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TEDxCaltech

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

January 18, 2013

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.)

David Anderson - Neurobiologist
Through his lab at the California Institute of Technology, David Anderson seeks to find the neural underpinnings of emotions like fear, anxiety and anger. Full bio

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Double-click the English subtitles below to play the video.
So raise your hand if you know someone
00:15
in your immediate family or circle of friends
00:19
who suffers from some form of mental illness.
00:21
Yeah. I thought so. Not surprised.
00:25
And raise your hand if you think that
00:28
basic research on fruit flies has anything to do
00:30
with understanding mental illness in humans.
00:33
Yeah. I thought so. I'm also not surprised.
00:37
I can see I've got my work cut out for me here.
00:40
As we heard from Dr. Insel this morning,
00:43
psychiatric disorders like autism, depression and schizophrenia
00:46
take a terrible toll on human suffering.
00:50
We know much less about their treatment
00:53
and the understanding of their basic mechanisms
00:56
than we do about diseases of the body.
00:59
Think about it: In 2013,
01:01
the second decade of the millennium,
01:04
if you're concerned about a cancer diagnosis
01:06
and you go to your doctor, you get bone scans,
01:08
biopsies and blood tests.
01:11
In 2013, if you're concerned about a depression diagnosis,
01:14
you go to your doctor, and what do you get?
01:18
A questionnaire.
01:20
Now, part of the reason for this is that we have
01:22
an oversimplified and increasingly outmoded view
01:24
of the biological basis of psychiatric disorders.
01:28
We tend to view them --
01:32
and the popular press aids and abets this view --
01:33
as chemical imbalances in the brain,
01:36
as if the brain were some kind of bag of chemical soup
01:39
full of dopamine, serotonin and norepinephrine.
01:43
This view is conditioned by the fact
01:47
that many of the drugs that are prescribed to treat these disorders,
01:49
like Prozac, act by globally changing brain chemistry,
01:53
as if the brain were indeed a bag of chemical soup.
01:57
But that can't be the answer,
02:01
because these drugs actually don't work all that well.
02:03
A lot of people won't take them, or stop taking them,
02:06
because of their unpleasant side effects.
02:09
These drugs have so many side effects
02:12
because using them to treat a complex psychiatric disorder
02:14
is a bit like trying to change your engine oil
02:18
by opening a can and pouring it all over the engine block.
02:21
Some of it will dribble into the right place,
02:25
but a lot of it will do more harm than good.
02:27
Now, an emerging view
02:30
that you also heard about from Dr. Insel this morning,
02:32
is that psychiatric disorders are actually
02:35
disturbances of neural circuits that mediate
02:38
emotion, mood and affect.
02:41
When we think about cognition,
02:45
we analogize the brain to a computer. That's no problem.
02:47
Well it turns out that the computer analogy
02:50
is just as valid for emotion.
02:53
It's just that we don't tend to think about it that way.
02:55
But we know much less about the circuit basis
02:58
of psychiatric disorders
03:01
because of the overwhelming dominance
03:03
of this chemical imbalance hypothesis.
03:05
Now, it's not that chemicals are not important
03:09
in psychiatric disorders.
03:12
It's just that they don't bathe the brain like soup.
03:14
Rather, they're released in very specific locations
03:18
and they act on specific synapses
03:22
to change the flow of information in the brain.
03:24
So if we ever really want to understand
03:28
the biological basis of psychiatric disorders,
03:30
we need to pinpoint these locations in the brain
03:33
where these chemicals act.
03:36
Otherwise, we're going to keep pouring oil all over our mental engines
03:38
and suffering the consequences.
03:41
Now to begin to overcome our ignorance
03:44
of the role of brain chemistry in brain circuitry,
03:47
it's helpful to work on what we biologists call
03:51
"model organisms,"
03:54
animals like fruit flies and laboratory mice,
03:55
in which we can apply powerful genetic techniques
03:59
to molecularly identify and pinpoint
04:02
specific classes of neurons,
04:06
as you heard about in Allan Jones's talk this morning.
04:07
Moreover, once we can do that,
04:10
we can actually activate specific neurons
04:13
or we can destroy or inhibit the activity of those neurons.
04:15
So if we inhibit a particular type of neuron,
04:19
and we find that a behavior is blocked,
04:22
we can conclude that those neurons
04:25
are necessary for that behavior.
04:27
On the other hand, if we activate a group of neurons
04:30
and we find that that produces the behavior,
04:32
we can conclude that those neurons are sufficient for the behavior.
04:35
So in this way, by doing this kind of test,
04:39
we can draw cause and effect relationships
04:42
between the activity of specific neurons
04:46
in particular circuits and particular behaviors,
04:48
something that is extremely difficult, if not impossible,
04:51
to do right now in humans.
04:53
But can an organism like a fruit fly, which is --
04:58
it's a great model organism
05:01
because it's got a small brain,
05:03
it's capable of complex and sophisticated behaviors,
05:06
it breeds quickly, and it's cheap.
05:10
But can an organism like this
05:13
teach us anything about emotion-like states?
05:15
Do these organisms even have emotion-like states,
05:19
or are they just little digital robots?
05:22
Charles Darwin believed that insects have emotion
05:25
and express them in their behaviors, as he wrote
05:28
in his 1872 monograph on the expression of the emotions in man and animals.
05:31
And my eponymous colleague, Seymour Benzer, believed it as well.
05:36
Seymour is the man that introduced the use of drosophila
05:40
here at CalTech in the '60s as a model organism
05:43
to study the connection between genes and behavior.
05:47
Seymour recruited me to CalTech in the late 1980s.
05:50
He was my Jedi and my rabbi while he was here,
05:54
and Seymour taught me both to love flies
05:58
and also to play with science.
06:01
So how do we ask this question?
06:04
It's one thing to believe that flies have emotion-like states,
06:07
but how do we actually find out whether that's true or not?
06:11
Now, in humans we often infer emotional states,
06:14
as you'll hear later today, from facial expressions.
06:18
However, it's a little difficult to do that in fruit flies.
06:22
(Laughter)
06:26
It's kind of like landing on Mars
06:29
and looking out the window of your spaceship
06:32
at all the little green men who are surrounding it
06:35
and trying to figure out, "How do I find out
06:37
if they have emotions or not?"
06:40
What can we do? It's not so easy.
06:42
Well, one of the ways that we can start
06:46
is to try to come up with some general characteristics
06:48
or properties of emotion-like states
06:52
such as arousal, and see if we can identify
06:56
any fly behaviors that might exhibit some of those properties.
06:59
So three important ones that I can think of
07:04
are persistence, gradations in intensity, and valence.
07:07
Persistence means long-lasting.
07:12
We all know that the stimulus that triggers an emotion
07:14
causes that emotion to last long after the stimulus is gone.
07:18
Gradations of intensity means what it sounds like.
07:23
You can dial up the intensity or dial down the intensity of an emotion.
07:26
If you're a little bit unhappy, the corners of your mouth
07:31
turn down and you sniffle,
07:34
and if you're very unhappy, tears pour down your face
07:35
and you might sob.
07:38
Valence means good or bad, positive or negative.
07:40
So we decided to see if flies could be provoked into showing
07:45
the kind of behavior that you see
07:49
by the proverbial wasp at the picnic table,
07:51
you know, the one that keeps coming back to your hamburger
07:54
the more vigorously you try to swat it away,
07:57
and it seems to keep getting irritated.
07:59
So we built a device, which we call a puff-o-mat,
08:02
in which we could deliver little brief air puffs to fruit flies
08:05
in these plastic tubes in our laboratory bench
08:10
and blow them away.
08:13
And what we found is that if we gave these flies
08:14
in the puff-o-mat several puffs in a row,
08:17
they became somewhat hyperactive
08:20
and continued to run around for some time after the air puffs actually stopped
08:23
and took a while to calm down.
08:27
So we quantified this behavior
08:30
using custom locomotor tracking software
08:33
developed with my collaborator Pietro Perona,
08:36
who's in the electrical engineering division here at CalTech.
08:38
And what this quantification showed us is that,
08:42
upon experiencing a train of these air puffs,
08:45
the flies appear to enter a kind of state of hyperactivity
08:48
which is persistent, long-lasting,
08:52
and also appears to be graded.
08:55
More puffs, or more intense puffs,
08:57
make the state last for a longer period of time.
09:00
So now we wanted to try to understand something
09:04
about what controls the duration of this state.
09:06
So we decided to use our puff-o-mat
09:10
and our automated tracking software
09:13
to screen through hundreds of lines of mutant fruit flies
09:15
to see if we could find any that showed abnormal responses to the air puffs.
09:19
And this is one of the great things about fruit flies.
09:24
There are repositories where you can just pick up the phone
09:26
and order hundreds of vials of flies of different mutants
09:29
and screen them in your assay and then find out
09:32
what gene is affected in the mutation.
09:35
So doing the screen, we discovered one mutant
09:38
that took much longer than normal to calm down
09:41
after the air puffs,
09:45
and when we examined the gene that was affected in this mutation,
09:47
it turned out to encode a dopamine receptor.
09:51
That's right -- flies, like people, have dopamine,
09:55
and it acts on their brains and on their synapses
09:58
through the same dopamine receptor molecules
10:01
that you and I have.
10:03
Dopamine plays a number of important functions in the brain,
10:05
including in attention, arousal, reward,
10:09
and disorders of the dopamine system have been linked
10:12
to a number of mental disorders including drug abuse,
10:16
Parkinson's disease, and ADHD.
10:19
Now, in genetics, it's a little counterintuitive.
10:23
We tend to infer the normal function of something
10:26
by what doesn't happen when we take it away,
10:29
by the opposite of what we see when we take it away.
10:33
So when we take away the dopamine receptor
10:36
and the flies take longer to calm down,
10:39
from that we infer that the normal function of this receptor and dopamine
10:41
is to cause the flies to calm down faster after the puff.
10:45
And that's a bit reminiscent of ADHD,
10:50
which has been linked to disorders of the dopamine system in humans.
10:52
Indeed, if we increase the levels of dopamine in normal flies
10:56
by feeding them cocaine
11:01
after getting the appropriate DEA license
11:03
— oh my God -- (Laughter) —
11:06
we find indeed that these cocaine-fed flies
11:10
calm down faster than normal flies do,
11:13
and that's also reminiscent of ADHD,
11:16
which is often treated with drugs like Ritalin
11:19
that act similarly to cocaine.
11:21
So slowly I began to realize that what started out
11:24
as a rather playful attempt to try to annoy fruit flies
11:27
might actually have some relevance to a human psychiatric disorder.
11:31
Now, how far does this analogy go?
11:35
As many of you know, individuals afflicted with ADHD
11:37
also have learning disabilities.
11:40
Is that true of our dopamine receptor mutant flies?
11:43
Remarkably, the answer is yes.
11:46
As Seymour showed back in the 1970s,
11:49
flies, like songbirds, as you just heard,
11:52
are capable of learning.
11:54
You can train a fly to avoid an odor, shown here in blue,
11:56
if you pair that odor with a shock.
12:00
Then when you give those trained flies the chance to choose
12:03
between a tube with the shock-paired odor and another odor,
12:06
it avoids the tube containing the blue odor that was paired with shock.
12:09
Well, if you do this test on dopamine receptor mutant flies,
12:13
they don't learn. Their learning score is zero.
12:17
They flunk out of CalTech.
12:19
So that means that these flies have two abnormalities,
12:23
or phenotypes, as we geneticists call them,
12:28
that one finds in ADHD: hyperactivity and learning disability.
12:31
Now what's the causal relationship, if anything, between these phenotypes?
12:36
In ADHD, it's often assumed that the hyperactivity
12:41
causes the learning disability.
12:45
The kids can't sit still long enough to focus, so they don't learn.
12:47
But it could equally be the case that it's the learning disabilities
12:50
that cause the hyperactivity.
12:54
Because the kids can't learn, they look for other things to distract their attention.
12:55
And a final possibility is that there's no relationship at all
13:00
between learning disabilities and hyperactivity,
13:03
but that they are caused by a common underlying mechanism in ADHD.
13:05
Now people have been wondering about this for a long time
13:10
in humans, but in flies we can actually test this.
13:13
And the way that we do this is to delve deeply into the mind
13:16
of the fly and begin to untangle its circuitry using genetics.
13:19
We take our dopamine receptor mutant flies
13:24
and we genetically restore, or cure, the dopamine receptor
13:26
by putting a good copy of the dopamine receptor gene
13:31
back into the fly brain.
13:34
But in each fly, we put it back only into certain neurons
13:36
and not in others, and then we test each of these flies
13:40
for their ability to learn and for hyperactivity.
13:43
Remarkably, we find we can completely dissociate these two abnormalities.
13:47
If we put a good copy of the dopamine receptor back
13:52
in this elliptical structure called the central complex,
13:55
the flies are no longer hyperactive, but they still can't learn.
13:57
On the other hand, if we put the receptor back in a different structure
14:02
called the mushroom body,
14:04
the learning deficit is rescued, the flies learn well,
14:06
but they're still hyperactive.
14:09
What that tells us is that dopamine
14:11
is not bathing the brain of these flies like soup.
14:13
Rather, it's acting to control two different functions
14:16
on two different circuits,
14:20
so the reason there are two things wrong with our dopamine receptor flies
14:21
is that the same receptor is controlling two different functions
14:25
in two different regions of the brain.
14:29
Whether the same thing is true in ADHD in humans
14:32
we don't know, but these kinds of results
14:35
should at least cause us to consider that possibility.
14:38
So these results make me and my colleagues more convinced than ever
14:41
that the brain is not a bag of chemical soup,
14:45
and it's a mistake to try to treat complex psychiatric disorders
14:48
just by changing the flavor of the soup.
14:52
What we need to do is to use our ingenuity and our scientific knowledge
14:55
to try to design a new generation of treatments
14:59
that are targeted to specific neurons and specific regions of the brain
15:02
that are affected in particular psychiatric disorders.
15:06
If we can do that, we may be able to cure these disorders
15:09
without the unpleasant side effects,
15:12
putting the oil back in our mental engines,
15:14
just where it's needed. Thank you very much.
15:17
Translator:Joseph Geni
Reviewer:Morton Bast

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David Anderson - Neurobiologist
Through his lab at the California Institute of Technology, David Anderson seeks to find the neural underpinnings of emotions like fear, anxiety and anger.

Why you should listen

How is emotional behavior encoded in the brain? And what parts of the brain are affected by depression, ADHD and anxiety? This is what neurobiologist David Anderson researches in his lab at the California Institute for Technology by studying the brains of lab mice and fruit flies. By looking at how neural circuits give rise to emotions, Anderson hopes to advance a more nuanced view of psychiatric disorders -- that they aren’t the result of a simple “chemical imbalance,” but of a chemical imbalance at a specific site that has a specific emotional consequences. By researching these cause-and-effect relationships, Anderson hopes to pave the way for the development of new treatments for psychiatric disorders that are far more targeted and have far fewer side effects.

Trained by two Nobel laureates, Gunter Blobel and Richard Axel, Anderson is also an investigator at the Howard Hughes Medical Institute.

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