The Origins Podcast with Lawrence Krauss - Mark Mattson: Building the Brain: Glutamate as Sculpture and Destroyer

Episode Date: May 29, 2024

You’ve probably heard of Serotonin, or Dopamine. Those are the sexy neurotransmitters that get all the press. However, you have probably not heard of Glutamate. Which is a shame because it is probably the most important neurotransmitter in the brain, responsible in large part for its growth, and also its plasticity. Mark Mattson is a neuroscientist with a distinguished career as Director of the Laboratory of Neurosciences at the National Institute on Aging. While initially interested in developmental biology in animals, Mattson’s work in endocrinology led him to become to study the effect of hormones on the brain. Eventually he began to focus on the role of the Glutamate in neuroplasticity and Alzheimers disease. He realized how essential that neurotransmitter was for understanding the very formation of the brain, the growth of neurons, and the formation of axons and dendrites, as well as its key role in brain functions including learning and memory .I first got to know Mark when we co-organized a workshop on Pattern Processing in the Human Brain, where we invited well known neuroscientists as well as computer scientists and AI researchers to come together to discuss areas of joint interest. The idea was to explore key features that may underlie consciousness, and also to explore how to ensure how to avoid the error-prone brain functioning such as one finds in Schizophrenia as AI systems are developed. The public event associated with the workshop was entitled Creativity and Madness, and involved a dialogue between me and actor Johnny Depp. Most recently, Mark has written a fascinating book, entitled Sculptor and Destroyer, to describe and explain the importance of Glutamate in brain formation and functioning. We had a fascinating discussion about that, and also how he became interested in the brain after initially planning to become a veterinarian. I hope you find the discussion as enlightening as I did. As always, an ad-free video version of this podcast is also available to paid Critical Mass subscribers. Your subscriptions support the non-profit Origins Project Foundation, which produces the podcast. The audio version is available free on the Critical Mass site and on all podcast sites, and the video version will also be available on the Origins Project Youtube. Get full access to Critical Mass at lawrencekrauss.substack.com/subscribe

Hi, and welcome to the Origins Podcast. I'm your host Lawrence Krause. In this episode, I had the opportunity to talk to an old friend and colleague, Mark Madsen, who was head for a while of the former chief of the Laboratory of Neurosciences at the National Institute on Aging. I first got to know Mark a number of years ago when he and I co-organized a workshop for the Origins Project on pattern processing in the human brain. we brought together scientists from neuroscience as well as computer scientists to talk about

how pattern processing is handled in the brain and the computer scientists to talk about how pattern processing is handled there. And of course, that's an emerging field with a large language modules now that didn't exist back then. But the idea was, among other things, to try and ensure that the mistakes of pattern processing that happen in the human brain like schizophrenia don't get carried over to machines. And having that discussion of, neuroscientists and machine scientists was fascinating for me, and I hope for all the participants at the meeting. After that, Mark continued to work, and in fact recently, most recently published a new book called Sculptor and Destroyer, Tales of Glutamate, the brain's most important neurotransmitter.

Now, many of you have heard of dopamine or serotonin, other neurotransmitters. They get discussed a lot in the news, but glutamate turns out to be the chief neurotransmitter in the brain that's responsible for brain growth, synapse formation, and many of the aspects of consciousness. It's unheralded, and Mark's book discusses all of the aspects in which glutamate is important. We discussed that, we discussed his own interest, how he got involved in neurosciences, and then ultimately what it was about its early work that led him to realize the importance of glutamate. And we discussed its importance for learning, memory, synapse growth, and ultimately for understanding issues that will be relevant for AI development.

It was a fascinating conversation. Mark is a serious scientist, and it was great to get back together with him and talk about this issue and about this subject that's really unheralded, but ultimately important for anyone who wants to understand how the brain works. You can watch this episode ad-free on our substack site, Critical Mass. that site, if you subscribe to it, the donations go to support the Origins Project Foundation, the nonprofit foundation that produces this podcast, or you can watch it on our YouTube channel, our Origins podcast, YouTube channel, or listen to it on any site that you can listen to

podcasts on. No matter how you watch it or listen to it, I'm sure you'll be fascinated and informed by this discussion about this ultimately very important subject. Well, Mark, thank you very much for agreeing to be on the podcast. It's nice to see you. It's been a while since we were together, and I forget exactly when that was, but it was a while back in Arizona. Yeah, it was in 2015, I think, you know, I've been following your work where you started this Origins Project initiative down there, and we're having workshops and symposia, and I was, you know, tuning into some of them. I was just it was interesting I I'd had this back and forth with Francis Collins who was the director of NIH then about combining actually what really happened is I we went family went up to the science museum in New York City and they had an exhibit where Francis Collins was like they had a video of them going through a reel and he was talking about you know the I don't know what that the synergy between you

science and religion. Religion. I know that. I think it was maybe the Natural History Museum maybe. Yeah, yeah, I think that was it. I remember seeing that and I was shocked to see that. Yeah, and I got a little upset. And then I wrote an article for Frontiers in Neuroscience called Superior Pattern Processing is the essence of the evolved human brain. And I talked about the different domains of cognition and humans have this interesting feature of imagination, creativity, which has been important for evolution. But it can also lead you astray. Yeah.

In fact, I remember when we first start, when you talk to me, it's good that Francis Collins's misperceptions about the world got you interested in this. But I remember when we were talking about a workshop, it was pattern processing, partly because that's the key thing we understand that. I was interested, of course, in creativity and the origins of creativity, but it's a very hard topic to really get your, your, your, your mind around and the knowledge is such that it was very early in that stage but the fact that the brain is a great pattern processor was was a key and that's why we and and i think you were the

one that that suggested it that and it influenced the last chapter of my of my new book that the way to get to understand how something works is sometimes see when it's broken and and to understand the kind of diseases that break pattern processing like schizophrenia might teach you more about how the brain works. And so that was neat. And then we, as you know, I like to have a public event associated with each of the workshops. And we decided to do a public event on creativity and madness and decided that there's no better person than my old friend Johnny Depp. And we had a great work, we had a great public event there. You may remember. Yeah. And back then, you know, that's not that long ago, but since then there's been an explosion and like workshop, you know, combining

neuroscience with AI, artificial intelligence. Yeah, in fact, that's the other thing we did. Yeah, in fact, I think, again, it was you. I don't know what we decide, but we, that was the other thing I was going to mention, that workshop, we decided to combine it with AI and, and, and, and, and, computer science people, because pattern processing, of course, is a crucial part of AI. But in particular, I think, once again, I think you were the one who influenced this thing. Well, if we're going to make pattern processing and eventually get maybe intelligent AI, we don't want the AI to be schizophrenic, so we should perhaps understand how it works in humans. And I thought that was, to me, a fascinating idea. It was an interesting, it was a little premature at the time that there wasn't

much give and take between the two areas as I, as I might have liked, but it was interesting to see what was known in each area. And for me, it was interesting to learn. And that's the joy. And we're going to talk about, for the most part, your new book, Sculptor and Destroyer, which sounds like a science fiction movie with Arnold Schwarzenegger or something, but it's not. It's about a particular about glutamate, as we'll talk about in the brain, and it's fascinating. But I want to, but before we, before we get there and talk about brain science more generally, I've read your CV, and I know a little bit about you, but it's the gaps in that that are important. I especially like to find from scientists where they sort of got into science and how. But you were brought up at a farm,

right? Yeah, I was born in the city in Rochester, Minnesota, and my dad was the county attorney, prosecuting. Not a farmer, okay. He didn't know, but he grew up around horses because my grandfather trained and raced standard bred horses, trotters and pacers. Okay. And so my father did that. And they were doing this at the county fairgrounds. They had kept their horses there. But my dad wanted to have his own training track, and he was able to buy 100 acres outside of Rochester and put it in his own training track.

And then what we did is, for the rest of the farm, we had the neighbor farm the land, and we split the crops 50-50. Oh, I see. Yeah. But us kids, me and my younger brother, helped a lot with baling hay,

you know, riding on the hay rack, pulling the veils onto the rack, then going into the barn and stacking them and things like that. Well, well, okay. So you were surrounded by nature in that regard. He was an attorney. I also see, I'm going to pretend like I know something, but we were talking earlier and he pointed out those out to me. But behind you, those are, I think you still have some interesting horses.

Those were from, people are wondering what they are. Those are, uh, these are horse bits for harness horses. there's a driving bit that you put in the mouth to steer it and pull back. And then there's what's called a check bit that it goes in the upper part of their mouth and there's a strap that keeps their head up. Because if horses more likely to stumble if it's starting to get it, you know, get its head down. So you want to keep their head up.

They don't do it naturally. They don't keep their heads up so they don't stumble. You think the brain would figure that out, wouldn't you? Well, some do and some don't, but you don't want to stumble in the middle of a race. Yeah, yeah, yeah. So, okay, so go back, getting back, your father was an attorney, but you didn't want to necessarily that. You didn't want to go into law or anything like that. You didn't interest you? No, I had a, I never was really that interested, although my father would kind of talk with my mom about not a lot of details, but some,

things about, you know, cases he was prosecuting. And it was one exciting day when one of the people he put in jail had escaped. And it's someone that had threatened his life, you know, during the trial. Oh, God. And so one day, all of a sudden, there's a bunch of sheriff's deputies show up on the farm. And they say this guy's escaped. We think he might be in the vicinity. And actually, they caught him not too far away from our farm. Oh, geez. But, yeah. That'd be enough not to want to be a prosecutor, I guess.

Yeah, but I was interested in nature more than anything, I think. Now, what did your mom do? Yeah, she was a nurse at St. Mary's Hospital, which is the main hospital for the Mayo Clinic, which is in Rochester. Oh, yeah, sure, in Rochester, of course. And she was there at a time, so this would be, well, around World War II and then in the 50s in particular, when polio was, there was a lot of polio and kids getting polio and the vaccine was just coming out at that time. And yeah, so she saw a lot of kids on the polio award where she worked. Of course, it's St. Mary's Hospital, so it's a Catholic hospital, so there are a lot of nuns that she didn't have acted with, and she'd tell interesting stories about the nuns.

I assume you weren't brought near your parents religious, or were they, or did you? No, not really. I think when we're young, I do remember going to church a couple times when we lived on town after we moved out in the country, we never went to church. they were, but they didn't discourage it or encourage it. Sure. Okay, well, that's fine. And they, so neither, they didn't, I mean, they didn't want to be like a doctor or a lawyer, necessarily. They didn't tell you, you know, be.

No, but I went to, I went to Mayo High School. It's named after the Mayo Clinic. No connection between the two directly, just named after. No, no connection. It's a public school. And a lot of the kids there were, doctor's kids. In fact, one of my friends who was on pretty, he was in all, essentially all of my AP biology, chemistry, and physics. His name is Thor Sunt. Thor Alf Sunt. And his father was a

famous neurosurgeon at the Mayo Clinic, a pediatric neurosurgeon. Oh, okay. He was actually featured on, yeah, 60 minutes way way back. Okay. And because he he got, I think it was multiple my bone cancer. And he kept doing surgeries even though he had to be like propped up. Oh. And, but then Thor Jr., his son, he's now the chief of thoracic surgery at Mass General. Oh, well, there you go, like father, like son in that regard. You didn't exactly follow you. You went to us, so the high school was having a lot of the kids of doctors that sort of got you, I guess, sort of peer, peer influence encouraged in that. And did you read, by the way, did you read any science? Did you read science when you were a kid? What got you interested in science? Was it being around the kids from other

doctors or what was it? I think it was reading this, you know, the biology and chemistry and the physics courses. I had my biology course. My teacher, Mr. Welty, was particularly a good, great teacher. And then, big difference. But also, you know, I would get subscriptions, the popular science. I remember that distinctly. I would get, you know, I got kind of a typical thing, a chemistry set. Okay, so was that from you? Or did you, I mean, I mean, so you were reading pop science outside of school and stuff? That was me. That was all me, my, not my parents. So being on a farm or being around the animals, or was it? I think so. And there's a lot of of mechanics around the farm too yeah yeah but okay then you uh but it was by it was the biological

part of sciences you wanted not not not the not not the physical sciences right why was that well i wasn't i wasn't that great in math even you know i did fine a's and b's but i don't know i didn't really see that the practical applications of of like the thing you know the algebra I like geometry. I liked it a lot. Visual, yeah, it's visual. Yeah, visual and then eight. Yeah. Yeah, so it's, okay. Well, it's, and then you, so then you, but you, then you went on to Iowa State. Yeah. It was in pre-bett. That was going to be a veterinarian. You want to be a veterinarian. So you, so that was, again, obviously from the animal experience. Yeah. And I had back then in the early

70s you could apply for vet school after two years of undergraduate work. I applied my grade point was like 3.5 which wasn't high enough. No and and then I didn't I in the ensuing two years I decided not to reapply. I did I made a decision I'd rather go into science so it was a big must have been a big change a big disappointment at first that you didn't get in and then and then a realization that maybe you were interested in in something else. It was some classes, upper level classes, or what was it? Yeah, exactly. It was upper level classes in endocrinology and developmental biology. I was fascinated in development, you know, from the fertilized egg gone up and how remarkable, how quickly it occurs, right? It's

amazing how quickly these cells are dividing and this thing, these are developing. It is amazing. Well, it's a big, but it's a big emotional change, especially had you wanted to be a veterinarian from the time of your young? Well, it had to do with the harness horses, right? And, you know, it was interesting. One summer my dad sent me to a betting track in Ohio. It was actually in Toledo. Okay.

And he did this purposely because he didn't want me to train and race harness horses for a living. Oh, I see. It would be so much of them. Yeah, and it's the kind of thing. if you have a lot of money to start with, so it's a kind of thing, the rich get richer, and then there's these people that

they can't buy the expensive yearling horses, you know, and get the good horses, and so they're kind of struggling. And, you know, in retrospect, I'm glad that he didn't encourage me to do that. So he had the real world experience and decided that wasn't the life you wanted to live.

But you did, but you obviously were interested enough. You entered university thinking, wanted to be a veterinarian. Yes. Yeah. I mean, I remember my own case, I remember when it was like mid-level of high school somewhere. I grew up wanting to be a doctor when it suddenly realization it that I didn't want to be a doctor. And it was a shock for me. It was a bigger shock for my mother. But it took a while to get over it. A lot longer for her. But, you know, then decide that the science is interesting. I had thought about going to, you know, trying to get into med school. And by the way, it's much easier to get into med school than it is veterinary medicine school. I've heard that, yeah.

Because there's not, there's not many veterinary medicine schools. Okay. And, but anyway, you think the opposite. From a psychological standpoint, I just didn't like the idea of, you know, you're doing something to a patient and then you mess up and they die. Yeah. But somehow, if it's an animal, if it's a horse, it didn't seem as traumatic or? rats know if it was my horse it would be traumatic yeah okay well okay so upper level courses you knew we wanted to biology but what uh what drove you eventually or maybe it wasn't initially but what drove you towards brain science did was that was that immediate or did it was an evolution towards that no it started with interest in endocrinology you know that there's cells in one little

organ, the hypothalamus at the base of your brain or your adrenal gland or your thyroid gland, and they produce one protein hormone or in the taste of gonad steroid hormones, and those hormones go in the blood, and they can affect cells all over the body and brain. So I did a master's degree down in Texas at a small university. I noticed you went down to Texas. That was a strange Well, it was interesting. Well, as you know, so when you go to graduate school,

I guess there's kind of two considerations. One is, you know, the the stature of the institution, but maybe as important is whose lab, who are you going to, who's going to be your mentor? Oh, absolutely. And so I applied a number of places, got accepted, number of places, a bunch of state universities mainly. I didn't apply to Ivy League schools or anything. I didn't really. But anyway, so I got in a university in Texas, North Texas State University,

and I decided to go there because there was an endocrinologist that was studying the mechanisms that control production of cortisol from adrenal glands. It's, it's, it's stress hormone, right? Yeah. And, you know, so, and that was actually, it turned out to be really good because I met my wife in Texas. Well, that's important. Yeah. Yeah. She was a, girl. She's a Texas girl from Waxahatchee. Oh, Waxahatchie. I've been to Waxahatchez myself many times because of the Superconducting Super Collider when it was being built there. Oh, that's right. Yeah. But they never finished it. They never finished it there. But it was a lab. They had a lab built and I went down there and lots of us even,

considered moving there. And then a lot of people did. And then they had to move somewhere else when they canceled it. But it was a, yeah, one of the biggest holes. It was the biggest tunnel in the world for a while before they filled it in. Yeah, it was huge. Yeah, it was going to be 40, 50 miles around. And my wife was in the med tech program, medical technologist, and she was in work studies. She was essentially washing dishes that I dirty did in the lab. Oh, I did a lot of something about that continuing later on, but that would be, that would be. No, no. So, but anyway, I did a lot of radioamino assays for to measure levels of cortisol.

And, you know, things have changed a lot. We are using glass tubes, right? And we're using tritium, which is a pretty innocuous radioisotope unless you drink a bunch of it or something. And so we'd actually reuse. the tubes. Okay. Right.

And so, but she was washing it. Anyway, so, you know, I talked with her and we played badminton. She's actually a good tennis player, and she was good and badminton, and then we just hit it off. And so she didn't mind moving back up north, because after Texas, you went back to Iowa, right? Yeah, to the University of Iowa. city. Yeah. That's where you did your PhD. Yeah. And that was in neuroendocrinology. So, okay, so let's see the jump, you did this hormonal activity in Texas and both hormonal and studying

and obviously hormonal and related to your life. But was that directing you? Well, anyway, how did that influence your decision to go into neuroendocrinology? Yeah, I actually, I kind of got, I got, applied to a number of places for PhD programs and um because I definitely didn't want to do a PhD where I was it was yeah and um and so I there's a guy there Gene Spasiani he's passed away a few years ago now and he was studying this fascinating neuroendocrine system that controls molting in crabs okay so crabs have a hard shell in order for them to grow in increase size they have to shed their exoskeleton and this is there's a steroid hormone produced from cholesterol you know cortisol is produced from cholesterol this the the molting hormone called

like dynesone is produced from cholesterol and the malt the molting hormones produced in a gland and kind of the chest of the crabs and there's a neuros secretory cells in their brain actually in their eye stalked anglia that release a protein mult inhibiting hormone into the blood and it tonically inhibits the production of the molting hormone okay then when a cell when the crab gets ready to mold it usually tries to find a safe place because it and uh kind of a non-stressful safe hole under the ocean and then then multiburbing inhibiting hormone quits being produced in the animal's mold. And so we could remove the eye stalks.

If you remove them, that will immediately cause them to molt. Oh, really? You know, so we could, you know, time exactly when we're initiating the molting process. I have to say one of the many reasons I never went into biology. And, yeah, the idea of removing the eye stalks. Anyway, go on. But kind of my main discovery, instead of, in addition to looking at the signaling maxisisms within the glands that produce the molting hormone, the mechanism by which

M-I-H-molting-H-inhibiting hormone inhibits molding hormone production, I discovered that serotonin, a neurotransmitter that we have in our brains, and these crabs, serotonin controls the release of this multi-inhibiting hormone from the neurons in the brain. Oh, I see. So, and then I had a... And serotonin, just so we, that's the thing that a lot of people like to take when they're traveling or something? Oh, that's melatonin.

Oh, that's melatonin. Okay, good. Serotonin is, what is serotonin use for... Well, antidepressants. That's right. Serotonin antidepressants. They increase serotonin levels. Okay, okay.

Just making clear we understand that. Okay, we'll get to it. Well, we'll get to various hormones and neurotransmitter stuff in the human brain in a bit. But that's a pretty interesting segue right there. So the most commonly used antidepressant drug is now like Paxil, or Prozac, Paxil, et cetera. They act by increasing the amount of serotonin at synapsis.

That's right. And the resell. for serotonin are on neurons that use glutamate as their neurotransmitter. Okay, well, we'll get the, okay, hold that thought. No, no, no, I know we'll get there. Yeah, I mean, the book's about glutamate, which is, you know, and that's the point. You hear about dopamine, you hear about things like serotonin, all these things, when you hear about, and yet glutamate isn't something that's on people's, people's tongue.

Yet, as your book points out, and we'll talk about it, it's really essential to most, if not all brain functioning in many, many ways. So we're almost there, though. I want to- Listeners, listeners and viewers, keep watching. Yeah. Stay tuned. Stay tuned for the big, because it's kind of amazing what you can learn about the brain and how glutamate has this really ubiquitous role in so many different ways.

But I do want to get, I want to focus on you for a little bit longer before we focus on the science. And so anyway, that work on the realization of serotonin. you did that when you're in North Texas? No, that was in Iowa. Okay, but I wonder when Iowa did, but you chose to go into neuroendocrinology, and I was just wondering if,

if you already knew you sort of that, were interested in the brain part of them. Yeah, because when I was in Texas, you know, we had to study, you know, what's controlling the production of cortisol, and it's a protein called adrenica, corticotropic hormone, ACTH, it's released from neurons in the pituitary gland, and it's released

in response to activation of stress circuits in your brain. Okay. Right. So I was really studying kind of the end readout of what happens, you know, when you're under stress. Yeah. And then the other part of that is the sympathetic nervous system and epinephrine, adrenaline. Yeah. Yeah. So anyway, that's why I get to the brain. Okay. And so then so you, and you did get to the brain there and you did her PhD and neuroendocrinology.

And then and then you went to and you, so you did a postdoc in neuroscience and neurobiology. And I guess that was a formative time intellectually because that's where you made a discovery, right? Yeah. I was fortunate on my dissertation committee when I was a, I was a, I was a, I was a, I was a, was Stan Kater, who was very prominent neuroscientist and for his work in studying mechanisms that control the growth of neurons and formation of synapses during brain development of nervous systems. But actually, he was using a very interesting system. It was snail brain neurons. And the reason is that individual nerve cells in the brains of these snails, are 10 well they're up to about 20 times as big as nerve cells in our brains and you can

actually see the individual neurons in the snail brains when you look at them just under a dissecting like a low magnification you can see the individual neurons and we would actually pull out the individual neurons put them in culture and then study their growth over time. Back then, there wasn't any digital photography. So we had to take individual 35 millimeter pictures with a 35 millimeter camera on the microscope at different time points. Then we had to go to the dark room, develop the film. We had to keep track of the pictures, obviously. And then to quantify the, for example, the rate of outgrowth of an axon or a dendron right, we would have, essentially what we did is we took the photographic negative, put it in a

photographic enlarger that used for printing. So you put the image and then you trace on a piece of paper. This is time one. This is time two. Wow. You take a ruler and we had like a calibration thing thing. Yeah. It's very time consuming. Yeah, people don't realize. I mean, we often complain about it. It's just amazing how much easier so much, especially data analysis and data taking in all of sciences because of the technological changes. I remember as a physicist, I'm a theoretical physicist for good reason, but I partly did a degree in math, so I wouldn't have to take an extra experimental physics class, which I regret now in retrospect. But when I became chairman of department. It was really interesting to see how in the teaching of introductory physics labs,

how my colleagues, my experimental colleagues, how important it was to begin to make the transition, even in the earliest classes, from the old-fashioned, you know, writing things down in a notebook and to the new kind of data taking directly from the experiment and interface into a computer and taking the data. It's changed everything. And it's obviously changed our ability to understand the brain. And then in the early days of the computers, making sure you, you back everything up. Yeah. That's not just the early stages.

Let me tell you. Well, it's still true. Yeah, yeah, yeah, yeah. Yeah, yeah, yeah, yeah, absolutely. But it's changed everything. And so that, that is, and certainly understanding brain function, the ability to be able to just do the experiments of the techniques that are now available as a huge step forward.

In any case, you were, in those back in those dinosaur days, you were working on your, you had a PhD, you were a new postdoc in Colorado. And you went there because of the laboratory again? Yeah, it was. So I mentioned the Stan Kater was on my dissertation committee. He had just got recruited to Colorado State University to start to head up a new program in developmental neurobiology. Oh, I see. And so essentially he took me with him.

And then, so I started out working on these snail neurons, but then, you know, I was more interested in humans ultimately. Yeah. And kind of the intermediate stage is some lower mammal, like a rat or mouse. Yeah, somewhere between snails and us, yeah. So what I did is I went to a lab and, what is it, Sunni, Albany? Yeah, yeah. State University of New York and Albany. Yeah.

And there's a lab there that had just developed methods to, essentially what you do is you get a female mouse pregnant. And then at a certain stage of development in the womb, 18 days in the case of the rats, you take out the embryos. And then, of course, we euthanize the mother, right? So she died a painless death. And the embryos, actually the embryos also interestingly get exposed to anesthesia.

Oh, you wouldn't imagine, of course. Yeah. And so then we take out the brains from the embryos. And I focused on a brain region called the hippocampus. It's shaped like a seahorse. It's sea-shaped. The name hippocampus is from, I think it's Greek or sea horse or something. Oh, okay.

I wouldn't know. Okay. Interesting. But anyway, so this is a brain region that's critical for learning and memory. Pretty much all the basic science, most of it on learning and memory, is focused on the hippocampus is very critical for spatial navigation. Okay. So if you go out a hike in the woods, right, as you're walking along, hopefully your brain is processing where you're going.

And at least that information is being encoded somewhat so you don't get lost. Or you carry a GPS, but it's nowadays. But this is kind of very fundamental for evolution, right? Yeah, sure. Navigation. Yeah, absolutely. And also it's where short-term memories are established on synapses in the hippocampus. And the reason is the information from all of our senses, whether it's vision, what's coming from the back of your,

information from your eyes goes to the back of your brain, occipital cortex, and then from there, the information converges ultimately on the hippocampus. it's the same for your ears and your other senses. All that information is converging in time and in space as far as the the synapses on the same neurons. And it's that pairing of, for example, sight and a sound at the same time. So like if you're up, if you've never seen or heard a bear

before and you're walking in the woods and a bear, comes out on the trail and growls at you. Right, you encode that. It's kind of a stressful experience. Probably. And so the next time you go out, if you hear a growling, you'll kind of, in your mind's eye,

you know that's a bear. And that's, that wouldn't happen if your hippocampus wasn't working. And that's what happens if you have Alzheimer's disease. Oh, really? We'll get to that because, you know, one of the things I was going to get to it later, but when we will get to it later. But I mean, for most of your career, you were chief of the laboratory neuroscience at the

National Institute of Aging. So obviously thinking about about aging effects in humans and obviously Alzheimer's a big part of it. And so we'll get to there. But your books about glutamate and it was, and your interest in glutamate began in when you were post hoc, right? It was a discovery you made while you were, why you're postdoc. What was the work you were doing?

and how did we relate to it? Right. So I'd take these embryonic neurons from the hippocampus and put them in the culture dish and they settle on the surface, their spheres, and then they attach, we have a certain molecular composition to the bottom of the dish that they like.

So they'll attach, and then they start to grow several processes radially away from the sphere. The sphere, that's the cell body. Yeah. And that's where the nucleus is. Yeah. And so these processes will start to grow out.

And then one of them, after about the first day or so in culture, one of them will start to grow faster than the others. And it will become very long. That's the axon. The other processes, they'll grow more slowly and they'll branch a lot, form a lot of branches, like the branches of a tree. Those are dendrites. In fact, neuroscientists often use the dants.

often use the term dendritic tree to describe that's what they look like. Now, I wanted to ask you a question, and I didn't get it. It may be a silly question, but before we get there, I remember early in the book, and in general knowing that one of these things goes long, the long part of the axon, the smarter ones of dentists. It made me wonder whether that's pre-wired in some sense or whether it's kind of like a real forest, where it's competition, and the one that wins out suddenly gets all the resources to grow

and the others, you know, whether it's predetermined which is going to become the axon or whether that's a stochastic process at all. It appears to be stochastic, and the evidence for that, we did some really cool experiments where these neurons, after a few days in culture, again, they have one process that's longer. That would become the axon. But if we cut it, if we sever it, we just take a, actually, these are, now, these are, the cell body of these neurons is like 10 micrometers, right? Okay, so pretty small.

And the diameter of the, of the axon is like one micrometer. But anyway, there may be, at that point, I don't know, what if, 50 to 100 micrometers long. So if we cut it. at that point, then what will happen is one of the other processes that would have previously become a dendrite will become the axon. So the cell still has this ability to switch its polarity. So that shows that that you can do some environmental manipulation and it will switch. So it certainly hope it would. I mean, it makes sense to think that the brain, you know, that it could do that because there could be lots of reasons the one that's designed doesn't you know just like again like a tree if you know

suddenly another tree gets in the way it's important to be able to put branches out somewhere else and yeah okay so um anyway i interrupt you but i always wondered whether that was such a gas for process so so uh you're you're looking at the growth of the basically the the beginning growth of a neuronal tree with axons and dendrites and go on yeah and so my mentor and i were we're thinking about And at that time, this is like the mid-80s, at that time, the conventional wisdom was that neurotransmitters, their function is for neurons to communicate with each other at synapses after synapses have formed.

But we and others had evidence that these neurons, even these embryonic neurons, they're starting to grow. They do produce these neurotransmitters. So we got to start doing experiments, we asked, well, does for example glutamate, which is a major excitatory neurotransmitter in the brain? Does it play a role in regulating the growth of the dendrites, the formation, and maintenance of synapses? So the initial experiments were pretty simple. We just add glutamate at different concentrations to the culture medium, bathing the neurons. and then just follow them over time and see what happens and i found that um low to moderate

levels of concentrations of glutamate would selectively slow down the growth of the dendrites without without affecting the growth of the axon and then i showed the reason is because the receptors for glutamate the proteins in the membrane uh that mediate the response to the of glutamate are located in the dendrites, but not in the accent. Oh, I see. And that kind of makes sense, too, even from the standpoint of the adult brain, where you have these long axons, and they're releasing glutamate from the presynaptic terminal. And then it's acting on the postsynaptic cell on the dendrites. But, okay, go on. Well, I was going to,

Why don't you finish what you're going to say, and then maybe I'll answer my question. And then I went on to show that glutamate released from a, so you've got a growing, growing axon, have to back up a little bit. The end of each dendrite and axon, there's this highly motile structure. It's kind of like a hand. Okay. And it's called a growth cone. Okay.

And it has kind of fingers that are kind of probing the environment as, it moves along and grows and kind of directing it and deciding which way to turn or whether to keep going or stop and so the axon growth cone releases glutamate as it's growing and as it encounters a dendrite so this is a dendrite here and it's releasing glutamate onto this dendrite and then what happens is it kind of stabilizes the growth of the dendrite and allows for interactions that lead to the establishment of a synapse that stays there and functions. So it's okay, so yeah, when we get to the brain development, it's relevant then to establishing this synaptic structure. But I guess the question I was going to ask, and it sounded like you were saying it earlier.

Originally they thought in order for a synapse for two neurons to interact, they had to touch, right? Right? But now, but was part of the discovery that they don't have to, that the glutamate can, even if there's a gap, can cause that signal transfer? Yes, exactly. But further events have to occur that do require touching. Yeah. Okay. Well, look, let's talk about the brain now. Let's talk about gloomé. I mean, the book is called Sculptor and Destroyer for a reason. And I think, I think I want to read what you, I'm not known if it's from the preface of the book or what you wrote me. I mean, it basically, you argue it's basically involved in almost all areas. In spite of the

fact the public knows about things like dopamine and seroton and everything else. The glutamate is really not only just important for development. It's also for involved brain changes, something called Doroplastis city, which we'll talk about, the energetics of the brain, and finally, diseases which are relevant for aging and other things. And it's also a response to healthy lifestyles, etc. And so I want to go through those things in order. But I thought it was kind of poetic because he wrote me about this. You said, in a very real sense, this book was written by glutamate, acting with the neuronal

circuits of my brain. Glutimate played a fundamental role in generating my thoughts and the words they encode, which I then transferred to a computer keyboard. It's humbling to know that compared with the eons of evolution, the construction of neural networks during the development of my brain, the actual writing of this book seems trivial. I thought that sort of put it in perspective. That mainly, and I think I'm right,

that your group in the 80s were the first kind of the ones to realize how potentially ubiquitous glutamate was and important in this, that it really plays a role in all aspects of neuronal networks. And they also, in the death of neural networks, So too much, it can be too much of a good thing. Yeah. And so therefore, I thought it was interesting, and obviously the purpose of your book, too, to use glutamate as a way of understanding how the kind of how the brain works and responds to,

and certain issues, which we want to know more generally. And I'd like to talk about that and then your own context of your work in aging. And then some other interests I know you have in healthy lifestyle. So we'll go there. Let's start with the development of the brain and glutamate. role in the development of the brain. And so let's start. You know, you just pointed out that it was, it's, it helps in the development of these,

ultimately the synapses by governing how dendrites grow and meat. But maybe you want to take us through that in a little more, in a little more detail. Yeah. So during brain development, actually before, actually, sorry, I realize I just that I lost a note for here, but before we get there, I keep trying to think of the, of people and, and put this in perspective. We talk about glutamate, but let's talk about what glutamate is before we even go into this other stuff. It's, it's, it's an amino acid, right? And it's one of the smallest, the simplest of them, right? So what is that? Yeah, so most people would know glutamate or glutamic acid as an amino acid that's a building block of proteins.

There are 20 different amino acids. And when the DNA encodes, essentially DNA codes for proteins. Amino acids are the building blocks of proteins and glutamate's one of the building blocks. it's also and it's a simple molecule in that it has only five carbons it has it's an amino acid so the amino group means it has an NH2 nitrogen in it and it also has a couple oxygens you know so it has kind of the key fundamental elements of life yeah and there's an interesting story and I'm sure you this caught your eye Lawrence, because it has to do with cosmology and exoplanets and the possibility that there's life on other planets.

But there are my understanding, and this was, let's see, what was her name? Her name is, I have this somewhere because I wrote it down just for, do you know Catherine Neish? Catherine Neach? N-E-I-S-H. Now she's at, what is it, University of Western Ontario. And she works on exoplanets and done out of work on Titan, Titans, a moon of... The interest in looking for life on Titan, which always amazes me, but anyway.

Yeah, and so she did some experiments, you know, so there's ways of measures of detecting certain chemicals in the atmosphere of planets. And the way this atmosphere, and my understanding on Titan, is that there's like these molecules like drifting down towards the surface. And it's nitrogen rich, apparently. And there's some evidence there could be water there. So now you got, I mentioned nitrogen's in amino acids. hydrogen and oxygen, and then the only other thing you need is carbon, right?

Yeah. And so, for example, if there were CO2 or something, that is actually CO2 is the carbon source for all these molecules and all of us, right? CO2 is what seems to be ubiquitous in the early evolution of systems. But Titan has a lot of methane, liquid methane, I guess. Oh, yeah, methane could. Maybe that's what she used. Yeah, I think methane is what they did. She did this experiment where she kind of mixed these kind of potential precursors of amino acids and then I think she had she did exposed to UB. light, kind of like Stanley Miller. Yeah, I was just going to say, just like the

Yury Miller experiment in the old days. And she got four different amino acids, one of which was glutamate. Yeah, because it's one of the simple. simplest. Yeah, it's one other. I think it's interesting because you make this statement early in the book, and I want to quote it, it turns out that genes encoding the receptors for glutamate are ancient and have been discovered in simple multicellular organisms such as slime molds and mosses. And scientists have shown that glutamate controls the growth of these primitive creatures.

It's also been, glutamate has also been shown to control the growth of the roots of plants and mediate the plants responses. Therefore, very early in evolution, long before there were nervous systems, Glutumate came to function as an intercellular signal that controls growth and responses to environmental stimuli. So I think the point that it's a simple amino acid easily formed and potentially one of the earliest ones easily have an abundance, probably it's not surprising in some sense that glutamate is so ubiquitous in biology. Yeah, that's right. And another aspect of this has to do with energy metabolism, how cells acquire and use energy.

And in bacteria, and in ourselves, too, glutamate plays a role in energy metabolism. And these are the kind of critical things for growth you need energy, right? Yeah, yeah, yeah. And with plants, you know, I mentioned this dendritic trees of neurons, right? And in many cases, these dendrites exhibit fractal geometry. Uh-huh. Like the branches, so the branches of growing tree, they're essentially trying to maximize the amount of sunlight,

which is energy, you know, because they convert CO2 into glucose. Yeah. And so I think, and, you know, this is this kind of speculation with a lot of good evidence. evidence, although we do have some, that essentially what these neurons, individual neurons are doing is they're trying to maximize their access to other neurons and ultimately energy. And there's a role for the vast blood vessels too. They have a fractal.

So being out like trees are the same trees. They have a price. What is a scarce resource? We'll get to it. I'm still always, I mean, I don't, for me, the biggest, one of, there's so many big mysteries of the brain, but one of them is energetics, you know, the brain uses like 20 watts and versus, I remember when I was, when I first wrote about this, there's maybe 20 years ago, 15 years ago, in a different context, I suppose, to try and estimate what, what the energy usage of a

electronic computer would be that would have the storage and transmission power, the brain was something like 20 terawatts, which is a million, million times more power. And the brain somehow does in 20 watts. That to me is the biggest, if you want to say quote unquote miracle, that's the most amazing aspect for me of the brain. It's definitely the most energy efficient information processing machine. By orders of magnitude, by me, it may have been, you know, computers change so that what then was a million million may only be a hundred million now or a million, but it's still a big difference between that and electronic computers and and and energy now with the supercomputing and stuff that's a big big factor getting enough energy to run these oh yeah absolutely

the energy farms and and the the environmental costs of bitcoin and other things just the yeah it's a big deal but our brains somehow do it on a donut which is uh or you know maybe not a donut for those people they had uh whatever a 3.8 billion years or well not neurons per se but you know they've had millions of years anyway yeah yeah or hundreds of millions maybe but yeah yeah no in any case so so that is amazing and so i want to let's go through let's go through those topics brain development neuroplasticity and then bioenergetics and then disorders and finally get to lifestyle when i want to talk about your interested lifestyle and aging and the brain in general and then talk maybe about what um um um what what you where you think the future

is in terms of brain science. So in terms of brain development, we started way back when talking about the glutamate playing a role in those formation of those trees and the synapses. What else? Yeah. Okay, so neurons are electrically excitable like your muscle cells. And so when glutamate binds to its receptor, what happens is sodium channels open in the membrane. Sodium has a positive charge. The sodium concentration outside of the neuron is much higher than inside the neuron. So when glutamate binds to these receptors, which is a sodium channel, it opens the positive charge rushes in, and that's called depolarization. Yes. Okay. And then there's another glutamate receptor.

It's a little complicated, not too bad. So you got sodium going in. Then glutamate also causes calcium to go in. Calcium is much higher concentration outside than in. And it turns out throughout evolution, calcium is a very important regulator of, for example, gene expression, you know, determining which genes are turned on or turned off.

and that means which proteins are increased or decrease. But anyway, so glutamate will stimulate the nerve cell, sodium rush it in, it will fire what's called an action potential, which quickly transmits the electrochemical signal along the axon to the next neuron. And it reminded me, I've always read these things, and I hadn't thought of to think about it enough until I was reading your book, and then it occurred to me.

So this is, again, a stupid question, but a question of physicists might ask. But you say that the neuron fires, but it occurred to me, is it really the opposite? I mean, so if you're depolarizing, then I'm assuming if there's polarization, there's already a potential there. When you depolarize, you remove the potential.

So I'm wondering, does the firing really mean that what you're happening is, it's the firing is really things in reverse. If you remove the potential here, but the next neuron has a potential, then you'll get some current flow between you and the next neuron. But it'll be motivated by the fact that the next neuron has the potential and you don't. So I'm just wondering, am I missing it?

When you depolarize, is firing happening? It's like the bullet is going in the opposite direction or no. No, but the key thing, Lawrence, is the synapse, which is a space between the neurons. Oh, okay. So the membrane isn't continuous between one neuron and another. Okay, I guess what I'm wondering is, so the synapse, the synapse is where there's a flow, right, across the fence synapse, right?

Yeah, it's like that. And if you depolarize this one, then the current is going to flow from the one that isn't depolarized to the one that is, right? I mean, the one that's still polarized to the one that isn't. No, it goes in the opposite direction. No, the current is flowing because the ions are moving across the membrane, but there's no, the membranes of each cell are separate. But when you say it, when you say it fires, I guess I want to know what, what do you mean when you say it fires? That's propagation of the impulse along the membrane of an axon.

Yeah, that's what I'm wondering. And so the propagation, I'm just, I mean, it's a stupid question, maybe. I'm wasting people's time, maybe. But I would have thought if you start, if you're at this end and people have to watch instead of listen for this. But if you're at the left end and it depolarizes, I would have thought the signal would go from the part of the brain brain that wasn't a polarizing. Okay.

What you're saying is, will it ricochet? Well, to some extent, ricochet, I just figure you remove a potential here. It's like a ball rolling down a hill. You have this potential because of it's polarized. If you remove it here, the ball starts. rolling from the other end back to here. You'll still get a current, but it'll partly, it won't be like it fires because the potential's higher at the end where the glutamate was than the other end. It's the opposite. It's right. The potential's gone away here where the

glutamate acted. And the signal comes from the other end. Yeah. Yeah. No, so what happens is there's energy dependent pumps that pump the sodium back out quickly after it comes in. So it's only a transient sodium influx. And does the firing happen after the sodium is restored? No, no. It's as the sodium rushes in. It's a tech. I won't waste time on it.

I still, I was trying to picture where the actual signal comes from if you've got rid of the potential. It's called an action potential, right? Isn't it? Yeah. Yeah. And that's. And it's initiated by opening of those sodium channels in one specific

location in the membrane. Yeah, and then, okay. And I kind of, as a physicist, I think I know what's happening in my mind, and I won't bother other people, but I think I, but later on, I'll bog you after, after we record, because I think I kind of figure what's happening in the physics of it, but, or the chemistry, depending upon you happen. Anyway, go on. Yeah, so, right. So, um, what's I going to say? So during development, glutamates released from a growing axon onto a growing dendrite. It promotes the formation of a synapse between the presynaptic cell and the post-synaptic dendrite. And then that's fixed in place. You got the synapse.

And when this neuron fires by being stimulated by a preceding neuron, then it will cause glutamate release. and then that stimulates receptors here and cause this neuron to depolarize. Okay. Okay. So each time the effect of nerve firing is to stimulate glutamate release? Yes. That's basically what it means. When you fire, you stimulate the glutamate release, which then carries a signal, if you wish, and depolarizes the next one.

So the firing is really, and it really is 100% glutamate, that's the, that's the, that's, That's the medium of this. Yeah. In the brain, it's that way. You can take a stimulatory electrode and put on a neuron and stimulate it. Yeah, yeah. But in the brain, glutamate is the excitatory neurotransmitter. And the reason, there's a number of reasons I put in this book, why I call it the most important neurotransmitter.

first more than 90% of all the neurons in the brain the neurotransmitter they deploy is glutamate the other neurotransmitters we mentioned dopamine and serotonin there's also gaba which is a it's kind of the brakes of the system it's an inhibitory neurotransmitter yeah the only way these other neurotransmitters affect activity in the brain and behavior, any behavior, emotions, learning and memory, imagination, whatever. The only way these other neurotransmitters affect those processes is by modifying the ongoing excitatory activity through these circuits of glutamate using neurons. So you can imagine you. you've got like this spider web of neurons that are using glutamate,

and on top of that spider web, you've got these other neurons that are affecting the electrical impulses coursing through that spider web in important ways. But kind of the bottom line is, without glutamate, you're dead of it. But the other guys, you know, the other ones get all the publicity, you know, all the right, because they're moderating. Glutamate is sort of the backbone of sort of the unheralded, you know, people run in the engine of the train. And it's the, and there, and these other ones are more like the valves that are sort of changing what happened. The reason, the reason glutamate is not known as well is because it's so important, because if you, drugs, drugs for glutamate,

a very tricky business, drugs that affect glutamate receptors, for example, because it's critical for everything we do. Yeah. And if we mess with it, even a little, it can screw us up. Whereas you can mess with dopamine and serotonin and not... I can mess with them a lot, and yeah. And that's what people do, I guess, is mess with them a lot. But that's why they're more well-known is because they're the ones that people talk about, because they're the ones that pharmaceutical companies or other, they're the ones that people are clinical, you know, techniques and mediation are designed to affect because you can affect things with them.

Psychedelics, too, you know, they're increasing serotonin, at serotonin release onto glutametergic neurons. So that's why, that's why, okay, so now we understand that glitone, but now we understand both why they're more well-known and why glutamate is so basic. But what about what else, is there any other major factor in terms of brain development that glutamate before we get to neuroplasticity, which I want to get to next, but the basic fundamental development that you want to mention? I do. There's one other important thing. During brain development, there's a lot more neurons that are born, that is, arise from stem cells, than all. Ultimately, we end up with an adult brain.

Okay. So there's an overproduction of neurons, and there's kind of a pruning back. So some neurons die in the developing brain, and the ones that die are the ones that have not been able to form during synaptic connections. And what happens there, it's pretty interesting. The activity in the glutamatergic neurons will cause an increase in the preemptic neurons. will cause an increase in the production of what are called neurotrophic factors. These are proteins that promote the survival of neurons. They're also important in what we'll get to later,

synaptic plasticity, you know, changes in the function and structure of connections. And so that's kind of the second most important thing, that glutamates not only involved in forming a cell. synapses, it's involved in determining which cells survive. So if the glutamate, the glutamate produces the the release of these neuro, what are they called neurotrophic? Neurotrophic factors. So glutamate promotes their production? Yeah, yeah.

And then, and the ones that die don't have that production, and that's because glutamate isn't being released because they're not, they're not, it's not, there's no enduring synapse. Yep, yep. Okay, I think I got that. Good. Yeah, that's exactly right. Okay, good. Okay, good. Okay, good. For the formation of healthy brain, basically, Lutumate is, is a key in all of the aspects before, because the brain is based on, on the, on, being able to create lots of synapses and, and how many are there in the human brain, trillions of trillions or something? About a hundred, trillions. About a hundred trillion. there's about 100 billion neuron nerve cells and about a thousand times more synapsed. Yeah, so it's like, so it's like if I think of cosmology is 100 billion stars,

and then the brain is like a, is like a thousand galaxies, 100 billion stars in a galaxy, 1,000 galaxies put them together. That's about the number of synapses in it. It's interesting to think of those numbers because those numbers are so big to try and put them in perspective. And okay, so brains develop. but the brain isn't just developed and that's really important. And again, I think it's kind of relatively recent in my life anyway,

the realization that the brain, when I was a kid and I used to, you know, I don't think I told you, but I wanted to be, actually, I wanted to be a neuroscientist. No, I didn't want to be a neuroscience. I didn't know what neuroscience was. I wanted to be a neurosurgeon because my mother wanted me to be a doctor. And the brain is what I found most interesting for the time I was a kid. And I remember getting psychology today, a subscription when I was a kid. and I wanted to be a neuroscientist because I didn't know what a neurologist was meeting my parents

finished high school and and and um but the brain was fascinating so I you know I have this 50 year old awareness from all that of of brain science at that time but it seemed to me at the time that the that it looked like oh the brain develops when you know from in in utero and then when you're a child and then it's fully developed and that's it but but but but but but but but But then, of course, that's not it, and the brain has great plasticity. And I kind of think that's in that scale, relatively recent discovery about placidity. Maybe I'm wrong. Yeah, it is.

You're right. Within that scale, it is recent. I should mention, you know, on that time scale back then, I think it's 50s and 60s, there's a very famous neurosurgeon in Montreal, Wilder Penfield. Wilder Penfield. Wilder Penfield. Well, you know. So you know the story.

it's, you know, he was treating patients with epileptic seizures, and, you know, back then, they still do this in some severe cases nowadays. There's, they try to figure out where in the brain these neurons are just firing like crazy. And by the way, that's because they're releasing too much glutamate too often. We'll get to the diseases, but okay, good. And, and, but what he did, there are no pain receptors in the brain. So you can poke around in a brain as much as you want and the subject wouldn't feel pain. But anyway, that's great.

But anyway, what he did... It reminds me of an awful movie I saw. Okay, go on. He would, you know, in trying to figure out where, which small piece of brain is going to remove to try to stop the epileptic seizures, he would kind of put his stimulating electrode around different places and these patients were not anesthetized because they didn't have to be.

Because they don't pain. Yeah. And it was, he described how, you know, he'd stimulate in one place and the patient would say, and he'd ask the patient, what did you experience? And they may say, well, I saw my wife coming in the room or something or, you know, so he could, essentially by stimulating these people would recall sequences, not real long sequences, but nevertheless, sequences of events.

And so that was really some of the first evidence for, you know, the brain storing specific sequences of events occurring, you know, and kind of like a movie. Yeah, like a movie. Yeah. Wow. And I mean, and that's, by the way, of course, that's what. What's one of the many things now that's changed with being able to new technology is you don't actually have to go into the brain so much now that we can use magnetic fields. And other things we can try an image without non-invasively and see what's going on in vivo in the sense of seeing what people are doing or thinking at least what nerve, what processes are occurring, maybe not seeing the thoughts so much. But without without actually doing what he had to do, which is go into the brain and and excited. But as far as the neuroplasticity aspect, you're right, it's only in maybe the last four or five decades. Four decades, let's say this has become clear that the brain is not hardwires. It's not like an electrical circuit in this computer or, well, maybe an older computer.

Yeah. But it's the structure of the brain can change. And it can change and does change. in response to experience. And in fact, when we learn new things, there are subtle changes in the structure of the brain occurring. Maybe a change in the size of a few synapses, or it could be even the formation of a new synapse,

or even the elimination of the synapse. And moreover, certain things we do, lifestyle factors, and we'll get into this last, later, like physical exercise has robust effects on structure and function of the brain. It's a great antidepressant, but it's also actually facilitates learning and memory. It will promote the formation of new synapses. It will stimulate the production of new nerve cells from stem cells, at least in the hippocampus. You know, so these developmental mechanisms.

that occur so dynamically and really overtly and just remarkably during brain development, they can still occur using similar mechanisms involving glutamate, neurotrophic factors, there are some other mechanisms involved in adult brains, and moreover, we can affect those in good ways or bad ways, by what we do throughout our life. Okay, good. Yeah, that's important. And we'll focus on that at the end.

I want to talk about what we can do, because I think that's what people are interested in. But right for the right now, I want to know the mechanism. What, this neuroplasticity is incredibly important, the fact that it's amazing, the structure of the brain. Obviously, learning is a form of neuroplasticity because something was there that wasn't there before, somewhere the memory is stored.

And obviously we know that that is real because you can retrieve it later on. So it's there, it's not ephemeral. it's in some biochemical to the extent that all sensible people realize that all everything about us is just biochemistry the so it's that that's an obvious form of neuroplasticity but it's even broader real real structural changes but how how does glutamate specifically relate to those structural changes yeah so what's been shown and again looking at the hippocampus, there was a number of Nobel prizes given for studies of the hippocampus in various regards. One is this spatial navigation, learning and memory, how that works. And another one for the scientists discovered that by putting a, so say you've got two neurons

in the hippocampus and you, in the pre-synaptic neuron, glutametergic neuron, you've put a stimulating electrode so you can stimulate that neuron however you want different frequencies or intensities and then there's a recording electrode in the post-synaptic neurons so you're recording the responses of that post-synaptic neuron to the stimulation of the presynaptic neuron and these are both glutamatergic neurons okay this one group is actually up in Scandinavia they discovered if you stimulate this presynaptic neuron at a high frequency 100 hurts 100 times per second and you do that several times and then you wait 10 minutes or

you wait an hour and then you come back and just stimulate at once the strength of the response of the post-synaptic neuron will be stronger because you had previous stimulated at high frequency. Ah, okay. So it remembers that it had been stimulated at high frequency. This is called long-term potentiation.

And then that was later shown that the size of the synapse actually increases as a result of that. I was wondering about the physical... Since I'm a physical, I was wondering about the physical mechanism for that. So, so

stimulating a lot basically causes more dendrites to be connected or something like that or more, and therefore more potential sources of glutamate? Yes. And the strengthening even of an individual synapse. Okay. Making a bigger. Making it bigger. But again, maybe I'm understanding.

Individual synapse involves not just two dendrites. Does it involve a bunch of them together or just just two dendrites? No, one axon and one dendrite. One axon and one dendrites. So there are lots of dendrites. So what I'm wondering is if it becomes larger, does that mean there are more dendrites involved? More dendrites grow?

More synapses and more dendrites. And you can get additive effects of stimulating more than one synapse or dendrites at the same time. Is it because, again, I'm just trying to understand that prolificol glumate. So you excited a lot, and it means that there's more, that somehow there's more glutamate being released because of that of that synaptic connection. And that is encouraging more dendrite growth and therefore more.

And so it's in that way that glutamate is related to the plasticity of the brain by increasing that size of that synaptic connection. Yeah. And it's more complicated than that. It involves actually elevation of calcium levels within the cells. And actually, I did a lot of work on that. Even beginning in my postdoc work, Roger Chen was a chemist at, where's he at?

Ah, I think he was a Caltech or Berkeley. And he actually got a Nobel Prize. He developed, it was one of the co-developers of, green fluorescent protein. But more importantly, I think for the neuroscience field, he invented chemicals that their fluorescence changes when calcium binds to them. They're based on a, you may have heard of this, EGTA or EDTA. It's a calcium chelator molecule.

So he modified that so that it's fluorescent and that the fluorescence changes when calcium binds. And you can introduce this into living neurons. You can image them. You can activate a synapse and you'll see it increase in fluorescence, increase in calcium levels. And you can correlate that with strengthening of the synapse. You can even correlate it in vivo now with modern technologies using fiber optics. You can even... I was going to say, how do you see the fluorescence? So the original fluorescence was seen this was done in a test tube, not in the brain. It was just you could watch it there. But now you're saying you can actually put fiber optics in and see the fluorescence in vivo. And then the key thing, so this is all showing correlations,

right, between activation, release a glutamate, increase in strength of the synapse, increase calcium. That's all correlation. But that doesn't establish that glutamate is necessary. It's not causation. Correlation, not causation. So then the other big but development, that came about, that's close to 25, 30 years ago was the development of highly specific drugs that selectively block glutamate receptors without affecting any other receptor. And by using those specific blockers of glutamate receptors, it was shown that activation of glutamate receptors is essential for learning in memory, it's essential for strengthening of synapses in this particular long-term potential, and it's essential for the changes in calcium

and the structural changes. Okay, okay, so the fact that, so Blu-Demate really is an essential part of the brain literally changing structure, and by changing structure, you mean the synaptic connections in the brain, which are favored and how they're connected. Okay, okay, I get that now. Now, what about bio-energetics, which is the subject we mentioned earlier, the amazing, amazing energy efficiency of the human brain. So all cells have energy factories, the mitochondria, which arose from, we think, bacteria-like cells, kind of a symbiotic relationship.

Yeah, yes, it's like the Borg. Actually, Carl Sagan's first wife, yes, was a woman. And she, Magulis. Lynn Margulis, who. Yeah. She was a, and she, you know, she was one of the early people to have this idea.

And she also thinks like out of the box and she also had this concept of Gaia. Yeah, yeah, yeah, yeah. That like, well, it's, you know, we're made of billions of cells, right? Yeah. So each cell in our body, our brain is part of a bigger organism. Yeah.

You know, could we be part of a bigger, well, we are, the earth, right? You wrote a book on the climate. change, right? Yeah. So we are part of a bigger in a way. Your son got quite interested in the Gaia hypothesis. Somehow, if cells and an organism could be symbiotic, then maybe all the organisms on Earth could have a relationship. And it's the guy, it is in a spiritual way, it's the Gaia thing. And I kind of, but there are probably some, go on. You recently had a podcast with one of my good friends, Robert Sapolsky. Yes. Right. And on free will. And so, yeah, with the guy,

thing, I guess we could hypothesize that we don't have any free will like cells in our body and we're part of a bigger organism and maybe, you know. I'm always worried about over emphasizing analogies

and I think Gaia has some nice features. To me the biggest Gaia thing is frankly the fact that carbon dioxide I wrote a book called Adam but the fact that there is a carbon dioxide cycle in the earth, but life dramatically changed it because it's carbon dioxide cycle on the earth used to be 100 million

years having to do with you know carbon dioxide being absorbed in the ocean being being accreted on the ocean floor with calcium carbonate and then and then and then with plate tectonics being subducted and then being emitted 100 million years later in volcanoes in that cycle work yeah they've changed it from 100 million years to 100 years you know cycling carbon in the atmosphere so that's a definitely an impact of life on the environment in a big way Yeah. Okay, but anyway, so the mitochondria are the energy factory of cells and neurons have a lot of mitochondria, which makes sense because they, as you mentioned, they need a lot of energy. Your muscle cells, particularly if you exercise a lot, have a lot of mitochondria. In fact, if you exercise a lot, each of your individual muscle cells will have more mitochondria than a colleague who doesn't have.

exercise, right? So exercise will increase the ability of your muscle cells to provide energy in the form of ATP, the energy currency. The same is true with your neurons. If you use them, it will increase the number of mitochondria in the individual nerve cells. Oh, okay. Oh, that's important to know. It's why I do this podcast. It forces me to keep using them. But anyway. And we showed that using some modern molecular genetic mechanisms, we didn't use CRISPR, but we used another one called RNA interference, which also got a Nobel Prize. There's a certain what we call transcription factor that regulates a bunch of genes that are critical for the division and growth of mitochondria, a process we call mitochondrial biogenesis. And by manipulating that critical transcription factor, we showed that mitochondrial biogenesis,

that is an increase in the number of mitochondria, was essential for these developing neurons to form synapses. If they don't produce more mitochondria, they can't, they'll stay alive, but they won't be able to form synapses and their growth, slows down a lot. And then, yeah, we had some evidence that aerobic exercise will also increase the number of mitochondria neurons. So, you know, both what we're doing now, intellectually

challenging, or turns out when we do exercise, physical exercise, a lot of neural circuits all over the brain, not just the motor neurons and the sensory motor system, but even neurons important for learning and memory, regulation of mood, anxiety, they're all activity changes. It's interesting, yeah. Well, we'll get to the life's, the flow backwards. We'll think of the flow forward now,

which is how, you know, working, how the brain, how glutamate and the brain affects the efficiency, of energy. So glutamate, when glutamate stimulates a neuron, energy is required to restore these ion gradients across the membrane.

There's ATP dependent pumps that pump these ions back out. Yeah. And when you get the sodium and calcium influx, they have to work harder. And so they need more ATP. So

when your neurons are active, when are stimulated by glutamate, they are, the mitochondria produce more ATP to provide that ATP to run these pumps that restore the gradient. And it turns out that you mentioned these modern brain imaging techniques. There's one called functional magnetic resonance imaging, fMRI. And essentially what it's measuring is not directly measuring activity in neurons, but it's measuring blood flow. And just like your muscle, when your muscle cells are exercising,

the blood flow to your muscle increases. Yes. Okay? The same is true with neural networks in your brain. When they're active, the blood flow increases to them. And this magnetic resonance imaging, essentially what they're measuring is protons.

It's just protons in the blood moving. Yeah. And blood. But it's a very, accurate measure of activity because there's a tight coupling of activity of neurons and blood flow. And so actually I would make the case, and I did in my book, is what these clinicians and clinical investigators when they're doing these human studies with fMRI, what they're actually looking at is a readout of glutamaturgic neuron activity because it's,

It's glutamate that's mediating the increase in activity. Oh, I see. And therefore the increase in blood flow. And the increase in blood flow, okay. And the increase in blood flow, of course, yeah. So it's initiating the activity and the increase in blood flow is required to deliver the ATP. The glucose, the ketones, glucose or ketones to the neurons, yeah.

And oxygen, of course. And yeah, exactly, an oxygen, which is required for the, whole thing to work efficiently. That's another interesting story. I think I mentioned it in my book. So oxygen, we need it to live. It's also very toxic. Yeah. If oxygen was around in the environment at the beginning of the earth, we wouldn't be here. No. Because it oxidizes. So we developed ways to deal with. There's oxygen free radicals for them, right? Yeah. It's oxidizing. And so we have antioxidant defenses, actually many of them. There's multiple ways that our cells protect themselves against the oxygen

pre-radicals that are produced during the production of ATP in the mitochondria, which is essentially you got glucose and oxygen. And just like when you're light your fire in your fireplace, you need oxygen. You need that to produce ATP. Yeah, so the increased blood flow, Increased oxygen, increased energy sources. Well, this is a good segue because I want to talk about, if we read it, well, I want to talk about neurological disorders.

Before we get there, as you pointed out, I mean, and I think I described, and I think it's accurate to describe life as controlled burning. We really, what it is, and if there was too much oxygen really in the history of the earth, there would have been uncontrolled burning. There wouldn't have been any energy left for organic materials to, And we're only there because we do controlled burning pretty effective. That's true. We were going to get to, you know, you point out the free radicals in oxygen.

And we're talking about controlled burning a little bit. Life is controlled burning, which is, as I say, the way I think of it. And the energetics. We kind of understand how glutamate helps with that. The production, producing more ATP and having more sites for ATP, which is the energy generating molecule in all of life. This may seem a stupid question, but I can't resist asking you,

especially someone like you, I know exercises a lot. But as you point out, when you're not exercising, the brain is using much of that energy in the body. And I do find in my periods of intense intellectual activity, it may be because I'm eating less too. but that, you know, I exercise. But in terms of controlling my weight, I find that my weight also gets controlled well.

If I have periods of intense intellectual activity, I seem to be burning a lot of calories and controlling my weight almost as effectively as if I'm exercising. Is that crazy? No, it's not crazy. You can, as you said, at rest, but you can, right now what you and I are doing,

we're burning more, brains are burning more calories than if we were just watching a movie or, you know, something like that. Yeah. Yeah. And I mean, the human body is about an 80 watt,

90 watt heater when you're just at rest. And then when you're doing stuff, you know, maybe 120, 100, something, whatever. So, and the brain is using 20 watts,

I guess, an average. I don't know, I don't know what the total. Actually, do you know the number? You must know the number, maybe. How variation of the maximum audits when the brain is intensively working versus when it's resting, or do you know? I don't know off the top of my head.

It's fascinating for me to know. It's overall less at sleep, and it's most when either interesting, maybe. Actually, physical exercise, we don't know for sure because it's hard to measure. Yeah, yeah, yeah, that's true. When you're moving. Yeah, it's true. to measure when you're moving even if you have electrodes i guess in your head but but you know being nice to know if it was varying by 20 watts or fifth you know whatever it'd be interesting

oh i see how much what you know and then one could work out but i certainly have that that it could be you may be eating less you may be eating less too correlation is not causation as we point out earlier and it's got to remember that so i've always been suspicious but i've did i have noticed those periods of intense intellectual activity that that i seem to control my weight almost as well as when I'm exercising, because I'm not always doing both. Sometimes I'm doing both, and then, of course, it's conflated and it's hard to tell. But before we get to health, let's get to not health. You point out free radicals and the body has to get rid of them

because they're toxic in different ways, and we hear about it all the time. I think a lot of verbiage is meaningless that's put in, in a lot of the media. But let's talk about glutamate and neuronal disorders and aging to some extent. How all that combines together. Yeah. Well, but there's an interesting story on really the first evidence that glutamate can excite the brain was during World War II, there was this Japanese scientist at Keogne University in Tokyo

So, Hayashi was his last name. And he had dogs. He drilled a hole in their skull, and he was essentially exposing the brain to different chemicals and seeing if the dogs had any responses. And then when he found when he put a lot of glutamate on the dog's brain, it had seizures, like epileptic seizures. So that was really kind of evidence that glutamate could cause excitation.

And so what happens in epileptic seizures is that, oh, then there was this incident in Canada, another very important thing. Some people had, they'd all eaten at the same restaurant, and shortly thereafter, within a day or two, they had seizures. And these are people who they never had a seizure before. One of them died even if seizures were so bad. And then they also had amnesia. What's called antrograde amnesia, they couldn't remember anything new.

Kind of like what happens in Alzheimer's disease. Oh, okay. And so what happened, a very interesting story. They'd all eaten shellfish. They ordered the same thing from the menu, the shellfish. and then it turned out the shellfish had high levels of a chemical called demoic acid which selectively and with very high potency activates glutamate receptors oh so that's what was causing their seizures and and then we actually

use this in the lab that the first study we'll get to this maybe but our first intermittent fasting study was we found if we maintain rats on in fasting and then give them this same demoic acid or another one canic acid, they're protected against seizures and their memory is preserved, relatively anyway. And so anyway, but then actually the... Yeah, we'll get to that eventually. My first... So when I was looking at the effects way back in my postdoc at glutamate on outgrowth of

dendrites and synapse formation. I discovered that a high-level glutamate would kill the neurons. Okay, that's really important. It overexcites them or something, right? It excites them to death. They cannot, they cannot restore the ion gradients. They keep firing like crazy. Pre-radicals just keep being produced like crazy.

Free radicals damage all the molecules and cell DNA, proteins, membranes. And they can die. And we call that excitotoxicity. So you can demonstrate that in a dish like I found when I was a postdoc. You can demonstrate it in animals, rats, mice, dogs. And we think that's what's... And then the drugs used to treat epilepsy are drugs that quiet down the neurons, either by...

They don't really use glutamate receptor blockers much because they have more side effects with learning and memory. you know, have any problems. But sodium channel blockers, so there's drugs that block the movement of sodium in. So it lessens the depolarization. And then there's other drugs that enhance the GABA, the inhibitory neurotransmitter. Like Valium was one, you know, you and my generation may know about Valium used to treat anxiety. But anyway, so.

neurons can be killed by too much glutamate. That's what's occurring in epileptic seizures. That's what's causing the seizure is too much glutamate, and there's just all this random firing? Okay. Yeah. But also the death of neurons that occurs following a stroke and following a traumatic brain injury,

to some extent that involves overactivity, of glutamate receptors because what happens is when you get damaged to neurons, they they spew out their glutamate. So they have a high concentration glutamate inside. It's low outside. You know, and the only place glutamate should normally be is inside the neurons or the synapse, but not else. But anyway, stroke, traumatic brain injury in animal mouths anyway, if you give the animals drugs that block the glutamate receptors, it can lessen the amount of brain tissue that's damaged and improve the outcome. There were clinical trials in stroke of some of these drugs,

but they didn't pick out in effect. These stroke trials are very hard to do because there's so much variability between individuals in which blood vessel was included, How long was the cloud in the blood vessel? How long did it take the person to get to the hospital? Another problem, and I think one of the reasons for a lot of problems in translating animal findings to humans is, in our animal studies, we generally use genetically peer animals. Yeah.

Humans are not, we have a lot of gene intermixing. And so there's a lot of variability between individuals on, for example, how much brain damage they will have following a stroke. And there's environmental factors that- By the way, just so we clear, the stroke is just an occlusion of the blood, and therefore the energy, you know, get the nutrients and necessary oxygen and causes local kind of brain death, I guess. Yep. Yeah. And when the neurons continue to be excited by glutamate when they're not getting enough energy, that is not going to take it. Okay. And so the point is, yeah, the glutamate, they're still exciting it, but there's no energy. And so, and that's... Exactly. Now, does, so we know that glutamate's related to these issues, these disorders, but do we know what is causing the, in the one case, the excess of glutamate, or as you age, or, or what?

Or do we know what's causing that? Or is that just an observed effect and we don't yet know the causes? Well, with a stroke and traumatic brain injury, we know the cause. Yeah, with a stroke, but yeah. With the epileptic seizure, you know, the ultimate cause, you know, there's genetic factors, there's even developmental factors. Some children will have seizures when they're little, but then they disappear. And, you know, it's, so the answer there is we don't know exactly what's causing this imbalance

between excitatory glutametergic and the gabergic inhibitory that leads to an excitatory imbalance that then starts to cascade out of control and a seizure. Now, I guess we could talk about aging. So with aging, everything goes wrong. tell me about it yeah so there's increased oxidative damage to DNA proteins membranes mitochondria don't work as well as we age and and then there's this process called autophagy which you may have heard of no it's a kind of a cellular garbage disposal and removal system so we have these really elegant systems when there's DNA repair mechanisms.

The removal mechanism removes things like free radicals as well? Yeah, yep, yeah. So there's both removal of the potentially damaging things like free radicals or abnormally aggregated proteins like the amyloid and Alzheimer's, for example. And then there are repair mechanisms. DNA repair is very elegant system where, and that's what prevents us from getting mutations. Our DNA is being damaged all the time by free radicals,

but it's very efficiently repaired. But with aging, with aging that repair efficiency goes down, and that's why aging is a major risk factor for cancers, because cancers are generally caused by a mutation that's not repaired. Oh, I see. And there are other problems that occur, that are more specific. There's a tendency

towards an excitatory imbalance that occurs. Elderly people are more likely to get seizures than middle-aged people or young people. Yeah. We think in Alzheimer's disease, there's a very early excitatory imbalance.

Patients with Alzheimer's disease have about a 30-fold increased likelihood of having seizures compared to someone the same age who doesn't have Alzheimer's disease. Oh, interesting. Okay. So problems with mitochondria means cells maybe can't generate enough ATP with aging, problems with damage and repair systems, and then problems in controlling excitability,

which may be downstream of some of these other generic age-related changes. Okay, now these are all effects and certainly relate. These are, okay, these are the problems. What role, what I want to, since we're talking about glutamate, in what sense is glutamate related to these particular problems? Yeah. Okay. So in most of these disorders, epilepsy, Alzheimer's disease, stroke,

it's glutametergic neurons that die. and at least in the animal models, the neurons seem to be dying because they're being over-excited by glutamate. Okay. And then the other evidence has to do with disease specific, it has to do with Let me interrupt a second. Does that mean that whatever, that there are inhibitory mechanisms that are not operating effectively for the, good, good, good, yes. Thank you. True. Okay. Particularly this has been shown in Alzheimer's disease in particular.

With epilepsy, maybe, it's not quite so clear. With Alzheimer's, very early on, okay, I have to back up just a little bit. These, the inhibitory neurons that use GABA as a neurotransmitter, they are much more active than the glutametergic neurons. So they're firing normally like, crazy and they're firing then inhibits the glutametergic neurons. Yeah, okay. Okay.

And they are loaded with mitochondria, these inhibitory neurons. They have a high, they have a high energy demand. I see. And they also have a high pre-radical exposure load. So they seem, with aging and Alzheimer's disease, they seem to be particularly vulnerable early on. Okay, so you're not getting many mitochondria that are efficient. They're not firing as effectively, and then the inhibitory mechanism is less effective. I got you.

Yeah, the brakes are. The brakes are wearing out. Yeah, they're wearing out. You're going down a mountain and the... Yeah, yeah, they're, yep. The Alzheimer's cascade. Yeah, okay. And then your brakes are failing.

Okay. And that also explains why you're more exposed to. seizures as you get older too. Okay. Excellent. But I should say we did, I've got another interesting anecdote at the time once. Sure, sure. It has to do with Alzheimer's disease. We've done a lot of work trying to understand what goes wrong in Alzheimer's disease. And, you know, others had shown that there's amyloid protein that accumulates in the brain, forms what they're called plaquesies, and spherical deposits and associated with the amyloid neurons degenerate, suggesting some potential cause-effect relationship between the amyloid accumulation

and the damage to the neurons. And then some of my earliest experiments after I got my first faculty position, which is actually at the University of Kentucky, I was there before I went to NIH. Yeah, you're there for a while. the geneticist had identified a family in which a genetic mutation in the gene that encodes for the production of this amyloid protein, that gene had a mutation. And the people who had that mutation, they would get Alzheimer's disease at an early age in their 40s or early 50s, okay, which is unusual. It's usually genetic if it's that early.

And then so the gene was sequenced, and then that means the amino acid sequence of the amyloid was established. And then everybody started, my lab was one of the first. There was a lab Bruce Yankner at Harvard. His lab was actually the first, and then my lab, to show that this amyloid peptide self-aggregates, and when that happens on surface, of neurons, it can cause them to die.

But my main contribution there is I showed that even low levels of this aggregating amyloid can make neurons very vulnerable to excitotoxicity. So if you combine even low levels of the amyloid with glutamate, you can kill. So we think, at least I do, other people in the field now too, that early on in Alzheimer's disease, you know, there's kind of this interplay between the amyloid and the control of excitability of neurons and glutamate and you get to some tipping point and things go downhill fast. Okay, okay, okay, okay. So, okay, let's go from the sad to the positive.

Let's talk about lifestyle and the ultimate. talk about lifestyle and and the ultimate implications. First for in the context of glutamate, for understanding how healthy lifestyles can impact on healthy brain function. And then afterwards, I do want to talk about, because I know from the first time we met, I was, this idea of intermittent fasting as well. So let's first just talk about lifestyle more generally. We've alluded to it already. You've alluded to already that exercise. Anyway, why don't you talk about how you can improve rate function and maintain longevity, etc. For the most part, what's good for the health of your cardiovascular system is good for your

brain health. And that's been established in both epidemiological studies and in longitudinal, including longitudinal studies and in even clinical trials. And so what happens in the brain with exercise is that it's very interesting. There's increased neural network activity. It's kind of a mild, kind of the key take-home message of this is exposure of your brain cells, your muscle cells, your cardiovascular cells to a mild metabolic challenge, metabolic stress, if you will, as long as it's done intermittently and not too much intensity is good for them. and that our cells have evolved what doesn't kill you makes you stronger is that the idea yes it's exactly right that's something called hormesis is another word people used to talk about this

and it's very well established with exercise and your cardiovascular and muscle during exercise it's a huge stress on your muscle cells and they respond in good ways by they become more resistant to stress more resilient and have better endurance and And conversely, if you're sedentary and you overeat, it's bad for everything, including your brain. Even in children. So this is, let's start this way. Obesity is a big problem in developing countries. It started by the United States and marketed elsewhere.

fast food. And there's really good evidence that people with long-term obesity, type 2 diabetes, they don't think as well. Their learning in memory is poor. And this is true, even interestingly, in children. There's been multiple studies showing that middle school, high school, age kids that are overweight, perform more poorly on various tests of learning and memory. And then this is tied into socioeconomic status too, because as you know, in the United States, there are certain regions in the southeast where there's relatively higher levels of poverty. But there's higher levels of obesity, cardiovascular disease,

diabetes, stroke, many cancers. And it's because they have poor lifestyle, diet and lifestyle. And so I think down there, if we could get those kids, and the problem is it becomes transgenerational. Because if a kid grows up in a family that eats junk food all the time and their parents never exercise, they're not challenging themselves necessarily. intellectually all the time. They're more likely to have those habits and then it gets

passed on. Let me step back though. Okay, so it's clear it should, it's I think easy for most people to realize why eating poorly and not exercising doesn't produce the challenges that help your rest of your body, your muscles and other organs function, I guess. But what's the specific impact? Why the brain? Is it, do we know, why, you know, maybe it's poor blood flow. What, what, do we know what the sort of causatory mechanism is to poor brain function from poor lifestyle? That's, it's multiple mechanisms.

One is actually blood vessels because the blood vessels in your brain dislike in your ones that supply to your heart can get atherosclerosis and so on. But there's also more direct effects on neural circuits and even other cells in the brain. three things I can mention. One is, and I haven't mentioned yet, inflammation. Just as occurs in your blood vessels when cardiovascular disease or in your joints with osteoarthritis or in, you know, a lot of cancers, actually, there's inflammation associated with it.

In your brain, with aging and much more so in Alzheimer's, Parkinson's, There's local neuroinflammation that's occurring in the brain. That is suppressed by regular exercise. Also, the cells that are involved in inflammation in the brain, they're called microglia. They're the equivalent of macrophages in the peripheral. And they produce what are called pro-inflammatory cytokines, like tumor necrosis factor, interleukin-1 beta.

And so the regular exercise by affecting signaling pathways in these microglia can suppress their inflammatory properties. Okay, okay. I just wondered if we knew the mechanism. Okay, that's good. And then another mechanism is, I kind of mentioned it. So the exercise will increase production of BDNF, this neurotrophic, factor that's so important for learning in memory and and resilience of neurons under stressful

conditions. I mentioned that. It's a very potent inducer of the gene that encodes that BDNF protein. It's very robust if you measure in animals and it's looked at in cerebral spinal fluid of humans. That's the fluid that bays the brain. It's kind of a kind of a, you can get a kind of a readout of the neurochemistry of the brain in a general sense by doing a spinal tap and measuring these things. But anyway, so that's

the second one, increasing BDNF. And then a third is this increasing number of mitochondria in the neurons. Which then, since the brain needs so much energy, therefore effectively. Okay, no, that all makes sense. It's good to know. Healthy lifestyle, healthy, healthy being fit, not just being visibly fit, but mentally physically fit, but mentally physically fit is an important connection. Now, let's, I want to almost end, not quite, but almost end with this. So how does, so is intermittent fasting the same idea that what doesn't kill you will make you stronger, that by stressing your system by not eating? In general, I know it's a big deal for you, and I know you've written a book about it, and I know.

I don't know, did you get my book? You know what? You never gave it to me when we were together. I didn't say anything. No, I didn't have it. I didn't write it till I retired. Oh, good. Okay. Okay. Then I don't feel so bad. It's new. It came out last year. I know you were implementing it because you talked to me a lot about it together, but yeah. Yeah. And the NIH is funding a lot of studies now on humans intermittent fasting. But the first chapter of my book, similar to the first chapter of my sculptor and destroyer book,

intermittent fasting is an evolutionary perspective. So, during evolution, individuals whose brains and bodies function well in a food-deprived state had a survival advantage. Does that make sense? Sorry, go and run that one by me again? Individuals whose brains and bodies functioned well in a food-deprived state had a survival advantage. Sure, of course. Yeah, that makes sense. Right. So during evolution, our systems,

including our brain, evolved to function well in a food-de-brived state. Okay. So when you're having got food for a long time, you better be able to figure out how you're going to get food, use your brain, and then exert physical exertion to get the food, right? Yeah.

So all our genetic programs and probably beneficial gene mutations, many of them had to do with improving success in getting food and therefore being able to survive and reproduce. So nowadays, we don't challenge our systems that evolve to respond to this challenge of going without food. If you eat breakfast, lunch, and dinner, and one of the key ways things that happens is, evolutionarily is, if you were to stop eating now, during the ensuing 10 to 12 hours, all your cells, including your brain cells, would use mainly glucose, which comes from storage in the liver. But then after 10 to 12 hours, what happens is you no longer have those glucose stores,

and fats are released from your fat cells into the blood, and they're converted to what are called ketones. So this is what we call a metabolic switch from glucose to ketones. So that occurs with going without food for at least 14 to 16 hours. If you exercise in that fasted state, that enhances the elevation of ketones. Ketones, ketogenic diets actually are prescribed for patients with epilepsy. Oh, okay. Interesting. And if you go back to Roman times in some of the writings back then,

when people had epileptic seizures back then, they thought they were possessed by demons. Yeah. Right? They're having convulsions on the ground. And they found if they locked them in a room and leave them for a day or so, the demons go away. Okay. So what's happening, we now know, probably they aren't eating anything.

They throw them in the room without any food. They aren't eating anything. Their ketones go out. Their seizures go away. The demons go away. And so with intermittent fasting, the ketones play an important role in both providing an energy source for neurons.

We and others found that they enhance GABA, the inhibitory neurotransmit. smitter production and release onto the glutamatergic neurons. So ketones do something glucose doesn't do, is what you're telling me? Absolutely. But a lot of it, but there's this thing called ketosis, which is too much of it, right? That's a clinical problem. That's extremely high ketoacidosis, yes.

That happens if you don't eat for a long time, right? Oh, no, you won't get that even if you don't eat for a long time. Oh, okay. No, it's a medical condition, usually caused by problems with liver or other things. So the idea of intermittent fasting is in some sense it enhances ultimately your body has to turn over to ketone production rather than ketone utilization rather than glucose utilization. And ketones for some reason are good because they help with stimulate various aspects of brain function, among other things. Yeah. And there are, so I mentioned with epilepsy, there are, we did a trial, we have the paper submitted, so I can't really talk about the results, except to say we did a trial of intermittent fasting in people at risk for cognitive impairment and Alzheimer's because of their age and metabolic status. They're between 55 and 70 years of age. They have obesity and insulin resistance, but not frank diabetes.

okay and so we randomly assigned them to either an intermittent fasting eating pattern or kind of a regular one breakfast lunch dinner and then at baseline and after two months so baseline before we started them on in two months we did a battery of psychological test focused on cognition but also mood and other things and then we did functional MRI structural MRI. We can actually measure size pretty accurately of certain brain structures. We did spinal taps and took cerebral spinal fluids, so we'll be measuring BDNF. We'll be measuring things like antioxidant things, things that have to do with free radical levels, inflammation markers and so on. I can tell you that there are, effects in a good way of intermittent fasting on the brains.

Okay, and we have to wait for the rest to come out before we'll know. And then there are also clinical trials of what's called a ketone ester. It's essentially the ketone that's produced during fasting, just giving that, you can actually consume it. Yeah. Ingest it and it will increase the ketone in your blood. So are there at least two clinical trials in Alzheimer's patients? going on now. Okay, well that's interesting to see. We'll see what's next. In fact, that's a good way

to get to near the end here. I wanted to, I wanted, this is, as you point out, as the point of this, it was using glute, glutamate as an introduction allowed us to talk about a lot of fascinating aspects of the brain and your own work in it, which are fascinating for me and I think fascinating for people in general. And I've, I've, of course, learned a lot in the process. But what's, but, you know, there are, the future. I mean, we talked about how when you and I first met, we talked about we wanted to run a thing on creativity and madness, but it was we were a little far removed from that. Pattern processing was an early stage of what's talking about. And we've talked about brain function at some basic level and understanding the processes, but we're far away from consciousness.

And, and, but we are developing an AI. I just wanted to ask you to throw out, what's, what's the, what's the future in your mind of understanding ultimately the real questions, people want to know i mean obviously people want to know how to live longer and function better but also you know how how to understand the real things that make us human creativity longing consciousness self-awareness and um and and then to what extent AI might play a role in any of that so it's a lot big question but i'll give you a few minutes to answer well you know that that article i mentioned that i wrote superior pattern processing it yeah i put the word superior in there because where I think we're only better than animals in terms of not necessarily qualitatively, but quantitatively and maybe, you know, often people think, you know, we're way above other animals in so many respects.

I don't think we are. I think language, you know, the evolution of language was a huge, huge factor that propelled us way above. and you can you can pass information down and you can speed up things. You know, things like consciousness, I don't know, how do you define consciousness? Well, that's the problem. If you look at my book, it's, no, I don't think anyone can. You know, I have a podcast, Lawrence,

it's called Brain Ponderings. And I had a number of, I had one on consciousness. It was it with Kristen, I guess. Carl Friston as somebody else. But the key thing there, we're using a human term without really defining, it's like, to me, it's like saying, God, without defining what exactly,

what exactly do you mean? What are the particular characteristics? Yeah, look, I couldn't agree with you more. I mean, again, my friend, Nome Chomsky was saying to me, it's maybe the wrong question, calling consciousness. Yeah. We don't even, it's one of the, one of the most poorly defined terms and one of the most frequently

written about. But let's just talk about even, and let's being less of, less ephemeral. What's the most exciting area of brain research that you think is next? Now, I think this, this, kind of the transition and understanding from now we have a pretty good understanding of learning and memory, at least kind of the basics, you know, two neurons are required and you need glutamate and calcium and all this. But then we know a little bit about short and long-term memory.

What we don't have is this how the brain is taking all sorts of different information, integrating it, processing it in meaningful ways, arriving in a decision, and then, you know, imagination and creativity. and that that's really hard because, you know, we have 100 billion neurons, 100 trillion synapses, and in theory, to really understand that you're going to have to be to know what's going on in many or maybe even most of those.

Yeah, that's the problem. It's a comp, as I told, as I've said so often, that's why I do physics, because it's so much easier. So have you secured a seat to Mars yet or the moon? No, I'm not, I'm not, no, I'm not, I'm happy right here. I'm not going to. I mean, actually, the moon I would like to go to Mars. I have no interest in handing to, especially so I know it's a death sentence. But, no.

You know, Lawrence, whenever I, a lot of times at night, you know, I lay in my bed with a Kindle and you know I have a look at the latest James Webb images and this kind of lay there

for a few minutes and you know just kind of soak it in and think about how insignificant we are but yet how amazing it is. How amazing it is. Those are the things

and think about the brain and the universe together are the two things that make me realize how amazing and insignificant we are at the same time but you just convince you just it's a wonderful

way to end because it just occurred to me that James Webb Space Salscope is good for health and brain function because it causes us to think about lying bad and think about things, use exercise, those neurons. And that's what's great about thinking and being a human and being inspired by science. And the science you're doing is inspiring. And I appreciate you taking the time to not just write the book, but spend time with me. It's been a lot of fun. And I look forward to more good things. So thanks again. It's really great to see you again. Thanks. You're welcome, Lawrence, and thanks again for T-U. I hope you enjoyed today's conversation.

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