Ann Graybiel, On Receiving the 2001 National Medal of Science

[MUSIC PLAYING] brain we work on, it's called the basal ganglia. And these regions of the brain lie deep underneath the cortex, which is the part most people know about and see in all the pictures of the brain. And that's a beautiful rind of nervous tissue on the outside of the brain. And it's probably our strongest computer. It's a fabulous machine. But underneath that are deep lying brain nuclei. And the basal ganglia are the largest of these. They're tremendously important in a number of disorders, Parkinson's disease, Huntington's, OCD, obsessive compulsive disorder, Tourette, depression. How can all these disorders be related to one set of nuclei in the brain? And if this cerebral cortex is so special in our great computer, what is it that these other brain regions do? When we set out to study them, not much was known about these deep structures. Partly because they're deep, it's hard to study them. Very difficult to study them. So we were in the very lucky position of discovering, like an archaeologist at a town that had been buried and not that much was known about it. So we can just begin to look at the road maps, what were the inputs and the outputs? There are so many neurotransmitters that are the chemical messengers in the brain. And this region is very, very rich in these. And so again, we were lucky because we could begin to map out these chemical messengers in relation to the traffic flow coming in and out. And so that's where we started. Then it turned out, well, gee, when we learned about this architecture, it looked a lot like learning architectures that had been studied by the computational people who were interested in the logic of the brain. And so we were very excited by that. Because it meant that maybe this region of the brain that we were specializing on had a lot to do with taking inputs from that great cortical computer and reconfiguring them, mixing them up, making new combinations, and then helping the outflow of this system produce actions. And the more we looked, the more it became clear from the whole field, it's not just our work, that the outflow goes not only to motor actions, as is so famous in the case of the terrible disorders such as Parkinson's disease or Huntington's disease. But the outflow also goes to organize our cognitive actions if you will. The way we think, whether we're up or down, whether we're happy or not. So it's a very, very rich system. We were lucky to be early in on trying to work on it. I guess what this has led to is that we now are looking very, very hard at how this system might learn. How do we learn the kinds of things that are mediated by the system? For example, there's a lot of evidence that the basal ganglia have to do with learning habits. Learning just simple behavioral routines. Just the kinds of things that all of us do. And so it turns out, if you really think about it, that most of what we do every day, we do without really thinking about that. It's almost the definition of a habit. And what that means is that that frees up our big cognitive machine to do all sorts of other things, to take in new inputs, think great thoughts. I mean, at MIT there are brilliant people here. Maybe think of a new equation. Something about the origin of the universe. So having this deep brain system helping us get regularities in our lives is tremendously important. Contributing maybe a little bit to this whole enterprise of learning about these structures and how they influence this cerebral cortex, or big computer, has been what we've done and we're very, very privileged to be able to work on it. It's a very wonderful thing that people are becoming aware of Parkinson's, and how many people can become afflicted with it. And the whole family of disorders related to Parkinson's disease. Thinking about what we've learned, there's an explosion of new information that's directly relevant to trying to develop therapies, and even prevent Parkinson's disease. Many forms of Parkinson's disease are not hereditary, but some are. The fact that some are means that people are able now to go and find the genes that are responsible for those hereditary forms. And getting your hands on genes means getting your hands on the molecules that control the way the neurons function. So that surely is terribly important. And then coming to these neural circuits and the chemical coding of them, the primary cause of Parkinson's disease is the loss of the neurotransmitter dopamine. It's an amazing neurotransmitter, really. A remarkable system, and as this dopamine and its nervous tracks die back, then Parkinson's ensues. So therapies now are directed toward replacing the dopamine, or, most recently in using, for example, either a lesion in the brain or stimulation deep in the brain to help undo the damage that the loss of dopamine has done. I guess a crude analogy would be that in Parkinson's disease, the wrong messages are coming out of the basal ganglia. And they're really wrong. It's sort of like static coming out of a radio or a high-fi. So getting rid of the static, even though it may not produce a perfectly normal brain, nevertheless is a tremendous help to many people with this disorder and with related disorders, disorders related to Parkinson's disease. Things are very hopeful. So why is it so difficult to get at the root disorder in Tourette syndrome or obsessive compulsive disorder? And those, I might say, are well-known examples of a whole family of disorders. Let me come back one more time to this idea of circuits. Imagine that we have this beautiful cortex, which is computing things about the world. And then the basal ganglia are interacting with this system, over and over again, in a giant neural loop, so to say. It's now thought that that loop, at least one very particular part of that loop, is disordered in OCD, obsessive compulsive disorder, and probably in Tourette syndrome too. So what does that mean? For example, in obsessive compulsive disorder, people may have a huge, uncontrollable feeling that they have to do something. Somebody leaves the house, says gee, did I remember to take the things I had to take? So they go back in the house. They check, it's okay, and they leave. And then they are really obsessed with, did I really have what I needed to take? And they go back and so on and so on. These obsessional ideas lead people to do things repetitively over and over again. One idea is that the reason it's difficult to understand every little piece of the neural mechanism underlying these disorders, is that they aren't disorders of one tiny little piece of brain, but of a whole neural network which is churning away, and somehow got stuck. Things are going over and over again. And so what we're trying to do is study the neural basis of repetitive behaviors. And my colleagues and I have been trying to understand what genes are turned on in the brain when, in model systems, repetitive behaviors are generated just over and over again. Also, what neural systems, what's exactly the loop? And what are the neurotransmitters exactly in that disordered loop? So if we can find that out, then we're a long, long way forward toward therapy. Yes, so the question is, what is the basis of addiction? And how do we form habits, and how are habits related to addiction or addictive behaviors, if they are at all? What are we doing in the lab? Let me just say that one of the things that we are studying, we're very interested in how we learn habits. How we learn them, and then how habits can be broken. How do you make a habit? How do you break a habit? How come some habits are good and some habits are bad? And why is it that sometimes something that seems relatively innocuous, like having one cigarette, could lead to a real addiction to cigarettes? Or to any other substance that tends to make us do it again and again, and want it more and more. I must say that it's been thrilling to begin to look at the neural basis of habit formation. Because what we're seeing, and others too, is that as an animal acquires a simple habit, just a simple, simple little habit, the neurons in the basal ganglia and also in the cortex, these nerve cells really dramatically change the way they fire. They become "interested", in quotes, in different aspects of the outside world. And so they develop a whole new kind of world map, where one thing or one trigger becomes very important. And then the other thing that seems to happen is that as we do develop these habits, at least as animals do, then in the brain the various elements of the whole action, let's say we have a habit of putting your hand in your pocket and rattling your keys, or fiddling with your hair, or something like that. Actually if you look at it, any one of these little mannerisms or habits that we have, any one is made up of many different components, little sub-parts. So one of the things we think is that maybe as habits are formed, these get chunked together so they naturally link to each other and then, bang. If you see the trigger, or you have the internal trigger coming out of your brain or your mind, then the whole thing comes out. And that's what makes it so hard, one of the things that makes it so hard to break a habit. Again, if you think of the person who smokes a cigarette, for example, it turns out the context is so important. Like, you like to have a cup of coffee, or a cigarette, or something in a given place, in a given context. Or you just see something where you usually get your cup of coffee, and then you want it really badly. So the triggers for behaviors can become out of proportion important to our behavior. And that may be part of what gets these loops going. And some of the very same loops that are disordered in OCD or Tourette may in fact be the ones that are driving us when we have addictive habits. But I must say that there's a very wonderful side of habits. And that's that if you have a habit and you don't have to think. Say you get in the car. You want to drive, you see a red light. You automatically put your foot on the brake. It never even occurs to you, you don't think it all out. What that means is you can be thinking of other things. And so it is with the rest of life. So really, I think it's profoundly important to understand what neurotransmitters, what genes, what neural pathways, what loops in the brain are going when we have normal habit formation or addictive habit formation. And then what little tricks can we use to break the bad ones? That's very central to what we work on in the lab. You know, I'm not even sure that we understand the code that's used in the brain. I don't think there are many people who would dare to know whether we are even beginning to know just the code, the language of the brain. We're learning many different potential codes of the brain. So how far are we off? It's anybody's guess. But I'll tell you, I think the progress, just even in the last very few years, has been, it's fabulous how much we're learning. You know, I think that's reflected in the fact that so many people who actually don't work on the brain for their livings, so many people are getting interested in the brain because it's becoming more accessible to us. Will we know in five years, 10 years, 15 years, 20 years, what's the nature of consciousness, or how does the mind relate to the brain, or how is it that you and I have emotions, or that sort of thing? I don't think we're going to know the answers to that kind of question very soon. But I do think we're going to be able to help many, many, many people. People with neurodegenerative disorders. People with various disorders that affect their brains. One thing that I'm particularly interested in adding to the group of things that we work toward in neuroscience is that we try to help normal people too. Because I think we have extraordinary potential that has hardly been tapped, or maybe isn't tapped in most of us. Brain potential, potential to do things, to think things, to be happy or sad, or to have fuller lives. And I think learning more about the brain, I think that's going to help us learn how to tap that potential. Well, I want to say that it's tremendously meaningful to me to work with the students, and postdocs, and coworkers, and staff members. It's very, very exciting to see a young person learn, and grow, and come of age. So I mean, that's part of being a professor, and I thrill to that. But the subject matter to me is so intrinsically interesting, and so potentially important just for our daily lives that I must say, I get a high. So I just feel frankly, I feel very, very lucky, very privileged. And I'm absolutely determined to do the very best we can to help people by what we learn. So I just want to say that I'm a product of MIT. I was trained at MIT, both as a grad student, and then later as a faculty member, because faculty members at MIT are always in training. And it's been a fantastic experience. MIT is a place with so many talented people and people talented in so many different ways. And people can play pranks and discover great things. So it's an enormous place of energy. And I was lucky enough to be working in neuroscience. And I think everyone at MIT now knows of the great new enthusiasm for neuroscience at MIT, with the development of the McGovern Institute, and the Picower Center, and the Department of Brain and Cognitive Science, and the real commitment that MIT feels toward neuroscience. I can say as a neuroscientist, that one just feels the energy of having MIT move forward in this realm. I believe that this is just great for MIT because the brain is a communication system, and MIT has premiered in this study of all kinds of communication, including fabulous kinds of virtual reality, telecommunication, robotics, and so on. So this is an extraordinary time at MIT, both in my field and in others. And so I just want to say to the graduating class of 2002, go for it. I think the best thing to say is that there will be more, and that I very much hope that in at least some way I can be a role model. That's a tough thing, but I do want to say that I've had the pleasure to have many women in the lab, undergraduates. Some undergraduates are graduating today. Hello. And graduate students, post-doctoral Fellows, visiting scientists, and they're wonderful. They're brilliant, they're beautiful, they're talented. And I think this will all disappear in the course of time. Just from my own experience at MIT, the amount of talent in the group of women students is just explosive.