David Anderson: Your brain is more than a bag of chemicals

163,597 views ・ 2013-03-12

TED


Please double-click on the English subtitles below to play the video.

00:00
Translator: Joseph Geni Reviewer: Morton Bast
0
0
7000
00:15
So raise your hand if you know someone
1
15890
3228
00:19
in your immediate family or circle of friends
2
19118
2647
00:21
who suffers from some form of mental illness.
3
21765
3488
00:25
Yeah. I thought so. Not surprised.
4
25253
2784
00:28
And raise your hand if you think that
5
28037
2295
00:30
basic research on fruit flies has anything to do
6
30332
2825
00:33
with understanding mental illness in humans.
7
33157
4462
00:37
Yeah. I thought so. I'm also not surprised.
8
37619
2793
00:40
I can see I've got my work cut out for me here.
9
40412
3320
00:43
As we heard from Dr. Insel this morning,
10
43732
2588
00:46
psychiatric disorders like autism, depression and schizophrenia
11
46320
4213
00:50
take a terrible toll on human suffering.
12
50533
2875
00:53
We know much less about their treatment
13
53408
3213
00:56
and the understanding of their basic mechanisms
14
56621
2606
00:59
than we do about diseases of the body.
15
59227
2619
01:01
Think about it: In 2013,
16
61846
2643
01:04
the second decade of the millennium,
17
64489
1955
01:06
if you're concerned about a cancer diagnosis
18
66444
2365
01:08
and you go to your doctor, you get bone scans,
19
68809
2519
01:11
biopsies and blood tests.
20
71328
2928
01:14
In 2013, if you're concerned about a depression diagnosis,
21
74256
3865
01:18
you go to your doctor, and what do you get?
22
78121
1963
01:20
A questionnaire.
23
80084
1987
01:22
Now, part of the reason for this is that we have
24
82071
2429
01:24
an oversimplified and increasingly outmoded view
25
84500
3823
01:28
of the biological basis of psychiatric disorders.
26
88323
3887
01:32
We tend to view them --
27
92210
1243
01:33
and the popular press aids and abets this view --
28
93453
2845
01:36
as chemical imbalances in the brain,
29
96298
3016
01:39
as if the brain were some kind of bag of chemical soup
30
99314
3684
01:42
full of dopamine, serotonin and norepinephrine.
31
102998
4200
01:47
This view is conditioned by the fact
32
107198
2327
01:49
that many of the drugs that are prescribed to treat these disorders,
33
109525
3406
01:52
like Prozac, act by globally changing brain chemistry,
34
112931
4671
01:57
as if the brain were indeed a bag of chemical soup.
35
117602
3976
02:01
But that can't be the answer,
36
121578
1901
02:03
because these drugs actually don't work all that well.
37
123479
3237
02:06
A lot of people won't take them, or stop taking them,
38
126716
3176
02:09
because of their unpleasant side effects.
39
129892
2657
02:12
These drugs have so many side effects
40
132549
2060
02:14
because using them to treat a complex psychiatric disorder
41
134609
3956
02:18
is a bit like trying to change your engine oil
42
138565
2689
02:21
by opening a can and pouring it all over the engine block.
43
141254
4113
02:25
Some of it will dribble into the right place,
44
145367
2150
02:27
but a lot of it will do more harm than good.
45
147517
3101
02:30
Now, an emerging view
46
150618
2238
02:32
that you also heard about from Dr. Insel this morning,
47
152856
2950
02:35
is that psychiatric disorders are actually
48
155806
2570
02:38
disturbances of neural circuits that mediate
49
158376
3474
02:41
emotion, mood and affect.
50
161850
3519
02:45
When we think about cognition,
51
165369
1762
02:47
we analogize the brain to a computer. That's no problem.
52
167131
3576
02:50
Well it turns out that the computer analogy
53
170707
2581
02:53
is just as valid for emotion.
54
173288
2383
02:55
It's just that we don't tend to think about it that way.
55
175671
2786
02:58
But we know much less about the circuit basis
56
178457
3283
03:01
of psychiatric disorders
57
181740
1899
03:03
because of the overwhelming dominance
58
183639
2070
03:05
of this chemical imbalance hypothesis.
59
185709
3352
03:09
Now, it's not that chemicals are not important
60
189061
3827
03:12
in psychiatric disorders.
61
192888
1537
03:14
It's just that they don't bathe the brain like soup.
62
194425
3972
03:18
Rather, they're released in very specific locations
63
198397
3649
03:22
and they act on specific synapses
64
202046
2725
03:24
to change the flow of information in the brain.
65
204771
3688
03:28
So if we ever really want to understand
66
208459
2437
03:30
the biological basis of psychiatric disorders,
67
210896
2705
03:33
we need to pinpoint these locations in the brain
68
213601
3032
03:36
where these chemicals act.
69
216633
1734
03:38
Otherwise, we're going to keep pouring oil all over our mental engines
70
218367
3479
03:41
and suffering the consequences.
71
221846
2957
03:44
Now to begin to overcome our ignorance
72
224803
3059
03:47
of the role of brain chemistry in brain circuitry,
73
227862
3534
03:51
it's helpful to work on what we biologists call
74
231396
2680
03:54
"model organisms,"
75
234076
1579
03:55
animals like fruit flies and laboratory mice,
76
235655
3334
03:58
in which we can apply powerful genetic techniques
77
238989
3425
04:02
to molecularly identify and pinpoint
78
242414
3625
04:06
specific classes of neurons,
79
246039
1563
04:07
as you heard about in Allan Jones's talk this morning.
80
247602
2903
04:10
Moreover, once we can do that,
81
250505
2461
04:12
we can actually activate specific neurons
82
252966
2749
04:15
or we can destroy or inhibit the activity of those neurons.
83
255715
4211
04:19
So if we inhibit a particular type of neuron,
84
259926
2714
04:22
and we find that a behavior is blocked,
85
262640
2465
04:25
we can conclude that those neurons
86
265105
2214
04:27
are necessary for that behavior.
87
267319
2964
04:30
On the other hand, if we activate a group of neurons
88
270283
2382
04:32
and we find that that produces the behavior,
89
272665
2814
04:35
we can conclude that those neurons are sufficient for the behavior.
90
275479
4074
04:39
So in this way, by doing this kind of test,
91
279553
3009
04:42
we can draw cause and effect relationships
92
282562
3523
04:46
between the activity of specific neurons
93
286085
2356
04:48
in particular circuits and particular behaviors,
94
288441
2913
04:51
something that is extremely difficult, if not impossible,
95
291354
2437
04:53
to do right now in humans.
96
293791
5051
04:58
But can an organism like a fruit fly, which is --
97
298842
2837
05:01
it's a great model organism
98
301679
2200
05:03
because it's got a small brain,
99
303879
2538
05:06
it's capable of complex and sophisticated behaviors,
100
306417
3787
05:10
it breeds quickly, and it's cheap.
101
310204
3150
05:13
But can an organism like this
102
313354
1795
05:15
teach us anything about emotion-like states?
103
315149
3843
05:18
Do these organisms even have emotion-like states,
104
318992
3300
05:22
or are they just little digital robots?
105
322292
3363
05:25
Charles Darwin believed that insects have emotion
106
325655
3200
05:28
and express them in their behaviors, as he wrote
107
328855
2550
05:31
in his 1872 monograph on the expression of the emotions in man and animals.
108
331405
5193
05:36
And my eponymous colleague, Seymour Benzer, believed it as well.
109
336598
3519
05:40
Seymour is the man that introduced the use of drosophila
110
340117
3414
05:43
here at CalTech in the '60s as a model organism
111
343531
3523
05:47
to study the connection between genes and behavior.
112
347054
3597
05:50
Seymour recruited me to CalTech in the late 1980s.
113
350651
3607
05:54
He was my Jedi and my rabbi while he was here,
114
354258
4434
05:58
and Seymour taught me both to love flies
115
358692
2388
06:01
and also to play with science.
116
361080
3049
06:04
So how do we ask this question?
117
364129
3116
06:07
It's one thing to believe that flies have emotion-like states,
118
367245
4060
06:11
but how do we actually find out whether that's true or not?
119
371305
3163
06:14
Now, in humans we often infer emotional states,
120
374468
3950
06:18
as you'll hear later today, from facial expressions.
121
378418
3905
06:22
However, it's a little difficult to do that in fruit flies.
122
382323
3720
06:26
(Laughter)
123
386043
3313
06:29
It's kind of like landing on Mars
124
389356
3137
06:32
and looking out the window of your spaceship
125
392493
2705
06:35
at all the little green men who are surrounding it
126
395198
2470
06:37
and trying to figure out, "How do I find out
127
397668
2406
06:40
if they have emotions or not?"
128
400074
2355
06:42
What can we do? It's not so easy.
129
402429
3543
06:45
Well, one of the ways that we can start
130
405972
2185
06:48
is to try to come up with some general characteristics
131
408157
4125
06:52
or properties of emotion-like states
132
412282
3748
06:56
such as arousal, and see if we can identify
133
416030
3464
06:59
any fly behaviors that might exhibit some of those properties.
134
419494
5376
07:04
So three important ones that I can think of
135
424870
2820
07:07
are persistence, gradations in intensity, and valence.
136
427690
4672
07:12
Persistence means long-lasting.
137
432362
2334
07:14
We all know that the stimulus that triggers an emotion
138
434696
3961
07:18
causes that emotion to last long after the stimulus is gone.
139
438657
5016
07:23
Gradations of intensity means what it sounds like.
140
443673
3090
07:26
You can dial up the intensity or dial down the intensity of an emotion.
141
446763
4583
07:31
If you're a little bit unhappy, the corners of your mouth
142
451346
2600
07:33
turn down and you sniffle,
143
453946
1687
07:35
and if you're very unhappy, tears pour down your face
144
455633
3138
07:38
and you might sob.
145
458771
1832
07:40
Valence means good or bad, positive or negative.
146
460603
4379
07:44
So we decided to see if flies could be provoked into showing
147
464982
4452
07:49
the kind of behavior that you see
148
469434
2451
07:51
by the proverbial wasp at the picnic table,
149
471885
2810
07:54
you know, the one that keeps coming back to your hamburger
150
474695
2685
07:57
the more vigorously you try to swat it away,
151
477380
2529
07:59
and it seems to keep getting irritated.
152
479909
2284
08:02
So we built a device, which we call a puff-o-mat,
153
482193
3647
08:05
in which we could deliver little brief air puffs to fruit flies
154
485840
4345
08:10
in these plastic tubes in our laboratory bench
155
490185
2776
08:12
and blow them away.
156
492961
1725
08:14
And what we found is that if we gave these flies
157
494686
3239
08:17
in the puff-o-mat several puffs in a row,
158
497925
2848
08:20
they became somewhat hyperactive
159
500773
2689
08:23
and continued to run around for some time after the air puffs actually stopped
160
503462
4435
08:27
and took a while to calm down.
161
507897
2864
08:30
So we quantified this behavior
162
510761
2189
08:32
using custom locomotor tracking software
163
512950
3012
08:35
developed with my collaborator Pietro Perona,
164
515962
2800
08:38
who's in the electrical engineering division here at CalTech.
165
518762
3612
08:42
And what this quantification showed us is that,
166
522374
2814
08:45
upon experiencing a train of these air puffs,
167
525188
3224
08:48
the flies appear to enter a kind of state of hyperactivity
168
528412
4314
08:52
which is persistent, long-lasting,
169
532726
2598
08:55
and also appears to be graded.
170
535324
2504
08:57
More puffs, or more intense puffs,
171
537828
2859
09:00
make the state last for a longer period of time.
172
540687
3913
09:04
So now we wanted to try to understand something
173
544600
2036
09:06
about what controls the duration of this state.
174
546636
3714
09:10
So we decided to use our puff-o-mat
175
550350
2851
09:13
and our automated tracking software
176
553201
2055
09:15
to screen through hundreds of lines of mutant fruit flies
177
555256
3782
09:19
to see if we could find any that showed abnormal responses to the air puffs.
178
559038
5079
09:24
And this is one of the great things about fruit flies.
179
564117
2347
09:26
There are repositories where you can just pick up the phone
180
566464
2793
09:29
and order hundreds of vials of flies of different mutants
181
569257
3641
09:32
and screen them in your assay and then find out
182
572898
2172
09:35
what gene is affected in the mutation.
183
575070
3319
09:38
So doing the screen, we discovered one mutant
184
578389
3512
09:41
that took much longer than normal to calm down
185
581901
3474
09:45
after the air puffs,
186
585375
2277
09:47
and when we examined the gene that was affected in this mutation,
187
587652
3950
09:51
it turned out to encode a dopamine receptor.
188
591602
3605
09:55
That's right -- flies, like people, have dopamine,
189
595207
3011
09:58
and it acts on their brains and on their synapses
190
598218
2772
10:00
through the same dopamine receptor molecules
191
600990
2550
10:03
that you and I have.
192
603540
2389
10:05
Dopamine plays a number of important functions in the brain,
193
605929
3486
10:09
including in attention, arousal, reward,
194
609415
3113
10:12
and disorders of the dopamine system have been linked
195
612528
3413
10:15
to a number of mental disorders including drug abuse,
196
615941
3100
10:19
Parkinson's disease, and ADHD.
197
619041
4234
10:23
Now, in genetics, it's a little counterintuitive.
198
623275
2790
10:26
We tend to infer the normal function of something
199
626065
3260
10:29
by what doesn't happen when we take it away,
200
629325
3710
10:33
by the opposite of what we see when we take it away.
201
633035
3003
10:36
So when we take away the dopamine receptor
202
636038
3013
10:39
and the flies take longer to calm down,
203
639051
2557
10:41
from that we infer that the normal function of this receptor and dopamine
204
641608
3846
10:45
is to cause the flies to calm down faster after the puff.
205
645454
4485
10:49
And that's a bit reminiscent of ADHD,
206
649939
2950
10:52
which has been linked to disorders of the dopamine system in humans.
207
652889
3975
10:56
Indeed, if we increase the levels of dopamine in normal flies
208
656864
4606
11:01
by feeding them cocaine
209
661470
1710
11:03
after getting the appropriate DEA license
210
663180
2972
11:06
— oh my God -- (Laughter) —
211
666152
4000
11:10
we find indeed that these cocaine-fed flies
212
670152
3172
11:13
calm down faster than normal flies do,
213
673324
3042
11:16
and that's also reminiscent of ADHD,
214
676366
3199
11:19
which is often treated with drugs like Ritalin
215
679565
2045
11:21
that act similarly to cocaine.
216
681610
3019
11:24
So slowly I began to realize that what started out
217
684629
3149
11:27
as a rather playful attempt to try to annoy fruit flies
218
687778
3649
11:31
might actually have some relevance to a human psychiatric disorder.
219
691427
3976
11:35
Now, how far does this analogy go?
220
695403
2226
11:37
As many of you know, individuals afflicted with ADHD
221
697629
3122
11:40
also have learning disabilities.
222
700751
2337
11:43
Is that true of our dopamine receptor mutant flies?
223
703088
3566
11:46
Remarkably, the answer is yes.
224
706654
2720
11:49
As Seymour showed back in the 1970s,
225
709374
2628
11:52
flies, like songbirds, as you just heard,
226
712002
2451
11:54
are capable of learning.
227
714453
1733
11:56
You can train a fly to avoid an odor, shown here in blue,
228
716186
4443
12:00
if you pair that odor with a shock.
229
720629
2388
12:03
Then when you give those trained flies the chance to choose
230
723017
3384
12:06
between a tube with the shock-paired odor and another odor,
231
726401
3154
12:09
it avoids the tube containing the blue odor that was paired with shock.
232
729555
4200
12:13
Well, if you do this test on dopamine receptor mutant flies,
233
733755
3502
12:17
they don't learn. Their learning score is zero.
234
737257
2465
12:19
They flunk out of CalTech.
235
739722
3811
12:23
So that means that these flies have two abnormalities,
236
743533
4748
12:28
or phenotypes, as we geneticists call them,
237
748281
3050
12:31
that one finds in ADHD: hyperactivity and learning disability.
238
751331
5512
12:36
Now what's the causal relationship, if anything, between these phenotypes?
239
756843
4363
12:41
In ADHD, it's often assumed that the hyperactivity
240
761206
3913
12:45
causes the learning disability.
241
765119
1906
12:47
The kids can't sit still long enough to focus, so they don't learn.
242
767025
3719
12:50
But it could equally be the case that it's the learning disabilities
243
770744
3296
12:54
that cause the hyperactivity.
244
774040
1872
12:55
Because the kids can't learn, they look for other things to distract their attention.
245
775912
4470
13:00
And a final possibility is that there's no relationship at all
246
780382
3057
13:03
between learning disabilities and hyperactivity,
247
783439
2404
13:05
but that they are caused by a common underlying mechanism in ADHD.
248
785843
4915
13:10
Now people have been wondering about this for a long time
249
790758
2342
13:13
in humans, but in flies we can actually test this.
250
793100
3488
13:16
And the way that we do this is to delve deeply into the mind
251
796588
3084
13:19
of the fly and begin to untangle its circuitry using genetics.
252
799672
4266
13:23
We take our dopamine receptor mutant flies
253
803938
2462
13:26
and we genetically restore, or cure, the dopamine receptor
254
806400
4564
13:30
by putting a good copy of the dopamine receptor gene
255
810964
3235
13:34
back into the fly brain.
256
814199
2051
13:36
But in each fly, we put it back only into certain neurons
257
816250
3835
13:40
and not in others, and then we test each of these flies
258
820085
3714
13:43
for their ability to learn and for hyperactivity.
259
823799
3668
13:47
Remarkably, we find we can completely dissociate these two abnormalities.
260
827467
4818
13:52
If we put a good copy of the dopamine receptor back
261
832285
2663
13:54
in this elliptical structure called the central complex,
262
834948
2961
13:57
the flies are no longer hyperactive, but they still can't learn.
263
837909
4077
14:01
On the other hand, if we put the receptor back in a different structure
264
841986
2726
14:04
called the mushroom body,
265
844712
1518
14:06
the learning deficit is rescued, the flies learn well,
266
846230
3085
14:09
but they're still hyperactive.
267
849315
1830
14:11
What that tells us is that dopamine
268
851145
2250
14:13
is not bathing the brain of these flies like soup.
269
853395
3392
14:16
Rather, it's acting to control two different functions
270
856787
3162
14:19
on two different circuits,
271
859949
1634
14:21
so the reason there are two things wrong with our dopamine receptor flies
272
861583
3904
14:25
is that the same receptor is controlling two different functions
273
865487
4175
14:29
in two different regions of the brain.
274
869662
2863
14:32
Whether the same thing is true in ADHD in humans
275
872525
3062
14:35
we don't know, but these kinds of results
276
875587
2376
14:37
should at least cause us to consider that possibility.
277
877963
3477
14:41
So these results make me and my colleagues more convinced than ever
278
881440
3973
14:45
that the brain is not a bag of chemical soup,
279
885413
3412
14:48
and it's a mistake to try to treat complex psychiatric disorders
280
888825
3527
14:52
just by changing the flavor of the soup.
281
892352
2711
14:55
What we need to do is to use our ingenuity and our scientific knowledge
282
895063
4217
14:59
to try to design a new generation of treatments
283
899280
2708
15:01
that are targeted to specific neurons and specific regions of the brain
284
901988
4288
15:06
that are affected in particular psychiatric disorders.
285
906276
3338
15:09
If we can do that, we may be able to cure these disorders
286
909614
3200
15:12
without the unpleasant side effects,
287
912814
2047
15:14
putting the oil back in our mental engines,
288
914861
2746
15:17
just where it's needed. Thank you very much.
289
917607
3184
About this website

This site will introduce you to YouTube videos that are useful for learning English. You will see English lessons taught by top-notch teachers from around the world. Double-click on the English subtitles displayed on each video page to play the video from there. The subtitles scroll in sync with the video playback. If you have any comments or requests, please contact us using this contact form.

https://forms.gle/WvT1wiN1qDtmnspy7