Washington State University VCAAP Seminar Series.; Lecture with Dr. Robert Sapolsky on Stress, Neural Degeneration, and Individual Differences.

Welcome and good afternoon. My name is Dr Heiko Jansen. I'm a faculty member here in the department of VCAAP at Washington State University. And it's my pleasure to introduce to you today Dr. Robert Sapolsky as part of our VCAAP seminar series but also as this year's Grass Traveling Lecture speaker, and his visit is being hosted by myself and also the Northern Rocky Mountain chapter for the Society of Neuroscience. Dr. Sapolsky's career is long and distinguished, although his age belies that fact. He got a young start in academia and with his birth in New York City, moving on then to Boston where he did his undergraduate work at Harvard University, and he received his bachelor degree in biological anthropology summa cum laude and Gamma Phi. Dr. Sapolsky then went on to do his Ph.D. at Rockefeller University, so he returned home, in the field of neuroendocrinology.

After that Dr. Sapolsky went on to the Salk Institute as a post-doctoral fellow, and during that time he received numerous honors, including the Lindsley prize for outstanding thesis from the Society of Neuroscience. He received a MacArthur fellowship and also the Young Investigator award from the Society of Neuroscience. Following those distinguished few years, he then went on to Stanford University, where he's been ever since. Dr. Sapolsky is now a full professor in the Department of Biological Sciences and his career has continued to skyrocket from there. He has authored nearly 300 publications, four books. He's a frequent contributor to USA Today and writes frequent opinions and editorials for USA Today. He's published in The New Yorker, and he's published in the lay press as well as many scientific journals as well. His career is

one that has spanned more than 10 years but the number of publications that he has produced is quite significant and astounding. And I think you'll appreciate his candor when he speaks and appreciate the depth to which he understands so many of the areas both related to his field of interest and areas that are not necessarily directly related. Dr. Sapolsky also has the distinguished honor of serving as a member of the National Museum of Kenya where he goes for three months every summer to study primate behavior. And I think Dr. Sapolsky will entertain you as well as inform you about the model that he uses, which is the non-human primate, and how that ties in together with the topic of his talk today. And that is stress, neural degeneration, and individual differences. And so I'd like to welcome Dr. Sapolsky here to Washington State University. This is his first visit, and I hope we all make him feel welcome. And with that, we'll turn the microphone over to

him and enjoy the talk, and questions afterwards will be answered, and time with faculty and students has also been scheduled. So enjoy the conversations, enjoy the discussions, and sit back and relax. Thank you. OK. Good. Well, thanks, and it's great to be here in Portland. OK, let me start off. I obviously don't know anybody here, having just gotten here, and I'm dimly aware of what state I'm in, in the broadest sense of the word state. Since I don't know anybody here, let me start off by seeing if we all had a very similar childhood experience, because I think this winds up being relevant to something I'll be talking about. OK, here's the scenario. You're a kid, it's during the summer, your mother takes you to the beach, it's one of those hot days, you're at the beach or at the town's swimming pool, you're splashing around, you're having a fine time. Eventually it's lunch time, you get dragged out, you eat your egg salad sandwich, you complain about the sand in the food, everything is going to terrifically. And then you're done with

lunch and you're about to go back in the water. And suddenly your mother, in a complete panic, stops you from doing so because of the well-known fact that at that point if you so much as get your big toe wet, you will instantly get stomach cramps and die. OK, first question here, how many had that experience when you were a kid? OK, lots of us. Who had to wait 30 minutes after lunch? Who waited an hour? Two hours? California 15 minutes, that's the problem down there. All of us had the same experience. All of our mothers knew this. This was one of those cases where if you went swimming after lunch, you get stomach cramps and die, all of our mothers knew this and knew this enough to constrain our behavior. One of those classic cases of folk knowledge, something everybody knows is true but simply isn't. So untrue, in fact, that the Red Cross even puts out a pamphlet saying that you can go swimming after lunch, it's OK to do that. Yet all of our mothers knew this. And this is one of these examples of some sort of folk wisdom where everybody knows that there's giant alligators in the sewer system, the New Yorker,

Einstein failed math when he was a kid, or any of those sorts of deals. Now if you're a neuro- scientist, there's at least two bits of this folk wisdom, things that everybody knows is true but which is not true in the slightest, that winds up being relevant to what I'll be talking about. The first one is one where, I have no idea what the origins are of this but we've all heard this one. If you're a neuroscientist, you always get this one somewhere around Thanksgiving, the relative that corners you and says "Is this true, and if so why can't you people do something about it?" - the well-known fact that we only use 10 percent of our brain potential. And I have no idea where this one came from, but this always comes with a corollary, corollary, which is that when they examined Einstein's brain, it turned out he used 15 percent of his brain potential and that's how he managed to pull it off. Everybody knows that one is the case. That one is absolute nonsense. It's not even clear what that even means, yet everybody out there knows this is true. The other bit of folk wisdom has something to do with how the brain ages, and it goes as follows. You're 18, you're 20, life is great, your

synapses are plastic, you're potentiating stuff all over the place. Things are going wonderfully, and then amazingly, the very morning of your 21st birthday, something happens, something happens, and you start losing neurons. Your brain cells start dying. This is what happens. Now we all know this one well enough. We even know the magic number. You lose 10,000 neurons per day every day for the rest your life unless you have a drink, in which case you lose 10,000 more. That part's probably true. But this part about normative aging, this is what aging of the brain is like. This is natural, this is inevitable, this is inexorable, until you're 40 years old and you're neck and neck with anaplesia[?], and this is what your nervous system does as you age. And this is what everybody knows is the case: massive neuron loss as a normal part of aging. And it turns out this bit of folk wisdom and folk knowledge is based on a really influential, totally wrong study that was done in the 1950s, where some people did the first obsessive round of counting number of neurons and age of human brains, and they decided "well, let's get some really aged brains, let's get some brains from those

people with Alzheimer's disease." Aha. We know now, confusing normative aging with a disease of aging. And they came up with these horrifying numbers and extrapolating backwards, suddenly you're losing 10,000 neurons per day somewhere from senior year in college. OK, what we now know to be the case is, catastrophic neuron loss is not a normative feature of brain aging. It turns out there's only a subset of areas in the brain that lose a fair number of neurons. And number one on the list is the substantia nigra and you do lose a lot of neurons there. And that gives rise to the Parkinsonian tremor that's typical of aging, at an extreme that gives rise to Parkinson's disease. Number two on the list, though, is an area called the hippocampus. Hippocampus, anyone who's taken Psych 101 in the last millennium, hippocampus is ground zero for learning and memory, critical for declarative memory, and hippocampus loses a fair number of neurons during aging. Now what I'm going to spend the first half of the talk covering is when you try to figure out why this occurs, you round up

the usual suspects for neurological damage. You get autoimmune attack or slow viruses or environmental toxins or who knows what. None of them are suspect, and what you wind up seeing is the most likely explanation for hippocampal neuron death over the course of a lifetime is your cumulative exposure to stress, your cumulative exposure to one class of stress hormones. What I'll tell you about is the mechanisms for that as we understand it these days, the cell biology, the molecular biology for it. And that'll take us about halfway through. If you're still awake at that point, you should be depressed as hell, because one of the main punch lines of that section is, this is not just about rat hippocampi, or neurons in dishes. More and more evidence that this is quite relevant to the human hippocampus. Bad news for all of us. OK, what I'll focus on in the second half, though, is amid all that depressing news, there is lots of room for optimism, built around the fact that this is one example of stress-related disease. Despite that, most of us have not collapsed into

puddles of stress-related disease. And what I'll do in the second half is shift the gears fairly dramatically. And another aspect of my work, looking at individual differences. Why are some of us more vulnerable to stress-related diseases than others? What are some of the mechanisms, in terms of how our bodies work and probably more importantly how our psyches work, in explaining who is more or less vulnerable to the ravages of stress over the course of a lifetime? OK, so starting off when I talk about stress, stress is this fairly amorphous thing. What I'll be talking about throughout is very explicitly one class of hormone secreted during stress. These are the villains in this set piece, glucocorticoids. These are adrenal steroid hormones released during stress. Classic neuroendocrine cascade, something stressful occurs, within a couple of seconds hypothalamus is releasing CRF and related peptides, which within about 10 seconds triggers the pituitary to release ACTH, clinical term, ACTH, there are a number of other such terms.

Within a minute or two, the adrenal is beginning to release glucocorticoids, cortical steroids, human version, primate version, cortisol, also known as hydrocortisone, rodent version, corticosterone. These are the villains in the piece, these are the hormones which turn out to have the capacity to damage the hippocampus. This is now about a 30- year-old story, and you sit down, an endocrinologist, and you tell this person about it, and this still seems the most counter-intuitive thing on earth, for the simple reason that the glucocorticoids are essential for life. You are dead without these hormones, yet they wind up damaging your nervous system. Where do they get off killing your brain cells? And the way to begin to approach this is to begin to look at what they do, because glucocorticoid action, OK, placebo, there, that one. OK. Glucocorticoid action absolutely typifies everything you need to know about stress, when it is bad news for you, when it is good news for you. What we have on the left are glucocorticoid actions in the ways in which they are

perfectly adaptive, the ways in which they are great for you, as long as you are getting stressed like a normal mammal does, you are some zebra, a lion has leapt out, ripped your stomach open, your innards are dragging in the dust, and you still need to get out of there. Or you were that lion who is half starved to death and if you don't chase after something, you are not going to survive the night. A short-term physiological crisis, and everything the glucocorticoids do are brilliant for the zebra or the lion. Above all else, if you are going to survive that crisis, you need energy, right now, in the circulation, not tucked away in your fat cells for some building project next spring. Glucocorticoids, along with sympathetic catacolamines, glucagon, mobilize energy from storage sites. You go to the bank, you empty out the savings account, and you turn it into cash, circulating glucose, circulating fatty acids. The next thing you do is equally logical with glucocorticoids. In concert with sympathetic catacolamines, you increase cardiovascular tone. Your heart rate goes up, your blood pressure, your

breathing rate, all is part of a strategy. Get the glucose, get the oxygen to your thigh muscles in 2 seconds instead of 3. You're that much more likely to survive. OK, the next things you do are logical as well. Glucocorticoids shut off all sorts of long-term building projects, built around this logic, that if there's a tornado due this afternoon, this isn't the day you spend outside gardening, you don't worry about the long-term projects until you know there's a long term. You shut down digestion. If you are that lion, you are not just staggering up from some all-you-can eat buffet. If you are that zebra, you're mobilizing energy in the first line from your fat cells and your liver in the next two seconds. Digestion takes hours, it's expensive. You're trying to avoid being somebody's lunch. don't worry about breakfast. You shut down the digestive tract. In addition, you shut down growth, you shut down reproduction. Big, expensive, optimistic things to be doing with your body, especially if you are a female mammal. And this is no time for it. You know you're running for your life, the lion's two steps behind you, ovulate some other time.

Don't do it right now. Grow antlers next week, hit puberty tomorrow, don't even think about sperm. What glucocorticoids do is shut down growth, tissue repair, suppress every reproductive hormone on earth, all as part of this logic of delaying. In addition, very significantly, glucocorticoids suppress the immune system. Immune defenses are obviously very useful, your immune system spots some tumor that would otherwise kill you in six months, your immune system makes antibodies that are going to be fabulous somewhere around Halloween. Your immune system is going to do nothing for you in the next three minutes as you run for your life, and that same logic again, immunity doesn't come cheap. Make your antibodies around the campfire tonight if there is a tonight. Don't bother right now. Finally, glucocorticoids get into the brain where, dramatic foreshadowing, their highest levels or receptors are in the hippocampus, and short term they sharpen cognition. You remember things better, you retrieve memory better, your sensory systems are sharpened, all that's part of that acuity, that vigilance which

comes with the onset of a stressor. So everything you see on the left here is exactly what you want to be doing with your body if you're getting stressed like a normal mammal. And all you need to do is look at somebody who can't do that, can't secrete glucocorticoids, somebody who's Addisonian, adrenal insufficiency, and this is somebody who drops dead running for a commuter bus. If you plan to sprint across the savannah or plan to sprint across a parking lot, if you try to do it without secreting glucocorticoids, you've got about a 30-second life expectancy. For most of us, though, far more important is the issue on the right. What if you get stressed too often? What if you secrete glucocorticoids too long, too chronically for purely psychological reasons? And suddenly we're in this realm where you sit down a hippo and try to explain to a hippo what RR1s are or tenure or GPAs or any such thing and it's going to have no idea what you're talking about, and suddenly we're in this very primate, very human realm of being able to secrete glucocorticoids merely with thoughts,

merely with emotions, merely with memory. This capacity to chronically turn on the stress response for reasons of psychological or social stress, do it chronically, and you're going to get sick. The system didn't evolve for chronic activation. Chronically mobilize energy, you never store it, you're more at risk for adult onset diabetes. At the cardiovascular level, stress-induced hypertension. Increased risk of ulcers. Glucocorticoids inhibiting repair mechanisms in stomach walls. With kids, chronic glucocorticoids, chronic stress, you've got disorders of impaired growth, psychogenic dwarfism, psychosocial dwarfism. At the reproductive level, stress-induced amenorrhea, decreased testosterone levels, decreased libido, things of that sort. At the immune system, the centerpiece of psychoneuroimmunology, the notion that chronic stress, chronically suppressing the immune system, can increase your risk for infectious disease. So we see this double-edged sword here to glucocorticoid action. You had better appropriately secrete this hormone if you're

going to be stressed the way 99 percent of the beasts on this planet get stressed. But if you secrete it too often, too long, for purely psychological reasons, you increase your risk for disease. OK, so it's in that context that we could begin to appreciate the final line. This ability... this ability of glucocorti short term enhancing hippocampal function, their ability in the long term to damage the hippocampus. It's in this context that we can now begin to see the story. First evidence now 25, 30 years old. Lots of glucocorticoids will kill hippocampal neurons. And here we see an autoradiogram of the hippocampus glucocorticoid receptors, and this is screaming out. This is where the glucocorticoid receptors are in the brain. From the first demonstration of this in the late 60s by Bruce McEwen and colleagues at Rockefeller, from ever after, if you think about stress, if you think about the brain, if you think about glucocorticoids, you gotta think about the hippocampus. This is where the receptors are.

And a ver- variety of studies from various groups, and each one of these slides summarizes a dozen years work from different groups and I list the main ones in each slide, what you see here is a series of studies showing lots of stress, lots of glucocorticoids over the course of months for a rat and you accelerate hippocampal aging, more dead neurons, more reactive glyosis, more of the memory problems you would expect to see, and what you see here, high-resolution autoradiography, the neurons that you lose are the ones that used to have the glucocorticoid receptors. Those are the vulnerable neurons. Conversely, a whole body of studies showing if you get rid of the glucocorticoids, surgical means, behavioral means, pharmacological, get rid of the glucocorticoids and you slow down the hippocampal aging. And put those pieces together and what you see is, in an aged rat, the cumulative glucocorticoid exposure over the lifetime is the single best predictor of how many neurons you're going to wind up getting. OK, so we've got a first version of

trouble here. The ability of glucocorticoids to overtly kill hippocampal neurons. Now I'm beginning to think about that. What's that about? What this dealt with was a notion of glucocorticoids being neurotoxic, and sort of in the mid 80s as I was dealing with this, it struck me that glucocorticoids didn't actually have to be neurotoxic in order to explain this. All they needed to do was in some metaphorical way mess up a neuron, mess up a hippocampal neuron and leave it dangling on the edge of a cliff. At that point, if nothing else happened, the neuron recovers from that period of stress and everybody lives happily ever after. On the other hand, if at that point where this neuron is dangling and you push it with something else, the neuron is that much more likely to go over the edge of the cliff. What this idea of endangerment predicted was that all sorts of neurological insults that damage the hippocampus should become more damaging in the presence of lots of glucocorticoids. And this turns out to be the case with a vengeance.

By now a whole variety of insults that specialize in killing hippocampal neurons, the higher the glucocorticoid levels at the time of the insult, the more dead neurons you wind up getting. Prolonged epileptic seizures, damaging the ca3 region of the hippocampus, hypoxyia-ischemia, global ischemia, cardiac arrest. We all know, cardiac arrest, no blood flow to the brain, you gotta get the heart beating within four minutes or else you start getting damage. You get it first in the hippocampus. The higher the glucocorticoid levels at the time of the stroke, of the cardiac arrest, the more damage. Hypoglycemia, oxygen radical generators, two very disturbing things on this list. First one, beta amyloid, lots of you will know beta amyloid is the rogue protein implicated in the hippocampal neuron death in Alzheimer's disease, and people by now understand a lot about how this is neurotoxic, predominantly by way of generating oxygen radicals. A number of groups now showing glucocorticoids make beta amyloid more

toxic. Beginning to raise the possibility of glucocorticoids as being a modulating factor in Alzheimer's disease. And what's worrisome about that, people with Alzheimer's get very elevated levels of glucocorticoids. It probably exacerbates the damage. The other one on this list, and something my lab's been working on the last few years, gp120. Glycoprotein 120. It's the code protein of the AIDS virus. About half the people with AIDS get AIDS-related dementia, hippocampal damage, memory loss, tremendous cognitive impairment, and gp120 appears to be the key peptide in killing the hippocampal neurons, a very complicated indirect route. And what my lab has been seeing is every bad thing that gp120 does to a neuron, glucocorticoids make worse. And that one is really disturbing, not just because people with AIDS are under stress, but people with AIDS come down with pneumystis pneumonia and for the severe cases, the only treatment is to give people the highest doses of glucocorticoids that are ever used in clinical

medicine. I mean, lots of you will be familiar with 70, 80 mgs of prednisone a day for somebody with a lupus flare up. These folks are getting 300 mgs of glucocorticoids a day and it melts their neurological status at that point, and this probably has something to do with it. And that's going to raise a really tough clinical issue. You give the person the steroids, you save their life, and they get an extra six months in diapers having no idea where they are. I know how I would vote were I in that situation. OK. Collectively what this slide is showing is, this is a lot of different ways to mess up a neuron, all of them made worse by glucocorticoids. Whatever these hormones are doing, it's a very generalized endangerment that they're inducing. It's a very generalized cliff that these neurons are dangling on the edge of. So what's this endangerment about? Obviously from a couple of slides ago, it could be a zillion different things, given how many things glucocorticoids can do in the body. It could be changing insulin levels, it could be changing cerebral profusion

rates, it could be doing a billion things via secondary peripheral physiology. What's the best way of showing that this endangerment is not due to the peripheral physiological effects of glucocorticoids? Get rid of the periphery, do the entire thing in vitro in tissue culture systems - hippocampal neurons here are growing in culture - where you can come up with in vitro models of a stroke, a seizure, etc., and quantify the number of surviving neurons, and it's the exact same story. The higher the glucocorticoid levels in the dish, the fewer neurons survive. For example, here, a model of status epileptic seizures, prolonged seizures, kainic acid, and here's the number of surviving neurons, seizure with no glucocorticoids, and increasing amounts of glucocorticoids in the media, fewer surviving neurons. Critically, these are not levels of glucocorticoids that kill neurons. You're not explaining killing. You're endangering. You're just making the neurons more fragile. And in a very crude way, this is equivalent to basal resting levels of glucocorticoids: moderate

stress, maximal stress. OK. So with in vitro systems like this, you could then do your basic endocrinology, you can show other steroids don't do this. Estrogens, androgens, progestins, it's only glucocorticoids. You can show you don't get endangerment like this in cortical cultures, hypothalamic [?] cultures, cerebellar, you can show which receptor it works by . For those of you who care about such things, it's the low-affinity type 2 glucocorticoid receptor that mediates it. This is a hormone working through its receptor in the target tissue to make the target cells more vulnerable to anything you throw at them. So what's this endangerment about? OK. The previous slide. All of those different neurological insults. The theme I was emphasizing there is, look at how many different ways there are of messing with these neurons. They're all made worse by glucocorticoids. Nonetheless, all of those neurological insults have one thing in common, which is they all ultimately constitute an energy crisis for the neuron. Either they

impair the ability of neurons to generate energy, cardiac arrest, you're not delivering glucose or oxygen, hypoglycemia, or you're placing such high energy demands on the neuron, as in during a seizure, that the neuron can't keep up. All of these are energetic crises. All of these involve catastrophic drops in ATP levels. These are all energetic, and looking at that, I speculated that perhaps what this cliff is about is an energetic one. In some way, glucocorticoids are energetically endangering hippocampal neurons so that whatever you throw at them at that point, they're more likely to go over the edge. Now if that's the case, that generates a real simple experimental prediction, which is you should be able to take one of these insults that causes this much damage, and now insult plus glucocorticoids and causes this much damage. Now take the insult plus glucocorticoids and give the neuron something extra to eat. Supplement them with excess energy and you should be able to subtract out this endangerment, and that's precisely what

you wind up seeing. Here's one example of this, and a number of different versions out there, but here's one example from my lab. Here's an insult that mimics hypoglycemic damage: insult alone, insult plus glucocorticoids. As I showed you, far more damage. Insult glucocorticoids plus mannose. Mannose, this wonderful monosaccharide that is taken up by the brain. It's got its own transport system. Give these neurons this extra sugar and away goes the endangerment. Do the same thing with the one other type of food that neurons can normally eat, ketone bodies like beta hydroxybutyrate, and away goes the problem. It's an energetic endangerment. So what is this energy problem about? And about 10 years ago, my lab figured this out, and as neurobiologists we were thrilled, because we were the first ones to see this. And as endocrinologists, we were totally bored because everybody had known this for 50 years. It had something to do with the logic of zebras running away from lions. OK. You were that zebra, you're running for your life. You've mobilized all this energy, all this glucose into your

bloodstream. What would be the stupidest thing on earth to be doing with your circulating glucose at that time? Storing it away in your fat cells, storing it away in your liver, storing it away in your fibroblasts, storing it away anywhere instead of turning it into energy to be consumed right now from your, by your muscles. And what people have known for 50 years is, in the periphery glucocorticoids inhibit glucose uptake and glucose storage in tissues throughout the body except for exercising muscle. And people even understand the molecular biology underlying it. Glucocorticoids bind to their side as all the receptor translocate of the DNA, induce a protein called sequesterin, which sequesters glucose transporters off of the cell surface, sticks them into intracellular mothballs. And this is now a cell that doesn't take up as much glucose. Exactly the opposite of what insulin does, which is to mobilize glucose transporters to the cell surface. So glucocorticoids shut down 70, 80 percent of glucose transport in a fat cell. Really effective. And what we

did was go and look in the brain, and it turns out it's the exact same thing in the hippocampus. Much more subtle, 20, 25 percent inhibition of glucose transport. That's not enough to kill the neuron. That's not even enough to depress basal ATP levels. But it's enough to endanger the neuron now. Throw an insult at it, and it's a little bit energetically vulnerable. ATP levels crash faster, mitochondrial potentials crash faster, phosphor creatine levels go down. You are energetically endangering the neuron. You're making it just a little bit queasy, and a little bit nauseous, and a little bit lightheaded, and then you hit it over the head with a major neurological insult, and the crash comes that much faster. OK. So when this energy crash occurs, what goes wrong and what goes worse when you have glucocorticoids around? Now to orient you to this, this is the dogma these days as to how a neuron dies during a stroke, a seizure, etc. In the hippocampus, for those of you who are

not a neurobiologist, standard dogma, this neuron is electrically excited, releases neurotransmitters, the way it flows is required by law, all neurons go from left to right, so that's the flow of information here. And in the case of the hippocampus, the critical neurotransmitter being released is of this class called excitatory amino acid neurotransmitters, most famously glutamate. And glutamate is the most excitatory neurotransmitter in the brain and it's no surprise that your hippocampus is the most glutamaturgic part of the brain. That's how you pull off learning and memory. You need this super excitatory neurotransmitter. And what you wind up seeing is, what neuron death in the hippocampus is about is, glutamate levels get too high. And when they get too high, the jargon in the field is you're no longer talking about glutamate as an excitatory neurotransmitter. The jargon now is it's an excito- toxin. When the levels get high enough, glutamate becomes neurotoxic, binds to a number of receptors, the most notorious being the NMDA receptor, that causes a

tidal wave of calcium to come in, and at that point calcium activates calcium-dependent proteases, and nucleases, and oxibases, and you generate oxygen radicals and blow apart your cytoskeleton, and you've got a dead neuron shortly after that. This is a very credible pathway. Everybody works on this one these days. Major clinical effort focusing on blocking the NMDA receptor, blocking calcium channels, chelating calcium, clinical trials for all of that. Critically, every step in this pathway is made worse if you're running out of energy. If you're running out of energy, this neuron is going to be more likely to be polarized, dump more glutamate. Even more importantly, this neuron doesn't have the energy for these really expensive high- affinity re-uptake pumps. More glutamate that sticks around longer. As a result, more calcium rushes in. This neuron can't afford the very expensive calcium extrusion mechanisms. More calcium, you can't afford to repair the oxidative damage. Very

energy dependent. So at this point, you don't have to be a brain scientist to come up with a perfectly obvious scenario, insofar as this pathway mediates neuron death during stroke, seizure, etc., insofar as this pathway is very energy dependent, insofar as glucocorticoids worsen the outcome of these insults in an energy-dependent way. Maybe what they're doing is, by inhibiting glucose uptake, they're just messing with every step in the system. This neuron can't afford to do this as readily, this neuron can't afford to do that readily. And about a decade later of work in my lab, that's exactly what you wind up seeing. Starting with the first step in the system, the glutamate excess, what you wind up seeing is during one of these insults with more glucocorticoids around, you wind up with more glutamate. Here's a rat undergoing an epileptic seizure, microdialysis in the hippocampus, measuring glutamate levels there. This is seizure with no glucocorticoids, and this is how much glutamate winds up there. Seizure plus glucocorticoids, and you wind up with more glutamate there. Is this due to the

energy problem? Yes. Here is how you show it. Seizure plus glucocorticoids plus mannose and away goes your problem. Mechanistic question, if one cares about such things, the excess glutamate here, is that because the neurons are dumping more glutamate into the synapse, or is it because they can't remove the glutamate? It's the removal step. That's the vulnerable one. OK. So given this first step, one can readily then go through a syllogism: if glucocorticoids make for more glutamate, I bet you they make for more calcium as well, and that's exactly what you see. Here we have cultured neurons, calcium imaging techniques, calcium-sensitive dyes. Seizure insult alone, no glucocorticoids, to this much calcium mobilized. Seizure plus glucocorticoids, a lot more calcium mobilized in that neuron. Seizure, glucocorticoids, and enough extra glucose in this case to override that inhibition and away goes the problem. Same mechanistic question, is this mostly due to more calcium rushing into the cytoplasm or more trouble getting rid of this calcium? Once again, it's the

getting rid of. And that's a theme over and over again. A neurological insult, all hell breaks loose, and you can still carry on business pretty well. You just can't afford to clean up after yourself. That's a theme again and again. So if you've got more of this, the next step in the syllogism, that should be going wrong as well, and that's precisely what you see. With glucocorticoids around, more oxygen radicals being generated. With glucocorticoids around, more cytoskeletal breakdown. This key cytoskeletal protein spectrin, which gets broken down in dying neuron. Seizure alone, this much spectrin, protealysis. Seizure plus glucocorticoids. Seizure, glucocorticoids, plus manose. Here we have an abnormally phosphoralated microtubule protein. And for those of you who are Alzheimer's fans, you will recognize this is the abnormally phosphoralated protein which causes neurofibrillary tangles in Alzheimer's disease. And what we see here is during a seizure, during all of these neurological insults, you make a little bit of tangle, the higher the glucocorticoid levels, the more of this abnormal protein there.

Every single step along the way is made worse. And that's basically the model we're working with these days. You've got glucocorticoids inducing this mild, non-fatal, energetic vulnerability and along comes the worst day of that neuron's life, and every single step spirals more out of control, and the neuron is that much more likely to die. Now intellectually this is really pleasing because this absolutely fits with neuron death during these neurological crises. These are not cases of a single bullet and a lone gunman. These are cases where instead everything is going wrong, and here's a hormone making virtually every single one of those steps go a little bit more wrong than it would have otherwise. OK. So this is pretty much the model these days. A couple of more pieces in the story. One, it turns out that neurons don't just sit there passively being blown away by a stroke or a seizure. There's all sorts of defenses that they mobilize. They release what are called retaliatory neurotransmitters that inhibit glutamate release to try to turn off the faucet. They up-regulate heat

shock proteins, they up-regulate antioxidant defenses, they increase energy transport. There's a whole bunch of things, and a theme where all of these defenses come in is, these defenses don't come for free. You gotta pay for them, and you can absolutely guess the next piece. What we're seeing in my lab in the last few years is glucocorticoids mess up a whole bunch of these defenses once again by impairing neuronal energetics. You can't afford to do anything quite as expensive as these things. One additional piece we're seeing very recently in my lab is, during an insult, counter to what everybody knows as folk wisdom, in the nervous system glucocorticoids are not working in an anti-inflammatory manner. They're working pro-inflammatory. They're increasing cytokine release, they're increasing neutrophil infiltration. And when you look at the literature on the use of glucocorticoids to decrease inflammation in the brain, it is the literature that's not very convincing, because glucocorticoids are not really anti-inflammatory in the brain. They sure are in the periphery in

60 years of clinical data. They're not very anti-inflammatory in the brain, and I'll talk about that shortly. OK. So this is pretty much the picture at this point. So at this stage you should be utterly depressed, built around this whole notion of all of this bad news. What does this have to do with the human hippocampus, the primate hippocampus? Up until a few years ago, all of the evidence for any connection came from a pair of studies from my lab showing that glucocorticoids could do the exact same thing in the primate hippocampus. Prolonged stress, prolonged glucocorticoid exposure, and you damage the hippocampus in a primate. These were vervet monkeys, and I emphasize this was not actually a planned study. This was an opportunistic study done with a population of vervet monkeys in a primate center in East Africa. This was not a planned study to stress these animals, but these we were being given these brains post-mortem, and compared to controls, massive hippocampal damage, higher magnification EN healthy normal neurons, dying ones there. Unfortunately we now have a population of about 30 brains showing this:

only damage in the hippocampus, the exact same story as in a rat. So up until a few years ago, this was, OK, well, this kind of occurs in a primate. This makes one a little bit nervous, this is getting in the ballpark of the human brain. And in the last few years, a body of studies have come out that absolutely place this within the realm of human neurobiology. And all the news here is bad. Three different models. The first one, Cushing syndrome. Any of a number of different tumors where you hypersecrete glucocorticoids and you get every one of those pathologies on that table back when, and in addition what people have known for 60 years is, you get memory problems called Cushingoid dementia and you get declarative long- term memory problems, and for those who care about such things, that's the signature of hippocampal function. And in the last couple years a group at the University of Michigan doing imaging on people with Cushing's and showing atrophy of the hippocampus, only the hippocampus, the higher the cortisol levels, the more hippocampal

atrophy. Is this due to dead neurons? Almost certainly not, because what they have also shown is, surgically correct the tumor, and over the next year the hippocampus comes back to normal volume. What's that one about? This is work from Bruce McEwen's lab in the last decade, showing before glucocorticoids actually kill hippocampal neurons, they cause them to atrophy, to retract their processes. Stop the stress at that point and in a rat, over the next few weeks to months, the processes grow back. This is probably reversible atrophy of the neurons. The next two models are probably not reversible. First one, people with a history of severe stress, people who come down with PTSD, post-traumatic stress disorder, combat vets, childhood sexual abuse, and a half dozen different groups in the last few years showing the exact same thing: atrophy of the hippocampus, only the hippocampus. The more severe the history of stress, the more hippocampal atrophy. In some of these studies, up to 25 percent volume loss in the

hippocampus and that's the range you're talking about with Alzheimer's disease. You see the exactly predicted cognitive impairments in these folks. Is this one reversible? Sure doesn't seem to be. Because these are people decades after Vietnam, decades after their childhood abuse, whatever is going on there, it appears to be permanent. And the third model is the most worrisome one, because it applies to probably 15 percent of us in this room, those of us destined to have a major clinical depression at some point or other. Depression in its more severe biological forms associated with very elevated levels of glucocorticoids. And people have known for years, memory problems that are associated with hippocampal dysfunction. In the last few years groups at Yale and Washington University showing atrophy of the hippocampus, only the hippocampus. The longer the duration of depression, the more hippocampal atrophy. Is this one permanent? Almost certainly, because these were not studies of depressives. These were studies of ex-depressives, people up to decades

after their depressions had been gotten under control with antidepressants and the atrophy was still there. And what the neuropsychological studies show is some degree of the memory loss persists even after depression is resolved. This is a very sparse literature. Collectively this is 15 studies by now. None of it has involved cell counts post-mortem. All sorts of confounds, all sorts of groups that weren't controlled for. Collectively though, what this begins to suggest is the hippocampus in the human brain is probably vulnerable to the actions of chronic stress and chronic glucocorticoids as well. Okay, this is horrible news. What are the implications of this? First off, right off the bat, what it suggests is, if you've just had some stroke, the last thing on earth you want is for your neurologist to give you glucocorticoids because it's going to make the brain damage worse. And as lots of you will know, if you've just had a stroke and you wind up at one of the less than leading medical institutions in this country, the first damn thing they're going to do is give you 80 megs of Dexamethazone to take down the brain

swelling, the post-stroke edema. People have known for 40 years glucocorticoids are fabulous for brain tumor edema. They really work well, and people have known for about thirty nine and a half years that glucocorticoids don't do anything to post-stroke edema. For those of you who care, it's because it's a different type of edema. It's a cyto- toxic edema versus a vascular one. Glucocorticoids do not work for post-stroke edema, and in fact they make the neurological outcome worse. And the best people in the field have been saying for 40 years, Don't use cortical steroids for post-stroke edema, use non-steroidal alternatives like mannose or mannitol because the glucocorticoids don't work and they make the outcome worse, and this almost certainly is a biological explanation for it. And it totally amazes me as a basic scientist when I go out and lecture a roomful of neurologists about this, that afterward one of them inevitably is going to come up and say, you know, "I did my residency at the Mass General in 1903, and we're learned to use cortical steroids then" and this tremendous clinical

conservatism. The best clinical neurologists for almost 40 years have been saying corticosteroids don't work for post-stroke edema. This is probably part of why that's the case. Okay, so that's bad news. What else is bad news? You probably want to think very carefully about the hundreds of thousands of people there are taking high-dose corticosteroids. 16 million prescriptions written in this country each year, the vast majority of which are totally benign, hypercortisone cream for your poison ivy, hydrocortisone injection for your swollen knee, nasal inhalant steroids for your asthma, none of those are ways of getting a lot of steroids into the brain. Nonetheless, hundreds of thousands of people taking high-dose steroids for their lupus, their rheumatoid arthritis. Do they get memory problems? Yes, indeed. It's called steroid dementia. And the more glucocorticoid exposure they have had historically, the worse the dementia is. Do they get hippocampal damage? Nobody knows yet at this point. My lab is part of a consortium collecting brains from people like that,

and in 20 years when we have an answer, I bet the answer is going to be that's one of the downsides of long-term big-time steroid use. That's got to be balanced in into the pluses and minuses. OK, so all that's bad news. What's possibly the worst news, though, is, go have yourself a stroke or a seizure and you don't even need your neurologist to give you glucocorticoids to get into trouble at that point. You're secreting boatloads of the stuff on your own. Get somebody who's just had a grand mal seizure or cardiac arrest, and they will have the highest levels of glucocorticoids in their bloodstream that you will ever see in a human except for someone in sepsis or a whole-body burn. And it makes the damage worse. How do you know? Because of a number of labs including mine showing, get rid of the glucocorticoids in that animal right after the stroke or seizure, adrenalethanize the animal, and you decrease the hippocampal damage. In other words, what we've been taught to think of as the typical amount of brain damage you have after one of these insults is damage made worse by the fact that your body

stupidly goes and has a stress response at that time. You think about how bizarre this is. Lion is chasing you, you secrete glucocorticoids in order, in order to mobilize energy for your thigh muscles. Saves your life. Psychological stress, you're on a blind date. You secrete glucocorticoids in order to mobilize energy to your thigh muscles. Probably irrelevant. You have a stroke and you secrete glucocorticoids in order to mobilize energy to your thigh muscles. Totally bizarre and counter-intuitive, and yet that's what your body does, simply because we have not evolved for surviving things like strokes. There's been very little selection to differentiate between a stressor like running for your life and a stressor like your brain is getting no oxygen for four minutes. Almost certainly a lot of what we think about when it comes to brain damage is brain damage being made worse in this part of the brain by us having stress responses. OK, so what can you do about this? Obviously you can't edreamelectasize [?] somebody just because they had a seizure. However, there are all sorts of drugs that are clinically approved, that have been

FDA approved for decades, used in any clinics, that will shut down glucocorticoid secretion for 24, 48 hours or so. Metyrapyrone, aminoglutethemide, others, and a number of labs, including mine, show that you give this to an animal right after the stroke or seizure, block the stress response, you decrease the damage. So first option, keep the glucocorticoids from being secreted. But what if you're too late for that and you've already secreted the hormone? Obvious strategy, block the glucocorticoid receptor. Is there an attagonist [?] out there? Yes indeed it works fabulously. And you've all heard of it. RU486, the abortion drug, famous for blocking progesterone receptors in the uterus, even better at blocking glucocorticoid receptors in the brain and people only now are just beginning to get the ability to do the studies, thanks to the political climate here in the 80s and more recently as well, to be able to test the RU486. That is neuroprotective as well. So block the receptors. But what if you're too late for

that and the glucocorticoids have already gotten to the receptors and are beginning to mess up the neuronal energetics? What you can do there is just what I showed you, supplement the neurons with excess energy and those various strategies that I showed you. Finally what if you're too late for that and you're already in this realm of too much glutamate, calcium, oxygen radicals, etc.? And the main thing that my lab works on these days, which I won't go into, is to use gene therapy techniques to bring in viral vectors at that time to over-express calcium-binding proteins, anti-oxidant enzymes, things of that sort. OK, so all of this is built around the nuts and bolts level of how to save neurons from stressors and glucocorticoids and such. And you could begin to imagine similar scenarios when you think about glucocorticoids and your stomach walls and hypertension, the reproductive function, all that sort of thing. When you're beginning to look at this more global level, the fifth possible thing to put on the list is one that is so stupidly, idiotically obvious that it's not even worth putting in there, which is don't get stressed. Oh

great. Don't get stressed. Obviously, if we're talking about something like this, you are going to get stressed. Finish this lecture, go outside, and unexpectedly get gored by an elephant, and you are going to secrete glucocorticoids. There's no way out of it. You cannot psychologically reframe your experience and decide, you know, you didn't like this shirt, here's an excuse to throw it out, that sort of thing. Go outside after this and get stuck in a traffic jam, though, and only a subset of us will secrete glucocorticoids, and suddenly when we move away from stressors like you're having a grand mal seizure or concussive head trauma, and now instead thinking about the stressors that most of us deal with in everyday lives, these are the psychological stressors, the social stressors. And we come to this absolute critical issue that, virtually by definition, that whatever stresses the hell out of you, somebody else in this room would pay to do as their favorite hobby, the individual differences as to what constitutes a stressor. And this ushers in this last part of the talk. Now beginning to look at this issue. Get gored by an elephant, have a concussive head

trauma, we will all have stress responses. Go through the ambiguous social events of our lives and only a subset of us do. Why are some bodies and some psyches better at dealing with stress than others? What are the mechanisms that explain individual differences and vulnerability to stress-related disease, whether at the level of the brain or stomach walls or blood pressure etc.? What goes into these individual differences? OK, so suppose you want to study that. Who are you going to study? You can study humans, and there's all sorts of amazing literature out there suggesting a certain style of personality that sees hostility everywhere sets you up for cardiovascular disease, what we call Type A personality. But these are incredibly tough studies to do, to understand the intervening physiology over the course of 20 years. You outlive your thesis committee waiting to finish your studies. Very tough stuff to do. OK, so you give up on the human approach. So you study even the lab rats, you can control the stressors, you can monitor the physiology. They only live for a couple years. That's

great. However, if a rat is a good model for your emotional life, you are in big trouble. Obviously all sorts of issues having to do with our psychic lives that rats don't go anywhere near. OK, so let's get a compromise. How about non-human primates? Long lived, close relatives, socially complex, physiological similarities, etc., etc. And what lots of you will know is, if you're dealing with captive primates, unless you are spectacularly ethologically subtle and sensitive and really well funded, you are going to have some sort of demographic distortion going on there. You are going to have a tropical primate living in a primate center in Oregon, you're going to have animals in the wrong size group with the wrong, wrong sex ratios. And if you don't watch it, you could very inadvertently wind up modeling human imprisonment. OK, so given that, 23 years ago I decided to sort of open up a second part of my research and begin to look at these issues, individual differences, who gets the stress-related diseases, looking at primates, but looking at them in their own habitat, primates in the wild. And I

fairly randomly grabbed the whole bunch of slides here, so I give no promises here this is going to go in a logical sequence. These are the animals I've been studying for these last 23 years during my summers, a population of baboons living in the Serengeti in East Africa. And this is the ecosystem they live in. This is your basic Robert Redford, Meryl Streep, grassland sort of thing, and you find baboons living there in troops of 50 to 150 animals, living in these troops out in the grasslands there. Now for what I study, a critical feature, a critical prerequisite, is that this is a great ecosystem for a baboon. This is where you would want to live. You only have to work three hours a day for your calories. You're organized enough that the predators don't mess with you much. Your infant mortality rate is lower than amongst the neighboring humans. It's a great place to live if you're a baboon. What's the implication of that? If you only have to work three hours a day for your calories, you've got nine hours of free time every single day to be unspeakably shitty to some other baboon.

And that's critical. That's absolutely critical. Think about it. None of us get ulcers because the locusts have eaten our crops or we've got to wrestle people for canned food items in the supermarket. We are ecologically buffered enough that we have the luxury to invent social and psychological stress and make ourselves sick with it. And out in nature bloody in tooth and claw, these are some of the only folks out there who are also ecologically buffered enough that they could spend most of each day making each other miserable. Overwhelmingly, if you are a baboon in the Serengeti and you are miserable, it's because some other baboon has worked in a very premeditated fashion to bring that state about. OK. So what is the misery about? A large part of it is the dominance hierarchy. You study these animals for a week and what you'll see - I'm not sure if I got the right slide in here. Nope. - But you study these animals for a week and it becomes obvious there's a Number 1, a Number 10, a Number 20 in the hierarchy. Completely different qualities of life, and it determines who gets groomed, what sort of

parasite load, who gets to mate with who, how hard you work for your calories. Here's one example of the power of the dominance system. Here's a middle-ranking male who's just predated an impala. This is hot stuff. This is two days worth of protein he's about to get in the next 20 minutes. He spent the whole morning stalking this thing, and along comes Number 1 in the troop, and you see our guy marches off. And Number 1 winds up with the kill here, exploiting the labors of the working class, winds up with the kill, and the most striking thing here is, this did not involve fighting, the other guy walked away without a nasty word under his breath. What you see is this tremendous status quo in the system. These animals are smart enough that when the hierarchy is stable, they know their place. The dominance system very dramatically substitutes for punching it out over every difference. So you've got this very organizing dominance hierarchy. So of course the first thing you want to know is, what goes into being high-ranking in a system like this? And a big feature of it is violence. These are extremely aggressive animals. Baboons have the

highest rates of aggression of any non-human primate. They have teeth that are bigger and sharper than you find on adult male lions, and these are not just for ritualized fighting. This was a male who had joined that particular troop, my troop, about two weeks before, and the only way to describe him is that he had a lousy political skills. He was challenging all sorts of males he had no business going near. And one evening a coalition of six of them ganged up on him, and this is what was left in the morning. And in the 23 years I've studied these animals, the leading cause of death amongst male baboons is male baboons. OK. Much more than violence, though, what these animals specialize in is threats of violence. These conventionalized gestures where they will flash their canines, display their teeth - wrong slide there - display their teeth, and basically what they're saying is, "look, you remember what happened last time. I've got the same teeth that I had last week. Do yourself a favor and don't push your luck." And most of the time that's precisely what they do. Conventionalized gestures of dominance of

subordinates rather than aggression, most of the time threats of aggression. Now if all these animals were about was either violence or threats of violence, they would not be very good models for us. Most of what they do, though, is something much more subtle, something that we would have to categorize as just stressing the hell out of each other. Sorts of examples here. To begin to appreciate this, we've now got to talk about what makes for psychological stress. Not getting gored by elephants but when you have ambiguous social interactions. What is it that makes a psychological stressor stressful? And what the studies have shown is, for the same physical stressor, you are more likely to have a stress response, more likely to perceive the event as being stressful, and more likely to get a stress-related disease if you perceive yourself as having no control over what's going on; if you have no predictive information about the stressor, when it's coming, how bad it's going to be, how long it's going to last; if you have no outlets afterward for the frustration caused by it; and if you have no social

support. And these are these classic studies where you give two rats the same pattern of shocks. One of them gets a warning light 10 seconds before each shock; that rat doesn't get an ulcer. It has predictive information telling when the stressor is coming. These sorts of studies give the rat a sense of control. Give the rat a bar of wood to gnaw on afterward, give it control, predictability, outlets, social support, and stressors are less stressful. So what psychological stress overwhelmingly is about is lack of control, lack of predictability, lack of outlets, lack of social coping mechanisms. Look at how well these guys can tap into this. OK, here we have a male who is in a sexual consortship with this female. This female is in estrus, in heat. He's grooming her, he's been with her around the clock for the last three days, they are a number. And what you will see is just happening to be six feet away on the other side of the bush is this high-ranking male who just happens to have been six feet away for the last three days, never an inch closer, never an inch further. He's not

threatening the guy, he's just around. He's just on the scene harassing the consortship, and this is an incredibly costly strategy. This guy hasn't slept for days, he hasn't eaten. What you wind up seeing is about 40 percent of the time this guy will pick up and voluntarily relinquish the consortship to this male without so much as a threat yawn from this guy. This is not violence, this is not threats of violence. This is grinding psychological stress, and these guys are really good at it. The next version. Here we have one of the wild-card strategies for a male baboon, which is get yourself a coalitional partner, get yourself somebody who's going to cover your back during a fight. And these coalitions are really hard to pull off. It takes a day's worth of very complicated gestures and such, built around your basically saying to the other baboons "I'm not angry at you, are you angry at me? Good because I'm not angry at you, and we're not angry at each other and we're really pissed at him and I'm not angry at you" and all this triangulating stuff, and you get one of these coalitions to work and they're great. And here we have two coalitions facing off against each other and if

you don't know your baboon body language, these are four very uptight baboons, and violence is about to break out, and a second later, yes indeed it does. And these guys - anybody see the fourth baboon? There he is. There he is, showing us this important principle of these close relatives of ours, which is when the going gets tough, you get the hell out of there. What you wind up seeing is almost half the time your coalition partner bails out on you. And of those occasions when he does, nearly half of those times he joins the other side. Talk about psychological stress. You are going to a fight that's life threatening and you don't even know who's on which team. Lack of control, lack of predictability. Final example of a stressor. Here's one, virtually unseeable. What we have here is a male in a consortship with a female, grooming her again. And in this case he's being harassed by this other male at very close quarters. This is an extremely tense moment. Major, major stressor on this guy in the middle. And you know violence is going to occur, he's going

to do something aggressive any second now. And yes indeed, a second later he spins around and bites the female. Aha, displacement aggression, another trait of these close relatives of ours, which is when the going gets tough, you find somebody smaller to take it out on. And almost half of baboon aggression is third-party bystander aggression. A male loses a fight who chases a subadult male who knocks an adult female out of a tree who bites a juvenile who slaps an infant. Almost half of the aggression is on to a third party. What does that mean? You were sitting there, minding your own business, birdwatching, and somebody else is having a bad day, and you may have to pay for it. Lack of control, lack of predictability. Now when you look at this sort of landscape, you realize this is an extremely complicated social world, and what goes into success for these animals? Obviously being healthy and big and strong and sharp canines and all of that, but also knowing which fights to get into, and even more importantly which fights to walk away from, which coalitions to form,

which ones not to form, which coalitional partners to stab in the back. And looking at these guys 23 years ago, it occurred to me, another feature of this going into success is having a body that deals well with stress. And this is what I decided to study in these guys starting then, asking what does your social rank have to do with how your body deals with stress? And this is what I set about studying and wasted my first 15 years doing that, because that turned out to be an idiotically simplistic question, and it turned out there is much more interesting stuff going on with these guys, much closer to home. OK, so how do you study this? First off you need to do your basic Jane Goodall scene and this whole science of observing primates in the wild, and there is a whole science for how you do that. In addition, you also have to get physiological data out of these animals. You need to anesthetize them. And there's lots of constraints with that. You have to use an anesthetic that doesn't change the steroid hormone levels that you're looking at. You've got to dart everybody the same time of day, the same season, to control for circadian, circannual rhythms. You've got to, you can't dart somebody

if they're sick, if they're injured, if they've mated that day, if they've had a fight that day, because you're trying to get basal hormone levels initially. I'll show you some cholesterol data where those had to be from animals that haven't eaten breakfast yet. All those constraints. Finally you can't dart somebody if he knows it's coming. There can't be any anticipatory stress, so you can't just get in your Jeep and chase the guy back and forth for three hours, and then exhaust him and finally nail him. All these constraints. What I use is a blowgun system. And this was a perfect darting. This baboon was glancing over at my Kenyan assistant, looking over when he heard me inhaling. And you may be able to see a white flash, that's a frame where this blowgun dart was exploding, anesthetizing him. And this is a perfect darting. And the final constraint is you need to get a first blood sample within about 90 seconds of the guy going down to get basal steroid hormone levels. So given all those constraints, this works flawlessly about once a decade, and at that point you have an anesthetized baboon and you can do CSF taps and tissue biopsies and hook up your heparin drip on your

acacia branch and all of that. The guy recovers overnight in a cage. Let him go the next morning, process your samples on a hand-crank centrifuge, get your dry ice shipments from once a week, and sneak the samples through customs, and you're all set. OK. So given that, not surprising that what I've been most interested in initially looking at these animals - let me see which slide I picked. OK. OK. Not surprisingly what I was most interested in right off the bat was looking at glucococorticoid levels in these guys, and what seem to come through right off the bat was a resounding message about dominance rank determines everything. OK, what you know by now from glucocorticoids is what would constitute the perfect profile. Obviously what you want is really low basal levels of glucocorticoids when nothing's happening. When there's a psychological stressor, you want those levels to still stay low, don't get suckered into thinking that's the lion chasing you. When a real stressor finally does occur, you want a massive stress response as fast as possible, and the second it's over with, you want to recover as fast as possible. And that's exactly the profile you see in

dominant males. You look at low-ranking males and they have elevated basal glucocorticoid levels, they have a sluggish response to stressors, they have a sluggish recovery. For those of you who are oriented to these sorts of tests, low-ranking baboons are dexamethazone resistant. You see all sorts of things wrong with them, built around this picture of, when you're a low-ranking baboon, even everyday basal circumstances are stressful. You just spent 20 minutes digging some tuber out of the ground, anybody can rip you off. You get somebody to groom you, anybody else can disrupt it. Any second somebody could slash your rear because they're having a bad day. Lack of control, predictability, outlets, etc., and this is a theme now shown in 20 different social species, low-ranking animals tending to have elevated basal glucocorticoid levels. Now I put in about a decade's work working through the neuroendocrinology of this. OK, the rank differences in basal levels, is this due to something at the level of the adrenals or the pituitary or hypothalamus? I will spare you the details just to tell you what the overall punchline is. A low-

ranking baboon has these traits for the exact same reason that you see the identical profile in a human with clinical depression. Humans with major depression, elevated basal level, sluggish recovery, resistance, the negative feedback control, a low-ranking baboon in lots of ways on the neuroendocrinological level is like a human with major depression. And I think it's not for nothing that the organizing concept in cognitive psychology as to what a depression is, is a case of learning to be helpless. Learned helplessness, that's the jargon and that certainly describes these guys. Now it turns out that's the tip of the iceberg of - OK missed that slide there - that's the tip of the iceberg of stuff going wrong with these animals. If you're a low- ranking baboon, in addition you have elevated blood pressure, you have suppressed levels of HDL cholesterol, your testosterone levels drop more readily during stress, you have fewer circulating lymphocytes, you have less insulin-like growth factors in your bloodstream. Every single physiological system I've looked at in these animals over these 20

years, what comes through over and over again is totally different physiology depending on your social rank. And if you've got a choice in the matter, you don't want to be a low-ranking baboon. The classic picture that is pathogenic setting you up for stress-related disease. OK. So this appears to give an absolutely clear punchline. You want to go out and be a high- ranking primate and compete and win win win in one big social Darwinist blowout. Let me spend the last couple of minutes showing you all the ways in which this is stupidly simplistic and this is not actually what's going on. A whole bunch of more important qualifiers. The first one has to do with rank. Rank is definitely important in these animals. But it turns out far more important than rank is the sort of society in which the rank occurs. OK. All of the data from the baboons that I've shown you so far have come from stable dominance hierarchies. What do I mean by a stable hierarchy? You look at Number 5 in the hierarchy and Number 5 is being trounced by Number 4, 95

percent of the time and Number 5 is trouncing Number 6, 95 percent of the time. On the other hand, if 90, if Number 5 was trouncing Number 6 only 51 percent of the time, that's an unstable dyad. They're probably just about to switch places. All of the data that I showed you came from seasons where 90 percent of the interactions were reinforcing the status quo. Stable dominance hierarchies. Every now and then, though, you get, some critical male dies, somebody is injured, somebody transfers into the troop, some coalition forms or falls apart, something happens, and the hierarchy totally destabilizes for three months. All hell breaks loose. Everybody is fighting all the time, ranks are shifting every 3 hours, coalitions form and fall apart three minutes later, nobody's grooming, nobody's mating, the mail stops being delivered, everything comes apart, and eventually the thing settles back in. And what you see here is a big difference depending on if the hierarchy is stable or unstable.

Here are nice low resting glucocorticoid levels in high-ranking males during stable seasons. These are the same males during a rare period of instability. They are just as high-ranking, but the psychological baggage that comes with high rank is totally different. In a stable hierarchy, being high ranking, you've got all the psychological advantages, control, predictability, etc. In an unstable hierarchy, you're right in the middle of the revolution. I would not have wanted to have been the czar of Russia during the winter of 1917. You don't want to be in a palace if the peasants are rioting at the gates. All of the psychological advantages of dominance disappear when the hierarchy destabilizes. All of the physiological advantages of dominance disappear as well. So it's not just rank. It's the sort of society in which the rank occurs. Second qualifier. It's not just rank. It's not just the societal setting. But it's your personal experience of both. Two examples of this. Typically, male baboons change troops at puberty, and it's this horrible process. You join a new troop and you're as low ranking as can be, and you go years without anybody

grooming you, and you're - everybody dumps on you and it's horrible. Every now and then, though, a male transfers into a troop. He's particularly big or aggressive, or maybe his mother was high ranking back in his home troop, but he comes in cocky as hell, like a house on fire, and as long as he is just uncontrollably aggressive, he gets to be at the top of the hierarchy for about three months, because nobody wants to be the first guy to stand up to him and see what he's made of. And as long as he just keeps pushing, he can get away with it for a while. And a number of years ago, in one of the troops I monitored, right in the middle of the season, one of these aggressive males showed up and was making everybody miserable, and I had darted half the troop already and then got to dart the other half and got to do a before and after. Here are circulating glucocorticoid levels in the troop before and after he joined. Here are circulating lymphocyte counts before and after he joined. He's stressing everybody, he's immunosuppressing everybody. This was a very stressful period. Two weeks after he joined the troop I was able to dart this guy himself, and here were his glucocorticoid

levels, and here were his lymphocyte counts, the most immunosuppressed baboon I've ever seen. What's the punchline here? Physiologically it doesn't come cheap being a bastard 24 hours a day. This guy was paying an enormous personal physiological price for it. Ironic ending, two weeks after that he went down in a hail of bullets and was never seen again. OK, another example of this. One of the really charming things that this guy did was preferentially target females for attacking them, and this was no doubt to impress the guys with what a tough guy he was. And by the time he had been in the troop for two weeks, I kept track of how many times females had been attacked by him, ranging from females who had never been attacked up to females who had been attacked five times. I then darted a bunch of the females, and these are their circulating lymphocyte counts and what you see is this amazing dose- response relationship. The more often they were attacked, the more immunosuppressed they were. These were lymphocyte counts in the females before he joined the troop. So you asked the question, what are the effects of an aggressive de-stabilizing male on immune function in

female baboons? And the answer is, it depends. It depends. If you're lucky enough to be one of the females who is not attacked and is on the sidelines, it has no effect on your immune system as well, at all. It's not the abstract state of living in an aggressive society. In this very concrete way, it's how often is your own personal nose being rubbed in it. It's not just the society, it's your personal experience of it. The final variable is the most powerful one of all. Not just rank, not just its context, not just the personal experience, but personality. OK, what do I mean by personality? Obviously anybody who's ever had anything from a pet lizard on up talks about their animal's personality. Personality is a very real, very non-anthropomorphic term. In non-human primates, temperament, responsivity. Baboons differ as to how readily they form coalitions. After they lose a fight, do they go and mope by themselves, do they go groom somebody, do they go beat up on somebody, how often do they play with kids, how often they form consortships? These are stable personality traits over the

25-year lifetimes of these animals. And a number of years ago, I sat down with then 15 years of data and went through and invented every single personality trait I could think of in a baboon. I anthropomorphized like crazy. A baboon's equivalent of having a hobby, a baboon's equivalent of looking on the bright side. I came up with 60 different variables, controlled for rank, controlled for stability of rank, and out popped a really interesting finding, which is all of the good physiology you get if you are a high-ranking male in a stable hierarchy has nothing to do with being high ranking. It's all due to the subset of high-ranking males with certain personality styles. And you could be the highest-ranking guy on the block, and if you don't have those personality styles, you're going to have just as crummy a physiology as Number 20 in the hierarchy. It's not rank, it's personality, and thus the final critical question here. What personality works for a baboon? And the amazing thing is, like, I could spend my weekends going down to Big Sur and giving, like, stress management retreat lectures to baboons

and in hot tubs there and this is what you would tell a baboon to do. These are exactly the traits you would advise a baboon to have. First one. Can you tell the difference between threatening and neutral interactions? What do I mean by this? Baboon is sitting there. His worst rival in the whole planet shows up and threatens him in his face from a foot away. This is bad news. What does he do next? He stops whatever he's doing, he takes a very vigilant defensive stance. In contrast, baboon is sitting there. His worst rival in the whole planet shows up and takes a nap 100 yards away. What does he do next? He should keep doing whatever he's doing, that's not a big deal. The pathetic thing is your average male baboon gets just as crazed by having the guy take a nap at the other end of the field as threatening him in his face. Transitional probabilities, he is just as likely to stop doing what he's doing and get vigilant, because it's this personal provocation, this "Look at this, look at the way that guy's sleeping, I hate it the way he snores, he does that just to get me and get at my face." This is type A personality. This is seeing

provocations that other individuals don't. After controlling for rank, if you are a male who can't tell the difference between being threatened in your face and somebody sleeping at the other end of the field, twice the circulating glucocorticoid levels. You see stressors everywhere that nobody else does. The next variable. The guy is threatening you in your face. What do you do next? Do you passively let him start the inevitable fight, or do you at least get a little bit of control and start the fight? If you are the sort of male who sits there and passively abdicates control, two different ways of showing this, twice the glucocorticoid levels in your bloodstream. You don't even get any control, the little control available to you there. OK, the fight occurs. Can you tell the difference between whether you won or lost the fight? This sounds rather fundamental, but again, amazingly, your average male baboon can't tell the difference. He has the exact same transitional probability of what he does next. He can't tell whether it's good news or bad news, whether he's been positively or negatively reinforced. If you can't tell the

difference, significantly higher glucocorticoid levels. Finally, if you have lost the fight, what do you do next? Do you go and mope by yourself, or do you go and beat up on somebody smaller? As it turns out, if you go and don't beat up on somebody smaller, you've got higher glucocorticoid levels. OK, let me put a better spin on this. If you don't have a social outlet for your frustrations, you have higher glucocorticoid levels. Look at this collection of traits. Can you tell the difference between the big things and the little things? If it is a big thing, could you at least exert a little control over it? Can you tell if the outcome's good or bad? And if it's bad, do you have a coping mechanism? This is 95 percent of what they teach you in stress management courses. And it turns out some baboons just happen to be good at this. You look at these low-cortisol guys with this temperament, and you go back to their records back when they were juveniles, and that's what they were like back when. And you follow these guys out over the rest of their life span, and not only do they remain in the higher-ranking cohort longer than these guys, they outlive them by two to three years.

So that's the first critical cluster. Totally independent of that cluster, the second cluster is the strongest finding I've seen 23 years with these baboons. After controlling for rank, after controlling for stability of the hierarchy, after controlling for all of these male-male competitive traits, the single best predictor of having elevated glucocorticoid levels is being socially isolated. You look at males and you come up with this composite index of sociality. How often do they groom? How often are they groomed? How often do they sit in contact with a female? How often do they play with kids? And socially disconnected males have extremely high glucocorticoid levels and high blood pressure and all the other stuff. Great. Science has finally shown us that social connections are good for you. Science has been showing us this for years in behavioral medicine and health psychology. The single strongest predictor of health, all across the board, for all infectious diseases, is this critical finding. Never ever make the mistake in this country of screwing up and being born

to poor parents, because that sets you up for ill health your entire life, socioeconomic status. The second biggest predictor is degree of sociality. And you look at humans, the most socially isolated and the most socially connected. Almost a threefold difference in mortality outcome across the board for all infectious disease. Socially connected, a significant other, a group of significant others, a community group you're involved in, and this is after you control for stuff, like, oh, people who live alone don't have somebody to remind them to take their medicine each day, people who live alone just subsist on Cheetos, control for all of that stuff and social isolation is an aching stressor and a huge health risk factor in primates of our kind, and non-human primates as well. So what are we left with here at the end? First half of this talk hopefully horrified you because it's all bad news. Sixty years into us thinking about stress doing bad things to your stomach walls and blood pressure and everything else. We have to seriously begin to think about stress and our cumulative exposure to it over our lifetimes

having a lot to do with how our brains age and which of us will be aging successfully in the cognitive realm. And the evidence gets more and more relevant to the human brain. Amid all that bad news, what comes through in the second part of this talk is again this theme again and again, if some baboons just happen to be good at seeing waterholes as half full instead of half empty. It's this theme again and again here, we are not getting our ulcers because we're being chased by saber-toothed tigers, we're inventing our social stressors. And if some baboons are good at dealing with this, we should be able to as well. Insofar as we're smart enough to have invented this stuff and stupid enough to fall for it, we have the potential to be wise enough to keep the stuff in perspective. So on that note, thank you for your attention and - Nope I didn't put in the slide with the members of my lab, but the members in there who did all the lab work, and thanks. ...