Drugs, dopamine and drosophila -- A fly model for ADHD? | David Anderson | TEDxCaltech

Hello, first I would like to thank everyone who came here to learn that Caltech is more than rocket science and earthquakes. Not that JPL, rocket science, and space exploration aren't cool, but those of us who are neuroscientists here know that the brain is the final frontier, so raise your hand if you know anyone in your immediate family or family. circle of friends who suffer from some type of mental illness. I thought I wouldn't be surprised and raise your hand if you think basic research on fruit flies has anything to do with it. to do with understanding mental illness in humans, yes, I thought so.

I'm also not surprised to see that I have a lot of work ahead of me, as Dr. Insel told us this morning. Psychiatric disorders such as autism, depression and schizophrenia take a terrible toll on humans. suffering we know much less about its treatment and understanding of its basic mechanisms than about diseases of the body. Think about it in 2013, the second decade of the Millennium, if you are worried about a cancer diagnosis and go to your doctor. Get bone scans, biopsies and blood tests in 2013. If you're worried about a diagnosis of depression, you go to your doctor and receive a questionnaire.

Part of the reason for this is that we have an oversimplified and increasingly outdated view of the biological basis. Of psychiatric disorders we tend to see them and the popular press is complicit in this view as chemical imbalances in the brain, as if the brain were some kind of chemical soup bag full of

dopamine

, serotonin and neopinaphrine. This view is conditioned by the fact that Many of the medications prescribed to treat these disorders, such as Prozac, act by globally changing the chemistry of the brain as if the brain were actually a bag of chemical soup, but that cannot be the answer because these medications don't actually work that well.

Many people do not take them or stop taking them because of their unpleasant side effects. These medications have so many side effects because using them to treat a complex psychiatric disorder is a little like trying to change engine oil by opening a can and pouring some in will spread all over the engine block, some will drip in the right place, but some will much of it will do more harm than good. Now, an emerging view that Dr. Insel also heard about this morning is that psychiatric disorders are actually disorders of the nervous system. circuits that mediate emotion, mood, and affect when we think about cognition we make an analogy of the brain to a computer, that's no problem, well, it turns out the computer analogy is just as valid for emotion, just We don't tend to think about it that way. but we know that we know much less about the circuit basis of psychiatric disorders due to the overwhelming prevalence of this chemical imbalance hypothesis.

Now, it's not that chemicals aren't important in psychiatric disorders, it's just that they don't wash over the brain like soup, but they do. They are released in very specific places and 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 must identify these places in the brain where these chemicals act, Otherwise, we will continue to pour oil into our mental engines and suffer the consequences now to begin to overcome our ignorance of the role of brain chemistry and circuits.

It is useful to work on what biologists call

model

organisms, animals like fruit flies and laboratory mice. in which we can apply powerful genetic techniques to identify and pinpoint specific classes of neurons, as he heard about Alan Jones' talk this morning. Furthermore, once we can do that, we can activate specific neurons or we can destroy or inhibit the activity of those neurons. so if we inhibit a particular type of neuron and 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 find that that produces the behavior, we can conclude. that those neurons are sufficient for behavior, so by doing this type of testing we can establish cause-and-effect relationships between the activity of specific neurons in particular circuits and a particular behavior, something that is extremely difficult, if not impossible, to do. do right now. humans, but can an organism like a fruit fly, which is a great

model

organism because it has a small brain, is capable of complex and sophisticated behaviors, reproduces quickly, and is cheap, but can an organism like this teach us something about emotions like states do?

These organisms even have emotional states or are simply small digital robots. Charles Darwin believed that insects had emotions and expressed them in their behavior, as he and my freelance colleague Seymour Benzer wrote in his 1872 monograph on the expression of emotions in man and animals. He believed it too. Seymour is the man who introduced the use of dropa here at Caltech in the 1960s as a model organism to study the connection between genes and behavior. Seymour recruited me to Caltech in the late 80's, he was my Jedi and my rabbi while he was here and Seymour taught me to love flies and also to play with science.

So how do we ask this question? It's one thing to believe that flies have emotions like states, but how can we know if that's true or not? In humans we are often in emotional states, as you will hear later today from facial expressions. However, it is a bit difficult to do so. In fruit flies, it's like landing on Mars and looking out the window of your spaceship at all the little green men that are surrounding you and trying to figure out how I can tell if they have emotions or not. What can we do? It's not that easy.

Well, one of the ways we can start is to try to find some general characteristics or properties of emotion-like states, like arousal, and see if we can identify some fly behavior that might exhibit some of those properties, so I can think of three important ones: gradations of persistence in intensity and veil, persistence means lasting, we all know that the stimulus that triggers an emotion makes the emotion last long after the stimulus disappears gradations of intensity mean how it sounds you can increase or decrease the intensity of emotion of an emotion if you are a little unhappy the corners of your mouth turn down and you sob and if you are very unhappy, tears fall down your face and the son of a bitch veil may mean good or bad, positive or negative, so we decided to see if the flies could be caused to display the kind of behavior you see in the proverbial wasp on the picnic table, you know, the one that keeps coming back to your burger the more vigorously you try to squish it and seems to keep coming back. irritated, so we built a device we called a puffo mat where we could briefly administer some air.

We blew the fruit flies into these plastic tubes on our lab table and blew them, and what we found is that if we gave these flies several puffs in a row, they became somewhat hyperactive and continued to run around for some time after the blow. The puffs of air actually stopped and took a while to calm down, so we quantified this behavior using custom locomotive tracking software developed with my collaborator Petro Perona, who is in the electrical engineering division here at Caltech and what this Quantification showed us is that by experiencing a train of these puffs of air the flies seem to enter a kind of state of hyperactivity that is persistent and long-lasting and also seems to graduate to more or more intense puffs.

Puffs make the state last longer, so now we wanted to try to understand something about what controls the duration of this state, so we decided to use our puff and our automated tracking software to examine hundreds of lines of flies from the fruit mutants to see if we could find any that showed abnormal responses to puffs of air and this is one of The great thing about fruit flies is that there are warehouses where you can just pick up the phone and order hundreds of vials of flies from different mutants and examine them in your assay and then find out which gene is affected in the mutation, so by doing this screen we discovered a mutant that took much longer than normal to calm down after the puffs of air and when we examined the gene that was affected in This mutation turned out to encode a

dopamine

receptor that flies as if people had dopamine and acts in their brains and in their synapses through the same dopamine receptor molecules that you and I have.

Dopamine plays a number of important functions in the brain, including attention, 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 is a bit contradictory, we tend to infer the normal function of something by what doesn't happen when we remove it, contrary to what we see when we remove it, so when we remove the dopamine receptor and the flies take longer to calm down , from which we infer that the normal function of this receptor and dopamine is to make the flies calm down faster after the puff and that is somewhat reminiscent of ADHD, which has been linked to disorders of the dopamine system in humans.

In fact, if we increase the dopamine levels in normal flies by feeding them cocaine after obtaining the proper license from the DEA, oh my goodness, we find that these cocaine-fed flies calm down faster than normal flies and that is also reminiscent of the ADHD, which is often treated with

drugs

like rlin that act similarly to cocaine, so slowly I began to realize that what started out as a rather fun attempt at trying to annoy fruit flies could actually have some relevance to a human psychiatric disorder. Now, how far does this analogy go for many of you?

We know that people who suffer from ADHD also have learning problems. This is true in the case of our dopamine receptor mutant flies. Surprisingly, the answer is yes, as Seymour demonstrated in the 1970s. Flies, like songbirds, as you just heard, are capable of learning. You can train a fly to avoid a The odor shown here in blue, if you pair that odor with a shock, when you give those trained flies the opportunity to choose between a tube with the shock odor paired and another odor, they will avoid the tube containing the blue smell that was combined with the shock.

You do this test on dopamine receptor mutant flies, they don't learn, their learning score is zero, now they failed Caltech, which means that these flies have two abnormalities or phenotypes, as we geneticists call them, and ADHD, hyperactivity is found. and learning disability. Now, what is the causal relationship, if anything, between these phenotypes in ADHD? It is often assumed that hyperactivity causes learning disabilities - children cannot sit still long enough to concentrate, so they do not learn - but it could also be the case that it is learning disabilities that cause hyperactivity because children C cannot learn, they look for other things to distract their attention, and a final possibility is that there is no relationship between learning disabilities and hyperactivity, but rather they are caused by a common underlying mechanism in People with ADHD have been wondering about This has been going on for a long time in humans, but in flies we can test this and the way we do it is we go deep into the mind of the fly and start to unravel its circuits using the genetics that we take from our mind. 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's brain, but in each fly we return it only to certain neurons and not others and then we try Each of them highlighting these flies for their ability to learn and for their hyperactivity, we found that we can completely dissociate these two abnormalities if we put a good copy of the dopamine receptor back into this elliptical structure called the central complex.

Flies are no longer hyperactive, but they still can. On the other hand, they do not learn if we put the receptor back into a different structure called a mushroom body, the learning deficit is rescued. Flies learn well but remain hyperactive. What this tells us is that dopamine does not bathe their brains. Flies are like soup, rather they act to control two different functions in two different circuits, so the reason there are two things wrong with our dopamine receptor in the fly is that the same receptor controls two different functions in two different regions of the brain, whether they are about the same thing.

It is true in ADHD and in humans, we do not know, but these types of resultsshould at least make us 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 is a mistake to try to treat complex psychiatric disorders simply by changing the flavor of the soup. What we need to do is use our ingenuity and our scientific knowledge to try to design a new generation of treatments that target specific neurons and regions of the brain. brains that are affected in particular psychiatric disorders, if we can do that, we will be able to cure these disorders without the unpleasant side effects, returning the oil to our metal engines right where it is needed, thank you very much.