HOW DOES THE BRAIN gather information from the outside world and use it to guide behavior? Three neuroscientists who have spent much of their research careers trying to answer that question were awarded the 2012 Kavli Prize in Neuroscience:
Left to right: 2012 Kavli Prize Laureates Cori Bergmann, Winfried Denk and Ann Graybiel
- Cornelia (Cori) Bargmann—Professor at Rockefeller University and director of the Laboratory of Neural Circuits and Behavior and co-director of the Center for Mind, Brain and Behavior. Dr. Bargmann is also a Howard Hughes Medical Institute investigator and a member of the National Academy of Sciences.
- Winfried Denk—Director of the Max Planck Institute for Medical Research in Heidelberg, Germany and also a senior fellow at the Howard Hughes Medical Institute Janelia Farm Research Campus.
- Ann Graybiel—Neuroscientist at the McGovern Institute for Brain Research and Professor of Brain and Cognitive Sciences at the Massachusetts Institute of Technology. Dr. Graybiel is a member of the National Academy of Sciences and in 2001 she was awarded the President’s National Medal of Science.
The Kavli Foundation recently held a conversation with the new laureates to learn what led them to their specific lines of research, as well as hear the latest thinking about how the brain changes its behavior in response to environmental conditions, to what degree such responses are hard-wired or automatic, and how there are subtle influences on our behavior and decision-making of which we often are not conscious. Lastly, the three researchers debated the best approach to uncovering how the brain functions, and whether we will ever fully understand how our own brains work.
THE KAVLI FOUNDATION: Let’s begin by hearing about what sparked each of you to pursue your particular area of research.
ANN GRAYBIEL: My father was a physician who also did research, and we would talk about how wonderful the brain is—how so much depends on it, but how little was known about it. I got more and more interested in the brain and left the physical and chemical sciences, which I thought I would pursue, to study psychology and anatomy and then neuroscience.
TKF: At that time, psychology was just starting to delve into neuroscience, right?
ANN GRAYBIEL: Yes, and there was a tremendous sense of excitement but also awe in hoping that we could figure out how we think, feel, see and perform other brain functions. People were very excited about working out the brain pathways that underpin behaviors, and were making wiring diagrams in so-called “simpler organisms” that showed how their nerve cells made whole networks. But methods to look at the functions of these networks were just being developed, and we couldn't see the human brain in action then like we can now with functional MRI scans.
TKF: So how did you go about studying the human brain and what did you find?
ANN GRAYBIEL: I got the idea to stain brains for the chemicals in the neurons that might show the functional connections between them. When we did this, what we saw was quite amazing. The deep part of the forebrain was long thought to be primitive and lacking in the distinctive wedding-cake-like layers that are the hallmark of the neocortex in the upper surface regions of the brain. What we found, though, was a highly structured chemical architecture in the main nucleus of the basal ganglia in the human brain. This meant that these deep forebrain regions were actually quite sophisticated after all. This was very motivating—what could be the functions of this architecture?
TKF: Speaking of methods to peer into the brain, Winfried, what led you to pursue developing some of these methods?
WINFRIED DENK: I am an accidental neuroscientist. I am a physicist by training and really more of an engineer than a physicist. I like to tinker with machines and methods and sort of became the house physicist for the neuroscientists.
TKF: You’re the techie guy that everybody goes to?
WINFRIED DENK: Yes, I sometimes view myself as “Q” in the James Bond films because he only has short parts, but he persists in many movies and builds the gadgets. I always had some interest in biology, but traditional biology was too descriptive for me so I pursued biophysics. While I was working on my PhD researching hair cells, as a hobby I developed two-photon microscopy. I realized this would be a useful technique for imaging live cells and tissues because it would cause limited damage to what was being imaged. Then I went to work with a group of neuroscientists at Bell Labs and saw that the two-photon method would have some particularly useful applications in neuroscience.
TKF: What about you Cori, what lead you to your line of research?
CORI BARGMANN: When I came to science in the late 1970’s, there was a huge blossoming of molecular genetics. These tools that made it possible to take what we knew about genes in biological systems at an abstract level and bring it to a concrete level to understand how genes function and what they do. My PhD work took this genetic approach to cancer biology. This work was one step along the way to Herceptin, one of the first rationally designed targeted anti-cancer therapies, which is used to treat breast cancer.
TKF: How did you end up going from cancer research to neurobiology research?
CORI BARGMANN: I’d always been fascinated by behavioral neuroscience having grown up watching animals and hearing stories about the complex behavior of honeybees and geese. These behaviors manifest themselves in different ways in different environments but are innate, so they have to be genetically encoded. I wanted to use the language of genes to understand behavior. Then Seymour Benzer showed that the genetic approach worked for understanding fruit fly behavior, even though the fly brain remained a black box that no one fully understood. Then, a paper came out showing the wiring diagram for the worm I do my experiments on. It showed the complete nervous system of the worm—every connection between every nerve cell. This was, in principle, a map of the brain—you just had to figure out what that map was doing. And I thought I could use genetics to figure that out.
TKF: You each work on trying to uncover the neural circuits that underlie perception and behavior—the connections between nerve cells that enable them to communicate and explain their functioning. But you work on different animals and on different parts of the brain. Are you finding any unifying basic principles?
CORI BARGMANN: What all of us have shown is that there are specialized circuits in the brain. The brain is not an all-purpose general machine, but parts of the brain or different kinds of wiring within the brain allow it to carry out unique functions.
ANN GRAYBIEL: We also now know there are functional classes of wiring in the brain that can be found across an amazing variety of vertebrate brains. And we know that even invertebrates like worms use the same ions and proteins in their nerve signaling that we use in our brains. At the same time, all of us would be hard put to answer the question of what, exactly, is the medium of communication in the brain! There are all sorts of possibilities, from brain waves to chemical messengers, and that’s what makes it so exciting. But unlike physics, neuroscience has not yet developed enough to let us formulate basic principles or laws.
WINFRIED DENK: I think we’ll be able to figure many things out, but I think that the kinds of eureka moments that physics had when it discovered quantum mechanics or elementary particles will be rarer in neuroscience. The rules that built the brain are rules that have evolved, unlike the ones that built the universe. If you think of each interaction between two proteins as a rule, there are probably as many rules as there are genes governing the brain.
TKF: Ann, your work shows that the brain often chunks behaviors into automatic subroutines so we can walk, for example, without realizing that we first put one foot forward and then the next. But we also need some flexibility so we can learn a new routine, such as a dance. How does the brain maintain the optimal balance between fixed automatic behavior and flexible behavior?
ANN GRAYBIEL: It’s not so simple! We now think what seems like a fixed behavior is being monitored by some parts of the brain, so that even when we act “semi-automatically,” there are circuits deciding at any given moment what the animal should do. Even if we want to create such fixed behavior, these parts of the brain may prevent them from becoming habits. For example, we have behaviors that we’d like to make automatic, like jogging, but we have trouble doing them, even though we’re supposed to be so smart. It makes me think there may be firewalls around that habit-forming mechanism to protect us from making the wrong things automatic, and that maybe addictive drugs break down that firewall.
TKF: Cori—you found there were some kinds of behaviors that were genetically hard-wired in your worms, so does that limit how flexible their behavior can be?
CORI BARGMANN: What the hardwiring does is create a starting kit or skeleton of behavior that subsequent behaviors are built around. There’s a substantial ability to modify all of these behaviors based on context and what choices are available, and based on learning. That’s true even in the worm. For example, when animals are hungry, they’re willing to walk through a wall of odor that normally repels them to get food.
TKF: What about for humans?
CORI BARGMANN: Complex brains are like simple brains, only more so. There are innate rules built by our genes into the anatomy and physiology of the brain. These rules provide everyone with basic information, like sugar is good and bitter is bad. As infants, we follow those rules. Later we may modify them. Learning adds to the basic patterns, and eventually learned behaviors can become as automatic as innate behaviors. Habits, for example, are automatic learned behaviors in which your own experience modifies your brain to create new patterns.
TKF: Winfried, you’ve become an advocate for methods that reveal the structure of the brain so as to better understand how it functions—to visualize the brain anatomy that underlies the brain activity. Why this focus?
WINFRIED DENK: If you have an unknown piece of equipment that you find and are supposed to fix, the first thing you need to know is its structure. When it comes to the brain, there is maddeningly little known about structure and connectivity within the brain—just some statistical information, so even when you get brain activity information, you can’t make sense of it.
ANN GRAYBIEL: The entire field of neuroscience once seemed to have decided that anatomy isn’t very useful. Winfried is a hero because he is reminding people that the wiring diagram is incredibly important. People like Cori, who work in simple systems, know this in spades. But people who work on complex systems want to have information about activity, and this is critical also.
WINFRIED DENK: The value of a complete wiring diagram of the brain is that it will enable us to test our theories on how the brain works, and rule out that there is something mysterious hidden in there. Because if your theory predicts communication between neuron A and neuron B, but there is no connection between A and B, then there cannot be any information flow between A and B, and your theory is wrong.
ANN GRAYBIEL: But there may be communications going on in the brain that aren’t going through the “wires” (neuronal processes)—these could be communications going through brain cells that aren’t neurons, or communications through the space between cells (extracellular space), or ionic changes that have generalized effects. At a certain point, the answer to the question becomes as complex and even more complex than the question itself.
CORI BARGMANN: Although fast, accurate transmission of information goes through the wires, there’s definitely information that doesn’t go through the wires, as well. As a result, which of those wires are being used at any given time is unpredictable. So I would agree that the wiring diagram is essential, but I don’t think it’s sufficient.
TKF: Do you think we’ll ever be able to put together enough pieces of the puzzle to understand how the human brain works?
CORI BARGMANN: There’s a general feeling in neuroscience that to understand the big picture, we’re going to need certain kinds of abstractions or models. There’s a deep fear in everyone’s minds that at some point, we’ll be able to describe the brain mathematically but not verbally--that it will exceed human intuitive explanation to understand how it works. We’ll cross that bridge when we come to it.
ANN GRAYBIEL: There are billions of neurons in the human brain that are constantly changing in ways that can only be detected using a large range of methods. To figure out the human brain is going to be a very tall order for a very long time. But there’s always a chance that we can do it, and we ought to throw everything we have at it.
TKF: What has been the most surprising finding in your field that has changed your thinking about the underlying mechanisms in perception and behavior?
CORI BARGMANN: I was most surprised when the human and animal genomes came out and we realized there really was not much innovation in humans—no creation of fundamentally new genes and molecules to build a complex brain. This means that the complex and unique abilities of humans can be explained by reusing parts that exist in the worm, by regulating them differently, and by putting them together in larger assemblies. Like a computer, you could get more by having more processors in the system. It was a great discovery for those of us working on lower animals because it gave us access in our research to many of the parts needed to understand the human brain. That really surprised us.
TKF: Ann, do you have a surprising finding you wanted to relate?
ANN GRAYBIEL: It’s been a great surprise that the lower parts of the brain are not just influencing our movements and other motor functions, but our thinking and feeling abilities as well. It’s a very interesting set up. We seem to have master control regions in the upper brain, called the neocortex, that enables us to think, speak, do math and to create works of art. But we also have a very large system below it that is constantly teaching the cortex, coordinating its activity, deciding what’s good and what’s bad for the cortex to be doing, and changing goals and bringing in new habits of thought. The idea that lower brain regions so strongly influence cognitive abilities was a surprise and has been a great mystery so far.
TKF: So that lower portion of the brain you study—the basal ganglia--influences our decision-making, a function traditionally attributed to mainly the upper reaches of the brain?
ANN GRAYBIEL: Yes, to an amazing degree.
TKF: These would be subconscious influences that we wouldn’t be aware of?
ANN GRAYBIEL: Yes. This is a very interesting problem in that we can do things that we honestly are not aware of having done because we do them in automatic mode. Habits are examples of this—we often don’t remember what we did by habit because it happens automatically. The modulation of the cortex by the basal ganglia in a way that affects behavior is more important than we ever realized. The basal ganglia can fundamentally adjust how an animal thinks and reacts, making what once was imperative—like seeking food—no longer imperative. So the challenge now is to get in there and understand what physically accounts for this modulation.
TKF: To close, you are all recipients of the 2012 Kavli Prize in Neuroscience and will be honored for your achievements in Oslo this September. This is an honor conveyed to you by a committee comprised by your peers in recognition of the fundamental and great importance of your work. Can each of you take a moment to look back at your work and tell us what has motivated you?
ANN GRAYBIEL: There are two inextricable motivations for my research. One is to do basic science to understand the natural world. The other motivation is to help people with disorders due to problems in parts of the brain that I study. There is such a push for translational work—science that can be applied in the clinic—that pure basic research is in jeopardy of not being well funded. That would be terrible, because such fundamental research is intrinsically important and can be key to solving health or other problems in society. My passion is to make people realize that both pure research and its applications naturally combine with one another in many fields, including neuroscience. I myself don’t go through a day without thinking about some person with a disorder related to the research that we do; and I say to myself “Go work harder.”
CORI BARGMANN: For me, it’s been the joy of discovery and the importance of learning for itself, together with the fact that there’s nothing more fascinating to me than the brain. I find it infinitely exciting to do my work. At the same time, new knowledge leads to applications in unexpected ways. The 19th century British Prime Minister William Gladstone once asked the scientist Michael Faraday what the practical value of his newly discovered electricity was and Faraday replied, “One day sir, you may tax it.” When you make a new discovery, you don’t know the implications immediately.
WINFRIED DENK: I agree with Cori. The joy of discovering something and making something work that one has a general sense will ultimately be useful is a very powerful force. Plus it’s just fun. We are very privileged to be able to follow our curiosity.
- August 2012