Nutrition in Neuroscience Part 1 | Mastering Nutrition #53Randall Smitham November 9, 2019 14 Comments
This is Dr. Chris Masterjohn of chrismasterjohnphd.com, and you’re listening to Episode 53 of Mastering Nutrition. Today launches off a four-part series of Nutrition in Neuroscience. This is a Mastering Nutrition with Chris Masterjohn. Take control of your health, master the science, and apply it like a pro. Are you ready? Nutrition in Neuroscience. This is not a comprehensive introduction to neuroscience, and it’s not a comprehensive guide to every single role of a nutrient in neuroscience. What it is instead is a safari with me as your tour guide into the world of the leading neuroscience textbook, the 6th edition of Neuroscience, published in 2018 by Purves and others, where I as the tour guide point out all of the different things that connect to nutrition. In some cases I’m pointing out the things that are mentioned in the textbook as relating to nutrition. In other cases I’m connecting it to things that I’ve done research on or that I’ve studied outside of the textbook that I know have nutritional implications. So if you imagine if I was giving you— if you were taking a tour through New York City, the tour guide might point out things that you’re seeing and draw your attention to the key features, that would be like me pointing out things that the textbook talks about relating to nutrition. But the tour guide might tell some stories about things that had happened in those places, or about historical figures, or about all the different things that you’re not seeing before your eyes that relate to the place that they’re pointing out to you. That would be like me saying this textbook talks about such and such in a neuron. I can relate that from my research outside this book to all this stuff that’s nutritionally relevant. Some aspects will be practical. Some of them will just be brainstorming. I might point out that a nutrient is really important in some part of the nervous system, and there might not be any studies on what happens to that particular behavior, or that particular sensation, or whatever it is, if you give that person a nutrient or if they’re deficient. So this isn’t a guide about what to do. It’s a very grand tour about pointing out all the things that are. And, of course, what are has to be amazing in the connections between nutrition and neuroscience because everything that’s in your body, including everything that’s in your brain, is either something that you ate or made from something you ate, or maybe in some cases in the brain, made from something that your mother ate when you were inside her womb. So, nutrition just has to be richly related to neuroscience. Over the course of this four-part series, you will see things like the basic cells of the nervous system, how they operate and how that’s critically important to nutrients like sodium, potassium, chloride, magnesium, and calcium. I’ll look at all the major neurotransmitters and their roles, the nutrients needed to make them, the nutrients needed to control where they go and to break them down and clear them. The five senses, and the critical importance of vitamin A, salt, potassium, and calcium in perceiving those senses. The difference between your sense of touch and pain. Nutritional strategies to manage pain. Why hot peppers as far as your nervous system is concerned are literally hot and how the capsaicin in those peppers can be used to manage pain. Why anorexics might crave hot foods literally to get the perception of heat that their body is missing. The role of dopamine in the basal ganglia in all your subconscious calculations of value. Seeing Parkinson’s and the loss of movement that occurs in Parkinson’s as a loss of the subconscious calculation of the value of investing energy in controlling your movements and moving. How that is just the same process in a slightly different combination of neurons where dopamine is also signaling the value of focusing on your work, or the value of transitioning between being happy and being sad, or the value of investing effort for an extended period of time to get a reward in the future. How GABA in food and supplements can interact with this system to actually make you quicker at choosing tasks under pressure even though you think of it as an inhibitor. Why would it help you react quicker? We answer that question. The sympathetic and parasympathetic nervous systems, their relationship to the spine. Potential relationships to tightness in the spine. How the different nutrients that impact acetylcholine and norepinephrine levels might affect the balance between your fight-or-flight response and your rest- and-digest response. The role of histamine in wakefulness and panic. The role of choline in wakefulness and REM sleep. The role of the circadian rhythm in preventing you from waking up to pee. Why you can never use supplemental melatonin to mimic your body making its own melatonin at night. How nutrients and neurotransmitters might help you form memories and might help you get rid of memories that you don’t want, like conditioned fear responses to things that you shouldn’t be fearing. All of that and much more over the course of this four-part series. In this part, part one, we focus on the two basic cells of the nervous system: neurons and glial cells. Their basic functioning. How neurons transmit information from one place to another, and the critical importance of nutrients like sodium and chloride that you get from table salt, potassium that you get from potassium-rich foods, calcium, magnesium and all the B vitamins important in energy production, and energy production itself, which is dictated by other important things going on in the body, like your thyroid hormone and your insulin status. How all of this affects the basic ability of a neuron to transmit information from one place to another. The origin of this series is actually that as I was making lessons for Masterclass with Masterjohn on the ketogenic diet and how it helps epilsepsy, I just started digging into how epilepsy works, and I realized that I really needed a better foundation in neuroscience to make these lessons. As a result of putting all this work into acquiring that foundation, it’s been taking me forever to get the Masterclass with Masterjohn lessons out. You may have noticed that very little has come out out this year. In the meantime, I have some very, very patient MWM Pro subscribers who have access to all the content and the premium features that I’ve been putting out for these lessons, but haven’t been getting any new content recently. So while MWM classes will be coming out soon, I’ve realized that I really should change the nature of what I’m offering with MWM Pro, so I’m going to rename it something like Masterjohn Master Pass. And it’ll be an all-access pass to number one, content as soon as it’s produced, oftentimes weeks or months before it comes out; number two, all that content will be ad-free; and number three, transcripts and other ease-of-use functionality features will be part of the premium features with this Master Pass. So, this four-part series will come out with the ads for free once a week over the next four weeks, but if you want all of it now, ad-free and with transcripts, you can go to chrismasterjohnphd.com/pro, and you can get a big discount with the code masteringnutrition. Without further ado, let’s hear a word from my sponsors and then dig right in. This episode is brought to you by US Wellness Meats. I discovered this company at Paleo FX this spring, and I fell in love with them as soon as I tried their liverwurst. For years I’ve known that I feel best when I eat a diversity of organ meats like liver and heart. I have a clearer mind, I feel more energetic, and my energy is much more stable between meals. But it’s so hard and so time-consuming to make a sustainable habit out of preparing and cooking organ meats. US Wellness liverwurst is 15% heart, 15% kidney, and 20% liver, with the remainder grass-fed beef. That’s a whopping half organ meat. It takes zero time to prepare, tastes great, and finally makes consuming a diversity of organ meats a habit that I can easily sustain. But just because I’m obsessed with their liverwurst doesn’t mean it’ll turn out to be your favorite. US wellness makes an even milder Braunschweiger, that’s 35% liver, and 65% beef. And if you have a really sensitive palate and just want to get your feet wet with organ meats, their head cheese delivers the mildest taste with 15% heart, 15% tongue, and the remainder beef. They also sell an incredible array of other meat products in practically any cut you could want all from animals raised on pasture. Now, this isn’t just about high quality grass-fed meat products that can up your nutritional game and save you time in the morning. It’s also about saving money, and that’s because I worked out a special deal for you. 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This episode is brought to you by Ancestral Supplements. Traditional peoples, Native Americans, and early ancestral healers believed that eating the organs from a healthy animal would strengthen and support the health of the corresponding organ of the individual. For example, the traditional way of treating a person with a weak heart was to feed the person the heart of a healthy animal. Modern science makes sense of this. Heart is uniquely rich in coenzyme Q10, which supports heart health. The importance of eating organs though is much broader than simply matching the organ you eat to the organ you want to nourish. For example, natives of the Arctic had very limited access to plant foods and got their vitamin C from adrenal glands. Vitamin C is important to far more parts of your body than simply your adrenals. In his epic work Nutrition and Physical Degeneration, Weston Price recorded a story of natives who cured blindness using eyeballs, which are very rich in vitamin A. But now that we understand vitamin A, we know that we can get even more vitamin A by eating liver, making liver good for your eyes. Our ancestors made liberal use of organ meats both to be economical and to utilize their healing and nourishing properties. Animals in the wild do the same. Weston Price had also recorded a story of how the zoos in his era were capturing lions, tigers, and leopards, oh my, only to watch them become infertile in captivity. Researchers then observed what the lions did when they killed zebras in the wild. What they did was they went straight for the organs and bone marrow, leaving the muscle meat behind for the birds, but even the birds took what they could of the organs and bone marrow. Price reported that once the zookeeper started feeding the animals organ meats, boom, their fertility returned. The problem I often encountered though is that many people just don’t like eating organ meats. Let’s face it. If you weren’t raised on them, it can be very hard to acquire a taste for them. That is where Ancestral comes in. Ancestral Supplements has a nose-to-tail product line of grass-fed liver, organ meats, living collagen, bone marrow, and more, all in the convenience of a gelatin capsule. For more information or to buy any of their products, go to ancestralsupplements.com. Ancestral Supplements. Putting back in what the modern world has left out. And now begins our safari. The primary type of cell in the nervous system is the neuron. And the neuron is primarily tasked with transmitting information. Really, the nervous system is a giant information network. That neuron has three major parts. It has dendrites, which are information in, it has the cell body involved in information processing, and it has the axon, which is information out. Quite often, the dendrites can be highly branched, but they don’t have to be. Quite often, the axon can be very minimally branched and very, very long, but it doesn’t have to be. The key thing here is the dendrites are the information-in end, and the axon is the information-out end. Neurons often make synapses, connections to other neurons, sometimes to many, many thousands of neurons. And those synapses generally involve the axon almost connecting to the dendrite of another neuron, not quite touching it, but getting so close that signals such as chemical neurotransmitters can jump from one neuron from the axon terminal to the other neuron entering into the dendrite. The second type of cell in the nervous system is the glial cells. There are a few different types of glial cells, and they are the assistants of the nervous system. They assist neurons in transmitting information and especially assist neurons with their energy metabolism. They’re involved in clearance of metabolic wastes, especially during sleep. They are involved in synthesizing the myelin sheath that insulates some axons and not others, and those axons that are covered in the myelin sheath made by these glial cells are—the function of the myelin sheath there is to make the transmission of information much, much faster down the axon. Glial cells also participate in growth and repair processes. One of the first things that this textbook Neuroscience does is introduce us to the different types of cells and talk about the importance of polarization. Polarization means separation of one end and the other. We think of the North and South Pole of the earth; they’re on opposite sides. We might think of polarization in other kinds of things, like magnets, for example, where one side—similar sides repel each other, opposite sides attract. Polarization of electric charge into positive and negative does the same thing. Positive and negative attract each other, similar charges repel. In the case of the cells of the nervous system, polarization is not about repulsion and attraction. Polarization is about functional specialization. You want one part of the cell to do something very different from the other part of the cell. And we can think of, in our economy we have division of labor, which dramatically increases the amount of efficiency and wealth that we have. Well, in the economy of the nervous system, we have functional specialization to achieve the same efficiency and productivity. When you have a polarized cell, that has some implications for nutrition. The Neuroscience textbook does not talk about them. It does talk about examples of polarization, but it doesn’t really talk about the nutritional implications, so I will here. One of those implications is creatine. We think of creatine as primarily involved in supporting athletic performance and bodybuilding because those are the people that we really see supplementing with it. But creatine is important to any cell that is polarized, and that’s because creatine is a source of energy, like ATP, but it travels through space far faster, orders of magnitude faster than ATP does. So, let’s take an example of the polarization of a neuron. Well, one of the examples that they give is that typically you will have mitochondria located at the synapses, the connections between two neurons, and not in the other parts of the neuron, whereas you’ll have the machinery involved in synthesizing proteins in the other parts of the neuron but not at the synapses. Well, that makes sense because at the synapse, what you want is to be able to— typically what you want is to be able to release neurotransmitters into that space between the neurons, called the synaptic cleft, so you can transmit information from the axon of one neuron to the dendrite of another. But to control the release of neurotransmitters, you want to use calcium as a signal, and in order for calcium to be a very valuable signal, you have to concentrate calcium away from the space where it acts as a signal, and so you lock it in these tight compartments, or you push it out of the cell, but whenever you want to concentrate something, you need energy. That relates back to the second law of thermodynamics, which stated one way says that everything in the universe wants to maximally spread itself out. And so if you want to concentrate something, you need to invest energy to go against that natural tendency of everything to spread out. So, to concentrate calcium to be able to use it as a valuable signal is energy-dependent. You want energy, you need mitochondria. Why? Because mitochondria are the powerhouse of the cell. Repeat that with me. Mitochondria are the powerhouse of the cell. Mitochondria are the powerhouse of the cell. Okay, enough of that. Now, you also need to release neurotransmitters into the synaptic cleft, but those are signals, and so they need to be scarce, except when you want to communicate that signal. How do you make them scarce when they’re not communicating that signal? You need to concentrate them. What happens when you want to concentrate something when the second law of thermodynamics says everything wants to spread out? You invest energy. So that again requires energy. That again requires mitochondria, the powerhouse of the cell. The powerhouse of the cell. So, you want your mitochondria at the synapses, and you don’t want the mitochondria elsewhere just for the sake of division of labor. In other words, why would you have protein synthesizing machinery down there when what you really need is all that mitochondria making all that energy. So you put the protein synthetic machinery somewhere else, but when you do that, you still need energy to get over there because synthesizing proteins, like building up anything else, requires an investment of energy. So, if the mitochondria are on one end, and the protein-investing machinery are on another end, you’re going to need creatine to go back and forth and shuttle that energy. Because, again, creatine is really good at moving through space, and ATP is not. ATP is awesome at being used for energy, and it really sucks at moving around. So, creatine allows you to transport energy quickly in a cell where the ATP production is highly polarized, like in a neuron. Another example would be a specialized neuron called a photoreceptor that is in the retina of your eye. The photoreceptor is involved in transmitting light to the brain to create vision. And that photoreceptor is generally transmitting a signal communicating darkness most of the time, and then when it gets struck by light, it shuts off that darkness signal, and then later in your brain, all these signals are going through the optic nerve into the centers of your brain that synthesize all that information to create a visual picture. Now, in that retina you have a very long, highly polarized cell. And on one end, you have in darkness an ATP energy-dependent process of communicating darkness to the brain that is the default state of that photoreceptor. When it gets struck by light, that ATP-dependent process on one end shuts down, but for light to come in and be transmitted into a signal that shuts it down on that end, that requires ATP on the other end. So we have this very long, highly polarized cell that has extremely energy-intensive processes going on in one end in darkness, and then those extremely energy- intensive processes are going on in the opposite end when struck by light. So, a really inefficient solution to this process would be to put the mitochondria on both ends. And then sometimes the mitochondria just sort of shut down on one end, and the mitochondria on the other end start up, and then the opposite happens. So, that’s super inefficient because now you have a bunch of— you’re sort of doubling your need for mitochondria by having them on both ends, but you’re only using those mitochondria some of the time on one end and some of the time on the other end. That’s inefficient and stupid. Not only are you not making efficient use of the mitochondria, but you’re taking up space that you really want to be taken up with the light transmission machinery. Right? So, you put the light and darkness transmission machinery in the ends and the mitochondria in the middle. Now, how do you get the energy back and forth between the mitochondria in the middle and the ends? Creatine. This is why in the several hundred people in the world who have genetic defects in the ability to synthesize creatine, one of the most striking things you see about them are neurological problems, like severe speech impediments, hyperactivity syndromes, and autistic-like behavior, sometimes epilepsy. But more broadly for regular people, creatine supplementation has not only been shown to improve athletic performance or the size of your muscles in bodybuilders, it’s also been shown at 5 grams a day to mitigate depression in women diagnosed with major depression. And that probably to some extent reflects the role of creatine in supporting the energy metabolism of the nervous system. To get creatine from foods, you’re looking at meat, poultry, and fish. There is very little creatine in dairy, eggs, and shellfish. There is none in plant foods, and there is very little creatine in organ meats like liver, heart, and kidney. So, we’re talking about muscle meats, and that does include the muscles of fish, talking about fin fish but not shellfish. We can make creatine ourselves. Now, given that people involved in athletic performance take creatine to increase their muscular creatine by about 30 or 40 percent, and given that creatine supplementation has been shown to help women with depression, it’s clear that either we don’t synthesize creatine enough to get the optimal amount, or most of us just don’t have our nutrition dialed in correctly to synthesize the amount that would optimally support our mental and physical health. Either way, I think it’s best to consume a diet that has creatine in it and to also eat all the nutrients that support your own creatine synthesis, and if you have a valuable reason to do so, especially if you’re an athlete, but maybe if you have depression or you have anything else that might be helped by it, to supplement with creatine, which is pretty harmless. In terms of synthesizing it yourself, you need to get enough protein, and you need to get the nutrients that support a process called methylation. I won’t go into either of these here in great detail. Rather, I will link in the show notes to a podcast I did specifically about creatine, and to a database that I made about creatine in foods, and to a big resource page on everything you need to support the methylation system. But briefly here, I would say, to get enough protein, you’re talking about getting a half a gram to a gram of protein for every pound of body weight, unless you are overweight or you’re trying to build muscle, in which case instead of using your actual weight, I would use your ideal body weight. And then for glycine, you’re mainly getting glycine from collagen-rich tissues, like skin and bones. So if you’re eating, let’s say you roast a chicken, you are getting most of your protein from the actual meat, but if you eat the skin, that’s where your glycine is coming from, and then some of the smaller bones, you can gnaw the ends off of them, and you can actually eat the ends of the bones, and you’re getting glycine from that, and then if you take the bones, and you make bone broth where you boil it down to— you make a bone stock that you boil down to turn into sauces or gravies, you’re getting glycine in those. You can also supplement with gelatin, hydrolyzed collagen, or glycine itself to get glycine. And then for the nutrients that support methylation, you especially want folate, vitamin B9, vitamin B12, and choline. Folate is found in liver, legumes, and leafy greens, the three L’s, as I like to say. B12 is found in animal products, especially liver and shellfish, especially clams. And choline is found most abundantly in liver and egg yolks, and to a lesser extent in meat, nuts, and cruciferous vegetables, like broccoli and kale. A closely related compound called betaine can substitute for some of your choline, and you primarily find that in beets, wheat germ, and spinach. Now, for exactly how to manage all of this stuff like how much should you get and what ratio and this and that, the three pages that I just mentioned that are linked in the show notes on creatine and methylation will answer all those questions. Another implication, another nutritional implication of the polarization in the nervous system cells is the polarization of the astrocyte and of the obligate need for glucose in the brain. Now, normally, typically, glucose is the main fuel of your brain, and you go through about 120 grams of glucose a day on average just in the brain. But when you’re fasting, or if you go on a ketogenic diet, which is a high-fat, low-carbohydrate diet where your brain is not getting glucose in anywhere near 120 grams a day, then your brain will start running on ketones, which are breakdown products of fatty acids. When your brain runs on ketones, a lot of its energy can run on ketones, but even in complete fasting or on a ketogenic diet, the brain has an obligate need for glucose that won’t fully go away. And the reason is that astrocytes often have like star-shaped projections, and in these projections that come off of them, they are very often thin and branched, and they don’t have room for mitochondria. Now, you could say, well, they’ll just get their energy from creatine, but actually their choice is to run on anaerobic glycolysis, which is a process where you partially burn glucose for energy to generate ATP, and you generate lactic acid, or lactate, as a byproduct. Probably the reason for this specific choice is that the astrocyte often delivers lactate to the neuron that it is assisting, and the neuron uses that lactate to fulfill a number of purposes, including antioxidant defense and helping energy metabolism run in ways that it can’t do with ketones. So, probably since the neuron benefits from that lactate being delivered to it, then the sensible choice for the astrocyte to deal with the fact that in these projections it just can’t fit the mitochondria it needs for energy metabolism, the simple choice is to run those projections all on anaerobic glycolysis. And that is about 5 to 15 percent of the brain’s energy metabolism that just has to have glucose no matter what, and that’s why even in extended fasting or on a high-fat, low-carbohydrate ketogenic diet, you will need 25 to 30 grams of glucose to be consumed in the brain. And if that doesn’t come in in the diet, it’s going to be made through a combination of fat and protein in a process called gluconeogenesis, where mainly the liver, and to some extent the kidney, and maybe to a very tiny extent other tissues, are synthesizing that glucose from non- carbohydrate structures that you consume, protein and fat. Now, if you’re not on a ketogenic diet, then you do not have your glucose requirement of your brain go down from 120 grams to 25 to 30 grams. Your glucose requirement in your brain is going to be about 120 grams. And so I do think that for some people, if they restrict their carbohydrates, but they don’t go low enough, they might find that they, that they just don’t, that they’re in kind of a soupy, goopy gray space where they’re not fuelling their brain properly. And I’m not saying that necessarily happens to everyone, but if you are not going full keto, then you do need to be mindful of the fact that your brain is going to be really hungry for that 120 grams of carbs a day, and if you don’t give it to it, then things might start slipping in there. Since gluconeogenesis makes glucose partly from, and necessarily partly from protein, you need either the protein to come in your diet, or you need to break down your muscle tissue to get that protein. If you’re on a ketogenic diet, then it makes sense to focus on still hitting the basic protein requirements so that you’re not forced to get that protein from your muscle tissue. If you’re completely fasting, it may make sense to consume just a little bit of glucose, 10 to 20 grams, just so you can get that obligate need and rely less on breaking down your muscle tissue. Gluconeogenesis is also tightly associated with the stress response. So, aspects of your nervous system that initiate fight-or-flight response, as well as the adrenal hormones involved in the fight-or-flight response, are generally the things that make you engage in more gluconeogenesis. If you’re in a fight-or-flight response, you can imagine that’s because you want more glucose than normal to get to your brain to help you fight or to help you engage in flight to run away. But in the case of glucose deprivation, you need to engage in gluconeogenesis to get your glucose supply up to normal. In both cases, you may see elevations in the stress response, and if you’re on a ketogenic diet, it may be the case that you can get by best actually consuming 20 or 30 grams of carbohydrates a day if your ketogenic diet allows it because that amount of carbohydrate will minimize the need to make it to get that into the brain for fuel. Okay. Chapter 2 of Neuroscience gets into electrical signaling. Now, the main way a nerve cell knows what’s going on, whether it’s at rest, whether it’s being inhibited, whether it’s being stimulated, is the separation of charge across its membrane. So, imagine this beginning with the membrane of a dendrite, the information in point. Typically across that membrane you’re going to have a separation of charge, and we’re not talking about the difference between inside the cell in general and outside the cell in general, we’re talking about the immediate vicinity of that membrane. And you’re going to have the inside, the immediate inside, is going to be more negative than the immediate outside. And we express that difference in the inside relative to the outside. In other words, because the inside at rest is more negative, we refer to the membrane potential, by potential we mean the difference in charge on one side versus the other, as negative. And we measure it in millivolts. Typically the resting membrane potential is -40 to -90 millivolts. Again, that’s telling us the degree to which the inside is more negative than the outside. The main contributors to the resting membrane potential are salt and potassium, the overwhelmingly major electrolytes. Chloride is the major negative ion, regardless of whether we’re talking about the inside or the outside. Sodium is the major positive ion on the outside. Potassium is the major positive ion on the inside. Generally the way communication reaches the dendrite of the neuron is for some receptor in its surface to be stimulated. Quite often, the initial input is a sensory receptor. That has to be the case for all of our senses. We already talked about light coming in to the eye and reaching the retina. In that case, it’s light that’s interacting with the receptor. For our other senses, the same is true, and we’ll talk about those more later. But then internally we have these circuits, where that sense may be transmitted into the central nervous system, and then there are synapses to many other neurons. So, apart from those sensory receptors, we also occasionally have electrical receptors, where electric charges are directly interacting, but most of the time, we have chemical receptors, where a chemical neurotransmitter is the thing that’s interacting with the receptor. In all cases, what the interaction with the receptor does, the way it communicates information, is to change the charge differential across that membrane, to change the membrane potential. So, if the resting membrane potential is some given amount, usually -40 to -90 millivolts, the receptor potential, the potential once, whatever it is has interacted with the receptor in the membrane, is a new potential that carries some information. And that potential could get more negative or less negative, and that’s going to determine whether that neuron gets activated in some way, which we would call excited. To excite the neuron, you depolarize it by opening a sodium channel, usually. Remember, sodium is the primary positive charge outside the cell. If it’s concentrated outside the cell, as we said before, the second law of thermodynamics says that everything wants to spread out. So, if you open a sodium channel in the membrane, you allow that sodium to spread out and even out. That means that if there’s more outside the cell, then opening that channel will allow it to flow inside the cell. That makes the outside less positive than it had been. That makes the inside less negative than it had been. That reduces the separation of charge across the membrane and depolarizes the cell. Does that excite the neuron? It all depends on a third term, the threshold potential. That neuron will have its own threshold of depolarization that you must reach in order to excite it. So, you could depolarize the neuron, but not enough. You didn’t reach the threshold potential, nothing happened. Or you could depolarize the neuron to reach or exceed that threshold potential, and then, boom, the neuron’s excited. On the flipside, if we want to inhibit the neuron, we will hyperpolarize the membrane, and we mainly do that by opening a chloride channel. Remember that chloride is the main negative ion. Generally, most of the time, there’s more chloride outside the cell than inside the cell. So if we open a chloride channel, the chloride will flow from outside to inside. That will make the outside even more positive than it had been because negative charge is leaving, and it will make the inside even more negative than it had been because more negative charge is coming inside the cell. That exaggerates that charge differential. It takes it from polarized to hyperpolarized. And hyperpolarizing doesn’t actually do anything to the neuron. It just makes it harder to achieve depolarization. So you can imagine that a neuron may have multiple inputs. If some of them are hyperpolarizing the membrane, thereby inhibiting it, then you’re going to need more of the depolarization signal to reach the threshold potential. So if you depolarize past the threshold potential, boom, something happens. If you hyperpolarize, nothing happens. But because it’s hyperpolarized, it’s harder for other things to make something happen. So we can talk ’til the cows come home about neurotransmitters and what they do, what happens when X affects a receptor, but none of that is really meaning anything, unless, a) we have enough sodium, potassium, and chloride, and b) the sodium and chloride is primarily outside the cell, where it’s supposed to be, while the potassium is primarily inside the cell, where it’s supposed to be. Because if it’s not arranged in that way, and you open the channel by interacting with the receptor, then opening that channel doesn’t do what it was supposed to do, and you’re not going to have the desired effect on the neuron. So how do we get enough sodium, chloride, and potassium? Well, sodium and chloride is salt. It’s table salt. It’s what—the salt that you put on your food. So I think the best way to get enough salt is to obey your instincts and salt your food to taste. Now, it is the case that sodium can rise blood pressure in some people, chloride as well. And so I’m not saying that everyone always needs to eat more salt, but when salt raises your blood pressure, usually it’s because you don’t have enough of the other minerals involved in regulating your blood pressure. Chief among them is potassium, and also to some extent calcium, and magnesium, and maybe some others. So, rather than restrict salt, first I would optimize your intake of potassium and the other minerals to see if you actually need to restrict salt to normalize your blood pressure, but blood pressure is extremely important to health, salt can raise blood pressure, so if your blood pressure is elevated, and you have a problem with that, don’t exclude the standard advice about restricting sodium. But if you don’t have high blood pressure, or if you can optimize your blood pressure without restricting salt, then salting your food to taste makes a lot of sense because if you don’t have enough sodium and chloride in your nervous system, it’s not going to run right. And in fact, decreasing cognitive performance is one of the main concerns about the side effects of excessive salt restriction. Potassium is harder to get because we don’t have a craving for it like we have for salt. Our craving for salt is not something wrong with us. It’s not something addictive. It’s something that is hardwired into our physiology because it’s so important. But our distant ancestors, most of our ancestors, lived at a time where they had to go out of their way and do work to get salt, but they did not have to go out of their way to get enough potassium. Potassium is found in fruits and vegetables, and to a lesser but very significant extent in legumes and potatoes, and to a significantly lesser but still meaningful extent in whole grains. It’s also found in animal products in the lean portions, not the fatty portions, so egg yolks, the lean portions of meat, but it’s easily lost during cooking. If you’re cooking meat in a pan, you’re probably losing a lot of potassium into the cooking water, but if you stew that meat, or if you collect the liquids and consume them, or if you’re cooking it in a way that doesn’t result in loss of the juices, then that meat can be a very important source of potassium. Our distant ancestors, almost all of them were surrounded by foods like meat and low-calorie, high-potassium fruits and vegetables. And when they did eat legumes and grains and potatoes, they were eating smaller amounts, and they were eating them in their whole state, not in the highly refined state. Flip forward to today, and we are consuming a very large amount of refined grains. So, if you’re eating flour products, that enriched white flour, it’s not enriched in potassium. It’s lost most of its natural potassium. And it’s so easily available that it’s displaced the legumes, and the potatoes, and the fruits, and the vegetables. And it’s so easy to eat and get our calories in, and it’s so easy to make into pastries and other processed foods that are highly palatable that work on all those centers of our brain to make us eat more of them because it’s rich in all those things that we didn’t have in the distant past. So, we’re driven to consume things like sugar, flour, and salt because calories were limiting in our distant past. Because salt was limiting our distant past. And not only are we not driven to consume potassium because it was so abundant in our distant past, but all these highly palatable, flour-based foods are displacing the potassium from our diets. So, salt to taste is easy, but to get enough potassium, you actually have to try. And there’s basically three ways to do that. One is to go along with the government’s recommendations of five to nine servings of fruits and vegetables per day. If you do that, and you just diversify the fruits and vegetables— yes, bananas can be part of that, but eating a banana a day will not give you enough potassium. Five to nine servings of mixed fruits and vegetables per day will probably give you enough potassium. That’s one way. Way number two: if you’re not going to eat fruits and vegetables, you really have to eat a low-fat diet, and you have to minimize the amount of grains in that diet. So—and I don’t really recommend low-fat for everyone. I think there’s value in fat, but the thing is, when you cut out those big potassium sources of fruits and vegetables, then suddenly it matters that most of the potassium in milk is in the skim milk portion, and if half the calories are coming from the fat, it’s displacing that. Suddenly it matters that most of the potassium in an egg is in the white in contrast to most of the other nutrients. Again, I don’t recommend not eating the yolks because they’re important sources of other nutrients. But if you’re not going to eat fruits and vegetables, then suddenly it matters that if you just eat egg whites, you’ll get way more potassium than if you eat whole eggs. Suddenly it matters that if you’re adding olive oil to your food, I don’t care how healthy olive oil is, there’s no potassium in it. So if you’re taking up a bunch of calories with fat, you’re not going to get enough potassium. If you eat the five-to-nine servings of fruits and vegetables a day, then you can get away with eating the fat in those foods, and that’s probably better in most cases, particularly in the case of consuming the natural fats in the foods, especially in egg yolks. The third way is that if you are eating a high-fat, low-carbohydrate diet, then you really need to emphasize some of the foods that have the highest potassium-to- carbohydrate ratio. On nutritiondata.com, you can sort foods by their nutrient profiles, and you can search for the foods that are highest in potassium and lowest in carbohydrate, and that’s one way to find those. And I detailed all these approaches to potassium in my Testing Nutritional Status: The Ultimate Cheat Sheet, and you can get a copy of that at chrismasterjohnphd.com/cheatsheet, and you can also use the code MASTERINGNUTRITION to get $5 off. Now, let’s assume that we have all the sodium, potassium, and chloride that we need. Well, we still have to make sure that the salt is outside the cell and the potassium is inside the cell. How do we do that? We do that with, number one, the sodium-potassiaum ATPase, also known as the sodium-potassium pump. That pumps out three sodium ions out of the cell for every two that come into the cell. Well, what do we have to do when we’re trying to concentrate something on one side of a membrane and something else on the other side? We are working against the second law of thermodynamics that says everything wants to spread out, and so we need to use energy. That’s why this is a sodium-potassium ATPase. For every three sodium pumped out and two potassium pumped in, you use energy from ATP. Because you invested energy in concentrating sodium on the outside and potassium on the inside, you can actually use energy by releasing the potassium back to the outside or releasing the sodium back to into the inside. And so to get the chloride outside, you use the potassium-chloride transporter which uses the energy released from bringing potassium back out in order to transport chloride to the outside of the cell. Now, you’re not bringing as much potassium out as you’re bringing in, so this potassium is still concentrated on the inside, but you’ve used enough of the energy in that potassium gradient to bring chloride out of the cell. Now, even though the potassium-chloride transporter doesn’t use ATP, it used the energy in the potassium gradient that was created with ATP. So this entire edifice, this entire arrangement, all depends on the energy from ATP. This is one of the reasons why you want those mitochondria to be by the synapse. Well, what does that need for ATP imply for nutrition? First of all, every time you use ATP, I don’t care where it is or what it’s for, you’re using magnesium because every time you see the reference to ATP being used for something, what you mean is that ATP-magnesium is being used. The magnesium is bound to the ATP during that process. So magnesium is important. The B vitamins involved in energy metabolism are important. That means thiamin, vitamin B1; riboflavin, vitamin B2; niacin, vitamin B3; pantothenic acid, vitamin B5; vitamin B6, pyridoxine or pyridoxal; and biotin, vitamin B7. Iron, copper, and sulfur are also directly used in the production of ATP. You need enough oxygen, which means that you need to prevent anemia because your red blood cells and their hemoglobin need to carry that oxygen throughout your body. And preventing anemia means you need to have enough iron, that’s well known, B6, B12, folate and copper. Folate and B12 are a little bit well known. Copper and B6 are often neglected. There are very rare disorders of energy metabolism that would compromise the ion distribution at these nerve cells, but perhaps more common disorders of energy metabolism, like hypothyroidism or insulin resistance, might compromise the utilization of energy and therefore compromise the distribution of ions even when you have enough salt and potassium. Rather than going through in detail how to get every single one of these nutrients, which will make this podcast way too long, I’ll direct you first to Testing Nutritional Status: The Ultimate Cheat Sheet. Again, chrismasterjohnphd.com/cheatsheet. Use the code MASTERINGNUTRITION for $5 off. Or, for most of these nutrients, not all of them, I’ve done previous episodes of Mastering Nutrition for the long-form content, or short episodes Chris Masterjohn Lite for short snippets of how to get enough of these nutrients, and I will link to all of them in the show notes. If and when the neuron is excited, that initiates an action potential that travels down the axon. The action potential again depends on these same major ions, although in this case we’re not looking at chloride, but we are still looking at sodium and potassium. The action potential features two important channels. One is the voltage-gated sodium channel, and the second is the voltage-gated potassium channel. The voltage-gated sodium channel allows sodium to come in. It depolarizes the adjacent part of the membrane,. It opens when its part of the membrane is depolarized very quickly, and under sustained depolarization, it will inactivate, meaning not only is it not open, but it can’t be opened. When the membrane is repolarized, that puts the voltage-gated sodium channel back into its closed position, where it is not open, but it can be opened. The voltage-gated potassium channel allows potassium to go out. It causes the effect of repolarizing the membrane. It opens to depolarization, but much more slowly than the voltage-gated sodium channel does, and it closes upon repolarization just like the voltage-gated sodium channel does. So the basic sequence of the action potential is that depolarization, initiated by whatever happened up at the dendrite that we were just talking about, depolarization activates the sodium, the voltage-gated sodium channel. Sodium comes in. That channel depolarizes the nearby area of the membrane, the adjacent spot. That activates the adjacent sodium channel, letting sodium in, depolarizing the membrane at that position. There’s a lag where the potassium channel hasn’t done anything yet, but during that lag, the sodium channel from the first position inactivates because of the sustained depolarization. And that inactivation is important because that is what makes it so that the action potential can only go forward. Imagine the sodium channel at position 1 is depolarizing the one at position 2. Well, after that lag, the one at position 1 shuts down because the sodium ions that come in at position 2 could go to the left or the right. They could go—they could leak back to position 1 or go forward to position 3, and you don’t want the action potential traveling backwards, so position 1 is deactivated and nothing can happen to that for a certain period of time. And so the only effect is for the sodium to keep flowing forward to position 3. Position 3 depolarizes, lets sodium in, travels down to position 4, depolarizes, et cetera, et cetera, et cetera. Meanwhile, the potassium channels kick in late. They let potassium come out, and that repolarizes the membrane by reestablishing that the outside is more positive than the inside. Once that repolarization happens, those channels go back to their default state, and they can engage in the next action potential that is signaled. Now, once you’ve repolarized, you have done so by flipping the sodium and potassium on either side, but when you flip it, each action potential, you’re only talking about flipping .03 to .003 percent of the ions, so in the big picture, you really haven’t changed the ratio of sodium and potassium on either side, but over the long term, you certainly will, unless you have the sodium-potassium ATPase to create that general picture of more sodium on the outside and more potassium on the inside. So over the long term, just as up at the dendrite on the axon, none of this action potential stuff is going to fire properly, unless you have energy by ATP using the magnesium and all the other minerals and seven B vitamins that I had just mentioned to establish those gradients, those positions of the sodium, potassium ions. In some axons, but not all, the axon is wrapped in a sheath called myelin. That myelin is actually layers upon layers upon layers of cell membrane of the glial cells that sit on the axons. It’s extremely rich in phospholipids and cholesterol. There are of course many, many nutrients involved in making myelin. There have to be because this is a process of cell growth, so it’s basically going to require all of the nutrients. But the membrane itself is very cholesterol-rich. So, all cell membranes have phospholipids, all cell membranes have cholesterol, but some portions of some cell membranes are more cholesterol-rich and are to that extent somewhat less phospholipid-rich. And myelin is a very cholesterol-rich cell membrane, and cholesterol is the limiting factor for the production of myelin during development. Now, in the adult brain, you’re not synthesizing a whole lot of myelin, although the connections at synapses themselves are cholesterol-rich, and it’s been shown in animals that cholesterol is the limiting factor for synapse formation in addition to myelin formation. Now, there’s a couple caveats here. One is that your brain is thought to make all of its own cholesterol, and it’s thought that the cholesterol doesn’t cross the blood-brain barrier, so it doesn’t matter if you eat it. On the other hand, it’s been shown in animal experiments that when the brain has a very high need for cholesterol, dietary cholesterol will get into the brain, and it’s been shown in mouse models of multiple sclerosis that the remyelination needed to heal from the injury to the nerves is in fact helped by dietary cholesterol. So, I do think that it makes sense, even if we don’t 100% know how much cholesterol is getting from the diet into the brain, I do think it makes sense that for infants and small children who have very rapidly growing—who are making myelin and are making synapses at a high rate to have cholesterol in the diet, and indeed, cholesterol is found in breast milk. And I also think it makes sense that people with injuries in the brain that hurt myelin probably may—well, let’s just say may benefit from dietary cholesterol. One thing that’s been shown in animals is that one of the benefits of sleep is that when you sleep, you make more cholesterol in your brain, and I think one very unexplored area is whether some people just need some dietary cholesterol all the time. To take as an example, there is a genetic disorder called Smith-Lemli-Opitz syndrome. And this genetic disorder is quite rare, but the reason it’s so rare, maybe 1 in 60,000 births, is because usually it’s fatal in utero. So, you need to have a defective gene for cholesterol synthesis in both the mother and the father to produce a homozygous state, meaning both maternal and paternal genes are defective. And most of the time when that happens, it’s going to result in a miscarriage. But occasionally it results in a live birth, and when it does, the principal problems are neurological, and they are corrected by dietary cholesterol. Now, while only 1 in 60,000 live births actually results in Smith-Lemli-Opitz syndrome, or SLOS, the proportion of the population that carries the gene ranges from 1% to 3%, and they have lower levels of cholesterol in their blood, so although they don’t have the terrible neurological problems, they do have less cholesterol, they do have a lower rate of cholesterol synthesis, they presumably have a lower rate of cholesterol synthesis in the brain, and perhaps they, like their homozygous counterparts, would benefit from dietary cholesterol, and perhaps there are other genes that reduce cholesterol synthesis in the brain that would make dietary cholesterol have some important role. Unexplored, but I think it’s— look, traditional diets had cholesterol in them because cholesterol is found in all animal products. I think it makes sense to err on the side of the cholesterol that was found universally in human diets may have some important role, especially in some people. Now, once the action potential reaches the end of the axon, called the axon terminal, whether it got there super, super fast because of myelin, or it got there at its usual speed, and by this usual speed, I mean 0.5 to 2 meters per second instead of the 3 to 120 meters per second that you would get in a myelinated axon. The depolarization reaches voltage-gated calcium channels in the axon terminal. These voltage-gated calcium channels are the universal trigger of neurotransmitter release. So, the fact that right adjacent to the voltage-gated calcium channel, a voltage-gated sodium channel had let sodium inside the cell and caused that cell to become—and caused that portion of the membrane to be depolarized, that depolarization hits the calcium channel and lets calcium come in. That calcium acts as what we call a second messenger, meaning it carried the message of something else outside the membrane. And one of its roles there is to activate a protein called synaptotagmin, which facilitates the assembly of proteins that make vesicles of neurotransmitters fuse with the plasma membrane, which is the membrane that covers the outside of the cell so that they can release those neurotransmitters into the synaptic cleft, which is the space between the axon terminal on one side of the synapse and the dendrite on the other side. Now, calcium has many, many other second messenger roles. So, it is not always just at the axon terminal that calcium gets let in. It may be at the dendrite that one of the receptors had the effect of the receptor, the neurotransmitter bound to the receptor, the receptor caused some cascade of reactions that let calcium into the cell or let calcium into the cell directly, and then calcium activated a bunch of processes in so doing. And even outside the nervous system, this is a typical standard role of calcium. Many of these processes are initiated by, instead of synaptotagmin at the axon terminal, binding to calmodulin, a protein that’s in all cells that mediates many different second messenger roles of calcium. The ability to do that with calcium of course means that you have to have enough calcium, that’s one thing, but also means that you have to have all the things in place that will keep the concentration of calcium in the cytosol, which is the main liquid of the cell, very, very low. So to put some numbers on this, cytosolic calcium, that is, calcium in the main fluid of the cell, is 50 to 100 nanomolar. Outside the cell, it is several molar. One molar is a thousand times one millimolar, which is a thousand times one nanomolar, so one molar is a million times one nanomolar. If inside the cell, calcium is 50 to 100 nanomolar, and outside the cell at several molar, then we’re talking on the order of 50,000 times more calcium outside the cell than in the cytosol. That happens in a few ways. The energy of ATP is used to pump calcium from the cytosol to the extracellular fluid. Remember that there’s a sodium gradient where the sodium is outside the cell but wants to come in, and remember that when you concentrate an ion, there is energy stored in its gradient. So, there’s also a sodium-calcium exchanger that uses the energy of sodium coming into the cell to pump calcium out of the cell. ATP energy is also used to pump calcium into a specific compartment of the cell known as the endoplasmic reticulum, by doing so, concentrating the calcium there, the main fluid of the cell, the cytosol, the calcium gets lowered. And then finally there are a number of calcium-binding proteins that act as buffers so that if the calcium goes up just a tiny, teeny bit, they just bind to those proteins, and the actual cytosolic calcium doesn’t go anywhere. And so you have to have a big enough change in the calcium concentration to actually result in the liquid of the cell having a meaningful increase in its free calcium. And it’s that increase in the free calcium that will then carry out the second messenger effects. In addition to its role as a second messenger, calcium has some other roles in the nervous system. Sometimes in some neurons, it’s the main carrier of an action potential, not the usual one, usually it’s sodium and potassium. Sometimes it’s calcium, and sometimes it acts as a backup to assist sodium in generating an action potential to have the main result being that it prolongs the effect of the sodium processes that we talked about before. In addition, there are some neurons that have low-threshold calcium channels, where they carry signaling that affects cellular processes at changes in the voltage of the membrane that are beneath the threshold potential so that you initiate some communication and some cellular processes at voltage changes that go below the radar, so to speak, that do not generate an action potential. So, how do we nourish this? Well, there’s calcium obviously, and calcium, a lot of people take calcium supplements. If you’re taking calcium supplements, then the foods that you eat might not matter that much, but if you’re not taking calcium supplements, then calcium is not distributed that well in foods. You really want several servings per day of dairy products or edible bones, and this does not include bone broth because bone broth is a great source of the protein and some of the trace minerals but just not calcium. So, edible bones or dairy. There is calcium in dark green vegetables, and it’s good to have several servings of dark green vegetables, it’s just that most people will not eat a volume of those that are big enough to get the calcium that they need, so if you’re not eating dairy products and bones, then I think it makes sense to be mindful of your calcium intake, track it a little bit, and see if you need to supplement. Most people should be getting 1,000, maybe up to 1,500 milligrams of calcium per day. I will put a link in the show notes to an episode that I did on managing calcium status. But then this comes back to energy, right? Just as with salt and potassium, it’s not just that we have enough. It’s also that they’re in the right places. Well, in order for calcium to be valuable as a second messenger, it has to be cleared from the cytosol, except when it is there to act as a second messenger, and that’s a highly energy-intensive process that depends on the energy of ATP. That means it depends on magnesium, on the seven B vitamins, and on copper and sulfur, iron, and the other nutrients mentioned in preventing anemia. That means it could be compromised not only by rare genetic disorders in energy metabolism but by common—in more modest impairments in energy metabolism, such as thyroid disorders and problems related to insulin. This episode is brought to you by Ancestral Supplements. Traditional peoples, Native Americans, and early ancestral healers believed that eating the organs from a healthy animal would strengthen and support the health of the corresponding organ of the individual. For example, the traditional way of treating a person with a weak heart was to feed the person the heart of a healthy animal. Modern science makes sense of this. Heart is uniquely rich in coenzyme Q10, which supports heart health. The importance of eating organs though is much broader than simply matching the organ you eat to the organ you want to nourish. For example, natives of the Arctic had very limited access to plant foods and got their vitamin C from adrenal glands. Vitamin C is important to far more parts of your body than simply your adrenals. In his epic work Nutrition and Physical Degeneration, Weston Price recorded a story of natives who cured blindness using eyeballs, which are very rich in vitamin A, but now that we understand vitamin A, we know that we can get even more vitamin A by eating liver, making liver good for your eyes. Our ancestors made liberal use of organ meats, both to be economical and to utilize their healing and nourishing properties. Animals in the wild do the same. Weston Price had also recorded a story of how the zoos in his era were capturing lions, tigers, and leopards, oh my, only to watch them become infertile in captivity. Researchers then observed what the lions did when they killed zebras in the wild. What they did was they went straight for the organs and bone marrow, leaving the muscle meat behind for the birds, but even the birds took what they could of the organs and bone marrow. Price reported that once the zookeeper started feeding the animals organ meats, boom, their fertility returned. The problem I often encounter though is that many people just don’t like eating organ meats. Let’s face it, if you weren’t raised on them, it can be very hard to acquire a taste for them. That is where Ancestral comes in. Ancestral Supplements has a nose-to-tail product line of grass-fed liver, organ meats, living collagen, bone marrow, and more, all in the convenience of a gelatin capsule. For more information or to buy any of their products, go to ancestralsupplements.com. Ancestral Supplements, putting back in what the modern world has left out. This episode is brought to you by US Wellness Meats. 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If you’re on the fence or you’re not ready for a big order, don’t worry about it. You can use the promo code CHRIS not once but twice. So order the minimum your first time, and if you love this stuff as much as I do, you can order the max the second time around and get the same level of discount, or just max out your order both times and get just shy of 80 pounds of meat at the discounted price. Either way, head over to grasslandbeef.com, and make sure you enter CHRIS at checkout to get the discount. If you loved this episode and want parts two, three, and four without waiting for the next three weeks they’re coming out, part two will come out next week, part three the week after, part four the week after that. If you want them all right now, ad-free with transcripts, go to chrismasterjohnphd.com/pro and sign up for the Master Pass all-access pass the earliest content with transcripts ad-free, and use the code MASTERINGNUTRITION for a big discount. 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