Monday, August 07, 2006

10 Questions for Joseph LeDoux   posted by Coffee Mug @ 8/07/2006 02:37:00 PM

Joseph LeDoux is a University Professor and Henry and Lucy Moses Professor of Science, and a member of the Center for Neural Scienceand Department of Psychology at NYU. In addition to articles in scholarly journals, he is author of The Emotional Brain: The Mysterious Underpinnings of Emotional Life and Synaptic Self: How Our Brains Become Who We Are. His work has focused on the role of the amygdala in emotion and memory.

Be sure to check out the other interviews in the '10 questions' series in the sidebar. Below are 10 questions for Joe LeDoux.

1. Over the past two decades you have produced a detailed diagram of the neural circuitry involved in auditory fear conditioning, eventually tracing the storage site for such memories to a single nucleus of the amygdala. The fear system was appealing, in part, because it is relatively straightforward. Fear responses are stereotyped and have remained relatively constant throughout evolution. What, if any, emotional system(s) do you think will yield to this sort of fine-grained analysis next?

The key to doing all this for fear is that there was a good behavioral paradigm, fear conditioning, for studying fear. It's much easier to relate behavior to the brain if you have a simple and repeatable behavior that is reliably controlled by a stimulus. As soon as good stimulus-response paradigms are developed for other emotions, the brain will yield its secrets. There are good stimulus-response paradigms for reward but unfortunately these paradigms don't naturally relate to a specific emotion the way fear conditioning does.

2. In an Edge interview in 1997, you wondered about the interaction between a reactive emotional system and decision-making. Recent work in the fields of moral psychology and neuroeconomics are beginning to provide some insight into these mechanisms by integrating efforts across several disciplines. In what ways do your interests overlap with these fields? Have they affected your view of the mechanisms by which the emotional brain controls decision-making and vice versa?

I've been interested for a long time in a behavioral transition that occurs once you find yourself in danger. First, you react-evolution thinks for you. Then you act-you're dependent on past experience and your ability to make decisions in this phase. We've shown that the transition involves the flipping of a switch in the amygdala. I don't mean this literally. What happens is that reaction involves a circuit in which information flows from the lateral amygdala to the central amygdala, which then connects with areas that control reactive bodily responses (freezing behavior; changes in autonomic nervous system responses such as blood pressure, heart rate, breathing, sweating, pupil dilation, etc; and release of stress hormones). In order to take action, you have to inhibit this "freezing" pathway and activate a pathway in which active behaviors are controlled. This pathway involves the flow of information from the lateral to the basal amygdala. The switch flip metaphor refers to the output of the lateral amygdala, which is sent to different regions for reaction vs. action. Clinically, the reaction pathway is associated with passive coping, and the other pathway with active coping. Psychologists have shown that people do better in overcoming fear when they engage in active coping. So understanding how this transition occurs is important. All this is by way of answering your question about decision making. The brain makes a decision when it throws the switch. So I would say my interests do overlap a lot with the decision making disciplines but that really is a different world. I think part of the difference is that much of that field focuses on gains and losses of monetary rewards, which I think is very different from decision making in situations where bodily harm is at stake. However, the sophisticated analyses that have been developed in neuroeconomics might be very useful in the study of fear.

3. Several of the central mechanisms involved in synaptic plasticity (NMDA receptor, calcium signalling, AMPA receptor trafficking, spine dynamics, etc.) appear to be general, occurring at neocortex, hippocampus, and amygdala synapses. Are there major differences between mechanisms of memory in different brain regions? How could a drug, say for combatting phobia, target fear memory without affecting the other memory systems?

There is indeed a remarkable consistency of molecular mechanisms for different kinds of memory in different brain systems. This even holds across species as diverse as slugs, fruitflies, mice, and people. One implication is that the uniqueness of different kinds of memory is not dependent on the molecules so much as the circuit in which the molecules do their tricks. However, it is possible that so far we've mainly found the similarities and that subtle but important molecular differences are yet to be discovered. But let's assume that the first idea is correct-that the molecules involved are essentially the same. Even it the molecules that make memory in the amygdala and hippocampus are the same, it is likely that there are unique genes in these areas. If so the proteins made by these genes might be used as keys that unlock a molecular package that a drug is wrapped in. The drug goes everywhere in the brain but is only active in the area containing the protein that can unwrap it. Science fiction, but not science fantasy.

4. You have reported that some 30% of neurons in the lateral amygdala, and blocking AMPA receptor trafficking in just 10-20% of neurons produces impairments in fear memory. At this rate, it seems that a rat that is afraid of three things will have to overlap representations to fear a fourth. Does the fear system have limited storage capacity? What happens as you begin stacking multiple aversive memories into the same neurons, do they distort or overwrite previous memories?

Synapses, not whole neurons, are the units of information storage. Each neuron has many thousands of synapses. I'm sure the fear system has a capacity limit, and that would be very interesting to study. So far no one has studied that, at least as far as I know.

5. Have advances in genomics and bioinformatics (i.e. sequencing of several mammalian genomes and development of tools for exploring them) influenced your own molecular/cellular work at all? More broadly, what do you expect will be the relationship between genome research and neuroscience in the future?

I'm not very sophisticated when it comes to genomics. So I'm not sure I'm the best person to answer this question. But I do have an opinion. Genomics hit neuroscience in a big way. Probably neuroscientists were overly enthusiastic about the ability of techniques like gene chips to change the field overnight. It's easy to find genes that correlate with learning-too easy. The trick is analyzing all the data that come out and making sense of it. But genomics is here to stay and will make tremendous contributions in the years to come. The next generation of neuroscientists will be trained in both fields and will know better how to navigate the territory.

6. Several individual proteins and signaling pathways have been implicated in amygdala plasticity in the past few years. How do you conceptualize the interaction of these individual players in the bigger picture of the synapse? For instance, when a pathway like MAPK with multiple intracellular targets is implicated, do you mentally place more weight on the immediate downstream post-translational modification of synapse associated proteins or regulation of protein or mRNA synthesis?

I think we have to remain open minded about these kinds of things. To follow your example, we'd need to explore the various targets of MAPK to see which ones are critical and whether the critical ones lead to gene expression and protein synthesis. Then we could decide.

7. Some have proposed that a self-perpetuating 'mnemogenic molecule' (like a constitutively active kinase or a prion-like RNA-binding protein) might account for long-term synaptic plasticity and memory while others seem to suggest morphological changes are necessary. How do you think fear memories are maintained in the very long term? Are the same synapses even responsible for the memory trace throughout the life of the memory or do you imagine a systems consolidation type of mechanism where eventually the fear memory is moved to a remote storage site?

A few years ago we published a study showing that different cell groups in the dorsal subnucleus of the lateral amygdala participate in the initial learning of fear conditioning and in the long-term storage of the conditioned association. One, located in the superior part of the dorsal subnucleus learns rapidly and resets. The other, located in the inferior part of the dorsal subnulceus learns more slowly but retains the memory, even beyond behavioral extinction. So there is a nomadic quality to fear memory within the dorsal lateral amygdala. This means different synapses are involved in initial learning and persistent memory. The key issue is whether the synapses involved in forming the memory in the second circuit persist or change over time. I don't think anyone knows this. However, the fact that we could pinpoint a memory region in such a small zone in the amygdala gives us the hope that the question may be answerable.

8. You wrote a mild critique of Judith Rich Harris's book *The Nurture Assumption* when it was published eight years ago. In your own book *The Synaptic Self,* you expressed further reservations about the decidedly hereditarian perspective promoted by the emerging fields of behavioral genetics and evolutionary psychology. What do you think is the most crucial shortcoming of these new human sciences in their consideration of the causal influences on behavioral phenotypes? What role do you see for your own branch of neuroscience in the ongoing debate over the sources of human nature and individual differences?

I am a strong proponent of the importance of genes and heredity to behavior and mental life. But I think it's important to keep this stuff in perspective. Genes are important, just not all important. Indeed, I believe, as I argued in Synaptic Self, that important parts of personality are learned. This doesn't water down the importance of inheritance. Evidence for a genetic contribution to something doesn't mean that non-genetic factors are unimportant. Non-genetic factors influence gene expression from the moment the egg is fertilized. In terms of the brain, nature and nurture are not two different things but two ways of doing the same thing: wiring synapses. Through synapses, genes and experience influence who we are. The key issue is how synaptic change over the course of life determines what the brain knows and forgets, and what can be acquired or not.

9. The most obvious changes that occurred in primate brain evolution involve the building of more neocortex on top of the 'reptilian' brain. You tend to emphasize the continuity between the emotional brain systems from rodents to humans, but could you speculate some on how the emotional brain is different across species?

When studying animals it's important to ask questions of the animal that research on the animal can answer. When I study emotion in rats, I study how the brain processes the stimulus to elicit physiological and behavioral responses. The reason I study this in rats is because the brain mechanism that process danger and produce defense responses have been shown to be very similar in rats and people. Considerable evidence suggests that when we are conscious of a stimulus, whether its an emotional stimulus or not, prefrontal cortex is involved in the processing. I don't attempt to study conscious aspects of emotion in rats for two reasons. One is that there is no way to know what they consciously experience, and two because they lack the regions of the prefrontal cortex that appear important in conscious states in people.

10. If you had a chance to do it all over again what would you change about your education?

I grew up in a small town in south Louisiana. I don't think I really learned what the field of psychology was until I went to college. I had very little training in science in high school, and that didn't change in college since I majored in business. I went on to do masters level work in business as well. At one point I took a course with a professor who was studying the brain, and my world changed. I decided I wanted to be a neuroscientist. I was at a certain disadvantage not having studied science. On the other hand, everything I learned about science, once I started learning it, was relevant to what I was doing. So I wouldn't necessarily change my science education. I do wish I had more exposure to art, history, languages, and the humanities in general when I was growing up and in college. I think most scientists, most people in fact, could use better grounding in the humanities.