 So the way we process information, all the environmental stimuli, is based on the neurons. They talk to each other. They process and they make a decision. There are two, mainly two ways of communication. One is through the release of neurotransmitters. The other one is I mentioned through gap junctions. So the basic idea is that we want to develop a new, genetically encoded, non-invasive method to image the gap junction communication. So it's based on the channel between cells. We want in one cell, we want to generate a specific small molecule as a mediator and in the other cell, the mediator will go through the gap junction and in the connective cell there's a sensor for the small mediator. So once we triggered one cell, there's a response in the other cell, then this demonstrates that these two cells are communicated by gap junctions. That's the basic idea. So for now we know that the main function for electrical synapses is synchronized neurons firing. Like those neurons are connected by gap junctions. They will fire together. So they will release transmitters together. If you don't know how to code, you spend more time on boring stuff and be less efficient. Though someone's opinion may contradict yours. Where's my friend Allen? It's all about your perspective. Who are we and what is the nature of this reality? Five, four, three, two. Nihao, everybody. Welcome to Simulation. I'm your host Alan Sokian. We are on site in the beautiful Beijing, China at the Beijing University School of Life Sciences. We are now going to be talking about neural communication. We have Dr. Ling Wu joining us on the show. Hi. Thank you so much for coming on our show. Really appreciate it. Thank you. This is going to be a lot of fun. I'm really excited to talk about Ling's work. For those that don't know, she's a postdoc in the Lee Lab at Beijing University School of Life Sciences who developed Paris on optogenetic method for functionally mapping gap junctions. You can find the links in the bio below. Ling, let's start things off by asking one of our favorite questions. What are your thoughts on the direction of our world? So, yeah, that's a very interesting question. And to be honest, I'm a little bit pessimistic about the future of humans. Why? I mean, they, so we've done too much to the earth. Like, someday, someday we will extinct. Like, they decimate the environment, the resource. Though we are there, many scientists are working on solving those problems. But still, I'm a little bit pessimistic. But this is fine. It's fine for the earth, for the universe. Do we have a lot of people that come onto the show and tell us that we have a big challenge that we have to arise to. We have climate. We have geopolitical. We have exponential technologies. We have all of these things that are happening at the same time. And we need more young people and scientists and artists and inspirational leaders to step up and tackle these big challenges. Otherwise, the human species has big issues that we face. Do you think one of the big reasons why we have all the issues is because we're disconnected from nature, from what sustains us? What do you mean? Like the air, the food, the water, the nature, it sustains us and we're disconnected from it. So that's why we have problems. Do you feel that way? I feel, yeah, sort of. I feel we care, we care not enough about the nature. We're selfish. Most of us. And yeah. This is a big thing, too, is to figure out this Nash equilibrium between how much time and resources and energy I invest into myself and my own sustenance and success and how much I invest into the collective, into society, into my family, my community, my country, the world. This balance between those two things, how to harmonize them. Yeah. It's a very complicated issue. So I don't have a good answer. How can we solve this problem? Or, yeah. I'm glad that you bring it up, though, because it's something that is very close to our hearts and we talk about it a lot on the show. So I'm glad that you have a more realistic idea on the direction of the world rather than just naively optimistic or super pessimistic. It's good to be realistic about how challenging it is. Yeah. Let's talk about your journey. So who were you as a kid growing up? Where were you born? How did you get interested in science? Tell us about your story. Well, I was born as the only children in my family and from Anhui province by the Yangtze River. So the longest river goes across the middle of China. I was born by the side of the river. Since I was the only child in the family, I, my memory about the, when I was a child is that it's quite lonely and I will, although I will play around with other kids, but more often I was locked in the home when my parents were working. Yeah. And then what were your parents doing and what were you doing that got you interested in science? What were your parents doing? They were analysts. Analyst, yeah. About the chemicals. Chemical analysts, yeah. Yeah. Okay. And then what were you doing when you were young that got you interested in science? Well, I was pretty good at, at math, at chemistry and biology when I was in middle school and high school. So obviously I chose to become a STEM student in college. So because I, so maybe it's very typical Chinese student for, yeah. So because I have the best scores for my biology. So I chose the biology and also because I'm interested in the nature. Yeah. Yeah. I remember that I, I liked a lot that when we have a spring festival, spring holiday and the summer holiday, my mom will bring me back to my grandparent's place, which is located on the rural region of the city and the countryside. Yeah. Yeah. I, I love the forests, the lakes, animals. Yeah. Yeah. That's good. So okay. So so scoring really well in biology plus your love for nature got you to actually pursue biotechnology at Anhui University. Yeah. Okay. So now tell us about that. What were you studying when you were there? So it's not really biotechnology. So, so it's more general. You need to change your, your bio then, because it says biotechnology. So in the, yeah, in the certificates that bio, biotechnology, I mean, it's more general. I, we, we studied, yeah, plant botany, animal, animal biology for about a year. Yeah. Animal biology. Yeah. Yeah. And the microbiology. And microbiology, okay. So there in, in our university, more, more labs are doing botany and the microbiology. Yeah. Yeah. So we, so by biotechnology more related to using um, engineered my, my crop, uh, microbes to generate products. Yeah. Yeah. Yep. Engineering microbes to generate products. Yeah. Yeah. And I did a little bit, um, plant biology. I went to a lab and was focusing on a, find out, um, best condition to induce the a product, a product, production of, uh, garlic. Oh, wow. Yeah. Yeah. Because it's a very useful plant. We can have, uh, products out of it too. Oh, garlic. Yeah. Of garlic. It's a healthy food. Yeah. Yeah. Makes our breath smell. There's a lot, yeah. There's lots of, there's lots of good food with garlic. Yeah. Yeah. Yeah. How about the move to Peking University to the School of Life Sciences here after Anhui University? How did that move happen? Yeah. So we, I was, um, engaged in a summer camp, summer campus, um, here in Peking University. Also, um, Chinese academic, uh, institute. And, uh, yeah, basically I applied some universities as well as institutes for the summer, um, campus program. Um, in my, uh, when I was, uh, third year, third of my college and, uh, I came to Beijing, uh, the first time. And, uh, yeah, I, then, then the program goes like, uh, then there will be, uh, uh, introduction about different labs. And, uh, then you will be able to, um, work in the lab shortly for a couple of days if you, if you like. And you can talk to the PI of the lab. And that's when I met Yulong. So when I, the first time I met him, it's really like, uh, he was still like a college student. Yeah. That's when he just got back from U.S., just started his lab. So I didn't know that he is, uh, he was, uh, PI already. So I thought he, he is a student, college student. So yeah, then he, he was very enthusiastic talking to the new, new, uh, students because, yeah, one reason is because he, he wants to recruit a student to his lab. So then we have a talk, we had a talk and, uh, and, uh, I found that by that time I was, I was already interested in, uh, neuroscience. Okay. Because I think neurons are very unique cells. Like you can talk to them. Like you can stimulate them. They were firing a potential. And that, that time I was interested in, uh, uh, electrophysiology. I, I did a rotation in a lab and also impacting university only for one week. They were, they're a new, um, lab using electrophysiology, recording to study, uh, neural, neural functions and also a degenerative disease, diseases. And, uh, and Yulong kept showing up in the main hall in the building every day. And every day he will, we can catch up him and we will have a talk. We will have a talk and, uh, we talked a lot and, uh, he was a electrophysiologist and, uh, but he wants to do, uh, imaging with new lab. And I think it's, it's also very interesting. Yeah, imaging. I like, I like things like, um, you can you can have the results or the readouts immediately. Yeah. It's very, um, instant gratification. Yeah. Real tires. Yeah. And, uh, it's beautiful. Yeah. Right. It's very beautiful. So, so I joined the lab. And you, it was really, you, you got interested in neuroscience and you wanted to, like you really liked being able to stimulate a neuron and see action potential happen. You saw, uh, also this interest in being able to map neural activity. You wanted to be a part of, of doing that and see this immediate, immediate map, the immediate results of being able to map something. So in the combination of, of course, you coming here right on the time that you long was starting the lab and stuff. So what about how you picked what you were interested in doing at the lab out of everything in neuroscience? So I, yeah, the lab is more focused on, uh, technology, technology, techniques, developing new techniques. And, uh, the, the topic I chose was about, um, relatively underestimated field about elect, uh, about gap junctions or electrical synapses. So neurons will talk to each other. So the, the, the way we process informations, the, all the environmental stimuli is based on the neurons. They, they talk to each other. They process and the, the make a decision. So there are two, mainly two ways of, um, communication. One is the, through the release of neurotransmitters. The other one is the, I mentioned through gap junctions, which both happen in the synapse, both neurotransmission and electrical. Yeah. They, they can have, they can happen both at the same synapses or, um, gap junction is more broad. They can happen between not only the chemical synapse. So the chemical synapse can be a mixed synapse with neurotransmitter release as well as the channel. So wow, how do you know if a synapse is both for neurochemical and for electrical or if it's just for electrical? How do you, how do you know that? You can, uh, you can use, uh, electrophysiology recording. So imagine it is a two cells. Okay. The two cells, um, if you depolarize one cell, you stimulate one cell, you can record it. If, if it's, um, um, excitary cell. Yeah. So you stimulate one cell and you record the post-synaptic cell. Yes. It will give you an action potential if the pre-synaptic cell is the excitary cell. Yes. And if you block the chemical synapse, say it's blocked the neurotransmitter release, you can still record a signal. And that's the electrical. That means that that has electrical, can have a neuroelectrical communication. Yes. Not just neurochemical. Okay. Yeah. Okay. So out of, do we know out of all of the neurons in the brain, do we know how many of the connections, like what percentage of them are both neurochemical and neuroelectrical versus just neurochemical? Do we have any idea? We don't know. We don't know. We don't know. So yeah, that's the reason we need new technologies. But some are just neurochemical and some are both neurochemical, neuroelectrical and some are just neuroelectrical. So you have three, either chemical, electrical or both. Is that right or no? I think, I think they, they, probably there are no cells just electrical, communicate with just electrical. Just electrical. Okay. Yeah. So it's either both or just neurochemical. Or yeah, or they talk through different ways. So it's such as there's three cells, three cells. For example, there are three cells. Okay. These two only talk through gap junction, electrical synapse. Oh, wow. These two talk through chemical synapse. Wow. But for this cell, you have both electrical and the chemical communication. Interesting. Yeah. Interesting. How many, how many total can be at a, at a synapse? Can you have, how many nerves can be pointed at the same synapse? Sorry. You were giving this example of three, right? Yeah. Yeah. Three neurons in the same synapse. Yeah. It kind of doesn't have to be the same synapse. Neuron can have a lot of synapses. Yes. Yes. It kind of reminds me of streets because, you know, if you have the streets like this, this can look like four neurons, you know, with a synapse in the middle, right? And if it's maybe only, you know, wait, I don't know if I can make three. So this, so this is two. And then, you know, maybe this is like three, right? Something like that. But this is going that way. But then like, I'm wondering, could there be five or six? Yeah. One neuron can talk to many. Yeah. One neuron is connected to like a thousand or something, right? Yeah. Something ridiculously high. But, but then that, but, but out of, out of one synapse, one, one space, that synapse can be for two neurons or it can be for three or four, no? Or maybe? I think for one, just one synapse, perhaps it's only a uni, mono. Oh, unidirectional or monodirectional. One way. Yeah. Okay. It happens rarely that maybe they're, in some cases, they're maybe more than two neurons, and more than one neurons connected to. Okay. Cause you gave the example of three. But I mean, different synapses, different part of the neuron. Or if they, the, the chemical released for, for the chemical synapses, the released neurotransmitter can propagate, can travel long distance, if they're stable, they can, you know, along the way, they can talk to many neurons, other cells. Okay. This is already so interestingly cool and fascinating. So, okay, what is, so what's the, you called a, an electrical synapse is a gap junction. Yes. And a normal or traditional synapse is where neurotransmission can occur that is neurochemical, which is like dopamine, serotonin, and norepinephrine, etc. Yeah. Okay. So, we're still trying to figure out how many are traditional synapses versus also electrical synapses. And your specific study is on electrical synapses, gap junctions. Yes. Okay. Yes. So this is, so you have a, you have a nice visual of this and we can embed the visual here. But you have a, you have a, you have a pre-synaptic side and you have a post-synaptic side. And here's the synapse. What are, what are these called again at the end? This is dendrites. The ones that... Exon, this is dendrite. So the Exon. Yes. Pre-synaptic is Exon. Yeah. Post-synaptic is dendrite. Yeah. Okay. Exon, synapse, dendrite. Okay. Exon terminal is, Exon terminal and the dendrite. Yeah. These two membrane consist, consist the synapse, the structural synapse. Yes. Okay. Exon and then Exon terminal and then synapse and then dendrite here on the other side. Yes. Yeah. Okay. And then on the Exon terminal is super complicated stuff that I have no idea what I'm talking about. Yeah. It's where the neurotransmitter release. It's where the neurotransmitter release, but there's like vesicles, right? Yeah. Yeah. Yeah. So and the vesicles, they already have the neurochemicals in them. Yeah. And the neuron picks which one to release out of the vesicle. There are a bunch of vesicles docking on the presynaptic region. Yeah. So and they're very potential sensitive, calcium sensitive and yeah. If you stimulate the, the neuron will firing and the, the calcium will influx, well a calcium well goes into the cell and the trigger the membrane fusion of the vesicle. So they will. Whoa. Yeah. Release all together. Whoa. And is in the vesicles different neurochemicals ready to go? And then the neuron picks which one it wants to. They add the once terminal. Most of the time is just one type of chemicals. So all the vesicles contain the same type of transmitter. Oh. Okay. Yeah. Okay. And a different axon terminal, but same neuron is different neurochemicals? That's a very interesting question. And I think we don't, right now we don't have a clear answer to that. And that's why the method our lab developed is very useful. If you check out other episodes of yours, yeah, about the neurotransmitter sensors. So, so there are peptide neurotransmitters and a small chemical neurotransmitters. They can happen, they can be synthesized in the same neuron like for, for this neuron. Let's, let's say that dopamine neuron, they can not only release dopamine, but also GABA. And for other neurons, they can also, they can release GABA and neuropeptide. So, but how do different type of modulators in one cell being controlled to release? Yes. It's interesting. It's so interesting. Not clear yet. Okay. Yeah. Okay. So the neuron has some sort of, of modulation mechanism inside of it that, that based on what's happening in the environment as it gets stimulated picks, which neurochemical or neuroelectrical signals to pass on through its axon terminals to other neurons. Yeah, this is crazy. Okay. Okay. Different type of stimulation, different state of your brain. Some can happen very soon. Some can is a chronic effect. Yeah. Okay. So, okay. So let's talk about then, you picked electrical synapses. Why did you pick electrical synapses versus studying neurochemical transmission? So the rationale was very simple. I chose to study something less people study. Yes. Yes. Very good. Yes. Walk down the path that there's less people walking down. Yeah. Yeah. Less. Yeah. More scientific discovery potential, potentially. Who knows? Yeah. Yeah. Okay. Okay. Okay. So continue. That was the decision, but then how do you, you know, you start with, okay, so I've picked electrical synapses. Now, what the heck do I do? How do I even come up with something like Paris? Like, you know. Yeah. So they're relatively, so right now, or before this strategy developed, they're not too many or almost none of the methods to investigate gap junctions, which are non-invasive or genetically encoded. So we wanted, so the basic idea is that we want to develop a new genetically encoded non-invasive method to image the gap junction communication. By non-invasively, I mean, those existed methods, they are either used, I mentioned, the electrode recording. It will poke the cell. It damages the cell by the membrane integrity. Yeah. So basically, that's the traditional way where you inject dye, which also damages the cell. So we don't want to damage the cell. We want to remain the cell itself complete there. Yes. And so imaging is a very good method. Light is relatively non-invasive. Yeah. So the idea was use a imaging way to get signals from gap junctional communication. So how do we create the signal? So we came up the basic principle based on this channel, gap junction is a channel. So... This is so mind-blowing. Keep going. Yes. Are you still there? Yeah, yeah. I'm just with jaws dropped, just trying to compute all of the information. Yeah. Okay, keep going. So it's based on the, it's a channel between cells. So we want it, we want in the one cell, we want to generate a specific small molecule as a mediator. And in the other, the mediator will go through the gap junction. And in the kinetic cell, there's a sensor for the small mediator. So once we triggered one cell, there's a response in the other cell, then this demonstrate that these two cells are communicated by gap junctions. That's the basic idea. Yeah. So there's a, so Paris has to have one, on the pre-synaptic has to have an actuator. Yeah, the actuator. And on the post-synaptic has to have a reader. Yeah. A sensor, a reader. A sensor, a reader. And then you, when you see electroactivity, this actuator can be controlled. It can be controlled. Yeah. Okay. If we activate the actuator, it will generate. Via like my smartphone or like, how do I, you know, how do you, how do you like click a button and like you, the neuron active, how do you do that? How do you do that first part? I don't know whether you have heard of optogenetics. Optogenetics. So through light. Through light. Yes. Yeah, exactly. Okay. Use light to stimulate it, stimulate the actuator. And the actuator actually is a proton pump. It's a proton pump. Light-sensitive proton pump. Okay. Okay. So basically you're using the proton as the signal. As an actuator. As the mediator. As the mediator. The proton's the mediator. Yeah. You activate the actuator by the light. By the light. It will give you the mediator, which is proton. Which is proton? And proton can readily go through the channel. Yes. Okay. And the connected cell, there is a sensor for proton. For proton. Yeah. And then that sensor, you read out the data from that sensor. How do you read out the data from that sensor that the proton around? Yeah. There's a fluorescent protein. A fluorescent. It will emit fluorescence, which can be collected by the microscopy. Okay. Oh yeah. Okay. Okay. So you're literally stimulating with optogenetics on one side. And then you're cascading a proton to go across to the other cell that then is read out through microscopy by fluorescence on this other side. And then you know that the proton successfully made it across, which means this is an electrical synapse. And these two neurons are talking to each other. Yeah. And that's how you know, ah, a little bit of knowledge about neural communication. Yeah. Like you wonder what types are communicated by gap junctions, you can put the actuator in one type of cell, the sensor in another type of cell and stimulate one cell and imagine the other cell. Wow. That's the idea. Yeah. And we tried it and it worked as we expected. Nice. Yeah. That's always nice as a scientist. Let's set up this experiment. We think it's going to work and then you do it and it works and you can repeat it and you can get papers published and hopefully other scientists can use it and build on it. And then we know the chemo-connectomics better. And then in this case, it would be the electro-connectomics. Yeah. Or you can add them both chemo-electro-connectomics or electro-chemo-connectomics. It's so funny. The words are so good. But they're all encompassing, which I like about it. And in this case, it's literally, literally you're only doing one to one neuron. But down the line, you can possibly do maybe a hundred at the same time to try and see like big picture, more big picture neural communication. That's one of the goals. Is that right? More big picture neural communication? Yeah. The fact is that we don't, for now, we don't know yet which type of neurons, because there are so many neurons in the brain, which of them are talking through gap junctions. We don't actually know as a whole picture. We know some, but that's only a very small part of it. And how it being regulated, how it contributes to chemical synapses. Yeah. Yeah. Yeah. I asked you that at the beginning, and that's a really interesting point, is just what is the deal with electrical synapses versus ones that are neurochemical versus ones that are both neurochemical and electrical. There's so much information in this conversation, which has been so interesting. Yeah. Okay, continue. You're about to say something. So for now, we know that the main function for electrical synapses is synchronized neurons firing. Like those neurons are connected by gap junctions. They will fire together. So they will release transmitters together. Electrical synapses are used to synchronize, in many ways, neuronal communication, synchronize. So yeah, that's one of the functions. One of the functions. Yeah. Okay. Yeah. The others, because it can also... I have a question. So would it be like if I'm taking in some sort of a stimuli that is maybe becoming more frequent in my life, maybe it's like I'm going on the same route to school, or maybe it's I'm eating the same food, or drinking the same water, or talking to the same person, or hearing the same thing, or seeing the same thing, that would it then be that those... that neural communication is synchronizing through gap junctions to make it a little bit more efficient because I'm taking in the same stimuli? Eh, I think that's a little bit different. Yeah, that might be a lie. So by repeated stimuli, you probably are strengthening the connection between neurons. You're constantly stimulating the same circuits. So those neurons were not as connected as at the beginning, but you keep stimulating them at the same time, so they become more connected. So yeah, that... Yeah. What would be an example of a neural synchrony then with gap junctions? Like why? What outside stimuli in the environment would cause neural synchrony for me through the gap junctions? It's a constantly open channel, so it happens almost all the time. Like those neurons have gap junctions, they will fire together. They... any stimuli can stimulate this neuron, they they will fire together. It's constantly open there, so connected a bunch of neurons. For example, in the cortex, the interneurons, the interneurons are abundantly connected with gap junctions. The interneurons function is to modulate the primary neuron, which are the real executeer to do the job to control your behavior. So if... but interneurons can connect with... can regulate the activity of the primary neuron. So then those interneurons are connected by gap junctions, so they can fire together, so they can regulate a bunch of primary neuron together. So... How do you know what's a primary neuron versus a connector neuron? Does the primary neuron start the signal transmission? Primary neurons have long synapses. Have long synapses? Yeah, they have long projection synapses. Oh, long projection synapses, okay. Yeah. And connectors have shorter... interneurons. Interneurons. Interneurons, they look different, morphologically, they're different. Primary neurons have this long axon, and throughout different layers of cortex. Okay, primary neurons have a longer axon and a longer synapse, and interneurons. So primary neurons are the neurons who do... who does the job to control your behavior, because they connect... they have this projection... projected axons to control other neurons, to control... motor neurons. Okay, yeah. Motor neurons to control behavior, but its activity are regulated by interneurons. Yes. Are primary neurons primarily located in the cortex and in the... like especially the prefrontal cortex, or what? Or the... All over the cortex. Cortex, yeah. Okay. And then their long axons go to interneurons, which are then in lower, more like limbic structures. They project to... they control. They... it's very complicated. So they don't project to interneurons. They project to other primary neurons. Primary talk to other... Oh, the limbic talks to other primary. Where were... yeah, where were we on that point again? I was thinking about the cyclical potential, but... I know. I know. You're trying to make me come up with some examples about gap junctions function. Right? Yeah. And you were talking about like the interneurons have smaller... and gap junctions. Smaller... they don't have projection axons. They don't have... They don't have projection axons. Yeah. Okay. Interneurons don't have projection axons. Yeah. Interesting. Yeah. If you see a typical picture of a cortex, sixth layer of cortex, the primary neuron can go through all the layers, but interneurons can stay in the... there are many different types of interneurons in different layers. Yeah. But primary neurons span all the layers. Oh my gosh. Even the sight... even understanding like what a primary neuron does compared to an interneuron is so interesting. Okay. For another conversation. Okay. So to the applications, let's talk about of Paris. Okay. So what happens when you are using this optogenetically stimulated proton pump and then reading out the via fluorescence? That sounds really cool, but like what can it be, you know, applied for? So in the paper, we showed an application is to map the real location of electrical synapses. As I mentioned, neurons have complex morphology. They're axons and dendrites, but in a subcellular level, where does the electrical synapses, where does this channels localize on the cell? It's hard to study by other methods. So their cells, their cell body, they have bunch of processes. They can overlap. They can overlap with each other through at the different sites of those processes or between cell body context. So how do you locate them? Locate the channel. Using this Paris method, you can control the light. You can spot the light at different sites locally to induce the signal and to see where the channels is. If you spot the light, activate the channel on the dendrites and it gives you a signal. But if you stimulate the light, the actuator on the axons, you don't observe a signal. That might indicate those two cells communicate through dendritic interaction. That's one example for the application. We have spatial resolution and the localization of the channel in different sites of the cell might indicate something for how these two neurons can communicate more efficiently. We don't actually know. Such as if the channel is localized on the axon, it might be more efficiently to propagate the, to make the cell more easy to fire, easier to fire together. So basically they have spatial resolution. And for other application examples, I can come up like for drug screening. Gap junction not only exists in the brain actually, it also exists abundantly in the heart. So they synchronize the firing of the heart muscle making your heart contract. So the Gap junction blocker is used as a drug to protect heart from infarct ischemia. So we can use this method to screen more drugs that otherwise block Gap junction communication or regulate Gap junction communication. Yeah, can do this in vitro screening. Okay, so you have pharmacological applications, also just larger neural mapping and communicative of applications. Okay, okay. Because I can again get lost in all of the weeds of what you were just talking about. We're just so much nuanced. But that's, we can maybe, yeah, even get into another part of this, of a deeper dive into the brain science with you on all of these applications of another time because I just know that this is like way more nuanced. Like you were talking about ions earlier, right? I have no idea that ions were even a part of the brain neural communicative process. I didn't even know that. Well, you know what I mean? Like that ions are a part of it that there's primary neurons and interneurons that that there's just a better example. Well, this is also you're trying to teach about the edge of complexity to a big, we're trying to bring that down like explain like I'm five to me and to other people. And it's very, it's a very hard one to do, like electrical synapses versus traditional synapses with neurochemistry versus just electricity. Okay, so what are the applications for health and disease of this are mostly like you were saying of just having a better idea of mapping out neuro communicative infrastructure plus pharmacological understanding is like what where would you see like the most ideal applications of this technology in health? In health? Yeah. There are some disease, diseases caused by the mutation of channel protein. So one of them is called ODDD. It's a, I didn't remember the complete name, but it's a developmental disease. So the patient will suffer from abnormal development of their digitals like fingers, toes, and teeth. Interesting. Yeah. Their higher cognitive function also infected and not abnormal. And it's caused by a bunch of mutations on the on the protein, one type of the channel protein connecting 43. So you're asking about health, health. So how this method can help with health? I think we can use this method to study of the diseases caused by the mutations of the junction channels. Interesting. Diseases caused by mutations of the junction channels. Interesting. So there's mutations that happen at gap junction channels. Yeah. And those mutations cause diseases. Okay. Okay. Okay. Now I'm following. Okay. And so yeah, we can prevent those diseases by studying how those mutations happen at gap junction channels and either prevent them from happening or heal them. Maybe and at the mechanism level, how, how those mutations affect gap junction communications, whether this mutation caused disease by the abnormal, by altering the gap junction communication. Yeah. Because it seems like so many of our diseases are related to miscommunications. And so if there's a miscommunication happening at that gap junction, then it may be a leading to a serious disease. Yeah. Because some mutations might, some mutations might affect the communication, but some may not. So what indeed the mutation contributes to disease and it happens in a channel protein. So it's, it will be useful to test that, to test results consequence of the mutation. How about on a, on an, continuing our conversation about other diseased states of the brain and how those are issues of miscommunication or other neural communication, just issues in general. Where do you see all of the neurological diseases that we pick up? And I mean, neurodegeneration happens usually at end of life, but we're talking like 10 year old, 20 year old, 30 year old, like really young people are experiencing anxiety, depression, OCD, ADHD, blah, blah, they're like endless of the issues. What do you, what do you, what insights do you have about the development of those and why do you think they're happening and how do you think we can heal them? That's a very big issue and we don't have a clear answer what exactly happened in the brain, having those psychiatry disease now, but something we knew is that for those brains, so, so it's mainly happened like two levels, one is the molecular level, the other is the circuit level. So for the molecular level, it's like they, we know that the low level of dopamine, low level of serotonin is associated with diseases such as depression. So that's, that's a, that's a molecular level. And on the circuit level, it's the connection between neurons. There's something wrong with the connections. Either the region that controls the negative emotion, the connection are strong, strong, strengthened or the connection with a positive is too weak. Yeah, it can, yeah. So molecularly, the issue is about low levels of serotonin or dopamine and circuitry, it's either negative circuitry is too strong or positive circuitry is too weak. That's my understanding. It's your understanding, yeah. I like that understanding a lot. Yeah. Yeah, like if someone's like hyper OCD, it might be like, I've had like several times where I've seen like these two, there's like two hairs on the table over here. And I've been like, well, maybe I should just like brush them off like that. You know, like what's going on in my brain that's, that's so strongly wired that I must go and do that. Or is it, you know, too weak of wiring about like retaining or paying attention here or whatever it may be, or too strong of wiring of paying attention to all these other aspects of the environment or whatever, whatever it is. Depression especially, and has a lot to do with societally, like sociologically has a lot to do with being at the bottom levels of hierarchies, like people at low levels in hierarchies that don't have shelter, don't have water, don't have food that are constantly struggling to get by or is just harder for them to have high levels of happiness and low levels of depression. But there's a weird scenario where there's people around the world that have none of that stuff, but they're also really happy. Yeah. Which is very strange because then you wonder, well, what are the, the chemo kinectomics of their brain where they're totally happy when they have nothing, but then these people have nothing, but they're totally unhappy. How is that happening? Yeah, that's, that's interesting. And which reminds me of people, when people do, they research on mice, they will, they will use some way to make the mice stress and they will always find that some of group of, some mice will be depressed and the other mice will be resilient. Yeah. So there has to be something about the innate state of the brain. That's pretty interesting too. It's like, how, that could be an interesting question for chemo kinectomics or just a circuitry strengthening or weakening in terms of just how, how someone is resilient to stress compared to others. And is that have something to do with epigenetics? Is that have something to do with the ancestral genetics leading up to this point? Yeah, they, they're a lot, one way to study this is or powerful tool to study this is single cell RNA-seq. Single cell RNA sequencing. Yeah. Why? Why is single cell RNA sequencing so useful? Because it's at the, it looks at the transcription, uh, transcriptome level. What, what protein has the different expression level, like what's, so people can compare the mice with higher resilience and the mice with the sesame tea. By sequencing the RNA, you can see what a genetic difference is between high resilience mice versus low resilience mice to stress. Yeah. I think. Damn, RNA is so interesting. Yeah, RNA sequencing can give us a phenotypic, phenotypic phenotypal data. Yeah, can, can give you more. But we don't know. Maybe you, we will, you will find out a bunch of genes, a lot of genes. So yeah, by combining with other methods and things we already know, it can provide you some candidate at the molecular level to study to go further. Wow. Okay. I'm also really interested in how on the flip side of what we were talking about sociologically, there's lots of rich people that are high up on hierarchies that have high serotonin levels that don't experience depression. And there are also lots of rich people at the top of hierarchies that have low levels of serotonin and that have high levels of depression, which is like the opposite of what, it's the same thing we were talking about about the bottom, but it's the opposite in terms of people at the top having a similar effect. So there's a lot of interesting things sociologically and then molecularly in circuitry. Oh man, gotta love complexity. Gotta love complexity. It's a lot to understand scientifically, a lot to probe and try and like weigh variables and understand the nuance of these things. How about what would be your ideal neuroscience tool? What would give you ultimate power of understanding the brain? So I think there are three aspects we need to consider. One is how neurons connect, the connectome. Of course, it's very important. And the other thing is we need to perturb at the single neuron level to see. So at the first level, we need the connectome, we need the circuits, we know the circuits, we already know the neurons, how it connects. And the second step, we need to perturb it at the single cell level, either by. So now we have the optogenetic methods or other methods, chemogenetic methods to perturb it. And when we perturb it, we can know something about its function. The third thing is molecular level. You control the different protein molecules in the neuron. So like in pathologic condition, you already know that, for example, you already know this neuron activities changed. But what caused it? What's the molecular target basis? So you need to have the third strategy to control, perturb the protein at the protein level, molecular level. So combine those different levels, I think, more comprehensively for us to understand how the function works. I like that. I wonder how that would be packaged in like one tool that could do connectomics, perturbation, and molecular level. You can. I don't think you can. It's all possible. Everything is possible. We have to just design it. We have to design it. It's possible. We have to design it. And also, as I mentioned, the single RNA-seq is a very powerful level. I just think one database, one comprehensive database about incorporate all the information we have, like the connectomics information, connecton information, and the single RNA-seq information, and their behavior, related to the behavior, and the disease, the mutations. If we have all the informations at the single neuron level, and at the same database, like we have a mouse brain, we can click one neuron, then we can see the cell connected to which cell and where it locates. And we can also see the genomic of the transcriptome of the cell and what would have been done related to the behavior results that would be useful. Yes. To me, that sounds like a big simulation model of your brain, and me being able to click in and look through. But I would also have to have a history of your life experiences that have caused your brain to become exactly what it is today. I want to build a digital twin of you and me, of everyone, which is where we're heading in many ways. What about, how can we inspire more people around the world to work together? Because here we are in China doing these partnership interviews. Here you are about to do your postdoc in the United States. People around the world to go to other countries around the world and make friends and make relationships is very important. Yeah. How can we better work together? How can we better work together? I think for the PI in the lab, the group leader in the lab, they should encourage students more to attend more conferences and talk to people from different, go more to the happy hour and encourage them to join, attend those events, activities, and give them opportunities to present their work more often. I like that a lot. Okay. And then what do you think is a skill that young people should develop as we move into the exponential technology age? Coding. Why? Why do you say that? Because it's really powerful and it can make boring stuff take less time from you. I don't know. I feel like everybody can code. If you don't know how to code, you spend more time on boring stuff and be less efficient. Coding is also a way of perceiving the world in algorithms or in loops. There's so many. Yeah. You can train your logic. Train your logic really well. Yeah. Yeah. What do you think is the meaning of life? That's a really big question. I think the meaning of life is to make any contributions you can. I like that. That's good. What about where do you think consciousness originates from? Consciousness. So seems like basically consciousness is the activity of neuron. You think it comes from the biology of our body that it doesn't come from somewhere beyond the body? No. Okay. Then what about what do you think is the relationship between free will and determinism? Do we have free will? What do you think? I think we do. Why do you think so? Why don't we? Why do you think we have free will? Why don't we have free will? Can you give me some examples that people think they don't think we have free will? Okay. I was telling you a little bit about this before the show started. There's examples of people that have had a tumor pressing against their amygdala and they went out and killed people, their own family members. There's other examples of people being able to look back at your behaviors over millions of years, the evolution of human behavior, the evolution of microbes over billions of years before us that are now housed inside of our guts that are very much in control of our actions. Do you think it's you going to the refrigerator to get food or do you think it's your microbes telling you to go to the fridge to get food? If it's a microbe, if it's a microbe in your gut to tell you to get food, it's still you. Where is you? Where is you? Where is me? Is it in my brain, in my heart, in my gut, is it in my body or is there no me? Is there no you? Is this physical boundary of our skin not actually a real boundary but we're really all interconnected at a way deeper level than what looks like physical difference? I've thought about this question. Do we have free will? But I still think we have so it's like your will is still in you. The things you've been through makes who you are. The example you raised, like their patient have a tumor on their middle of the will go kill people doesn't mean they don't have free will. Well if they would have had free will, wouldn't have they been able to make the decisions themselves to not kill their family. So in that case, it's biology that has created something like a tumor that is pressing against my amygdala causing me to go do something. Just like biology like the microbes in your gut causing you to go and get food. Just like what is you? Is you your prefrontal cortex? Is you your brain or your heart or your gut? Where is you? Is you in this body? Is you outside of this body? Do you have a relationship with your with a higher self? Because these questions are crucial. They're critical questions. Because many people are overly wrapped in their egos and it doesn't give us greater collaborative potential when we're too wrapped up in our own egos looping us back all the way to what you said at the very beginning about selfishness. I don't know. I think it's kind of intermediate. We kind of have free will but we also kind of don't have it. Fair, fair. What is the role of love in life? It's very important. Tell me about why you said that. What is the role of love? So like for example for the being reports babies born with less parental caring will feel more insecure when they grow up? Yes. So love is important at the beginning of your life. Yes. If we all live in life in an environment with a lot of love it will help you become also a person feel more confident inside. You have more stress inside yourself which will make you more willing to give love to others. And if we could all work on that love within ourselves that we can then also give to others in our world a lot of those problems we were initially mentioning at the beginning just take care of themselves better. Last question what do you think is the most beautiful thing in the world? I think in my opinion is the ocean. Why? It's I'm looking for a word. It's endless. It's mysterious and it's powerful and every time I look at the ocean I am standing beside the beach looking at the ocean I will feel calm. I'm a big fan of diving. Every time I go under the water I can feel calm or calm and it's just amazing the underwater those animals living there are amazing and plants, corals and we yeah we need to pay more attention about protect our ocean. Yeah what a beautiful answer. This has been such a fun episode Ling thank you so much for coming on our show. Thank you. Thank you it's been such an honor this is so fun so mind-blowing across so many different aspects. Thank you thank you thank you thank you. Thanks everyone for tuning in we greatly appreciate it we'd love to hear your thoughts in the comments below on the episode let us know what you're thinking. Have more conversations with your friends families co-workers people online about neural communication in general the conversations we're having about electrical synapses about the chemo-electroconnectomics about all this crazy stuff and what it means for our future for our health for our longevity have more conversations about building better tools to study the brain and sharing those around the world. Also check out the link in the bio below to more of Ling's work and to youlongleelab.org and also support the artists, the entrepreneurs, the leaders, the organizations around the world that you believe in support simulation our links are below help us continue doing cool things like coming on site to China for more continued partnership interviews and go and build the future everyone manifest your dreams into the world. We love you very much thank you for tuning in and we will see you soon peace