:08 - 7:12Gradations of intensity means what it sounds like.
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7:12 - 7:16You can dial up the intensity or dial down the intensity of an emotion.
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7:16 - 7:19If you're a little bit unhappy, the corners of your mouth
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7:19 - 7:20turn down and you sniffle,
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7:20 - 7:24and if you're very unhappy, tears pour down your face
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7:24 - 7:25and you might sob.
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7:25 - 7:30Valence means good or bad, positive or negative.
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7:30 - 7:34So we decided to see if flies could be provoked into showing
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7:34 - 7:37the kind of behavior that you see
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7:37 - 7:39by the proverbial wasp at the picnic table,
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7:39 - 7:42you know, the one that keeps coming back to your hamburger
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7:42 - 7:45the more vigorously you try to swat it away,
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7:45 - 7:47and it seems to keep getting irritated.
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7:47 - 7:51So we built a device, which we call a puff-o-mat,
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7:51 - 7:55in which we could deliver little brief air puffs to fruit flies
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7:55 - 7:58in these plastic tubes in our laboratory bench
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7:58 - 7:59and blow them away.
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7:59 - 8:03And what we found is that if we gave these flies
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8:03 - 8:06in the puff-o-mat several puffs in a row,
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8:06 - 8:08they became somewhat hyperactive
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8:08 - 8:13and continued to run around for some time after the air puffs actually stopped
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8:13 - 8:16and took a while to calm down.
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8:16 - 8:18So we quantified this behavior
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8:18 - 8:21using custom locomotor tracking software
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8:21 - 8:24developed with my collaborator Pietro Perona,
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8:24 - 8:27who's in the electrical engineering division here at CalTech.
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8:27 - 8:30And what this quantification showed us is that,
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8:30 - 8:33upon experiencing a train of these air puffs,
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8:33 - 8:37the flies appear to enter a kind of state of hyperactivity
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8:37 - 8:40which is persistent, long-lasting,
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8:40 - 8:43and also appears to be graded.
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8:43 - 8:45More puffs, or more intense puffs,
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8:45 - 8:49make the state last for a longer period of time.
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8:49 - 8:51So now we wanted to try to understand something
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8:51 - 8:55about what controls the duration of this state.
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8:55 - 8:58So we decided to use our puff-o-mat
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8:58 - 9:00and our automated tracking software
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9:00 - 9:04to screen through hundreds of lines of mutant fruit flies
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9:04 - 9:09to see if we could find any that showed abnormal responses to the air puffs.
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9:09 - 9:11And this is one of the great things about fruit flies.
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9:11 - 9:14There are repositories where you can just pick up the phone
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9:14 - 9:18and order hundreds of vials of flies of different mutants
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9:18 - 9:20and screen them in your assay and then find out
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9:20 - 9:23what gene is affected in the mutation.
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9:23 - 9:27So doing the screen, we discovered one mutant
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9:27 - 9:30that took much longer than normal to calm down
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9:30 - 9:32after the air puffs,
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9:32 - 9:36and when we examined the gene that was affected in this mutation,
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9:36 - 9:40it turned out to encode a dopamine receptor.
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9:40 - 9:43That's right -- flies, like people, have dopamine,
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9:43 - 9:46and it acts on their brains and on their synapses
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9:46 - 9:48through the same dopamine receptor molecules
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9:48 - 9:51that you and I have.
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9:51 - 9:54Dopamine plays a number of important functions in the brain,
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9:54 - 9:57including in attention, arousal, reward,
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9:57 - 10:01and disorders of the dopamine system have been linked
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10:01 - 10:04to a number of mental disorders including drug abuse,
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10:04 - 10:08Parkinson's disease, and ADHD.
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10:08 - 10:11Now, in genetics, it's a little counterintuitive.
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10:11 - 10:14We tend to infer the normal function of something
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10:14 - 10:18by what doesn't happen when we take it away,
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10:18 - 10:21by the opposite of what we see when we take it away.
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10:21 - 10:24So when we take away the dopamine receptor
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10:24 - 10:26and the flies take longer to calm down,
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10:26 - 10:30from that we infer that the normal function of this receptor and dopamine
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10:30 - 10:35is to cause the flies to calm down faster after the puff.
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10:35 - 10:38And that's a bit reminiscent of ADHD,
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10:38 - 10:42which has been linked to disorders of the dopamine system in humans.
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10:42 - 10:46Indeed, if we increase the levels of dopamine in normal flies
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10:46 - 10:48by feeding them cocaine
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10:48 - 10:51after getting the appropriate DEA license
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10:51 - 10:55— oh my God -- (Laughter) —
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10:55 - 10:58we find indeed that these cocaine-fed flies
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10:58 - 11:01calm down faster than normal flies do,
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11:01 - 11:04and that's also reminiscent of ADHD,
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11:04 - 11:06which is often treated with drugs like Ritalin
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11:06 - 11:09that act similarly to cocaine.
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11:09 - 11:13So slowly I began to realize that what started out
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11:13 - 11:16as a rather playful attempt to try to annoy fruit flies
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11:16 - 11:20might actually have some relevance to a human psychiatric disorder.
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11:20 - 11:22Now, how far does this analogy go?
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11:22 - 11:25As many of you know, individuals afflicted with ADHD
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11:25 - 11:28also have learning disabilities.
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11:28 - 11:31Is that true of our dopamine receptor mutant flies?
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11:31 - 11:34Remarkably, the answer is yes.
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11:34 - 11:37As Seymour showed back in the 1970s,
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11:37 - 11:39flies, like songbirds, as you just heard,
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11:39 - 11:41are capable of learning.
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11:41 - 11:45You can train a fly to avoid an odor, shown here in blue,
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11:45 - 11:48if you pair that odor with a shock.
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11:48 - 11:51Then when you give those trained flies the chance to choose
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11:51 - 11:54between a tube with the shock-paired odor and another odor,
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11:54 - 11:58it avoids the tube containing the blue odor that was paired with shock.
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11:58 - 12:02Well, if you do this test on dopamine receptor mutant flies,
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12:02 - 12:04they don't learn. Their learning score is zero.
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12:04 - 12:08They flunk out of CalTech.
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12:08 - 12:13So that means that these flies have two abnormalities,
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12:13 - 12:16or phenotypes, as we geneticists call them,
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12:16 - 12:22that one finds in ADHD: hyperactivity and learning disability.
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12:22 - 12:26Now what's the causal relationship, if anything, between these phenotypes?
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12:26 - 12:30In ADHD, it's often assumed that the hyperactivity
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12:30 - 12:32causes the learning disability.
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12:32 - 12:35The kids can't sit still long enough to focus, so they don't learn.
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12:35 - 12:39But it could equally be the case that it's the learning disabilities
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12:39 - 12:41that cause the hyperactivity.
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12:41 - 12:45Because the kids can't learn, they look for other things to distract their attention.
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12:45 - 12:48And a final possibility is that there's no relationship at all
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12:48 - 12:51between learning disabilities and hyperactivity,
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12:51 - 12:55but that they are caused by a common underlying mechanism in ADHD.
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12:55 - 12:58Now people have been wondering about this for a long time
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12:58 - 13:01in humans, but in flies we can actually test this.
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13:01 - 13:04And the way that we do this is to delve deeply into the mind
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13:04 - 13:09of the fly and begin to untangle its circuitry using genetics.
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13:09 - 13:11We take our dopamine receptor mutant flies
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13:11 - 13:16and we genetically restore, or cure, the dopamine receptor
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13:16 - 13:19by putting a good copy of the dopamine receptor gene
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13:19 - 13:21back into the fly brain.
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13:21 - 13:25But in each fly, we put it back only into certain neurons
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13:25 - 13:29and not in others, and then we test each of these flies
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13:29 - 13:32for their ability to learn and for hyperactivity.
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13:32 - 13:37Remarkably, we find we can completely dissociate these two abnormalities.
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13:37 - 13:40If we put a good copy of the dopamine receptor back
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13:40 - 13:43in this elliptical structure called the central complex,
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13:43 - 13:47the flies are no longer hyperactive, but they still can't learn.
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13:47 - 13:49On the other hand, if we put the receptor back in a different structure
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13:49 - 13:51called the mushroom body,
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13:51 - 13:54the learning deficit is rescued, the flies learn well,
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13:54 - 13:56but they're still hyperactive.
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13:56 - 13:58What that tells us is that dopamine
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13:58 - 14:02is not bathing the brain of these flies like soup.
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14:02 - 14:05Rather, it's acting to control two different functions
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14:05 - 14:06on two different circuits,
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14:06 - 14:10so the reason there are two things wrong with our dopamine receptor flies
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14:10 - 14:14is that the same receptor is controlling two different functions
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14:14 - 14:17in two different regions of the brain.
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14:17 - 14:20Whether the same thing is true in ADHD in humans
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14:20 - 14:23we don't know, but these kinds of results
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14:23 - 14:26should at least cause us to consider that possibility.
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14:26 - 14:30So these results make me and my colleagues more convinced than ever
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14:30 - 14:34that the brain is not a bag of chemical soup,
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14:34 - 14:37and it's a mistake to try to treat complex psychiatric disorders
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14:37 - 14:40just by changing the flavor of the soup.
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14:40 - 14:44What we need to do is to use our ingenuity and our scientific knowledge
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14:44 - 14:47to try to design a new generation of treatments
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14:47 - 14:51that are targeted to specific neurons and specific regions of the brain
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14:51 - 14:54that are affected in particular psychiatric disorders.
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14:54 - 14:58If we can do that, we may be able to cure these disorders
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14:58 - 15:00without the unpleasant side effects,
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15:00 - 15:02putting the oil back in our mental engines,
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15:02 - 15:06just where it's needed. Thank you very much.
- Title:
- Your brain is more than a bag of chemicals
- Speaker:
- David Anderson
- Description:
-
Modern psychiatric drugs treat the chemistry of the whole brain, but neurobiologist David Anderson believes in a more nuanced view of how the brain functions. He illuminates new research that could lead to targeted psychiatric medications -- that work better and avoid side effects. How's he doing it? For a start, by making a bunch of fruit flies angry. (Filmed at TEDxCaltech.)
- Video Language:
- English
- Team:
- closed TED
- Project:
- TEDTalks
- Duration:
- 15:25
Morton Bast edited English subtitles for Your brain is more than a bag of chemicals | ||
Morton Bast approved English subtitles for Your brain is more than a bag of chemicals | ||
Morton Bast edited English subtitles for Your brain is more than a bag of chemicals | ||
Morton Bast accepted English subtitles for Your brain is more than a bag of chemicals | ||
Morton Bast edited English subtitles for Your brain is more than a bag of chemicals | ||
Joseph Geni added a translation |