Adaptive stress response in salamanders Salamanders prefer cold, dark and damp spaces in the woods, and when they leave that space, they experience a stress response to prompt them to return. These corrective responses are initiated by the body, independent of the brain. The speaker’s perspective changed in the 1970s when they began considering how society affects the body, mediated by the brain. Transcript: Speaker 2 Take a salamander out in the woods here in the Blue Ridge Mountains. The salamander likes a cold, dark, damp space where hopefully there’s some bugs. And if it goes out of that space, it mounts a stress response, and the stress response is for the purpose of getting it back to that space. Speaker 1 Yeah, so there are these corrective responses that the body initiates. It doesn’t particularly have anything to do with the brain. I was fine with this until the early 1970s when I began thinking about how society affects the body, which it does, and that was mediated by the brain. (Time 0:06:44)
Allostasis Transcript: Speaker 1 Yeah, so there are these corrective responses that the body initiates. (Time 0:07:07)
The role of the brain in regulating blood pressure Doctors monitor blood pressure multiple times to account for diurnal rhythm. The brain efficiently predicts and regulates blood pressure to support daily activities, rather than independently regulating the body through homeostasis. Transcript: Speaker 2 They talk about it in doctors’ offices. They take the first pressure, good doctors will take a second pressure later on after you settle down with it. That’s right. Speaker 1 At night, during sleep, we have a diurnal rhythm of our blood pressure, so our blood pressure goes way, way, way down during sleep. And then, next day, it goes up to support your daily activities, maybe up into the hypertensive range. When Joe and I realized this, we realized that actually the idea of homeostasis is not right. And it’s not the body independently regulating itself. It’s set by the brain. And the reason is, it’s a much more efficient way to predict what is going to be needed than to correct the brain. And then, to correct the errors. (Time 0:12:39)
The importance of predicting and preparing for bodily needs The key insight in this snip is the importance of predicting and preparing for bodily needs to prevent adverse conditions. The speaker mentions examples such as wearing a jacket before going out in the cold, bringing water when hiking in the desert, and emphasizing the concept of ‘allostasis’ - the body’s ability to predict and regulate based on anticipated needs. The term ‘stabilistasis’ is introduced to emphasize stability through constancy in regulating bodily functions, in contrast to the traditional idea of homeostasis. Transcript: Speaker 1 It’s closing the barn door after the horse is gone. Trying to close the barn door. Yeah, it’s pretty good. So, for example, prevent hyperthermia. When your body senses it’s too cold, there are a lot of mechanisms to… Wime, you shiver, you move toward a warmer place, you put on clothing, but you do huddle, you cuddle. But the best thing is to realize you’re going out in a cold, and put it on a jacket before you leave. And if you’re going into the desert, to hike, once you get there and you get thirsty, your body feels that there’s an error. So, you know, it needs to correct by drinking water, but you have to have remembered, you have to have anticipated this by bringing the water with you. Or certainly you’re going to be better off. Yeah, well, you will be dead if you didn’t. Speaker 2 I’ve come close to that condition. Speaker 1 Yeah, I have to. I went into the Grand Canyon one time and not enough water. It was difficult. Yeah. Speaker 2 So, allostasis is about predicting. Speaker 1 So, when Joe Iyer and I published a couple papers about this predictive sort of regulation and the importance of the brain, it wasn’t making a whole lot of headway against the standard Idea of homeostasis. So, we thought, well, we need a new term really to describe this new thought about how regulation occurs. Stabilistasis is from the Greek words stability through constancy. Yeah. That’s it. Yeah. Stability through constancy. Seinness. Seinness. So, I consulted a professor of Greek philosophy, who I happen to know. (Time 0:13:57)
Biological principles of neural design and cyanobacteria’s predictive regulation The principles of neural design focus on how central to peripheral systems work in simple organisms, showcasing chemical, electrical, and physical processes. The cyanobacteria, the first bacteria to evolve, originated homeostasis with a molecular clock formed by three proteins to keep time, raising the question of why a bacterium in the ocean would need to keep time. Transcript: Speaker 2 We’re going to talk about both of them but one of us called Principles of Neural Design and what I’m thinking of right now is Peter and Simon Loughlin. They diagram some of these central to peripheral systems and simple organisms early on and so you can really see how this works chemically, electrically, physically with pressure And things like that. Almost the way you could observe cogs in a mechanical device where you turn a lever and the cogs move, of course it gets, as Peter said, much more complicated than that as you go but it’s So useful to see it in action in a simple organism. Speaker 1 So yeah, so this is another point that I meant to make. The first bacteria that evolved at the beginning of life were called cyanobacteria and they were in the ocean. They were the originators of elostasis, a predictive regulation in the form of a molecular clock. They evolved three proteins to interact in a certain way that would keep time and why would a bacterium in the ocean need to keep time? (Time 0:24:54)
Reloj circadiano fue desarrollado por cianobacterias y se mantuvo filogenéticamente Transcript: Speaker 1 So yeah, so this is another point that I meant to make. The first bacteria that evolved at the beginning of life were called cyanobacteria and they were in the ocean. They were the originators of elostasis, a predictive regulation in the form of a molecular clock. They evolved three proteins to interact in a certain way that would keep time and why would a bacterium in the ocean need to keep time? Well because the bacterium has to replicate its DNA and then divide into two bacteria. So DNA replication is very vulnerable to ultraviolet light. These DNA molecules absorb ultraviolet light which causes mutations and breaks the DNA. And so it was very important for their survival to be able to know when the sun would be up and when it would be down and to replicate their DNA in the dark. And so that was really the first form of predictive regulation. What happened was it was a very effective clock and once it evolved maybe three billion years ago all subsequent organisms had a clock, very similar to this molecular clock. The first organisms that gave rise to bilateral organisms, they had organisms that had paired arms, legs, ears, eyes and so on by latarian worm, it was a worm and it had a brain in the front Of the body because if you’re moving forward that’s where you want your sense organs because that’s efficient to keep the wires short. At the core of the first brain was a clock and all subsequent organisms, this worm gave rise to insects and crustaceans and snails and ultimately to fish and amphibians and reptiles And mammals. And they all have this clock in the front of their brain and in mammals it’s called the super-kiasmatic nucleus. It’s a special little set of nerve cells, the base of the brain that keeps our clock. But you’d think, well that’s what wakes us up in the morning, let’s just go to sleep at night, that’s what gets messed up when we cross time zones and so on. But it’s very powerful in regulating our metabolism predictably because it’s efficient when we go to sleep that we don’t need to mobilize energy for moving around. So that’s the time to use our metabolism to rebuild our bodies, to make new muscle, to make repairs, all sorts of things to straighten out your brain, to remember the clean out the brain. Clean out the brain and make new synapses to firm up your memories and so on and that’s what happens when we’re sleeping. And then in the morning it’s time to do the opposite is to mobilize your energy metabolism and stop all of this repair stuff. It’s a very profound effect on our chemistry. (Time 0:25:51)
Evolution of the super-kiasmatic nucleus and its role in regulating metabolism The first bilateral organisms had paired sense organs located in the front of the body, which was efficient for movement. The initial brain of these organisms contained a clock, which gave rise to the super-kiasmatic nucleus in mammals. This nucleus plays a crucial role in regulating metabolism, coordinating the body’s activities during sleep and wake cycles. During sleep, the metabolism focuses on body repair and maintenance, whereas during wakefulness, energy mobilization takes precedence. Transcript: Speaker 1 The first organisms that gave rise to bilateral organisms, they had organisms that had paired arms, legs, ears, eyes and so on by latarian worm, it was a worm and it had a brain in the front Of the body because if you’re moving forward that’s where you want your sense organs because that’s efficient to keep the wires short. At the core of the first brain was a clock and all subsequent organisms, this worm gave rise to insects and crustaceans and snails and ultimately to fish and amphibians and reptiles And mammals. And they all have this clock in the front of their brain and in mammals it’s called the super-kiasmatic nucleus. It’s a special little set of nerve cells, the base of the brain that keeps our clock. But you’d think, well that’s what wakes us up in the morning, let’s just go to sleep at night, that’s what gets messed up when we cross time zones and so on. But it’s very powerful in regulating our metabolism predictably because it’s efficient when we go to sleep that we don’t need to mobilize energy for moving around. So that’s the time to use our metabolism to rebuild our bodies, to make new muscle, to make repairs, all sorts of things to straighten out your brain, to remember the clean out the brain. Clean out the brain and make new synapses to firm up your memories and so on and that’s what happens when we’re sleeping. And then in the morning it’s time to do the opposite is to mobilize your energy metabolism and stop all of this repair stuff. (Time 0:27:15)
The Importance of the Body’s Resting State The speaker suffered a heart attack but has mostly recovered. They learned from their cardiologist that their heart has issues when it’s in a resting state. All cells in the body undergo changes during rest, with different cells and organs switching their metabolism at night. It was revealed that a molecular clock exists in all cells, synchronized by the brain’s suprachiasmatic nucleus. Transcript: Speaker 2 Yeah, I had a heart attack and my heart is mostly almost 100% recovered but I’ve learned talking to my cardiologist that it’s when my heart gets into a resting state. That’s when I start having some weird issues and he accidentally created some poetry by saying Jim your heart doesn’t like to rest. Right, right. Speaker 1 All of the cells in the body undergo these sorts of changes. Some more than others, some more proteins than others. And I mean your liver completely switches its metabolism at night and your fat cells and your gut and so on. And it turns out that this molecular clock which started in the cyanobacteria exists in all of our cells and the job of the brain clock, the suprachiasmagniculus, is to sort of synchronize Them. (Time 0:30:17)
Allostatic Mechanisms and Health Allostatic mechanisms do not directly cause sickness, but rather, the lack of proper care and maintenance of these mechanisms can lead to health issues. Similar to a car, where mechanisms are vulnerable to breakdown without proper maintenance, chronic elevation of bodily mechanisms without sufficient replenishment can lead to increased demand and potential health issues. Transcript: Speaker 2 So it’s allostatic mechanisms all the way down. All the way down, yes. Yeah. How can these allostatic predictive mechanisms make us sick or is that even the right question? Speaker 1 Well, I mean, well, it’s a fair, I mean, any question is a fair question. There are no stupid questions. But I don’t, I think the answer is I don’t think that the mechanisms make us sick. The mechanisms, I mean, the mechanisms of your car don’t make your car break down. They are vulnerable in various ways to being, you know, messed with. Okay, so if you don’t put oil in your crankcase, your motor is going to freeze up. You know, if you don’t check your tires, you’re going to end up with a flat tire and so on. So there are many, if you don’t replace the brake linings, they’re going to fail. One of the things that happens is, in the course of life, we have many mechanisms to increase our effort and our attention and our alertness and so on. And those go up and down. If they’re chronically elevated, there’s more demand on them than there is replenishment. (Time 0:31:39)
Diferencias de presión arterial entre WEIRD y HG, y los efectos en términos de salud. Transcript: Speaker 1 And so, for example, it’s quite clear if you have a normal average blood pressure, which is around average blood pressure, arterial blood pressure in humans is about 100 millimeters Of mercury. That’s the pressure that people who live as hunter-gatherers, foragers, in sort of small communities, and don’t work too hard and don’t, you know, get too excited. That’s their normal blood pressure and it doesn’t rise with age. Old people have this blood pressure as well as young. In the U.S., blood pressure in children starts to rise when they leave home and go to school. And it continues to rise so that by graduation from high school, about 25% of young people have blood pressure in the hypertensive range. What happens? Well, if somebody has their average blood pressure, not at 100, but say 160, it’s pretty high, basically the other parts of the body adapt to this high pressure so that the arterial vessels, Which experience this high pressure, begin to thicken hypertrophy. And what’s involved is really something, it’s an adaptation to life and high pressure, just the way if you lift weights on a regular basis, your skeletal muscles get bigger, your biceps Grows, you know. So this is like the equivalent of lifting weights for your arterial vessels except that they’re hollow, and they sort of, the center fills up with this muscle, and other pathologies Develop around this. You get cracks in your vessels and you get a deposition of plaque which clogs them up, and that’s what causes heart attacks and strokes. One of the things. The problem isn’t with the regulation. The problem is basically living in ways that don’t allow enough replenishment, recovery, energy expenditure is called catabolism, breaking stuff down, rebuilding it is called Enabolism. And if you don’t spend enough time in enabolism, rebuilding stuff, repairing stuff, then bad things happen. (Time 0:33:00)
alostasis cazadores_recolectores salud WEIRD
alostasis cazadores_recolectores salud weird
Impact of High Blood Pressure on Arterial Vessels High blood pressure causes arterial vessels to thicken and hypertrophy, similar to how lifting weights causes skeletal muscles to grow. This adaptation leads to the development of pathologies such as vessel cracks and plaque deposition, which can result in heart attacks and strokes. The issue is not with regulation, but with insufficient time spent in rebuilding and repairing the body, leading to adverse health outcomes. Transcript: Speaker 1 What happens? Well, if somebody has their average blood pressure, not at 100, but say 160, it’s pretty high, basically the other parts of the body adapt to this high pressure so that the arterial vessels, Which experience this high pressure, begin to thicken hypertrophy. And what’s involved is really something, it’s an adaptation to life and high pressure, just the way if you lift weights on a regular basis, your skeletal muscles get bigger, your biceps Grows, you know. So this is like the equivalent of lifting weights for your arterial vessels except that they’re hollow, and they sort of, the center fills up with this muscle, and other pathologies Develop around this. You get cracks in your vessels and you get a deposition of plaque which clogs them up, and that’s what causes heart attacks and strokes. One of the things. The problem isn’t with the regulation. The problem is basically living in ways that don’t allow enough replenishment, recovery, energy expenditure is called catabolism, breaking stuff down, rebuilding it is called Enabolism. And if you don’t spend enough time in enabolism, rebuilding stuff, repairing stuff, then bad things happen. Speaker 2 I’ve heard it referred to as weathering, you know, weathering of the body. (Time 0:33:56)
Neural memory and foraging behavior in microorganisms and nematodes Microorganisms like bacteria have a short memory of a few seconds, which makes sense given their short lifespan. The brain of a nematode, such as C. elegans, is a third of its total cells and has been studied thoroughly due to its importance in foraging behavior. Nematodes have to find new spots for food, suitable temperature, and optimal pH levels, showcasing the intricate neural mechanisms involved in foraging. Transcript: Speaker 1 Well, no. Well, so it has to learn what a bacterium has to remember. And so the first one that’s found in a bacterium memory is this signal here higher than the one that it just came from. So its memory is only a few seconds long, which makes sense because a bacterium that’s in good shape is dividing. And so its own existence may only be 15 minutes. Okay. And so a few seconds is fine. But once you get to a, to say a worm, this first bilateral worm, it’s a, say, a millimeter, it’s long. It’s eating, it’s actually eating bacteria. And so when it’s exhausted the bacteria here, it has to find a new spot. Or when the temperature is unsuitable there, it finds a different spot. When the pH, the acidity of the medium is not quite right, it goes, it needs to find a better spot. And so the brain of a worm, of this little worm that I’m talking about, the C. Elegans, for example. I mean it was a descendant of this earlier bilateral worm, but it’s a very highly nematode, right? It’s a nematode and it lives in the soil typically when it’s not in some laboratory. And it’s about two millimeters long. And it is comprised of 900 cells very precisely. I think, I think it’s 900. It’s brain of those 900, it’s 302 cells. Okay, so it has tremendous investment in this brain. I mean it’s a third of its total cells. The brain of the nematode has been studied very thoroughly. (Time 0:41:19)
Neuroscience Insights from the Nematode’s Brain The nematode has a brain with 302 cells, which is a significant investment for its total cell count. Its brain contains a circuit that drives it to constantly move and search for resources. When it finds something unexpectedly, its brain releases a pulse of dopamine to signal it to pause and exploit the resource. Transcript: Speaker 1 I think, I think it’s 900. It’s brain of those 900, it’s 302 cells. Okay, so it has tremendous investment in this brain. I mean it’s a third of its total cells. The brain of the nematode has been studied very thoroughly. And what it has, one of the things it has is a circuit that drives it to search, to move. And so it’s constantly moving around and searching for either food or a better pH or more mates, and so on. And so when it finds one of these things accidentally, unpredicted by its brain, this is a circuit that gives it a little pulse of the neurotransmitter dopamine. And the effect of the dopamine is to essentially signal, okay, pause here, this is a good spot, and you can relax, you know. And so the worm stops and exploits whatever resource it has been delivered to for a while. (Time 0:42:41)
Role of Dopamine in Resource Exploitation and Learning Organisms receive a pulse of dopamine when they encounter something positive but unpredicted, which signals the brain to pause and relax. This dopamine teaches the brain that the encountered spot is good and helps the organism stay or return to that spot. The searching for resources and remembering of these resources are fundamental and involve dopamine. When organisms reach effective solutions in evolution, these are retained and conserved. Transcript: Speaker 1 And so on. And so when it finds one of these things accidentally, unpredicted by its brain, this is a circuit that gives it a little pulse of the neurotransmitter dopamine. And the effect of the dopamine is to essentially signal, okay, pause here, this is a good spot, and you can relax, you know. And so the worm stops and exploits whatever resource it has been delivered to for a while. And then this searching circuit, it research itself to satisfy the next need. And each time that the organism encounters something that was, is positive but unpredicted, it gets this pulse of dopamine. One of the effects of the pulse of dopamine is to teach the circuit, the brain, that this was a good spot. You should either stay here or return here. So there’s some amalgam of properties about that spot that it learns about. Yeah, or something specific. Yeah, but the point is the searching for resources and the remembering of these resources was completely fundamental. I was in the first brain and it involved dopamine. Well, when in evolution, organisms reach a good solution that’s really effective, these are retained. It’s called being conserved. (Time 0:43:17)
Optimal Learning through Reward Prediction Error The search for resources and the memory of these resources are fundamental aspects in the process of learning. Organisms retain effective solutions through evolution, which is termed as being conserved. The system for rewarding randomly found resources with a reward is the most effective and optimal way to learn, as discovered by Sutton and Barto, known as reward prediction error. Transcript: Speaker 1 Yeah, or something specific. Yeah, but the point is the searching for resources and the remembering of these resources was completely fundamental. I was in the first brain and it involved dopamine. Well, when in evolution, organisms reach a good solution that’s really effective, these are retained. It’s called being conserved. And so it turns out that this system for rewarding, randomly found something with a reward is mathematically the most effective, optimal way to learn. This was a rule that was discovered mathematically by Sutton and Bartow. It’s in all the textbooks and it’s called reward prediction error. (Time 0:44:26)
The fleeting nature of satisfaction and happiness Satisfaction and relief are fleeting emotions when accomplishing a task, as the need to move on to the next responsibility or goal quickly arises. This pattern of fleeting happiness is described in Freud’s ‘Civilization and Its Discontents,’ where it is noted that humans constantly adapt to new positive circumstances and seek the next thing. This dynamic suggests that lasting satisfaction is elusive, and the pattern of pursuing the next goal is a common theme in literature. Transcript: Speaker 1 You get a pulse of satisfaction, a little pulse of relief. You can stop. Ah, yeah, okay. I got my grant in. Okay, I got my blood pressure. Blood pressure can go down a little bit. Your blood pressure can go down and you can relax a little bit. Of course, it doesn’t last very long. I know. Because we need it to go on to the next issue. When you get your grant done, but then it’s time to go hook dinner, you have other responsibilities, you have other needs. If you’re warm enough, you’ll still have to find something to drink. If you have water, you still have to find food. And so I noticed that Freud in his last book called Civilization is this content. He says happiness is by design something that’s fleeting because we only always need to go on to the next thing. So this may be one of the few things he got right. Yeah, exactly. Yeah. And there are many examples in literature of this. So we’re never satisfied really. Because we adapt to whatever good thing we found and need to go on to the next thing. And I like Jertus as a lion. (Time 0:45:24)
The fleeting nature of happiness and human tendency to constantly seek the next thing Happiness is temporary because humans are wired to constantly move on to the next thing after achieving a goal. This pattern is observed in literature and exemplified by the idea that nothing is as depressing as a succession of fair days. Transcript: Speaker 1 You can stop. Ah, yeah, okay. I got my grant in. Okay, I got my blood pressure. Blood pressure can go down a little bit. Your blood pressure can go down and you can relax a little bit. Of course, it doesn’t last very long. I know. Because we need it to go on to the next issue. When you get your grant done, but then it’s time to go hook dinner, you have other responsibilities, you have other needs. If you’re warm enough, you’ll still have to find something to drink. If you have water, you still have to find food. And so I noticed that Freud in his last book called Civilization is this content. He says happiness is by design something that’s fleeting because we only always need to go on to the next thing. So this may be one of the few things he got right. Yeah, exactly. Yeah. And there are many examples in literature of this. So we’re never satisfied really. Because we adapt to whatever good thing we found and need to go on to the next thing. And I like Jertus as a lion. Nothing is so depressing. It’s a succession of fair days. (Time 0:45:27)