How Stress Alters the Brain and Behavior

Huda Akil: Thank you, Michael. I do want to switch gear a little bit because I am a neuroscientist. I know the room is full of neuroscientists so ... although not everybody is, but ... My intent is not so much to teach you specific neuroscience facts but more how to bring together a set of arguments that are of relevance, specifically towards solitary confinement. I'll tell you why in a minute.

But, I want to start by acknowledging that my whole interest in this area started with an invitation from Michael Zigman, who told me he was putting together a symposium at AAAS, and he said, "We want a scientific talk on solitary confinement." I said, "I don't know anything about that. I work with humans with depression, but that's not the same thing. I work with stress in animals. I'm not aware of any direct studies on this. And anyhow, why do we need neuroscience? Why isn't that just humanity, morality? Why is neuroscience relevant?"

Well, Michael can be very persuasive. I won't tell you all that went into it, but basically, he talked me into it. So, I'm at the meeting, and I meet Jules Lobel, who you will hear from. He's a lawyer who ... very thoughtful and creative and wise, and he and I also started to interact. I began, through him, to understand why it's important to bring neuroscience into it. I will let him explain it more clearly, but my understanding is that there is this gap between the way, as a society, we think about physical punishment and psychological punishment, and that this idea of cruel and unusual punishment, which is not Constitutional, applies to somebody when you break their leg, but not when you mess up their brain. This is why it becomes important to show that you are messing up their brain and not just to make a more general argument about the humanity, even though that is probably all our starting place.

And then I met Mr. King at that same meeting. The night before, we went out to dinner together as a panel to talk. We had a press conference followed by a panel discussion. He was kind of quiet, but he and I, cold Chicago night, decided to walk back to the hotel and everybody was talking, and he and I went walking, and I told him, "Is this ..." So, I have a terrible sense of direction. Well, he was completely lost. He would start to tell me, "Since I was in solitary, I have completely lost my sense of direction." In that moment, the light went on in my head like bingo, this is the angle. Because people don't want to believe that ... They have belief systems about what's important and what's not and what it does to you, but here is something where we know the biology.

If you have lost your sense of direction as a neuroscientist, when you used to be able to navigate, unlike me, then what could possibly have gone on? And so, we know ... I'm going to skip this and say that then I went back, and he said ... After he had written about it, he said, "After six months, I became almost totally blind." He shared that with you ... because I couldn't look in the distance, and my geography is completely messed up. I get confused if I have to go four or five blocks, even if I know exactly where I am."

And so, I thought, okay, this is probably one place we can start, which is to talk, of course, about the hippocampus, given that we all know how it plays a very important role in space exploration, while it is also a key player in stress responsiveness and in the early stages of memory. So that seemed like a very good place to start, not to say this is the only important place, but I felt like that is a place we could talk about in press conferences and in symposia, to say, "There is likely been a change in the brain, a biological change in the brain." As we know, and since then, there's been a lot of interest in that brain's GPS, so it's in the public awareness that the hippocampus is really important in spacial navigation.

Based on that start, I think this is the argument that one can deploy. It's just my way of deploying an argument as a neuroscientist, to hand it to other people who might be, then, able to use it for legal purposes. The brain, as we all know, is a self-remodeling machine. It really cares what environment it's in, over both short periods, but certainly over the long period, what we call neuroplasticity. We know that social and sensory isolation can be severely stressful. We heard a very eloquent description of loneliness and social ... but also perceptual isolation. You just do sensory deprivation for a while and see what that does to your ability to think and not hallucinate and completely lose track of reality.

We know, from a lot of neuroscience work, that chronic stress can change the activity, the volume, of the hippocampus. It can affect many ... has many other consequences, but we also have a lot of evidence from many other brain regions, the amygdala, fear, emotional processing; hypothalamus and drive. This is the final common path of stress responsiveness ... cortical structures and the like. We know also that people in solitary confinement are not seeing the light of day, I mean, in most cases, and that has to affect circadian function. We know that every cell has a circadian clock and cares about, and I'll say more about that. And we know that it causes clinical depression and that depression itself damages the brain.

So this is the body of the kind of the general outline of the argument, with the idea that it's possible, then, to talk about this at multiple levels of integration, from the whole individual, whole brain structures, like you heard from Stephanie with imaging, talking about circuits in animal systems, and talking about cell synapses and even at the levels of the genes. I think if we could bring information to bear on this argument about what extent that solitary confinement or solitary isolation, or deprivation in space, in sensory input, whether you're a very old person in isolation or a person in prison ... If we can bring to bear arguments at each one of the levels, I think it would be a lot more powerful ... and the idea that the brain and the lack of behavior or behavior remodels at all of these levels.

So, the argument, then, can be direct animal studies that can drill down to each of these levels, and it can also be human studies and even though we don't have direct human studies on people like Mr. King, who are in prison for many reasons we can discuss, we have a lot of human data about depression, for example, which is but one of many long-term consequences that has been proven to be true in people who experience that kind of treatment.

A few words about the animal study, as you know, the insufficient activity of brain cells can be the results of isolation, but there can actually be actual damage by stress. We heard a lot about the importance of social stress, isolation, and interaction. We can model the importance of social interaction in rodent models very beautifully. We can hear the difference between animals who are happy and chirping together, using ultrasonic vocalization, or distress calls when they are isolated. We can show that it matters to have somebody in the neighborhood if you're doing something as simple, maybe, as fear extinction, for example. So that even in a rodent, who is in the neighborhood, and whether you have a buddy or not, makes a huge difference on things that we consider very fundamental models that we study.

We know a lot about this wonderful hypothalamal-pituitary-adrenal axis and the role of glucocorticoids. One of the things that I wanted to remind you is that glucocorticoids go back and change the very structure and function of cells. This is an example of cells. With label green is the glucocorticoid receptor that's sitting in the cytoplasm, but if you expose them to glucocorticoids, the glucocorticoid and the receptor migrate into the nucleus where the job is to change gene activities, therefore remodel the activity of a lot of genes, which is how stress remodels cellular function, remodels maybe the actual structure of neurons and their connectivity. You'll hear much more about this from Richard, so I'm not going to dwell on it.

I want to quickly move to some of the human studies that can be brought to bear. Those happen to be ours, but I'm sure you each have ... or many of you have some. They come from human postmortem studies in humans who have suffered from chronic, severe, clinical depression, compared to normal controls. This is work from the Pritzker Consortium where we have been doing this for many years. This is how I would sum my entire conclusion. It's the difference between a tree in spring and a tree in winter. In other words, we talk all about circuits these days, and probably depression might start with a dysregulated circuit, but depression spreads throughout the brain. It affects every brain region we have looked at, some more than others. You see that it's a death by 1,000 wounds. Lots of gene pathways, lots of regions are altered, sometimes in little ways, and sometimes in big ways. It's a devastating illness where you can really see the damage in the brain.

So, this system-wide disorder, then, can be noted even, obviously, in living people. This is very old work from Yvette Sheline, who looked specifically at the hippocampus, since we started with hippocampus, and showed that the longer the duration of untreated depression, the smaller your hippocampus. There's many studies in PTSD, in many other areas, showing that depression damages the hippocampus.

This is a Pritzker Consortium I talked to you about where we do these dissections of many, many brain regions and then drill down with laser, capture microdissections and so on, so we have a lot of data. But out of that, a couple of three-gene families have really emerged as remarkably altered in depression. I'm going to give you two quick examples of relevance to this argument, circadian genes and growth factors.

As we all know, we all live in a system where we care about the light. We have this beautiful machinery, which is the circadian clock, in every brain cell. When we look at the brains of people who died, either controls or depressed people, if we keep track of what time of day they died, we can actually watch gene expression oscillate as a function of the time of day. These are all individual humans who died at different time, before or after sunrise, on the day of their death. You can see this gene, which is one of the clock genes, is highly expressed in people who died five hours before sunrise, much less expressed in people who died five hours post.

In fact, all the clock genes oscillates across subjects. You can see it. I find it amazing. And you can find that thousands of genes, actually, all over the brain, oscillate as a function of the time of death, so much so, that we can actually determine what time somebody died just based on the pattern of gene expression in their brain. So you could be blind to the time of death and predict it within an hour, if you're a normal control.

But, if you are depressed, all of that falls apart. The patterning, the timing, it looks like it's the wrong time of day, different areas are out of sync. This is just one example of one factor that people aren't seeing the light, and they don't have normal circadian activity that shows how gene expression changes throughout, is likely to change throughout the brain, and that we know that a disrupted circadian rhythm has itself, then, a big profound effect on mood.

And then, my last little bit is about these growth factors. Most of you who are neuroscientists know that there is a growth factor theory, hypothesis, about depression and antidepressants are thought to work in part by reactivating growth factors. You can think of them as our own brain fertilizers that they get really impoverished under certain conditions. They can get reactivated, and if appropriately reactivated, they can help in neuroplasticity. The fibroblast growth factor family is one that popped up from our human postmortem studies. We've studied it extensively now over the years, both in human and in animals. Animal studies clearly confirm that some of these factors like FGF2 is our own natural antidepressant, that we have it in our brain, and if we knock it down in a mouse brain, we make a more anxious and a more depressed animal, even just specifically in the dentate gyrus.

These are factors that are downregulated by social isolation in rodents. Within a week to two weeks of social isolation, these growth factors are diminished. In other words, we have a vicious cycle where isolation can cause depression. Depression can change many molecules using FGF2 as my example. In turn, if low FGF2 is, itself, depressing and anxiety provoking. This is but one of many such examples, but it's one for which we have direct, concrete molecular evidence.

I want to leave you with the thought that we really have many legs of evidence. These are just a few. I'm sure many, many lines of research can be brought to bear on this argument, that social deprivation is bad for brain structure and function, that sensory deprivation is bad for brain structure and function. Circadian dysregulation is bad. And then the consequences of the loneliness, the isolation, in itself, is also extremely damaging.

So the question is, even if we hope to set a very high standard before we isolate a human being in this way, if we do need to isolate somebody, can we do it without really damaging the brain quite as badly as the current setup does? This is an example of a room. I think it's in one of those ... Pelican Bay maybe. But you can see there is ... everything is really so confined. There is even a cage inside the cage, so the signals are terrifying. Everything is locked to the floor. You can't even move your bed. It's unbelievable to me.

So, to me, I would leave you with the questions, is it necessary to do this social isolation to people? And if it is absolutely necessary, if somebody is, in fact, a danger to themselves or to somebody else, can it be made more humane, even in a physical way, if not in a psychological way? Hopefully both. Can we minimize the stress and promote resilience? I am struck by the fact that Mr. King talks about active coping, really if you want to put it in stress terms, as opposed to passive coping, and has found a way to create his own resilience. I hope we can do better by people, and we can use neuroscience to help us do that job, put that signal out. Thank you.

Speaker 2: Have there been any other animal models besides mice that were used or looked at, knockdown FGF2?

Huda Akil: I'm sorry. I was ... Are you asking ... Is there a knockdown FGF2?

Speaker 2: Like you used mice models, right? Is that ... What kind of models did you use to look at the knockdown?

Huda Akil: We did the [inaudible].

Speaker 2: Okay.

Huda Akil: FGF2 is really important for development, so if you knock it down at birth, you don't have a normal brain. We went to this in adult brain, and [inaudible].

Speaker 2: Okay.