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Peripheral Nervous System in Health & Disease, Gut Health & Enteric Nervous System, Exercise

Updated: Oct 16, 2023


Full auto-generated transcript below. Beware of typos & mistranslations!

Moses Chao 4:31

Sure I'm a professor at New York University Medical Center. And I've been here for over 20 years now. I'm in the department of cell biology, neuroscience and also psychiatry. And my interests are in studying trophic factors in the nervous system.


Nick Jikomes 4:53

And you've got a new book. Can you give everyone just a brief description of you know what's the book called and what it's about at a very high level.


Moses Chao 5:03

Here, the book is about the peripheral nervous system. As many of you know, the brain and the spinal cord are the central parts of the nervous system. But there's also a peripheral nervous system that hits the rest of the body. And there hasn't been much written in the popular press about this nervous system. But it's very important in sensing many things sound, touch, smell, taste. And these signals, this information is taken to the central nervous system. So it's a very important part of how we process information. And so I wrote the book, partly to give people information about the periphery. And also, to aim the book at popular or general public. So it's not a textbook, it wasn't meant to be a science book, per se, but it's meant to tell people what's important about the periphery?


Nick Jikomes 6:16

And what exactly is the difference between or where's the line between the peripheral and the central nervous system? Are there anatomical or physiological barriers or distinctions between them that make it very clear when something is part of the periphery versus the CNS?


Moses Chao 6:32

Yeah, that's a great question. In fact, many of us get confused sometimes. So we make a demarcation between the central and the peripheral nervous system by saying that everything outside the brain and the spinal cord is part of the peripheral nervous system. But that's a little confusing, because the peripheral nervous system interacts or makes contact with the central nerves. So there's, there's a blurring of what's really central and what's peripheral. But in any case, the usual definition is outside of the brain and spinal cord exists network of nerves that are called the peripheral nervous system. And if you want to get more detailed, the peripheral nervous system includes sensory neurons as well as autonomic neurons. And this system also can be subdivided into the sympathetic and parasympathetic peripheral nerves. And there's a third component, which is the enteric nervous system, which covers the intestine, and, and the gut. So it's a it's a complicated system that hits all the organs, and again, is outside of the brain and spinal cord.


Nick Jikomes 8:00

I see. So it sounds like you've got neurons that live entirely inside the brain or the spinal cord, you've got neurons that live entirely outside of those places. But then there's also, you know, nerves that I think have their cell bodies inside the central nervous system that reach outside of it to the periphery, and are sort of the, that's where the lines get blurry. Right?


Moses Chao 8:20

That's right. And many of you know that there are cranial nerves that are considered in the central nervous system, but they, they go to many targets outside the brain. So that's why it's it can be confusing.


Nick Jikomes 8:37

And so, you said and many people have heard these terms, you can break down components of of the nervous system into things like the sympathetic versus parasympathetic nervous system. So what are those things functionally and also like is there is there like a physical or anatomical distinction there?


Moses Chao 8:56

There is. So the the sympathetic and parasympathetic systems often oppose each other and what they do in terms of regulating heart rate, digestion and many processes in the periphery. The autonomic nervous system which includes all these systems, is not looked at very often because it happens automatically. You don't you don't know that the autonomic system is working. So it's, it's it's not been studied as much recently than it was in the past. There's a lot of interest in the enteric nervous system because that's where bacteria the microbiome resides. And many people are interested in how bacteria in the gut may be influencing your behavior and events that happened in the in the brain So, there are many different processes that go on. And whether there's a defect in the peripheral nervous system that can affect many things, temperature regulation, of course digestion, how you perspire, if you have difficulty standing or breathing, they have fatigue, that may be a function of the peripheral nervous system.


Nick Jikomes 10:29

And, you know, I've spoken a lot on this podcast to evolutionary biologists or people who think of their particular field of study in evolutionary terms. Because I think that's really important for understanding you know, how and why things are set up the way they are in the body. And I think you you kind of do that in the book. In fact, the the first chapter is called The first system, it had a really fun first sentence which read, In the beginning, there was a worm. And I think that chapter is sort of about the evolution of the nervous system. And so why is that the first chapter and why did you start it out this way?


Moses Chao 11:08

It didn't start out originally like that. But it became a sort of a good introduction to the system, because it turns out very early during evolution, and that's why the worm comes in. We had a nervous system, and many of these organisms, and that nervous system consisted of a cluster of nerve cells that are grouped together. And that was not a brain, but it was it was for rather, the peripheral nervous system, that is clusters of neurons that were what we call ganglia. Now, the brain is a much, much bigger organization. And it has billions of nerve cells packed together. So in the beginning, simple organisms did not have a spine or spinal cord. And they didn't have a brain, they had these clusters of ganglia, that would dictate movement, eating patterns, things like that. So it wasn't until evolution dictated that there was a, there was a growth of a spine. And that happened from from early on as well, that the central nervous system was was formed. So in fact, the peripheral nervous system really existed before the central nervous system, which is, which is an interesting, evolutionary incident. And that's why we decided to start the book that way, because it emphasizes that the periphery, the peripheral nervous system, has a lot of important precedents, in terms of evolution.


Nick Jikomes 13:08

If you look at like the average neuron, in the peripheral nervous system and compare it to the average neuron in the central nervous system, are there any differences between them in terms of their their cellular anatomy, the structure of the cells or in terms of their neurophysiology?


Moses Chao 13:23

There are some differences. You know, we talked about sensory neurons, and they have what was called a bipolar organization, they have two processes that emanate from the, the, the, the cell body. And there, there's organization like that in the central nervous system that is very unique among sensory neurons, to have this kind of structure in terms of proteins, and the the function of ion channels, other molecules, they're very, they're a lot of similarities. There are, there are some differences, but there are a lot of similarities. One of the major differences between the central and the peripheral nerves is Myelin, the covering of nerve cells, and the constituents of myelin in the central nervous system, are quite different from the periphery. In fact, the cells that make myelin myelin is a coating over the process is the axons of nerve cells. The myelin is made by different cell types, but not from the neuron but by glial cells. And the glial cells are very different in the periphery. There's what's called Schwann cells, which cover the nerve. Whereas in the central nervous system, it's a different that cell type, it's called an oligodendrocyte. And those cells really make the same mieten type of myelin. But they have a different structure, slightly different structure, in that the oligodendrocyte can actually mine on a multiple nerve cells, whereas the schwann cell only donates one, one nerve cell. So that's a big difference between the two systems that the covering of the nerve is, is made by different cells and has different proteins.


Nick Jikomes 15:38

And, you know, I want to spend some time talking about the enteric nervous system and gut brain interactions. You've got an entire chapter in the book about this. And it's sort of a hot topic in research in recent years. Chapter Two starts off by saying that scientists are cautiously beginning to question the view that the brain is the sole and absolute ruler over the body. The gut not only possesses an unimaginable number of nerves, those nerves are unimaginably different from the rest of the body. The gut commands an entire fleet of signaling substances, nerve insulation, materials, and ways of connecting. And so can you unpack that for us and in particular, sort of talk about the ways that nerves in the gut can be unimaginably different from the rest of the body?


Moses Chao 16:23

Sure, that's a very good question. It turns out that there hasn't been as much research about the enteric nervous system, that is the nerves that innervate the gut in the intestines. Um, but they have this similar ways of communication. That is, you use neurotransmitters in both the central and the enteric systems. The big difference, I think, is that the environment of the gut is quite different than from the brain, the environment, or the gut has huge numbers of immune cells that are that are sitting there, sort of sampling what's going through the gut. And those immune cells can can cause good things and also bad things to happen. But they have to interact with the neurons that are present, that surround the gut. So that's a big area of research right now. After years of I think, neglect, I think people weren't so interested in what happens in the periphery. There are a couple groups want to Columbia, like Gershon, and several other groups that worked on the enteric nervous system, years before anybody noticed. But it turns out that they're very important. And there are ways that actions in the periphery can influence other organs and also the brain. And that's, that's why there's a huge amount of research going on right now. And how bacteria in the gut and the nerve cells enteric system and the immune system are interacting.


Nick Jikomes 18:22

And you say in the book, that there are even brain diseases or things that we think of as primarily brain diseases, that have their origins in the gut. So what are some examples and lines of evidence that can support the claim that at least some brain diseases have their origins in the gut?


Moses Chao 18:40

Yeah, I think this is an area that has enormous attention. But there's also some controversy. In other words, controversy comes that we don't have a complete picture of how these brain diseases might be influenced by things in the gut. But I can give you a couple of examples, that the evidence is getting stronger and stronger. And that is, there are proteins that are diseased proteins in the brain, and one of them was called Alpha synuclein. It's very well established that alphas Newfoundland, is elevated in Parkinson's disease, and many other diseases that involve aggregations called Lewy bodies. And these diseases are pretty devastating in that they really cause a lot of problems. We don't know how they do it, but they do cause problems. And one of the theories is not proven, convincingly, but one of the theories is that this alpha synuclein protein, may actually travel from the periphery, maybe even from the gut. out into the brain. And there is some some very interesting evidence that this might happen. It's a little provocative because you're saying, a protein can go from one place to another long distance, and cause the disease. But this is a an idea that is being tested right now. And there is some evidence that it might happen, but it's not proven yet. So that's why there's so this interest. The other issue is that we know that God has each person's God has at least 1000 different bacteria. And so another area of research is to figure out which of these bacteria might be involved in a disease, like a brain disease. And that's going to take a lot of work, you have to basically identify each one of the species and test whether they're the culprit in a brain disease, but this is what a lot of the research is, right now. And there's a lot of excitement, because people think that even psychiatric diseases might be influenced by your content in your gut, that is the bacteria in your gut. How that happens, we don't know. One theory is that your bacteria are making small molecules, and these small molecules might be able to migrate all over the body and cause and cause problems. So that's a that's a, an idea that many people are working on, they're trying to identify these metabolites or small molecules that might be linked to, to disease. So I think we're in our infancy about studying this, but it's it's caused a lot of excitement because of preliminary data, that indicates that there might be a lake. One One preliminary data I just mentioned is a few years ago, people were using antibiotics to kill off all the bacteria in your gut or in the gut of a mouse. And they saw that the incidence of Alzheimer's disease in the mouse or other diseases, wind down. So this is published published observations. The problem is we don't know. If this is just the correlation, you get rid of bacteria and have a better environment for for the brain disease to reside, or what the mechanism is, you have no idea what the mechanism but it is a link between bacteria in the gut and, and disease brain disease.


Nick Jikomes 22:55

Yeah, so I guess that's it sounds like, we don't really know what's going on there. We don't know, if we're the the arrows of cause and effect lie. But there are these weird and intriguing correlations that people have seen where you give an animal antibiotics, which is gonna kill bacteria, and there's gonna be lots of downstream effects for that. But then you get these phenotypes like decreases or changes in diseases of the brain are things that we wouldn't have imagined or naturally thought would be linked to the presence or absence of, of microbes elsewhere in the body.


Moses Chao 23:30

Another kind of experiment again, it's, it's, it's a bit of a correlation. There's a there's a cranial nerve called the vagus nerve that really extends from the bottom of the brain, throughout your body, it hits a lot of organ organs, including the gut. And, as you may know, people do get operations where they, where they cut the vagus nerve, they basically in or interfere with the vagus or, and in patients that have this operation, they find that the incidence of certain diseases like Parkinson's is really much lower. So that's really intriguing because a lot of materials pass up and down the Vegas term. Again, it's a it's a object of a lot of research right now. That is what is going up and down is metabolites or bacteria, or what kind of substances but the idea is that you, you have this highway of information going back and forth between the brain and and the periphery. And if you interrupt that, it may be may be better and in the case of disorder, like brain disease,


Nick Jikomes 24:48

and the vagus nerve. Can we talk a little bit more about that? Talking about like, how big it is, and exactly what it's innervating outside of the size?


Moses Chao 24:57

It's innervating many Oregon And there's a there's a nice diagram in the in the book from publish article that shows that the vagus nerve hits many of the organs, the liver, the stomach, and it's mostly parasympathetic is sort of a break on things. So there are a number of groups that are that are working very hard to, to understand what's going on vagus nerve. In fact, a lot of therapies are being proposed to take advantage of this vagus nerve, which is one of the longest nerves in the body.


Nick Jikomes 25:42

And so based on what you said before, it sounds like, you know, these cranial nerves, things like the vagus nerve, they have their cell bodies in the CNS, they reach out into the periphery, they touch organs and other parts of the body. And they're not only sending communication in the form of like electrical nerve signals, back and forth between the CNS and the periphery. But these are big cells, and people are chasing the idea that maybe they act as like, like a, like a tube of physical tube and molecules from the microbiome or from somewhere else might be able to get in and shuttled into and out of the CNS via something like the vagus nerve.


Moses Chao 26:20

Right? It can be likened to a gatekeeper of sorts, because it's, it's going both through the brain and away from the brain. So So there are a lot of possibilities here. And again, because of the number of bacteria that you have to consider the immune system as well, as well as the nervous system. It's a it's a complicated project to look at this, but I think there's enormous interest right now, and to Lynnie. Some of the events that go on


Nick Jikomes 26:58

and what this is gonna be kind of a vague question, but I think it's an important area to consider for people. Obviously, we often take antibiotics on purpose, you know, we get sick, we go to the doctor, sometimes we're prescribed antibiotics, because we have a bacterial infection. Sometimes people are given antibiotics, even when it's not a bacterial infection. You know, I was just at a friend's house yesterday, and they've got antibacterial soap in the sink, and there's antibacterial stuff all over the place, basically, that we've put there. And so today, in modern society, we're exposed to antibiotics probably at levels, much higher than than any time in human history. Do we know anything about what this exposure to antibiotics is doing to our microbiome? And to the extent to which that's good or bad?


Moses Chao 27:48

That's a very good question. I think you could probably find any result that you're looking for right now, because because the antibiotics, they are very powerful, but they're very, they're many bacteria that need to be characterized. But now with all the techniques and DNA sequencing, and, and, and also proteomic type of analysis, I think we'll have a better idea of which bacteria are the are the culprits here. And I think there's a huge amount of data that's coming out now from the number of labs that try to address this issue. So in the in the experience I mentioned before, where antibiotics were treating mice that had that had programmed Alzheimer's disease. I don't think I haven't seen anything recently, except for the result, that you can diminish the level of disease by getting rid of bacteria, but we don't know which bacteria. We don't know what the what the real mechanism is. But I think this is what people are working on right now.


Nick Jikomes 29:11

Are there any examples in humans have antibiotics being associated with either an increase or decrease in different conditions?


Moses Chao 29:21

Yeah, there's, there are a number of intestinal problems that that have been identified that really depend on the bacterial composition. And I'm sure you the audience has heard of probiotic measures to try to diminish the effects on intestinal diseases of this kind. So this is this is an area that has been studied quite a bit in the past. Like sort of without considering what the nervous system is doing, and also considering what the immune system is doing. So you have, you have these three parties that are interacting in the periphery. And they're large, they're large constituents, and they have powerful effects, particularly the immune system. But the three parties have to balance each other in order to have, you know, a healthy system. So it's, it's complicated, but I think it's going to be studied and, and, and reasonable ideas will come from this. You know, they're now new departments of medical schools that are concentrating on the microbiome or the bacteria. So it's a big area now.


Nick Jikomes 30:56

And, you know, to what extent, you know, because you see probiotics, and prebiotics all over the place. Now, lots of foods are marketed now as having prebiotics, which basically just means they contain fiber. There's all kinds of probiotic supplements out there with all different kinds of bacteria. To what extent does that stuff actually work? And does that require having a certain dietary composition? Is it only going to work? If you sort of deplete your gut microbiome first, to make room for new bacteria? How much of this stuff is actually going to have some effect on the gut microbiome of a human who goes out and buys these things? Yeah,


Moses Chao 31:39

those are all very good questions. And I'm not enough of an expert in this area of nutrition and food to know, but I'm sure these are issues that have to be worked out. And, you know, to do a clinical trial, and something like this takes a lot of resources. So we just have to wait and see what what these various Bye, biotics were telling us. But I think I think that's, that's something that's being done right now. We don't have all the answers.


Nick Jikomes 32:20

You've got a chapter in the book all about pain. And obviously, the peripheral nervous systems can be involved in pain sensation. So can you give us just like a basic sense of how pain is detected in the peripheral nervous system, you know, how it's sensed, and then how it's like, relayed to the brain for us to actually then have a conscious perception of pain.


Moses Chao 32:41

Sure, there have been some big advances in this area. I mean, everybody's interested in in the mechanism of pain. But down to the molecular level, this has been the subject of several breakthroughs. One breakthrough is the identification of a gene that senses temperature and pain. It's called the trip channel. And it was discovered by David Julius a number of years ago, he's at University of California in San Francisco. And the second type of sensor is a mechanical sensor. It's called piezo. And this was discovered by Artem Patagonian just a few years ago, both of them got the Nobel Prize two years ago in medicine, because it was realized that these molecules could explain a lot of features of pain, and how the pain is processed. So most of these molecules are found, again in the periphery, from sensory neurons, and also a mechanical sensors can be in many different types of cells. So the mechanical sensors, actually since pressure and mechanical action, and they're very large proteins that are found in the periphery. And they're very important in a lot of different disorders. So when when you have heat or some kind of perturbations, pain, the sensory neurons or mechanical sensors, usually located in the epidermis of the skin. They connect with neurons that go to the spinal cord and into the central nervous system, where much of the processing of the information goes on, but the initial the initial signal is usually from the periphery. That's why the peripheral nervous system is quite important. And you know a lot of the The treatments for pain are really targeting, not the periphery, they're targeting the central nervous system. And so there's a lot to be learned from some of the molecules that that have been discovered. The trip molecule is one of many trip molecules that are found. And the piezo, or the mechanicals sensation, also has several different family members. So it's, it's going to be interesting to see how these these networks of nerves in the peripheral nervous system, integrate their information into the brain and process the information. So I think it's, it's really advanced significantly in the last few years. I mean, pain has been studied for centuries. And of course, there are a lot of treatments for pain. Understand that, interestingly enough, in the brain, there are no sensory neurons that detect pain. So as as you may know, you know, you can have surgery in your in your in your brain, and not feeling any pain, at least at least, interior of the brain. So there's still a lot to be learned. And, of course, many people regard pain as sort of a warning warning signal. So it's not something you want to get rid of, it's something that is very useful to tell you that something's wrong. So So that's there's two aspects of pain, that that are very important. And, and there's a tremendous amount of research that's going on right now.


Nick Jikomes 36:57

And can you talk a little bit more about these trip channels and what they're sensing, you said that there's multiple flavors of this protein? What what kinds of stimuli? Are they tuned to detects? Specifically? Yeah,


Moses Chao 37:09

so one thing, one aspect of trip channels is that they can differ in syncing temperature. And there are trip channels that sense cold temperature, versus very, very hot temperature versus medium temperature. So the original observation for identifying trip channels is that there's a pepper called capsaicin that binds to these trip channels. That's how they were originally discovered. The hot hot red peppers contain an ingredient small molecule that interacts with the trip channel. And, and so it's not only temperature, but it's also related to pain that these channels receive their information. I see.


Nick Jikomes 38:03

So is that why like when we talk about a spicy food being hot, it's because they contain a small molecule that opens up specific trip channels that also literally open up in response to hot temperature.


Moses Chao 38:17

That's right. So it's pretty amazing. If you think about it, that molecule like that can sense temperatures, say from 35 to 45 degrees centigrade, but not detect other temperatures. I mean, it's a remarkable property. There are other channels that have been discovered recently that are involved in itch. So he is also related to pain. Because if you have a strong itch, you want to get rid of it, but scratching, and those involve different kinds of channels, which are not very well studied, but indicate that these channels which span the membrane and receive and transmit ions through the cell. They really are very specific. And they're specific for the cells that see the see the small molecule and also temperature. So it's it's a big discovery of these small molecules and the and the agents that regulate the channels.


Nick Jikomes 39:39

And you know, another thing you talk about in the book that you've studied, you mentioned this earlier, are these things called glial cells. And there's different types in the CNS in the periphery. And they're involved in things like you know, wrapping the axons of neurons with the the fatty insulation called myelin that helps them conduct to send signals faster basically. What? Can you go back over? Like, what are the glial cells in the periphery? And what are some examples of like neurodegenerative diseases that involve this part of the peripheral nervous system?


Moses Chao 40:14

Yes, that's a that's a very good question. The periphery has one major glial cell, among others. It's called the schwann cell. It was named after Theodore Schwann, who discovered this cell, actually 200 years ago. And the schwann cell is quite different from the cell in the brain that does the same thing, which I mentioned is the alga dendrite site. The Schwann cell is very amenable to keeping neurons alive in the periphery, they make a lot of growth factors, a lot of substances that keep neurons live, and they also facilitate regeneration in the peripheral nervous system. Very important. Whereas in the central nervous system, the glial cell there is usually inhibitory to regeneration. So it's a big difference in glial cells. And this was just discovered 3040 years ago. main questions why, why is it difficult for the spinal cord, and the brain to regenerate, as opposed to the peripheral nervous system. And it came down to studying glial cells, because they make a lot of substances that either inhibit or promote regeneration. So they're very important selves. And they also by recently, have been found to provide nutrients to, to neurons. So it's very important, they also pick up or take up. Neurotransmitters are garbage that's made by the neuron. So they become very, very important. And the other thing that's important about glial cells, is a vastly outnumber the nerve cells. So there are a lot of glial cells. And in the past, people recognize they're very important, but all the attentions on nerve cells, because they do the the learning and memory, the plasticity, everything. So it's only recently that there's been a huge amount of attention on glial cells.


Nick Jikomes 42:43

Hmm. And so you said regeneration? So to what extent can regeneration actually happen in neurons in the peripheral nervous system? And when you say, regeneration, do you mean neurons can die and be replaced by brand new neurons? Or do you mean that, you know, individual connections or processes can degenerate and then regenerate?


Moses Chao 43:02

Yeah, we're talking about cells that have have a break in the in the axon or in the process, and eventually can grow back to the process. And that happens much better in the periphery than in the CNS. So I'm sure you've been aware of all the attention to spinal cord injury, the fact it's very difficult to regain your movement after severe spinal cord injury, like the one that Christopher Reeve had. And that's still true. And whereas in the periphery, if you have an injury like that, it's it's a little better prognosis to to overcome the injury. So what it says is that the environment in the periphery is a little bit better along with the glial cells than in the central nervous system. And I've often wondered why, why would you set up the nervous system in this way that one part is, is amenable to regeneration? The other the other part, the brain doesn't have that? And I've asked a lot of people this question, you know, why, why do we have this system? One explanation is that in the brain is pretty hard wired. By the time you're an adult, it pretty well. The network is very hard wired. And you don't want any mistakes in that. So there's mechanisms to keep brain cells sort of stable. In the periphery, there's no more room for for have an injury to be to be dealt with. So I don't know if that's, that's a best explanation for why there's a big difference. But there are these big differences. And one of the experiments that was done to show that the environment is very important is was an experiment that was done by Alberta guaido, about 3040 years ago, where he put a bridge of Schwann cells on top of the spinal cord. And he could show that spinal nerves could grow into the, into the swan cell bridge that was made. So that that really said a lot of things, it said that those cells in the brain and the spinal cord have the capacity to grow or to regenerate. But it's the environment that's very important


Nick Jikomes 46:05

that the neurons are intrinsically limited in the CNS from regenerating, it's that they don't have Schwann cells and or other things that are also in the CNS that are actually stimulating them to regenerate.


Moses Chao 46:17

And this was just realized, let me think about this. Yeah, maybe 50 years ago, that experiment was a very important experiment. And then since then, the race has been on to figure out what things are inhibitory in the central nervous system. And there are a lot of molecules there that that block regeneration or growth,


Nick Jikomes 46:42

what would be like an example of some type of like injury in a human being that has some nerve damage, where you can get most or all of the damage reversed by regeneration?


Moses Chao 46:59

Yeah, there are, there are some injuries in the periphery persons I know there, there are some hand surgeons that deal with problems of injury in the hand where, where they they can find after surgery, some treatment, that those nerves can reconnect, and, and gi normal. So there, there are instances like that that have been studied. There are a lot of genetic diseases where the periphery is affected either in the muscle or the nerve. And those things have the potential of having treatments that would help much, much better than the CNS.


Nick Jikomes 47:59

Another topic that's interesting to think about what the peripheral nervous system is something like exercise. And so obviously, the peripheral nervous system is going to be involved in like doing the exercise, because because the neurons are going to control how the muscles are contracting and things like this. But you know, beyond that, what are some of the ways that exercise can stimulate the peripheral nervous system that induce important changes in the central nervous system that you know, you know, end up influencing, influencing things like reward and motivation centers in the brain is that is that an area that's being studied at all how, you know, the movement of the body in the context of exercise, you know, is going to affect the brain via what's going on in the periphery?


Moses Chao 48:40

Yeah, we've been interested in this in this problem, but through a different kind of angle, we've been interested in some of these growth factors that are made in response to exercise. So these are not endorphins, they're they're factors that keep the nervous system healthy. And we know from many experiments in animals and also humans, that when you exercise, your you make increased levels of these growth factors. And as I said, they help the neurons or the nervous system to be more healthy. But these growth factors, and one of them is called nerve growth factor. The other one's called brain derived neurotrophic factor. They also enhanced plasticity and brought about by what I mean is, is that they can change the way you the way you think, and they can enhance your learning and memory properties. So we've been interested in how these growth factors are working, especially after exercise because it's very clear. If you run if you run for a half hour or you do other exercises, where you're Learning something new, that growth factors go way up the CNS and also in the periphery. And we and others have been trying to figure out, well, how does that work, you know what's going on. And I'll tell you one example, there are many ways that this is gonna happen. We know when you exercise a lot, and this is animal experiments, your liver starts, you start using a lot of sugar, and glycogen and those kinds of resources. But if you exercise a lot, your liver starts also metabolizing lipids, this has been known for a long time. And the the products of these lipids are called ketone bodies. Small molecules are tiny molecules. And we know when you exercise, you make ketone bodies. You also make ketone bodies when you fast. It's almost the same as if you're exercise it.


Nick Jikomes 51:04

So is this the sort of unifying thing there, you know, the, the livers first going to use glycogen stores, it's going to use glucose. So basically, the carbs that are in your body right now, and, and the glycogen, the, essentially the carbs that you've stored up. And only after that runs out, you start metabolizing, these lipids to make ketone bodies, that happens both if you exercise a lot, and you run out of the carbs, and then you need to get the energy from somewhere else, but also fasting in particular low carb fasting.


Moses Chao 51:34

I think so. We were intrigued by this. I mean, we weren't doing metabolic experiments. But we realized that these ketone bodies can actually cross the blood brain barrier and get into the brain. And one of these ketone bodies, which is called beta hydroxy, butyrate. It's been studied by many groups more than endocrinology field can turn on and off genes in the brain. This out. In fact, it's pretty well established that it can happen. And so we tested whether BDNF, this growth factor I mentioned, was affected by this ketone body. And in fact, the ketone body can turn on the BDNF gene, you get higher levels of BDNF. And we showed that in the in the brains of these animals that were there running along a long time, week, some cases even more than a week. So we think that there are ways where exercise can change the metabolism, such that small molecules can be made to change the expression of genes that are very important for one's health. There are other molecules that have been found to that, that enhance the health of an individual. So a number of years ago, scientists at the Salk Institute sort of proposed that if you can find all these molecules that are good for you, maybe you can make a pill, that would be an exercise pill that would allow you to get the benefits of exercise without even exercising. Now, that hasn't happened. But it's sort of a pipe dream of some people, that if you can identify these key molecules that maybe you could generate a treatment for. That would enhance your ability to to get the benefits of exercise.


Nick Jikomes 53:51

So, you know, an interesting area to think about here is, you know, connecting what you just told us about exercise and its metabolic effects and the downstream effects that has on on plasticity, right. So so if you start fasting and or exercising enough, or in a certain way, you can start metabolizing lipids instead of just sugars and carbohydrates, that can lead to production of things like beta hydroxy butyrate, ketone bodies that you mentioned, those can get into the brain, they can change gene expression and increase things like BDNF which are involved in neuroplasticity. So one of the things this makes me think about is, you know, this could be why just getting you're changing your diet and or exercising can actually have the side effect, so to speak, of helping or facilitating the treatment of say psychiatric disease. So just you know, if someone has depression, say, at some level, what they need to do is rewire their brain. And so you know, higher BDNF, a more faciliate facilitatory plastic environment is going to help them do that. And so it would make sense that you know, Changing your metabolism via diet or exercise could then actually help help you change your brain so to speak.


Moses Chao 55:09

And a key part of this is changing your routine. I think that's very important. The brain and the nervous system, we think craves novelty, it likes novelty, like something new. So, you know, when you travel, even though traveling is kind of a mess. Now it's very crowded, it's, you know, you have planes that are canceled all the time. But you never come back from a trip and feel depressed. Why is that with all the problems of traveling, is because you've been exposed to a lot of new scenes and new sights. And I think that's good for your nervous system, to get that change, to see to experience something new. So what you mentioned about, you know, having some changes, I think it's very important, very important to keep healthy. And I think as you grow older, I've noticed with my family, you don't tend to want to do things anymore, you want to just sit down and watch TV, which is the last thing which is bad for you. So I think having some activity, it could be exercise, it could be, you know, learning a new language or doing something different is is very healthy throughout one's lifetime.


Nick Jikomes 56:36

I see. So just raw novelty going through in whatever form that that takes, that will have a tendency to increase things like BDNF and facilitate plasticity and things like that.


Moses Chao 56:50

So I can tell you there, there are groups here in New York that hold classes in dancing. One of the groups is dance company called Mark Morris. And there are many groups now. And they they enlist Parkinson's, patients to go to these dance classes, and their mood is so much better afterwards. And their movements are better, they're not as have the tremor as bad a tremor as possible. So we think that the dancing, the sort of exercise, which is new activity, I think, really helps the nervous system, and helps at least counteract some of the effects of disease of that kind, a movement disorder. So the same thing with music, I've heard of instances where listening to music really is therapeutic to some of these disorders. So again, it's it's encountering encountering something new, something that's stimulating. That is helpful.


Nick Jikomes 58:05

And you know, you've mentioned Parkinson's a couple times. So maybe that's an example. But I wanted to ask you if there are examples of neurodegenerative or psychiatric diseases that we normally think of as diseases of the central nervous system, which either have their origins in the peripheral nervous system or have a significant portion of their symptoms, originating from stuff going on in the periphery that we have historically not understood or under appreciated.


Moses Chao 58:34

Yeah, this idea is something that's written in the book, sort of got me stimulated about writing some of the book. And it comes from observations that were made many years ago in terms of Parkinson's. We know 200 years ago, that physician named James Parkinson observed people outside his window in London, who walked by and he noticed that it was only six or seven patients subjects developing a tremor, really bad tremor. But he took a lot of notes, and he realized that there were a lot of things before the tremor came about. One of them was paying another one is Sleep, sleep was disrupted. And the other thing involving the digestive system is constipation. So when I've talked to a lot of physicians that see Parkinson's patients, they say, oh, yeah, we see a majority of people with constipation problems. So that tells me there must be something going on in the gut that it's happening not working well. And again, this is an area that has not been really studied that much. But it really suggests there are symptoms that happen well before the tremors that are characteristic of the disease. And the other thing about Parkinson's disease is that the symptoms that develop, you see in many other peripheral diseases. It's really surprising even even autism. And there's a there's a case there's a rare genetic case called dysautonomia is this autonomia autonomic systems really messed up. They have the same symptoms, same exact symptoms as Parkinson's. So people have not really looked at those pre symptoms that much because it's difficult to study. I mean, it's hard to make a link, you know, with with the, with, obviously, a brain disease, you know, becomes a brain disease. But I think those symptoms are telling us something that that we should follow up on.


Nick Jikomes 1:01:06

And are there so I know that like one example, it's pretty well known now that at least for certain forms of epilepsy, one way to treat treat them that that can be highly effective for some people is the ketogenic diet. Are there examples of neurodegenerative diseases or psychiatric conditions? Where fasting, or changing the diet in a specific way like that can have a clear impact?


Moses Chao 1:01:34

Yeah, that's, that's a great question. I don't know. And in the human human case, but in some animal studies, this was actually some time ago, where they administered ketone bodies to a mouse that developed Alzheimer's disease or a mouse that developed Huntington's disease. And they got improvement, they got sort of protection against cell death in those models. Now, we don't know what the mechanism is. But I would bet that maybe those ketone bodies were turning on genes like BDNF. And that gave a positive effect. And in epilepsy as another great example of where the diet can change one's condition and the condition of absolute epilepsy is pretty severe. And as I understand it does work pretty well in some in some populations of epilepsy patients, not everybody, but some. So that's, that really says there's something about the diet, probably environment that is very important. And again, we don't know the mechanism, you don't know, what the ketone bodies are actually doing and epilepsy that comes the nervous system.


Nick Jikomes 1:03:04

Interesting. Is there anything else that you want to sort of any topics that you want to discuss that are in the book that you think are important that we missed? Or anything you want people to know, to give them a sense of, like, what's in the book and and how these things tied together?


Moses Chao 1:03:21

Well, there are a number of things. I mean, the book is actually written not as a textbook, I could have written it as a science book, but I tried to get away from using a lot of terminology, a lot of acronyms, because that, that can really confuse people. So it's not written as a as a science textbook, but it's written more as a historical account of how these problems were studied. So one thing I really liked about doing this book is reading about what people did 100 years ago, 200 years ago, with the same problems. And you know, there's some very bright people. Without the tools they have we have today, we made a lot of very important observations that I think really changed the way we think about the periphery and also the central nervous system. So that's one thing that the book has. And there's also a section about plasticity. And this has to do with what we just talked about that is doing some new activities, how does that help people? And, and, you know, although the plasticity is usually referring to things in the brain that change for the better, it also happens in the peripheral nervous system. Not not not as many examples, but I think it happens. And the other topic that I sort of got into But could use a little more work is the basis of longevity? Hmm. So, if you think about it, your nervous system has to last a long time, because nothing's gonna replace it. And there is some neurogenesis that happens in the brain. That's true. But for the most part, the nerves in your body when you're 6070 8090 years old, are the same nerves that you're going to have during your lifetime. And and how does that happen? How to how do these nerves stay alive for such a long time. And we know some molecules that are involved in this process. And one of the things that strikes me is very important is that a lot of these molecules are what we call growth factors. They're their factor factors that help keep the body healthy pieces. But we also know in a lot of diseases, especially neurodegenerative diseases, like Parkinson's, ALS, Alzheimer's, of course, these growth factors are diminished in their level. So as you grow older, your nerve growth factors are going down in levels. So how do you keep these neurons alive? I mean, this is this is something or how they keep them plastic. This is something I've been interested in. Because I think there are other ways that the body can keep these neurons alive. And that's the whole point. And we know some of the factors that are involved. But I think there are many others that are very important. Is it an important observation, because your nervous system doesn't have a mechanism to replace itself, like other organs in your body. And so you're left with what you have to start with. And there must be a lot of important mechanisms to keep those nerves going, after decades. And that's something I raised in the end of the book, but I didn't have a lot of answers. It's something we're interested in pursuing.


Nick Jikomes 1:07:25

Whether it's maybe it's that topic, but any other topics? Are there one or two areas where you guys are doing experiments right now, where maybe you're starting to see some interesting results, and you think we're going to make good progress in terms of the peripheral nervous system.


Moses Chao 1:07:39

Oh, yeah. We're interested in how cells communicate with each other. So it's a very basic fundamental topic. And we know that cells make all kinds of substances that can, that can impact other cell types. So one of the things we're doing is studying a group of molecules that can that are secreted and can impact other cells. So by that, I mean, there's a there's a trans activation process. One of the molecules we've studied recently is, is a very small, tiny peptide called oxytocin. And oxytocin has been around for a long time, it was discovered many years ago. And it was discovered to help the reproductive system. But now recently, there's been enormous interest in how oxytocin is working in the brain. Because because of its social interaction properties, in fact, there have been many clinical trials in the last 10 years of trying to use oxytocin on autism to increase social interaction. And some of the studies work pretty well, some don't. So it's still it's still unknown, whether we could use this therapeutically. But we think oxytocin can interact with other systems that can trigger more social interaction. So that's the idea. And we're trying to figure out, you know, who's communicating with who. And it's a small molecule, the, the way oxytocin is being used, it doesn't cross the blood brain barrier. But people use a technique called intra nasal application. So they, they they do this in mice and also allowing humans where they administer the small molecule through the nose, and hope that it gets to the right place in the brain. And as I said, some studies look pretty good. Some are, don't give the right results, you know, so. So we have a long ways to go. But this is an area, I think that that is going to be very promising for a lot of different psychiatric disorders.


Nick Jikomes 1:10:29

All right, well, Dr. Moses child, this has been fascinating. Do you want to remind people one last time what the title of the book is and where they can find it?


Moses Chao 1:10:39

Yeah, it's called periphery. And it's how the nervous system can predict what might happen in certain diseases. It's, it's on Amazon now. You can find it there. There's also another book company, that that features that it's actually not released yet. Yet, but it should be released in another week or so.


Nick Jikomes 1:11:10

Okay, great. Well, Dr. Chao, thank you for your time. This was really interesting. And good luck with the rest of your research.


Moses Chao 1:11:17

Thank you very much. Appreciate that.

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