Q: You have focused your research on the basal ganglia (BG) for many years. Why are you interested in this group of brain structures?
Graybiel: The question really should be how could I not be interested in the basal ganglia. They are endlessly interesting because it turns out they are involved in an amazing range of behaviors. That fact has only been appreciated in recent years, in part because of the location of this cluster of nerve cell nuclei deep in the forebrain. Before brain imaging came along, the BG were essentially off-limits because it was really difficult to get in there.
As a result, the basal ganglia were long thought of purely as motor structures involved in normal movement and in movement disorders, such as Huntington’s disease and Parkinson’s disease. Then a few people began to realize that they were also involved in neuropsychiatric disorders. One example is obsessive compulsive disorder (OCD), which can involve compulsive repetition of movements, but which also has a psychological element. About the same time, it began to become clear that the BG are deeply involved in addictive kinds of behaviors, from habitual risk-taking to drug addictions that highjack the brain’s reward system and are very difficult to overcome.
A vast amount of learning, including social learning, is related to just “doing it again.” The extreme of that is addiction...
Q: It seems that the more that science learns about the basal ganglia, the more evidence there is for their involvement in all sorts of behaviors. What’s the latest?
A: The latest thing that is really fascinating is that parts of the BG have now been implicated in social behaviors like love and affection. This probably reflects the fact that people have realized that dopamine, the very neurotransmitter that becomes depleted in Parkinson’s disease, signals “reward” to the brain. So it’s not a big step to go from thinking that we have a place in the brain that is activated by highly pleasurable behaviors to the idea that our brains can capitalize on that activation to train our behaviors toward things that are rewarding or pleasurable—the idea of “that felt good; do it again.” A vast amount of learning, including social learning, is related to just “doing it again.” The extreme of that is addiction, but the less extreme form may explain a whole array of human behaviors. In the social realm, for example, it’s human nature that if someone is nice to you, you associate with them, and if someone is not nice to you, you don’t.
Q: How are the basal ganglia involved in generating habitual thought patterns?
A: I’m high on the idea that maybe in addition to behavioral habits—habits that can be thought of as “action habits”—we also have habits of thought, habits of mind. My guess is that the BG help produce those and lay them down, just as they do behavioral habits.
I’m high on the idea that maybe in addition to behavioral habits—habits that can be thought of as “action habits”— we also have habits of thought, habits of mind.
So, one of the long-proposed roles of the BG is to help the lower-level motor regions of the brain stem and spinal cord generate patterns of nerve activity that subserve various motor behaviors. Our idea is that essentially the same kind of circuit applies to the cerebral cortex. The BG in this case project upstream, to high-level centers in the neocortex that control complex cognitive functions such as planning and reasoning. It may be that they help lay down and select patterns of cognition, so the BG modulate not just motor pattern generators, but also thought pattern generators, or cognitive pattern generators.
Q: What have you learned about how basal ganglia circuits adapt and re-adapt as habitual behaviors change?
A: We are doing a lot of work in our lab now trying to teach animals habits, and we’ve been really stunned with the plasticity of the BG. We’re looking at the activity of neurons in the striatum, which is in a key position to be involved in this habit-forming business, because it is the main part of the BG that receives the reward-related dopamine input on the one hand, and it gets massive inputs from the neocortex on the other hand. You’ve got the information flooding into the striatum and the dopamine signals saying either “yes, that’s good, do that again,” or “no, don’t do that again.” If these output pathways are right, a behavior gets stamped in bit by bit.
We’ve found that when this happens behaviorally, the firing of the neurons changes dramatically. When an animal is learning something new, such as turning a lever just the right way in order to get a reward, it initially learns by trial and error – called “exploration.” When the animal has figured out how to turn the lever to successfully receive the reward, that’s called “exploitation.” Based on the results we have so far, we’re beginning to think that there is neural exploration and neural exploitation in the brain.
When the animal starts out on a new task, he doesn’t yet know what information is salient, so essentially everything is important. Correspondingly, neurons in the striatum fire at almost everything, looking for clues as to which activity proves rewarding. As the animal learns, the neurons quiet down: they stop firing at everything and start firing much, much more selectively, especially at the beginning and end of the procedure that is being learned. When you take away the reward, the more selective patterns disappear. If you then give the reward back, boom! The patterns come back again right away.
People who have bad habits that they are trying to break know this phenomenon intuitively. If you’re trying to quit smoking, you don’t want to go to a place where you always smoked. I think we’re seeing the representation of that in the brain. To me, that’s very exciting, because if we can get a handle on what happens, then we can try to manipulate the process. And if we can manipulate it in an animal, then we may be able to produce a therapy, or some way to reduce the overwhelming power and strength of these highly ingrained habits.
Q: What might such a therapy look like?
A: Deep Brain Stimulation (DBS) is now being applied not just for motor disorders, but also for some disorders in the realm of psychiatry, so it’s clearly not crazy to think that DBS might help in breaking addictive or compulsive habits. Ideally, one hopes that there could be a pill, that a pharmacologic therapy could be developed that somehow mitigates or interrupts these patterns of activity in the brain’s reward system. Toward that end, it would be ideal to be able to screen these patterns, both their development and their disappearance or lack of disappearance, when different drugs are being tested to look for drug effects. In addition, our lab is now trying to identify the genes involved in these pathways, which could lead to new drug targets. While dopamine is a principal actor in the reward story, there are many other molecules that are downstream from dopamine, and maybe one of these could be targeted.
It’s a very, very hopeful time for research in these areas. I believe there are deep commonalities between the movement disorders in which the BG are involved and this habit-forming system that we’ve been studying, which at first seems kind of strange to think about. I’m convinced that a better understanding of the neural plasticity of this system will be key to advances on both sides.