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An Interview with Eric Nestler: The Dark Side of Brain Plasticity

How Learning Contributes to Depression or Addiction
Sandra Aamodt

Eric Nestler is Chair of Neuroscience and Director of the Friedman Brain Institute at The Mount Sinai Medical Center.


Sandra Aamodt: Why do you suppose we might have evolved brains that can become depressed or addicted?

Eric Nestler: I don’t know. My best guess is that modern levels of chronic stress or access to addictive drugs are not seen in the natural world. For example, we tried for decades in my lab to stress mice or rats in different ways. Despite trying several types of stress commonly used in rodents, the animals were more robust at the end of the stress. It was like Special Forces training for them. In contrast, we found that chronic social stress worked—it produced behavioral abnormalities reminiscent of those seen in people, but that kind of stress isn’t natural. A mouse in the wild, if it has an encounter with an aggressor, it's either going to escape or get eaten. Likewise, you can eat a coca leaf and never get the blood levels of cocaine as rapidly or as high as you get from snorting or injecting or freebasing cocaine. These stronger unnatural stimuli activate adaptive processes in the brain, which at lower doses, lower magnitude, or shorter duration can be helpful and protective but over the longer term become maladaptive.

What became powerful in evolution are habit memories. We think of them mainly as motor memories, but they spread to the emotional domain as well. The brain has an adaptive capacity to do things almost automatically, so it also has the capacity to maladapt to destructive stimuli that we uniquely put in our own environment.

Sandra Aamodt: People do seem to be suffering more from stress-related illnesses than they used to, but that's kind of strange when you're comparing to an era where, say, half your children might die before they reached the age of five.

Eric Nestler: I think maybe it just becomes part of life. As life becomes more precious, any possible assault to a perfect life becomes much more difficult to cope with. It may go back to the Special Forces training joke I made earlier. In a tougher life and world, you get tougher, whereas we all have been raised not to expect any adversity, so that even the slightest adversity can really get people stuck. Now public school, particularly high school, has become so pressured that if you get B's, it's no longer good. Whereas during times when half the siblings died, if you're getting a B and you're healthy, that's pretty good.

Sandra Aamodt: Tell me more about the role of learning in addiction. What is it that animals learn when they become addicted to a drug?

Eric Nestler: Several different types of learning are involved. On the simpler level, there are adaptations in the brain, which we may not think of as learning but nevertheless are very important. Circuits in the brain become used to having the drug on board, so they learn or adapt to the drug's presence and change their function accordingly. That can have a dramatic effect on the way a person functions. As a person becomes a hardcore addict, they become less and less responsive to natural rewards. Normally, we get rewarded by food, social interaction, sex, and more subtle things that we can only think of in humans—like love, going to a good movie, and things like that. People who get addicted have less and less positive responses to those rewards and become more and more dependent on stronger drug rewards. That probably has to do with maladaptations in primitive brain centers. As the brain is being hammered by strong rewards, the reward centers in the brain probably become less sensitive, so it requires the drug reward to stimulate them and for the person to thus feel “rewarded”.

Overlaid on top of those changes are more traditional forms of learning. People begin to have expectations of where to get the reward, what personal associations will lead to the drug reward, expectations of how they're going to be feeling when they get the drug, expecting not to feel good until they get the drug, and so on. That learning completely reorders the way a person faces the world every day. And somehow it begins to corrupt daily activities, subconsciously and then consciously, leading to a pathological pattern of behavior. In the extreme, a person will spend the entire day trying to get the drug, consuming the drug, enjoying the intoxication, and then as soon as that wears off, starting the process over again, so one’s entire life is focused around the drug.

Sandra Aamodt: At that point I guess you don’t have any habit patterns to fall back on that don’t involve drugs.

Eric Nestler: That's important because you've now extinguished most or all the positive aspects of life and are stuck with not having anything to do. I’m watching the HBO series, The Wire. Have you seen it?

Sandra Aamodt: I loved that show.

Eric Nestler: I’m only on the first season, so don’t tell me what happens next.

Sandra Aamodt: Okay.

Eric Nestler: There was a scene about a heroin addict who is getting clean. For the first time in three years, he hears the trees rustling and the dogs barking. He sees the sun coming down and reflecting off some flowers, and he’s amazed by suddenly having his senses back again, being connected with the world, as opposed to being focused solely on finding and taking a drug. That made a lot of sense to me.

Sandra Aamodt: Addictions are in some ways defined as much by the absences that they create in your life as they are by the presences. Depression is that way too, isn't it?

Eric Nestler: Absolutely.

Sandra Aamodt: How does learning figure into depression?

Eric Nestler: As people get depressed, they begin to develop negative learning styles. As this gloom lowers over them, whatever caused it—something on the outside, something on the inside, usually a combination of both—they begin to reinterpret everything that happens as being consistent with a negative view of themselves and of life. What cognitive behavioral therapy does is to challenge that viewpoint and help people to unlearn those negative styles.

Sandra Aamodt: You mentioned resilience earlier. I’m interested in individual differences in how people respond to the same circumstances or events.

Eric Nestler: We came into this research area from an interesting perspective, after a talk by Dennis Charney about resilience. In the audience was my MD/PhD student, Kris Krishnan, who was studying our chronic social defeat model in mice. Roughly a third of the animals didn’t show the deleterious response we expected. After the same ten days of social defeat, only two-thirds of the mice showed the bad consequences, which included social avoidance and anhedonia. They don't like to drink sugar solutions, don’t like sex, and don’t like high-fat food, for example. Yet they eat too much and develop obesity. After hearing Dennis's lecture, Kris said, "Maybe the other third of the mice are resilient."

What we’ve found since then is that resilient animals show some consequences of the stress, but they avoid the more severe depression- or PTSD-like symptoms because their brains undergo a series of independent adaptations that are protective. In this model, resilience is not the absence of the bad effects of stress at the molecular level but an active process, a series of changes in gene expression that are unique to resilience. We've been able to identify several of these key mechanisms and demonstrate that indeed they do confer resilience. Say gene X is induced in nucleus accumbens (a reward region of brain) of a resilient mouse, not in a susceptible mouse. If we now take gene X and overexpress it in the nucleus accumbens of an animal that's susceptible, we can make it resilient. Conversely, if we make it impossible for the resilient mouse to express gene X, we make it susceptible.

That's enabled a new way of looking for therapeutics. In addition to trying to undo the bad effects of stress, which is what the field has been doing for fifty years, we think another viable path would be understanding the neurobiology of resilience. Think of medications that would induce in less robust people some of the adaptations that occur in more inherently resilient individuals. It works in mice. Whether it will work in humans remains to be seen, but it's a path that we’re following.

Sandra Aamodt: I’ve always assumed that most differences in resilience between individuals would have to do with their genetic backgrounds. Do you have any sense of what’s going on here?

Eric Nestler: We know genetics is important because if we compare several strains of inbred mice in the social defeat protocol, some strains tend to be more resilient, while other strains tend to be more susceptible. Within a given strain, however, we still see a broad range of responses, which is presumably not genetic.

The other thing that we know is very important is the environment. If we take a C57 mouse and raise it differently, we can dial in very different inherent rates of resilience or susceptibility. We know, for example, that early life stress, if it's bad enough, makes a mouse more susceptible. On the other hand, if we just handle the mice and subject them to a milder level of stress, they become more resilient.

Yet we normally raise our genetically identical test mice as nearly identically as we possibly can. And the differences we observe in resilience and susceptibility are seen within litters, so it's not like one litter is resilient, while one is susceptible. It's something else.

Our hypothesis is that something random occurs during brain development. As 100 billion neurons are born and hundreds of trillions of synaptic connections are made, we think there are random changes that tend to make individuals respond differently to stress. What this random process provides is an ability to generate variability even in with the same genetic constitution and a constant environment.

What’s driving those random changes? We think it's epigenetics, long-lasting modifications to the chemical structure of DNA and the proteins it binds that influence gene expression. We think that as cells divide, the strength of synaptic connections and the potential of different genes to be induced are subjected to random epigenetic modification.

Sandra Aamodt: I think of epigenetic modification as being carefully controlled. Is that not right?

Eric Nestler: Much of epigenetic regulation is very carefully controlled, since epigenetics is what mediates the responses of the genome to the surrounding environment. But we know that random processes also occur. For example, the pattern of folds in the cerebral cortex is an example of a random process because even identical twins have different patterns. When the term epigenetics was first introduced, it was represented as a random process, so I think both are occurring.

Sandra Aamodt: There’s a relatively short list of solid epigenetics results in neuroscience, which of course includes your work. Is epigenetics going to turn to be as important as we’re thinking now, or is it hyped?

Eric Nestler: I agree it’s a fad right now. Some people use the term very loosely. But I think epigenetics is going to be huge. It explains how the environment interacts with the genome to produce a response or an adaptation. The effects of stress or drugs of abuse on the brain, and our ability to form long-term memories, as just some examples, all occur by epigenetic mechanisms. Learning the specifics, every gene involved, every chromatin modification involved at that gene, and so on is an important part of delineating how it happens.

I’m more skeptical about how often transgenerational transmission occurs. We showed that if you stress an adult mouse, wait a month, and then breed the mouse, its offspring are more vulnerable to stress. Other labs have taken that result out several generations. But when we harvested the sperm from the stressed mice and impregnated another group of normal females through in vitro fertilization, the offspring of those mice largely lacked any difference in stress responses, suggesting that the mother somehow knew she was having sex with a loser mouse or something [laughter]. There are caveats, and we need to do more difficult experiments, but those are the kinds of things that we’re thinking of.

I think the most important contribution is genetics. Also very important is an organism's lifetime environment from fertilized egg till death, which involves regulated epigenetic modifications. Transgenerational epigenetics is probably going to be small. And something random during development—we think it's also epigenetics—that generates significant differences within a species. If you look at twin studies in humans, where identical twins are discordant for an illness or a trait, you see large variations even in situations where the twins were raised similarly. So you have to think, "Is the organism so vulnerable to subtle differences in the environment, or is something else big happening during development?" I’m a real believer in that random contribution.

Sandra Aamodt: You hardly ever hear scientists talk about things being random.

Eric Nestler: It doesn't feel good, because you want to be able to control everything.

Sandra Aamodt: That brings me to the last question that I want to ask you, a slightly more personal one. How has what you've learned about science changed the way you live your own life?

Eric Nestler: I started getting interested in resilience when my children were teenagers. It's so easy for an entire family's emotional energy to be devoted to the shenanigans of a teenager’s life. Listen, everybody is subjected to stress. We want to be the fortunate people whose hardships are not as severe, but no one goes unscathed. Even if you do, then more minor things are perceived as crises. After taking stock of the challenges, I now address my family’s crises from the point of view of resilience. Don’t be a passive victim. Figure out how to respond positively, adapt, and move forward. I think that was a very useful lesson, and it derived directly from our research on mouse resilience to stress.

The right kind of training is exposure to stress, not so bad as to paralyze you, just enough that you can overcome it. Then you can be exposed to slightly stronger stress, overcome it, and build more resistance. It's basically Special Forces training. If the Army waterboarded any of us, which they do in Special Forces training, we’d become basket cases. But they take men and women who no doubt are inherently more resilient and train them to be super resilient. I think it's an important lesson even in adulthood. Building resilience is a great way to look at life.

Meera Lee
4 years ago

I had known, vaguely, that resilience in scientific terms was a quality one could reliably observe (or fail to see) in the individuals over time, but I didn't realize it had such deep genetic/epigenetic roots. It's simultaneously disturbing and marvelous that a trait that we feel, instinctively, to be so much a part of personality might have the capacity to be altered by neurochemical means. By the way, I think this is my favorite interview on the site so far. (Sandra's skillful questions + Eric Nestler's wonderfully vivid responses are a dynamite combination.)

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