Your brain is more than a bag of chemicals David Anderson

so raise your hand if you know someone

in your immediate family or circle of

friends who suffers from some form of

mental illness I thought so not

surprised and raise your hand if you

think that basic research on fruit flies

has anything to do with understanding

mental illness and humans yeah I thought

so I’m also not surprised I can see I

got my work cut out for me here as we

heard from dr. ensel this morning

psychiatric disorders like autism

depression and schizophrenia take a

terrible toll on human suffering we know

much less about their treatment and the

understanding of their basic mechanisms

than we do about diseases of the body

think about it

in 2013 the second decade of the

millennium if you’re concerned about a

cancer diagnosis and you go to your

doctor you get bone scans biopsies and

blood tests in 2013 if you’re concerned

about a depression diagnosis you go to

your doctor and what do you get a

questionnaire part of the reason for

this is that we have an oversimplified

and increasingly outmoded view of the

biological basis of psychiatric

disorders we tend to view them and the

popular press aids and abets this view

as chemical imbalances in the brain as

if the brain were some kind of bag of

chemical soup full of dopamine serotonin

and norepinephrine this view is

conditioned by the fact that many of the

drugs that are prescribed to treat these

disorders like prozac act by globally

changing brain chemistry as if the brain

were indeed a bag of chemical soup but

that can’t be the answer because these

drugs actually don’t work all that well

a lot of people won’t take them or stop

taking them because of their unpleasant

side effects these drugs have so many

side effects because using them to treat

a complex psychiatric disorder is a bit

like trying to change your engine oil by

opening a can

and pouring it all over the engine block

some of it will dribble into the right

place but a lot of it will do more harm

than good now an emerging view that you

also heard about from dr. ensel this

morning is that psychiatric disorders

are actually disturbances of neural

circuits that mediate emotion mood and

affect when we think about cognition we

analogize the brain to a computer that’s

no problem

well it turns out that the computer

analogy is just as valid for emotion

it’s just that we don’t tend to think

about it that way but we know we know

much less about the circuit basis of

psychiatric disorders because of the

overwhelming dominance of this chemical

imbalance hypothesis now it’s not that

chemicals are not important in

psychiatric disorders it’s just that

they don’t bathe the brain like soup

rather they’re released in very specific

locations and they act on specific

synapses to change the flow of

information in the brain so if we ever

really want to understand the biological

basis of psychiatric disorders we need

to pinpoint these locations in the brain

where these chemicals act otherwise

we’re going to keep pouring oil all over

our mental engines and suffering the

consequences now to begin to overcome

our ignorant of the role of brain

chemistry and brain circuitry it’s

helpful to work on what we biologists

call model organisms animals like fruit

flies and laboratory mice in which we

can apply powerful genetic techniques to

molecularly identify and pinpoint

specific classes of neurons as you heard

about an Alan Jones’s talk this morning

moreover once we can do that we can

actually activate specific neurons or we

can destroy or inhibit the activity of

those neurons so if we inhibit a

particular type of neuron and we find

that a behavior is blocked we can

conclude that those neurons are

necessary for that behavior on the other

hand if we activate a group of neurons

and we find that that produces

behavior we can conclude that those

neurons are sufficient for the behavior

so in this way by doing this kind of

tests we can draw cause-and-effect

relationships between the activity of

specific neurons in particular circuits

and particularly havior something that

is extremely difficult if not impossible

to do right now in humans but can an

organism like a fruit fly which is it’s

a great model organism because it’s got

a small brain it’s capable of complex

and sophisticated behaviors it breeds

quickly and it’s cheap but can an

organism like this teach us anything

about emotion like states do these

ordinance even have emotion like States

or are they just little digital robots

Charles Darwin believed that insects

have emotion and express them in their

behaviors as he wrote in his 1872

monograph on the expression of the

emotions in man and animals and my

eponymous colleague Seymour Benzer

believed it as well Seymour is the man

that introduced the use of Drosophila

here at Caltech in the 60s as a model

organism to study the connection between

genes and behavior seem were recruited

me to Caltech in the late 1980s he was

my Jedi and my rabbi while he was here

and Seymour taught me both to love flies

and also to play with science so how do

we how do we ask this question it’s one

thing to believe that flies have emotion

like States but how do we actually find

out whether that’s true or not now in

humans we often infer emotional states

as you’ll hear later today from facial

expressions however it’s a little

difficult to do that in fruit flies

it’s kind of like landing on Mars and

looking out the window of your spaceship

at all the little green men who are

surrounding it and trying to figure out

how do I find out if they have emotions

or not what can we do it’s not so easy

well one of the ways that we can start

is to try to come up with some general

characteristics or properties of emotion

like states such as arousal and see if

we can identify any fly behaviors that

might exhibit some of those properties

so three important ones that I can think

of our persistence gradations and

intensity and valence persistence means

long lasting we all know that the

stimulus that triggers an emotion causes

that emotion to last long after the

stimulus is gone rotations of intensity

means what it sounds like you can dial

up the intensity or dial down the

intensity of emotion of an emotion if

you’re a little bit unhappy the corners

of your mouth turned down and you

sniffle and if you’re very unhappy tears

pour down your face and you might sob

valence means good or bad positive or

negative so we decided to see if flies

could be provoked into showing the kind

of behavior that you see by the

proverbial wasp at the picnic table you

know the one that keeps coming back to

your hamburger the more vigorously you

try to swat it away and it seems to keep

getting irritated so we built a device

which we call a puff oh man in which we

could deliver little grief air puffs to

fruit flies in these plastic tubes in

our laboratory bench and blow them away

and what we found is that if we gave

these flies in the puffs I’m at several

puffs in a row they became somewhat

hyperactive and continue to run around

for some time after the air puffs

actually stopped and took a while to

come to calm down so we quantified this

behavior using look custom locomotor

tracking software developed with my

collaborator Pietro Perona who’s in the

electrical engineering division here

Caltech and what this quantification

showed us is that upon experiencing a

train of these air puffs the flies

appear to enter a kind of state of hyper

activity which is persistent long

lasting and also appears to be graded

more puffs or more intense puffs make

the state last for a longer period of

time so now we wanted to try to

understand something about what controls

the duration of this state so we decided

to use our puffs a mat and our automated

tracking software to screen through

hundreds of lines of mutant fruit flies

to see if we could find any that showed

abnormal responses to the air puffs and

this is one of the great things about

fruit flies there are repositories where

you can just pick up the phone and order

hundreds of vials of flies of different

mutants and screen them in your assay

and then find out what gene is affected

in the mutation so doing this screen we

discovered one mutant that took much

longer than normal to calm down after

the air puffs and when we examined the

gene that was affected in this mutation

it turned out to encode a dopamine

receptor that’s right flies like people

have dopamine and it acts on their

brains and on their synapses through the

same dopamine receptor molecules that

you and I have dopamine plays a number

of important functions in the brain

including an attention arousal reward

and disorders of the dopamine system

have been linked to a number of mental

disorders including drug abuse

Parkinson’s disease and ADHD now in

genetics it’s a little counterintuitive

we tend to infer the normal function of

something by what doesn’t happen when we

take it away by the opposite of what we

see when we take it away so when we take

away the dopamine receptor and the Flies

take longer to calm down from that we

infer that the normal function of this

receptor and dopamine is to cause the

Flies to calm down faster

after the puffs and that’s a bit

reminiscent of ADHD which has been

linked to disorders of the dopamine

system in humans indeed if we increase

the levels of dopamine in normal flies

by feeding them cocaine after getting

the appropriate DEA license oh my god we

find indeed that these cocaine fed flies

calm down faster than normal flies do

and that’s also reminiscent of ADHD

which is often treated with drugs like

ritalin that act similarly to cocaine so

slowly I began to realize that what

started out as a rather playful attempt

to try to annoy fruit flies might

actually have some relevance to a human

psychiatric disorder now how far does

this analogy go as many of you know

individuals afflicted with ADHD also

have learning disabilities is that true

of our dopamine receptor mutant flies

remarkably the answer is yes as Seymour

showed back in the 1970s flies like

songbirds as you just heard are capable

of learning you can train a fly to avoid

an odor shown here in blue if you pair

that odor with a shock then when you

give those trained flies the chance to

choose between a tube with the shock

paired odor and another odor it avoids

the tube containing the blue odor that

was paired with shock well if you do

this test on dopamine receptor mutant

flies they don’t learn their learning

score is zero they flunk out of Caltech

now so that means that these flies have

two abnormalities or phenotypes as we

geneticists call them that one finds an

ADHD hyperactivity and learning

disability now what’s the causal

relationship if anything between these

phenotypes in ADHD it’s often assumed

that the hyperactivity causes the

learning disability the kids can’t sit

still long enough to focus so they don’t

learn but it could equally be the case

that it’s the learning disabilities that

caused the hyperactivity because the

kids can’t learn they look for other

things to distract their attention and a

final possibility is that there

no relationship at all between learning

disabilities and hyperactivity but that

they are caused by a common underlying

mechanism in ADHD

now people have been wondering about

this for a long time in humans but in

flies we can actually test this and the

way that we do this is to delve deeply

into the mind of the fly and begin to

untangle its circuitry using genetics we

take our dopamine receptor mutant flies

and we genetically restore or cure the

dopamine receptor by putting a good copy

of the dopamine receptor gene back into

the fly brain but in each fly we put it

back only into certain neurons and not

in others and then we test each of their

these flies for their ability to learn

and for hyperactivity remarkably we find

we can completely dissociate these two

abnormalities if we put a good copy of

the dopamine receptor back in this

elliptical structure called the central

complex the Flies are no longer

hyperactive but they still can’t learn

on the other hand if we put the receptor

back in a different structure called the

mushroom body the learning deficit is

rescued the Flies learn well but they’re

still hyperactive what that tells us is

that dopamine is not bathing the brain

of these flies like soup rather it’s

acting to control two different

functions on two different circuits so

the reason there are two things wrong

with our dopamine receptor flies that

the same receptor is controlling two

different functions in two different

regions of the brain whether the same

thing is true in ADHD in humans we don’t

know but these kinds of results should

at least cause us to consider that

possibility so these results make me and

my colleagues more convinced than ever

that the brain is not a bag of chemical

soup and it’s a mistake to try to treat

complex psychiatric disorders just by

changing the flavor of the soup what we

need to do is to use our ingenuity and

our scientific knowledge to try to

design a new generation of treatments

that are targeted to specific neurons

and specific regions of the brain that

are affected in particular psychiatric

disorders if we can do that we may be

able to cure these disorders without the

unpleasant side effects putting the oil

back

in our metal engines just where it’s

needed thank you very much