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