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What's cookin' in the lab?
Well, we're trying to determine what parts of the brain are involved in fear and anxiety. There are two reasons why we're interested in fear and anxiety. One is that fear is a very natural adaptive response to danger, and it represents a very simple form of learning. So we're interested in what parts of the brain are involved in learning and memory. We think that using fear conditioning as our model of learning and memory is a very good way to go about that. Because fear conditioning happens so rapidly, yet lasts for such a long time.
If you burn yourself on a radiator when you're three years old, you'll never touch that radiator again. So that one episode in your life produces a memory that essentially lasts an entire lifetime. So there must be some very profound changes that take place in your brain, for a single episode to last an entire lifetime. That is of course very adaptive, because you don't want to go around burning your hands and touching hot things- so fear conditioning is very normal.
What we see in psychiatry, however, is that people who have had severe trauma in their lives, such as being sexually abused as a child or experiencing combat in war, also produces very strong fear memories. In those cases it's not particularly adaptive because the memories are so vivid that they come back and haunt you. You'll have a great deal of difficulty sleeping and concentrating and so forth. That leads to chronic anxiety disorders. The other thing we're interested in, then, is what parts of the brain are involved in chronic anxiety, and then hopefully, once we know more about that, we can develop medications that would be more effective in treating chronic anxiety disorders.
What sort of research into learning and memory are you doing?
The startle reflex is this very primitive, fast reflex. It only involves neural pathways in the lower part of the brain and the brainstem and spinal chord. Yet if you're afraid, then you will startle more. So what we do with people is, we put earphones on test subjects on them and play a small, sudden noise, she'll blink her eyes. If I play a louder noise, the test subject will blink much harder. So it's very graded in amplitude and size.
If I also have a pair of electrodes on your wrist, through which I tell you you might get a shock, and the instructions are that when a certain colored light comes on, let's say a blue light comes on, you might get a shock, and when a green light comes on you definitely won't get a shock. Then what we do is we turn those lights on at random intervals and startle you. If you're like essentially everybody else we've ever tested, you'll startle more when you're expecting a shock than when you're not expecting a shock.
That's an example of how this primitive unconditioned reflex can be modified by your emotional state.
One of the exciting areas in learning in memory is something called long-term potentiation. You can demonstrate if you take a slice of a brain out of an animal and keep the slice oxygenated and alive, and you can put a stimulating electrode in one part of that brain slice, and you can record in another part of that slice. When you stimulate one part, you can record the effect of that stimulation, and now if you stimulate at very high rates and then you retest what you find is that there's an increase in the size of response to the same stimulus strength. That's called potentiation, because you're potentiating the electrical activity, and it seems to last a long time, maybe weeks or certainly as long as you can keep the slice alive.
The exciting thing is that you can do that in tissue culture. You can grow cells in tissue culture, and show that when you stimulate and record in those cells, they show what looks like a form of learning, in other words they change as a function of this electrical stimulation. That effect is dependent on a particular protein in the membrane, called the NMDA receptor. It's thought that calcium coming in through the channel to which that receptor is attached leads to a number of intra-cellular events that lead to some long-term change in the shape of the cell or the number of proteins in different places so that cell undergoes something that in a sense looks like learning.
So we've taken those results and tried to apply them to real behavior in waking animals. What we've found is that if we block this NMDA protein in a particular part of the brain, then we block the development of fear conditioning. Our lab was actually the first to show that many years ago, and that's now been reproduced by lots of other different laboratories using different techniques.
The part of the brain that's critical for fear conditioning is called the amygdala. When we infuse locally into the amygdala, the compound that blocks the NMDA protein, the receptor, then it blocks the formation of fear conditioning. There's a lot of thought, then, that this mechanism called long-term potentiation may be the cellular analogue of learning and memory. So we're trying to use treatments and compounds that we know affect this long-term potentiation process, and apply them to natural fear conditioning.
More recently what we're doing is using a virus- you can engineer a virus, in our case the herpes simplex virus, to have a cDNA that would code for a protein of interest. One of the proteins that's thought to be involved in learning and memory is CREB. What we've found is that when we take a virus, and using molecular genetic techniques so that it makes CREB, and then we actually infuse that virus into the amygdala, and we can show that now the amygdala of the rat has more of this CREB protein than it normally does, and very excitingly, those animals seem to learn better; to remember longer.
So that's evidence that this CREB protein is important for fear conditioning, and more generally for learning and memory. So the benefit of all this to society is that if we can understand the normal learning processes using fear-conditioning as a model, because that's certainly a very normal kind of learning that all animals show, then presumably we could develop drugs that would improve fear conditioning, and then would perhaps be important for other kinds of learning.
How do you teach in the context of the lab?
I try to give students as much freedom as possible, because I think that when they have a lot of freedom, once they know the techniques, then it's a lot more exciting for them, to develop their own projects and feel like they're not just a technician but someone who can come up with creative ideas and carry them out in the laboratory.
What are some exciting projects you're currently working on?
One of these problems is that people have these unwanted fear memories. So if you were abused as a child, that's a very strong unpleasant memory that comes to mind when you don't want it to and it's very hard to suppress or inhibit or forget those memories. Probably you never forget these kinds of things, what you do is you somehow put them out of your mind.
So, for example, I got a C in organic, and that was the end of the world at that time. For a long time all I could think about was that C and what a failure I was and all that, so it bothered me for a long time. I still can remember it, but it doesn't really bother me that much. It hasn't interfered with my career at all and so forth.
So we've all had these bad experiences, but usually we can, not forget them, but after a while they don't bother us anymore. But with people who are chronically anxious, it bothers them all the time. Often because the things that happened to them are much worse. So one of the big questions is what parts of the brain are involved in the inhibition or suppression of natural fears. Lots of people have a fear of public speaking. There are some people who can never give a talk in public, or they avoid it at all costs. So they find jobs where there's not possibility that they'll ever have to give a talk in public.
Almost everybody has a fear of public speaking, but most people can overcome it, and some people can't. So the question is, even if you're afraid of talking in public, you can probably get up there and do whatever you have to do to make yourself not so nervous. So the question is, 'How does that work? What parts of the brain allow you to overcome your natural fears, and how are those broken or not working in people with chronic anxiety disorders?' It's a very exciting area, and there very little is known. We're trying to study that.
How did you first become interested in science? What was your educational path from that point to the present?
I always loved to figure out how things worked as a kid. I was always taking things apart. I loved to figure out how anything worked. Flashlights then radios then cars and car engines- and I loved to build things, and I loved to work with my hands. In college I was right on the verge of becoming an artist, of going into sculpture. I had a wonderful teacher who excited me about sculpture and kinetic sculpture, light sculpture and so forth.
But I also took psychology and was extremely interested in some of the questions in psychology. Then what happened to me is that when I was a sophomore, I did an undergraduate project in the laboratory of Steven Goodman, who was a well-known psychologist. For me that was the most exciting thing I could ever do because I was working with rats and implanting them with cannulas and putting drugs in the brain- things we still do today. To me that seemed the perfect combination of trying to figure out how things worked, doing something that had potential worth for humanity, and working with my hands. I was thinking of going to medical school, but decided that basic research would be much more interesting in the long run.
Then I decided to major in psychology and went to Yale where I was trained as a graduate student, and was trained by some excellent people there, and I started working with this startle reflex for very chance reasons. I realized that it was a very excellent way to study behavior because it was a very simple reflex and yet it can be modified. I figured that if I could figure out the neural pathway that actually mediated the basic startle reflex, then I could use that as a window to the rest of the nervous system.
So I spent a very long time trying to figure out what the neural pathway was that actually mediated the startle reflex. That took a long time. The latency of the startle reflex of a rat is only eight one-thousandths of a second. So if I go 'click' and measure electrical activity in the legs, that's only eight one-thousandths of a second, which is a very, very short time. In fact the startle reflex is the fastest reflex that we have in our body. Nonetheless, even though it's very fast, it's mediated by a very simple pathway. It took many years to figure it out, but we finally figured it out, and we were the first to show that in the world, and that was kind of fun.
Once we did that, we could start to figure out where this hypothetical state of fear modified transmission along that pathway by using various techniques. So figuring out the wiring diagram is what you really need to do to understand behavior. Without that it's very hard to know how to go about figuring things out.
So we continued to do that for almost thirty years now. I was a graduate student at Yale and then I was on the faculty for 29 years. I just came here in September.
Why switch from Yale to Emory?
I got offered a very nice position here, as a Robert Woodruff professor of psychiatry. It's a nice position, and there were a lot of interesting people in psychiatry with interests similar to mine. It was the offer and the atmosphere at Emory that attracted me. And my son went to Emory as an undergraduate, so I always had a nice feeling about it, but there's not connection there.
Describe the life of the research scientist.
I think it's the best job you can have, because, depending on how much teaching you have, you have enormous freedom to do research. That depends very much on the institution where you go. So if you go to a medical school, there's actually a relatively small amount of teaching in medical schools, relative to undergraduate schools. So if you're really interested in primarily research, then you would tend to want to go to medical schools rather than undergraduate colleges.
Whereas if you go into a psychology department, you can have a lot of time for research but you certainly also have more teaching commitments. That's a big decision, in terms of which direction one wants to go. There are always costs to those, for instance, if you're in a medical school, then you almost never get your salary paid by the university, then you have to raise all your salary by grant money, grants from the federal government. It's pretty hard to get grants, so it's sort of this balance between getting paid by a university and teaching, and therefore not having as much time for research, or not getting paid, having infinite time for research, but also having to raise your salary yourself. You tend not to make a huge salary, but you make a comfortable salary.
I think the luxury or the privilege of doing research is very unique, because in a sense you are your own boss, and it's totally up to your own drive as to how hard you want to work. I used to work until 11:00 every single night for years and years. The problem in our area is that there's so much reading you have to do. It's hard to keep up with the reading.
Where do you think this field is going?
I think there are some people who worry that if we're going to develop drugs that will improve learning and memory, is that going to fundamentally change society, and is everybody then going to have to take these medications in order to compete. I don't particularly worry about those kinds of questions, because I think there's such a need for treating senile dementias and Alzheimer's disease that the payoff is going to be substantial in terms of quality-of-life as people get older.
But one of the issues is, 'are we all going to need to take these so-called 'cognitive enhancers?'' As if every college kid would have to take these in order to get in to the college of his or her choice. But that's not going to happen in my lifetime, so I'm not particularly worried about that.
I think the future directions are going to be in molecular biology, because there the techniques are so powerful, in terms of gene therapy or psychiatric diseases, and gene therapy for other kinds of diseases.
So I think that if I were starting over again, I would definitely get into molecular biology.
What advice would you give to aspiring biologists in light of the reported glut of Ph.D.'s in the field?
That's a problem. I'm not sure who is looking out for that at the mega- level. I used to be chair of the admissions committee of the neuroscience program at Yale for many years, and we never had any sort of directives as to how many graduate students we should train in the life-sciences or the biomedical sciences. So we would accept as many students as we could.
I think that there has to be some guidance to all of the programs, in terms of, in the long-term, how many students should be admitted in order to generate a number of Ph.D.'s that will be commensurate with the job opportunities. And I don't think anyone's really been thinking that way for a long time, because the field has been expanding so rapidly that it just seems like there were always going to be jobs. So a lot of my students go to pharmaceutical companies, and have gotten very good jobs at pharmaceutical companies. But it's certainly the case that when a job comes up at the University of Vermont or something, there will be 260 applicants.
So it's a problem. In terms of people in the laboratory right now, the advice is 'don't shy away from industry.' Beyond that I don't know what to say besides it's a tough job market out there.
How would you characterize scientists in general?
I think they're passionately interested in what they do. I give lots of lectures to many universities around the country, and when you do that you go and you visit six or eight people at that school and they tell you about the research that they're doing. And without exception, when someone tells you about their research, they are so into it, and so enthusiastic, and they live it and they breathe it and they love it. So whatever it is that breeds that among people, that's very common among scientists, that they truly and passionately are interested in what they're doing.
So you never hear a scientist say, 'well, I'm bored with the work.' That's just not part of the vocabulary.
What do you do outside of work?
Golf. I love golf.
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