• njikomes

Ep #30 Transcript | Alex Kwan: Psilocybin, Ketamine, Neuroplasticity & Imaging the Brain

Full episode transcript (beware of typos!) below:

Nick Jikomes 0:27

Alex Kwan, thank you for joining me.


Alex Kwan 3:20

Thank you for having me.


Nick Jikomes 3:22

Can you start off by just telling people a little bit about who you are, what you do and what your academic background is?


Alex Kwan 3:29

Sure. So I'm right now and associate professor in the Department of Psychiatry at Yale University. My lab we focus on one of the interests that we do is we focus on drug action. And we're very interested in you know, what are some of the effects of different kinds of drugs on the brain. We studied these in mice. So if you go back to my background, you know, I actually have a PhD in applied physics. And then I did a postdoc in neuroscience before I came to Yale. So that that's a brief background. Interesting. So


Nick Jikomes 4:07

you're studying the effects of drugs on the brain. In mice, I was hoping at the beginning, if you could describe for people the difference between an in vitro study in an vivo study in an animal model, which is what your lab does, and a human clinical trial. So, what are those different types of studies and what are the major strengths and weaknesses of each general type of study?


Alex Kwan 4:33

Right. So, an in vitro study will describe a experiment that is done outside of an animal. So these are typically culture neuron on a dish, for example, that you keep in an incubator. So these are cells that you grow. Again, you take out a ticket out in the animal when you grow it in a in a controlled environment. And then that's in contrast to in vivo experiment where these also Typically animals study or could be human study. But now you're studying in an intact animal that's actually living and breathing. It's doing his own thing. So obviously, in vivo experiment has certain advantages, namely, being that the animal is functioning. So he's not in this kind of detached environment, you're actually studying your question in the proper context of getting a living animal with the whole organism, you know, with the brain and the organ and everything that's in a in a kind of a intact system. And then you can compare it to a clinical trial. So what I do, I will consider preclinical study, because we only study the actions of drugs and animals, with clinical trials are typically done in humans. And they focus on studying efficacy of drugs, against certain diseases, or looking at the safety of these drugs, and so forth.


Nick Jikomes 5:50

And so for the studies that you're doing, so these are in vivo mouse studies, so you're studying awake, living animals, in this case, mice. And by studying laboratory animals, you can actually dig deeper than what can be done in a human study, because you can use more invasive techniques. And one of the things that's really interesting that I think a lot of people don't even realize can be done, but it's done routinely in science labs, is you can literally look inside of the brain of a mouse and watch neurons. Can you explain for people how that's actually done in the lab using microscopy?


Alex Kwan 6:28

Yeah, sure, can. I mean, that is one of the primary tool we use in the lab using these optical imaging imaging methods to look at the brain. In fact, it was, the technique that we use is unethical two photon microscopy. And that was actually discover or first use in my PhD lab when I was at Cornell University. So my advisor at that time who sadly passed away last year, where he and a couple other people invented this microscopy techniques. So how it works is that for the mouse, at least, you would drill a small hole in the in the skull, so you can access a brain, and then you replace that with a glass window. And then, in terms of the microscope size, we have a fairly fancy actually expensive, so called femtosecond laser, which, and then we have some equipment to scan this laser into the brain. And then through also fluorescence imaging, we can then try and start visualizing the pathology of some of these brain cells. As well as also, there are now different sensors that you can use in conjunction with these imaging methods to look at different biochemical signals within the brain cells.


Nick Jikomes 7:46

So you literally put a window into the skull of a mouse, and then literally, point A microscope into that window so that you can see neurons, can you talk a little bit more about how you can actually see the neurons what allows them to be visualized?


Alex Kwan 8:03

Yeah, so I should explain a bit more about that for license. So the fact that we can see the neuron is because the neurons typically contain either fluorescent dyes, or fluorescent protein. So how fluorescent work is, is that a fluorescent molecule is a molecule in which when you if you shine light on it, then it exciting electron to excited state, and then when it comes down and miss a photon. So by virtue of this light that is released, you can actually detect it. So how it works in neuroscience lab and is pretty common. Now in these days, you can use different genetic methods to express proteins that are fluorescent into the brain cells. So in our study, for example, we have animals that contain neurons that have the fluorescent proteins. And then this allow us to basically visualize it, because actually, because their brain endogenously have very little fluorescence. So anything that you can see through fluorescence, and you know, it's something that you actually label,


Nick Jikomes 9:00

interesting. So you can engineer you can create mice that have brain cells inside of their skull that essentially glow in the dark, that can be made to look bright, so that you can see him with the microscope, and you can literally look inside the brain of a mouse and see individual neurons. Before we get to some of the some of the information we're gonna talk about. I just want to alert listeners on the audio podcast. So we will be showing a few interesting movies and images of some of the things that you're hearing about right now. We will explain those verbally so that people can imagine what they look like. But on the video version of YouTube, you will actually get to see what some of the stuff looks like. And it's pretty cool. But before we get to that, I want to talk about one of the drugs you've been studying in mice, and that's psilocybin, the active ingredient in magic mushrooms. So one of the one of the things that's interesting about psilocybin is it's the schedule one controlled substance. It's been used illicit And recreationally for many, many years. But recently, recently, it's received breakthrough therapy designation by the FDA, based on some results in human trials, with respect to its anti depressant effects that it appears to have. And one of the things that people may have seen, that I want to ask you about is, you often hear or you'll see a image that seems to indicate that when you give psilocybin to a human, the functional connectivity of the brain changes, and different parts of the brain connect to each other, so to speak, that don't normally talk to each other. And what's interesting about those studies is they're done in humans, and we know they have clinical relevance. But what you can't understand from those studies, is what's actually going on at the level of individual neurons and circuits in the brain. And so can you just start talking a little bit about what you know there from your research in terms of what psilocybin is doing to neurons and circuits inside the brain?


Alex Kwan 10:59

Yeah, so I think I can't actually visualize in my mind exactly which figure you're talking about, is that really classic, I think from Robin Carhartt. Harris, where they did human neuroimaging and show that they had this graph right where the graph gets more connected. So that level of study is definitely very fascinating and show how the human brain might change in response to psilocybin. Animal studies like the ones that we do, given I think, different view. One thing is that you alluded to it a number of times already, it's a, it's a, it's a precision that we can look at them in animals, when when you do neuroimaging and human, typically, the voxel, which is the volume that you can image, and how what is the spatial resolution, how fine you can image is still very limited. So each each of these boxes would contain, for example, a million cells, at least. So it's a fairly coarse way to understand brain cells and their function and conductivity. By contrast, and animals with the method that I talked about these laser scanning microscopy, you can go down to single neurons, so we can label them with fluorescent protein, as we talked about. And then when I measured connection between there, and we're talking about connection between individual brain cell, so there's a lot of power in that, because if you can look at individual individual cells, then you can start talking about, you know, different cell types, because in classifying neurons and the different types, you can talk about whether these connections are in certain brain areas, certain layers of the brains, you can get fairly specifics in terms of what the drug does. And I think that will speak a lot to in terms of, you know, what is the mechanism and what what the what the drug do to the brain Secretary,


Nick Jikomes 12:43

I see. So, I'm going to try and create an analogy on the spot. So when you, when you see an image of a human brain from an fMRI scan, every single pixel of that image might contain a million neurons within one pixel. So all of that information has been blurred together, maybe it would be like, you know, if you were flying in an airplane or something, and you pointed a camera down at the Earth, and one pixel of your image contained like a football stadium filled with many people. But the techniques you're using are sort of like zooming in so that you can take images of all of the individual people in that stadium, is that reasonably accurate?


Alex Kwan 13:25

No, I think that's, that's a good analogy. Yeah. And then the idea is, of course, then, if you can zoom into individual people, again, following your analogy, then, you know, we know that they're unique, and they might respond differently. So that's why I think there's value in doing these kinds of really precise measurements.


Nick Jikomes 13:41

Before we get into some of the imaging experiments, and things going on in the brain. What, what happens when you give psilocybin to a mouse? Is it akin to what happens when you give it to a human what like, behaviorally? How do they respond? And how do you actually administer it to a mouse.


Alex Kwan 14:00

So definitely, it's not like a human, I mean, a mouse, a mouse is not a small and tiny human. They're a different animal. So Well, first of all, to administer psilocybin to animal, we actually do a so called IV injection, so we inject it into the abdominal space of the mouse. That's already quite different, right in terms of the route of administration, which in human would be typically oral or intravenous. And the reason for this is in the mouse, this is just a way to deliver a large load of a particular compound. And then secondly, the behavioral consequences of psilocybin administration is also distinct from the mouse. So it's really obviously very hard to ask the mouse or assay whether they will have any kind of subjective psychological experience and, and definitely one do not want to speculate whether they would have any kind of mystical experience. And instead a very classic assay that you we'll do in the mouse. And the observation that they see is that when you give drugs like psilocybin or other classical psychedelics that have serotonergic action, the drug will twist, the mouse will switch their head. So it's a, it's a very characteristic head movement at about 90 hertz, so 90 times a second, they will move their head. This is a very stereotypical motor response that all kind of rat and mice do when they receive psychedelic compounds. And there was a very interesting study just came out, I think, last year from Adam, Albert's lab from Sandy San Diego, where they show that this kind of hedgewitch response actually correlates very well with the potency of the drugs in humans. So there is some correlation between how much these kinds of drugs can elicit a head twitch in mice versus how potent it is, for at least inducing the psychological experiences of human.


Nick Jikomes 15:56

I see. So the drugs are psychedelics, at least like psilocybin are clearly inducing some kind of behavioral response in the animal. So something is clearly happening. As we're going to see. There's also something clearly happening at the cellular level. Has anyone done any Perceptual Studies in mice to show that they have perceptual distortions?


Alex Kwan 16:17

I think that's a fascinating question. And I think a lot more can be done. So I don't know the full history of that. I know there is some recent study from Chris Neil's lab in Oregon. Chris is a visual neuroscientists, much like myself come from a very basic neuroscience background. And he, he has a very interesting paper looking at the effect of DOI on cortical neural activity to the brain activity in the visual cortex of a mouse. But yeah, I don't know as much I mean, we talked about in our lab, we will be very fun to do some visual perceptual tasks with mice, and see how some of these drugs may or may not affect their behavior. Hmm,


Nick Jikomes 16:55

interesting. So what does psilocybin actually do to the brain in terms of its mechanism of action, so as a drug, what kind of drug is it and what sort of receptors in the brain being affected?


Alex Kwan 17:08

So similar, some, in some respects, similar to human right, psilocybin, when it's administered a drug, it also get the phosphorylated and metabolize into C lowson. And then Seelos. And when it enters the brain is a agonist of different subtypes of serotonin receptors. So it basically binds to certain membrane proteins in the brain. And then, some of these proteins, some of these receptors are known to be involved in the behavioral effects. For example, the ones I just talked about the hedgewitch response that people have seen in the mouse is probably mediated by a subtype of the receptor called Five HT to a receptors. But beyond that, yeah, there's just actually not that much is known. So they bind to the receptors in the brain, and they definitely activate certain other kind of molecular signaling. But even in terms of some of the basic question, like, what kind of cell type Do they add on? What brain areas are they gone, there's not as much as one would hope that we know, some of it is because the drugs just again, have been heavily regulated. So there is that basically a 23 year gap, where neurosciences events but we were not able to study these drugs meanwhile, and, you know, a lot of what we know is still from the 60s and 70s.


Nick Jikomes 18:32

So this to a serotonin receptor that is responsible for this behavioral head Twitch effect you see in the mouse, and that's also the same receptor that is responsible for the hallucinatory effects in humans, correct?


Alex Kwan 18:46

Correct. Yeah. So there are a number of studies, pretty convincingly either you can give the mouse or human, a another drug that will block the action of the fat tissue to a receptor. And if you do that, then, and then following is administer psilocybin, and we did that ourselves to then you can block these behavioral effects in humans and mice. There's also other ways to do that, for example, you can do what's called PET scans. So you look at the binding potential of these receptors. And you can also show that the number of the two receptors in the binding of it due to the drug is also correlated with some of these psychological experiences in humans. So there's pretty good evidence that the two a receptor is involved in these behaviors.


Nick Jikomes 19:29

Interesting. So it's binding to this receptor, but it's also binding to a variety of other receptors. So it's, it's not a very specific drug in that sense.


Alex Kwan 19:38

That's correct. Yeah. It binds to a variety of serotonin receptors with different kinds of affinity. Probably, yeah, yeah.


Nick Jikomes 19:47

So one of the one of the things you see in humans, apparently, is this potential antidepressant effect, which can actually outlast the administration of the drug, and that's very interesting. Can you describe for people what you see in laboratory rodents in terms of any signs of antidepressant or anti anxiety effects of psilocybin?


Alex Kwan 20:09

Yeah, so to study depressive like the Adrian Rodin's, we use a paradigm that involves stress. Because depression is also a human condition. And it's to do that we need a mouse model to study. And then how we do it in at least in my lab is we have a assay called learned helplessness. So, in this assay, what we do is we expose the animal to a series of foot shot. So they will go into this box, and then the foot will get shot. And shot comes in unpredictable time, and the animals also cannot control it. So these kinds of very unpredictable and uncontrollable aversive stimulus is known to induce a tremendous amount of stress on the animal. So we subjected the animal to these situation for two days. And then subsequently, that they will display a distress induced phenotype, where they will start to learn to not escape. So what it means is like, initially, we shocked them, but later on we when we test them, they actually had the opportunity to escape if they will, they can actually now search for way to escape, but they will actually, after subjecting into these uncontrollable stress, they will exhibit what's called learned helplessness. So they learn to be out of despair. And then they will no longer want to escape. So this is again, a classic paradigm in the mouse. And what we show though, is if you give psilocybin to the mouse, and we compare it to either saline, which is a control, or with ketamine, we show that if you give an insert psilocybin to the mouse, they actually escape a little bit more. So suggesting that they're less affected by the effect of that stress. So it's pretty far from depression, right? But it's, you know, what we can do in mice.


Nick Jikomes 22:03

So the idea is a normal, psychologically healthy mouse, if you want to talk about it that way, we'll experience something like a mild foot shock, something it doesn't like, and it will try to get away from it, as you would imagine, it naturally would. But if you keep doing that, in this uncontrolled manner, eventually that persistent stress will cause the animal to give up and display what's called learned helplessness, which just means it stops trying to get away. But if you give psilocybin it sort of keeps fighting longer. That's very correct. Yeah. Yeah. And so what's, what's the purpose of comparing it to ketamine?


Alex Kwan 22:42

Yeah, so when we do this experiment, we want it to both have a negative and a positive control, negative control being saline, which is just as salt solution that doesn't contain any drugs in it. So we want to make sure that that injection alone does not do anything which it did not. And we also wanted a positive control, which is something that we know that should work. So in this case, we actually tested ketamine. So southern aesthetic, ketamine is also known to have these anti depressive effects in humans and also in rodents. So in this case, we see also a increase tendency for the animal to escape to similar direction as a salesman, but actually suicide man was even a little bit have a little bit even stronger effect than ketamine.


Nick Jikomes 23:27

Hmm. Yeah, I wanted to talk about the contrast and the similarities between ketamine and psilocybin. So on the one hand, you've just told us that there is a kind of convergence in their effects. The details are presumably different, but they seem to have these antidepressant like effects, both in rodent models like what you work with, and in humans, and yet, the drugs are very different. So can you describe what we are maybe starting to understand there? How different are ketamine and psilocybin as drugs? And How could two very different drugs acting different ways actually give you similar effects?


Alex Kwan 24:06

That's definitely an ongoing research question that is of interest to audiences, a lot of people if we can find some more general principle for how some of these drugs might exert is the rapid and long lasting anti depressive properties they'll be. There'll be incredible. So in terms of what we know about these drugs, molecularly they're very different right? So ketamine is a antagonist, so it blocks a receptor or the NMDA receptor and as we talked about, serotonin has a completely different target and they target mostly the serotonin receptor subtypes. So we already know out from from the from the get go that they just target different places in the brain. We in our lab Elise we have a we have a hypothesis, where we suspect that even though they target at a molecular level, different receptors, maybe on a systems level, at least in terms of, again, brain circuits and brain regions. Maybe they there's more similarity to these drugs. And then in terms of actually how they change the excitability of some of the dendrites. So in terms of how they affect the physiology of the brain cells. So again, I guess it does summarize a little bit, these drugs are definitely target and at the molecular level, at a small scale, definitely have key differences. But maybe on the system level and the whole brain level, maybe they do something more similar.


Nick Jikomes 25:33

And can you talk a little bit about the time course of some of these antidepressant like effects? So you mentioned rapid antidepressants, and we know in humans that you have this very rapid, remarkably rapid effect, where within hours, I think, or even less than an hour, you can get people who are depressed, they're not responding to any other drug, and yet, they are responding very quickly to ketamine. Psilocybin, I believe, has a longer half life and lasts longer. But can you talk a little bit about the onset and the duration of the effects that that we've been seeing between ketamine and psilocybin?


Alex Kwan 26:08

So ketamine, the time course, is more well established. There's more many more clinical trials on it. And just a plug, I mean, it's actually initially discover as any person in my department right now in the department psychiatry at Yale by my current Department Chair, John crystal, that was in the 1990s. So even that back then, if you look at the original paper, they already show, you can start to see the antidepressant effect at about the four hour time point in humans. And that's, and then it lasts for you can see it lasts for about a week or so, in that initial study. Subsequent follow up to that I mean, show similar time course, I mean, in terms of the duration, maybe now, between one or two weeks or so. That's a single dose, right. That's a single sub anesthetic, those Yeah, one IV infusion. And you can also compare it to the acute effects of ketamine also have acute psychotomimetic, this dissociative effect, and that has definitely wear off before the antidepressant effect kicks in, so that those effect lasts for about two hours. So you have this acute effect that's dissociative, and then the antidepressant effect kicks in. For psilocybin. Again, there's less study on it, fewer human subjects being tested in these clinical trials. Before Well, from what I understand, they also see, and also like, as you mentioned, for ketamine, a big distinction is that ketamine is a, it's an infusion that psilocybin is often done as assisted psychotherapy. But I think some of the measures, early measures that some of the earliest time points, let's say, within a day, they already see some of these changes, or a few days, they see some of these changes in behavior. And I think I believe, you know, some of the studies from Johns Hopkins, and also from Imperial College, it shows that you can see them as long as maybe even several months later, which is quite remarkable and much longer than what has been shown for ketamine.


Nick Jikomes 28:09

Yeah, so that's one of the interesting things about psilocybin and these other drugs is you administer them to humans, and you have these effects that lasts for weeks or months, apparently, and that's long after the drug will be out of the person system. And so it implies that there must be something going on in the brain, you would think that outlasts the drug. And that's where you start thinking about plasticity and some of the experiments that your lab has done. So can you talk a little bit about what you've seen so far in terms of psilocybin effect on neuroplasticity? And perhaps just start off by telling people? What is plasticity? And what are some of the key parts of a neuron that you look at when you're thinking about plasticity.


Alex Kwan 28:52

So plasticity, basically refer to changes in the brain. Some of these changes, some of these necessity could be short term, so they could be on the order of seconds and minutes. One example, like a very kind of short term plasticity would be like adaptation, if you keep receiving a stimulus, eventually you start to kind of respond to it. Some of these classes could also be very long term. So I think a good example would be for example, some other substance abuse, if you if you consume these kind of drugs that you can develop, for example, dependencies and things like that, that also reflect a plasticity in the brain. So at the cellular level, one can also study plasticity by looking at changes in the structure and function of the neurons. In my lab, particularly, we're interested in plasticity in the dendritic compartment. So the dendrite of a neuron is a part of the of the brain cell that receive synaptic input. So this is places where it received information from other neurons. So Each one neuron receive inputs from around maybe on the order of 1000s of other neurons. And the dendrite is where we receive it, and then also integrate and process these inputs. And then eventually, then that integration lead to the cell to fire its output. So we studied plasticity in dendrite, and we think it's very basically, it's very important for how neurons communicate and how neurons receive this information.


Nick Jikomes 30:26

I see. So they're short and long term versions of plasticity. Something like adaptation, or short term plasticity might be like, when I put my shirt on in the morning, after a couple of seconds, I don't really notice the shirt anymore, because it's persistently sitting on my skin, and my nervous system adapts to it, I don't need to worry about it anymore. And then long term plasticity would be some sort of physical and or functional change that would allow you to say form a new memory that you hold on to for weeks or months. Yeah. So I think this could be a good spot to sort of reiterate some of what you just said, and show people some of the results from your lab. So we're going to describe all this verbally. But I will do a screen share to share some video and image content from Alex's lab. That'll be on the YouTube version. So let me try this right now.


Can you see that on your screen, Alex?


Alex Kwan 31:30

Yeah, I can see it.


Nick Jikomes 31:31

So starting at the behavioral level, this was the head Twitch response that I think you were talking about. I'm going to hit play here. And can you just sort of describe for people what's actually happening in this video?


Alex Kwan 31:44

Yeah, so here, in this video, we have two mice. In my lab, the mouse is in small rectangular box is the arena. And what you're seeing is that the left mouse have received one milligram per kilogram dose of psilocybin and the mouse on the right is received, basically saline solution, just a salt solution with no drug in it. And you can see that when we record these mouse movement, with an overhead camera, which is in this case, is a very, very high speed camera again, hedgewitch occur very rapidly, you can see that the mouse on the left and receive psilocybin showed this again, hedgewitch response, which is rapid movement of the ad, going kind of left and right and left and right. And they do it for about, I mean, on order, like five to 10 cycle. This is actually again, a very well known behavior. It's known, even in the 60s, I don't know actually how they used to do it, because at that time, they don't have these high speed camera. I don't know how they notice it. But in the lab, now we can, we can, we can record it. And pretty precisely,


Nick Jikomes 32:51

I see. So it almost reminds me of like when a when a dog or something gets out of the water, and they kind of shake the water off. So they have this behavioral response. And it's a pretty good correlate of the potency of a psychedelic as we would think about it in a human.


Alex Kwan 33:07

That's correct. Yeah. So again, Adam hubbers das lab have compare, I think, a panel about 30 of these different hallucinogenic compounds. And he showed that if you make a plot of, you know how strong this drug is in human in terms of the effective dose, and then what is the effective dose in mouse, you can see a very strong relationship.


Nick Jikomes 33:27

So now we're moving on to the second image, can you start to unpack this a little bit, and I want us to describe for the next few images, basically just the parts of the neuron that we look at, in the brain when you're studying plasticity. So what are we actually seeing here.


Alex Kwan 33:44

So this is a section of the mouse's brain, this is called like a coronal section, which is a particular angle of the cut of the brain. So what we do here is we sacrifice the animal, we take the brain out, and then we put it in fixative. And then afterward, we can now we bring it to a fluorescent microscope to image it. And this is not a normal mouse, this is a transgenic mouse. So this mouse is engineered to have a fluorescent protein already expressing in some of these brain cells. So that's what you're seeing in green. You can see here, this is the frontal cortex of a mouse, which is where we do most of our studies. And what you can see is you can see the small green circles, and those green circles are the cell bodies. And you can see also lines coming out of the circles and sometimes the lines don't connect to the circle. But those are those those lines, those fairly straight line that radiate out from the circle. Those are the dendrites of the cell body. So that's exactly where the some of the synaptic input would come in for the neurons.


Nick Jikomes 34:49

I see. So we're literally for those listening, we're looking at a still image and you can see these bright spots and these bright lines on the image and it looks like the glow in the dark color. Almost and that's coming from these neurons in this mouse brain that have been specifically engineered to fluoresce to emit light so that they can literally see them. So you see these blobs in a certain part of this section, those are the cell bodies of the neurons. And these lines are the branches, the dendrites, you're talking about Alex, and those you said, they're sort of reaching up, and they're probably listening are connected to 1000s of other neurons.


Alex Kwan 35:28

That's correct. Yeah. And I mean, and also, another thing to note is that this this mouse line, it only label a specific kind of brain cells. So those brain cells that are laying deeper in the frontal cortex of the animal and their cortex in the animal. So that's why you see this kind of beautiful organization, again, of these deep lanes cell body that with dendrites that radiate upwards onto the more superficial areas of the brain.


Nick Jikomes 35:54

Yeah, and for those listening these images are, they're actually very pleasant to look at, if you had no idea what you're looking at, you might just think it was an interesting photograph or piece of art. But it's actually the brain of a mouse, which is pretty cool. So this is a still a fairly zoomed out image compared to some of the experiments you do. And this is also a slice from a mouse that is no longer living. But of course, you have this remarkable ability to use two photon microscopes to actually look inside the brain of a living mouse. And I believe we have a short video of what that starts to look like. So I'm going to play this a few times. And can you just describe what we're seeing here?


Alex Kwan 36:37

Yeah, so you know, just like what you said, Nick, this is the now going to the live mouse. So when we do these imaging, actually, for this mouse, the mouse is an exercise. But it has this glass window on his head. And we're using the two photon laser scanning microscope to now imaging these same fluorescently labeled neurons. But now in the life miles, so what you're seeing in this video is that we're taking the image, and then we, and then we take another image that's a little bit deeper, about two micron deeper, and then you go another segment deeper, and then you go another deeper. So this movie basically shows you as you go into the brain, how that dendritic branching changes. And you can see the organization have that, that those kinds of dendritic branches. I mean, one of the things to note is that, you know, we're still kind of on the top of the brain, right? So this imaging is done from the surface. That's why you don't actually see the cell body, or you see just the danger that come out of the cell body cell bodies too deep to see.


Nick Jikomes 37:40

Yeah, so. So this is also a remarkable image we're looking at, it's pretty much a black and white image, but the light spots are the insides of these branches of the neurons called dendrites that are lit up, and they really do almost look like tree branches or something. Can you comment on some of the finer morphology here? So what I'm seeing is, I'm seeing a series of line segments. Those are the dendrites, but it looks like each of these dendrites has a bunch of little bumps or blobs sticking off of it. So what are we actually seeing there?


Alex Kwan 38:13

Right, so as I mentioned, a dendrite, probably contact 1000s of other neurons. So those the knob coming out of the dendrites are what's known as a dendritic spines. So dendritic spines, most of those dendritic spines are the site of connections for this neuron, most of them, the majority of which contain an excitatory synapse, which means that another neuron make a connection there and has a possibility of exciting and depolarizing this neuron. Some of those dendritic spines might also be immature dendritic spine, so they have to shape and maybe come in matured, enjoy a mature connection. But they're not yet assumption of connection. But this is a kind of structurally how one could see the, again, the connectivity of these neurons and what may be the size of the connections.


Nick Jikomes 39:07

So how do you guys look at dendrites and spines and use that as a way to quantify plasticity?


Alex Kwan 39:17

Yeah, again, because these dendritic spines signifies the connection, the possible size of the connection, we in the lab would measure the density of these dendritic spines. So how many of them are present for each of the dendritic branches we see, which will then indicate the number of connections. The other thing that we will measure from these dendritic spine is we will also measure the size of them, which would be the diameter of the of these little knobs because it's also been shown and it's quite well known that the size of these dendritic spines relate to the strength of that connections. And so if you have a larger head and that's it phi typically signifies a stronger connection between these pairs of neurons. And at a smaller spine, then it's, it's a less mature connection. And it's probably a weaker connection.


Nick Jikomes 40:10

Interesting. So you can literally point the microscope inside of the brain of a mouse, you can make the neurons light up so that you can literally see them. And then you can go in and basically take images and movies that allow you to literally count the number of connections or potential connections between one neuron and other neurons.


Alex Kwan 40:31

That's correct. Yeah. And one thing I should note is that one of the power of this technique is, you know, with a glass window, the mouse can carry that around for a long time. So one good thing about this is you can go back day after day, and we do that in the lab, and then go and find that same dendritic branch and the same set of dendritic spines, and then track them over time and see how the number and the size changes and which is basically how we can characterize plasticity and changes over time.


Nick Jikomes 40:58

I see. So I think we have one more image here. And it is this one. So we've zoomed in even further now. And I believe this is an image that looks at plasticity, before and after psilocybin administration. So can you describe for people what we're actually seeing here?


Alex Kwan 41:21

Yeah, so in a lab, we would basically the pic, the movie that you just saw, but maybe typically in a more magnified view. So you can see the individual tangent dendritic spines more clearly. And then what we do is compare that movie from day to day. And this is now basically instead of showing the movie, I'm showing you a projection, so compressing that movie into a single image, and then compare it day by day. So this figure here basically illustrates our main finding, which is comparing imaging these dendrites and dendritic spines before administering psilocybin the day before, and then we image it again the day after. And then also the subsequent day, and here we show you day five, as well as day 34. So about a month later, and what you can see is we can pretty reliably go back to that same dendritic segment and look for those same fugitive new neural neuronal connections. And what's interesting you see is that, you know, some of the spines, and most of those connections are pretty stable. And that's actually, hopefully that will be true, right? You don't want your connection to constantly be changing. But what you see is also that after the administration psilocybin in this mouse, you can also see some addition of some new dendritic spines, adjusting the growth of some new neuronal connections.


Nick Jikomes 42:37

So we've got these little blobs, these spines that represent connections to another neuron, some of them are coming in new spines, new synapses potentially are forming after psilocybin. We also have some leaving, what's the net effect of psilocybin in the mouse brain? Is it to create more connections or fewer connections?


Alex Kwan 42:59

Yeah, so the net effect that we see is that suicide and promote the formation of new spines. So we have quantify these and look at how the numbers changes. And that's known as the formation rate and elimination rate. So we call that a spine is forming, if you can see one that were there previously was no spine and then now you look at next day, and you start to see a spine, that's a sign this form. By contrast, if you have an existing spine, and then you see that spine got removed, then that's the elimination rate. And what we have seen in our study is that psilocybin increases the amount of spine formation rate, so we just see more slides forming, whereas the elimination rate does not really change, leading to a net effect of more dendritic spines, or again, reflecting more neuronal connection in the mouse's head.


Nick Jikomes 43:52

So I guess the summarize so far, you guys can literally see plasticity see structural changes in the brain of a mouse, using these advanced imaging techniques. So you can actually quantify plasticity, when you give these mice psilocybin, it changes the dendritic plasticity of at least certain neurons. The net effect is that the connections the spines, representing connections on the dendrites of these neurons become more numerous, but you do have some coming and some going away. Can you talk about what the relevance is there for something like depression, and what the excitatory synapse hypothesis of depression is and how you start to think about what this actually might mean?


Alex Kwan 44:35

So there's a lot of evidence suggesting that in depression in humans, but also in stress models in rodents, or in mice and rats, that there is a loss of these neuronal connections or synapses in particular areas in the brain, specifically the prefrontal cortex and also other places like the hippocampus. So that's been borne out by a number of neuroimaging study. And then, by contrast is also known that a number of any depressant, so the more conventional one, but as well as ketamine has the ability to promote the formation of new neural connections in animals, at least in mice. So here, what we think we're seeing is also that psilocybin seems to also have this capacity to promote neuroplasticity. And the number, the enhanced number of neuronal connections might then serve to counteract some of the some of the impairments that when they see the synaptic impairments they when they see on my associated with depression. I should note that though, I mean, in this study, what we did is we didn't work with any stress mites, we actually, in this case, work with mostly wild type mouse, a mouse that are normal mice, if you will, I mean, none of these guys are truly normal, their laboratory animals, so they're in a very, again, a very controlled environment. And they're inbred. But as normal as they could be, I mean, they're not stressed. So I want to make that clear. But nonetheless, in these control animals, what we see is that they form new spines suggesting the possibility that, you know, if you if you translate it to depression, it could counter some of those losses that you see with the disease.


Nick Jikomes 46:15

And what we're seeing in the previous image was that you were seeing changes in spine formation and elimination. You were seeing plasticity the day after psilocybin administration, but also a few days later, and even a month later. And so this seems to parallel the observation of humans that you have these long lasting antidepressant effects. Is that the basic idea?


Alex Kwan 46:39

Yeah, I think the timescale is the most interesting thing here. So I think, generally, I think already a lot of people think that compounds like psychedelics may have plasticity and using effect. So that's sort of almost a given, even though I don't know how strong the evidence is. But most people seem to think that, and they're also very good study, very rigorous study, in industrial system, like culture neurons, from David Olsen's lab, for example, they show that when you give them psychedelics, you can also increase and promote plasticity. So here, really the innovation that we provide is, we're doing this in vivo in a live animal. And if you do in light animal, then one question that we could ask, which is what we show here is to look at the timescale. And that's also what struck us, which is how rapid the effect was in terms that we can see within one day. And then also how long lasting it was, when we look at it one month later, we can still see some of the changes in that spine density. And you have to know that, you know, one month is actually fairly long in the mouse lifetime. And they live demos live for typically about two to three years. So again, I think the that sustained increase in the spine density was quite striking.


Nick Jikomes 47:50

Interesting, I do want to talk a little bit about compartmentalization both at the whole brain level different brain regions, and at the cellular level in terms of different parts of the neurons and or different receptors aren't things. But starting at the higher regional level, you mentioned previously that the images we were looking at tended to be from a particular region of the brain, part of the prefrontal cortex, can you talk a little bit more about that brain region and why you chose to focus on that.


Alex Kwan 48:20

So the human have a very pronounced prefrontal cortex, we have a very big prefrontal cortex. There's a lot of evidence suggesting that that's the area for executive function and higher cognitive functions, things like working memory, attention, but also mood regulation, and so forth. And in mouse, the most likely, homologue is the medial frontal cortex, which is where we're studying. And it also have very similar kind of connection to certain parts of other brains like the striatum, and similar kind of cell type. So and it also have a pretty strong reciprocal, direct and also indirect connection. And hippocampus, again, is a is a brain area that's very well positioned to regulate mood and cognition that are relevant for depression.


Nick Jikomes 49:12

And very, in very, very general terms. What is this part of the brain generally known for? Like what happens when you break this part of the brain?


Alex Kwan 49:22

I think classically the most well known as working memory deficit. So talking booster is the one that talked about this where, yeah, if you if you lesion this area in a monkey, they will basically fail to do tasks that involve working memory. So this is working memory means you're holding item in your memory for a short time and then do something with it. So for example, if I asked you, what is three plus two, then get the whole three in your head and then two and then do this operation. So it's thought that that is a poker if you get rid of the medial frontal cortex. Although I also mentioned there's also other features I mean, that's a cognitive cognitive part. But there's also a lot of mood regulating part that's been implicated in this area. So it's a mix of both.


Nick Jikomes 50:07

I see. And is it accurate to say that the, this part of the frontal cortex has often been associated with things like, not just emotion regulation, but like executive control over behavior, like deciding not to do something that you might want to do? For example?


Alex Kwan 50:24

Yes, definitely executive control over other, I think lower order brain region, they also control choices and decisions. Yeah, so I think in addition to working memory is also quite important that decision making, I think that's actually maybe even more relevant to depression, I think, one really well thought theory for depression is that you the disorder might come about because of dysfunctional and processing of rewards, right? If you get a positive feedback, you might not be able to adjust adequately. But whereas if you get a negative feedback, then you tend to reinforce them. So this kind of aberrant learning process could also really hurt, both in terms of cognitive, but also emotional processing of this information. So this area is definitely important for processing these rewards or lack of rewards. So again, I think perturbation to the brain circuitry in this area could be some could lead to a lot of behavioral problems.


Nick Jikomes 51:25

And so, you know, this area has been implicated in in different aspects of cognition and mood that are relevant to depression. You also obviously, are seeing these plasticity effects in this region. That's what we looked at before. Are there regional differences in how responsive neurons are to things like psilocybin? Does that have anything to do with regional localization of serotonin to a receptors, for example?


Alex Kwan 51:53

Yeah, that is an open question, and I think is a very interesting one. We know a little bit about how the drug is distributed in the brain once is administer. There's some old study from 1960s, when they radio label the drug, and then see the distribution in the mouse brain, or PET imaging humans. But I think, but that's just where the drugs are, it doesn't speak to how strongly the drug or what the drugs doing in the different region? That's actually a fairly open question, I think. So in a lab, actually one of the MD PhD student right now he's trying to investigate his question. So he, he has a mouse where if the neuron is active, then it'll be a label. And he's trying to look at kind of in an unbiased manner, looking at the whole brain and see if you give a mouse this drug, then what happens? Because I do think that, you know, frontal cortex, it makes sense that the drug acts there, and maybe other places like hippocampus, but there are probably a lot of other unexplored area where the drug could have a big effect. But it just had a power you might not know, and you really should map to old brain and find out what it does.


Nick Jikomes 52:58

But in general, you would not expect a drug to probably have a uniform effect throughout the brain? Because is it generally true that different receptors are expressed at different densities in different parts of the brain?


Alex Kwan 53:14

I see we're getting that. Yeah, yeah, that is definitely true. So I think, but that's also a fascinating question that I think is active research like so because when you give drugs like psilocybin or even ketamine, the drug is applied systemically, which means that you either do IV injection or oral and there's no a priori reason why should act on one brain region over the other because the whole body has a right. So then why does it that some drugs may have some selective action? And why some, why a drug do this versus the other? Yeah, I think I think part of the equation is yes, which brain area have some of these receptors so regions that have more to say receptors might be more susceptible or receptive, if you will, to psilocybin? Another, I think, interesting way to think about this, which I think is also important in my lab is trying to work on it as we think that also the neuronal architecture, kind of what kind of cell type is in the brain area and how they're connected might also dictate whether a drug acts on a certain region. But I think those open questions, right, like in terms of what give the drug specificity on what brain region and cell types.


Nick Jikomes 54:27

So another question I have is, there's two parts to it, I think. So the effects that we were looking at, were you you were seeing spine formation and elimination in the dendrites of frontal cortex neurons in the mouse in response to psilocybin. Do you know anything about the first question is Do you know anything about the underlying mechanism there? For example, does that effect depend on the serotonin to a receptor, the so called psychedelic receptor, and the related question would be more generally, can you speak about the potential of for creating or modifying psychedelics such that their plasticity inducing effects are dissociated from their hallucinogenic effects.


Alex Kwan 55:09

Yes. So I think that is a question that interests a lot of people. And in fact, when we submitted his paper on this recent study, we initially did not include the experiment to test this, but a reviewer asked it, so we have doing it, which was, yes, whether the fidelity to a receptor that's responsible for these behavioral effects, whether it also may be responsible for these plasticity changes that we see. So how we did that was, we use this other antagonist is blocker called cancer and which blocks the 5g to a receptor, we give it as a pre treatment. And then follow that up with psilocybin and see the passes in Sukkur. What we find in the mouse at least is that yes, even with this CAD Hanson pretreatment, you can still see the psilocybin induced structural plasticity changes that we talked about in the dendritic spines, although I have to caution the mouse again, here, this is not a very definitive experiment, because I'm here that this shows the difference between a mouse and a human, the mouse is not a tiny human again, so the mouse have different metabolism for cancer. And it turns out that cancer is a much more effective blockers of to the to a receptors in the brain than the mouse. So here, probably when we give the mouse cancer, we only blocking about 30% of the receptors. So there are still remain some receptor that might still do the plasticity effect, which I think complicated stories, what I think needs to be done, and I think that should be done, there should be a study, you know, either by my lab or some other lab within a year to use some of these genetically engineered animals where these receptors are just completely knocked out. And then kind of repeat this experiment and see if you can still see the dendritic plasticity. And you know, the receptors are completely gone. And you can see the dendrites and still being modified by psilocybin.


Nick Jikomes 57:01

I see. So the idea would be you take a genetically engineer mouse that has no five HTT receptors at all and its neurons, you give it psilocybin, and you would expect a, that it would not have the head Twitch response, because that's a behavioral effect that apparently depends on that receptor. But it could, it may or may not, but it could have these other plasticity or other effects, which would imply that the drug is acting through some other receptor to do that.


Alex Kwan 57:28

That's correct, yeah, if we use it to a narco animal, and then we repeat the experiment, and we can still see that psilocybin has an effect on these dendritic spines turnover them, then I think that would be very strong evidence, at least, and again, in the mouse, that the psilocybin can act through other types of serotonin receptors, or maybe even other mechanisms to induce the spasticity. And that would be, I think, quite a convincing evidence that maybe some of these beneficial action, which presumably will depend on the assessee could be dissociated from some of the psychological effects.


Nick Jikomes 58:04

What other receptors do we know that psilocybin binds to? Are there any candidate receptors or interesting receptors, in terms of psilocybin binding to them, but we also know that they could plausibly mediate some of these effects.


Alex Kwan 58:18

So in the, in the frontal cortex, another prominent subtype of receptor that psilocybin bind to that also is present in a lot of the neurons is the five HT one a receptor. What's interesting about one a receptor is they tend to have the opposite effects on the neuron as opposed to the QA receptors. So what the two a receptor does is if you if there's a so either so Tonin, or maybe suicide, maybe binds to it, then it tends to excite the neuron is tend to depolarize and make the membrane potential go up. By contrast, that one a receptor actually tends to inhibit the neuron, so it makes the membrane potential go down. So there's a bit of a yin and yang effect. And then beyond, I think, the 5g one a receptor. There are also other kinds of five HT two receptor that might be relevant does not to a Yeah, I think that's quite a lot of possibilities. There's also other subtypes that are in other cell types, that we just don't know much about what they do.


Nick Jikomes 59:22

Mm hmm. Can you speak a little bit about the specificity or the so called dirtiness of a drug like this? So, so classically, right, in medicine, historically, there's been a focus to look on specific drugs, drugs that have a high amount of specificity for one receptor, and they do one thing at that receptor, and they don't have so called off target effects, because the idea is, you know, you want a very specific drug receptor interaction, and you want to minimize the chance of other side effects that would come from a drug interacting with other receptor types. Some drugs psilocybin included don't just bind to one receptor, they bind to multiple, or potentially a large number of receptors. Historically, those have been referred to as dirty drugs. Could you speak a little bit about the specificity of psilocybin and ketamine and what that means for things like dose dependent effects? And neurotoxicity?


Alex Kwan 1:00:21

Yeah, so I think another word for that would be a quality pharmacology where you're trying to have a method that actually target different receptors be, you know, a single drug that does that as a dirty drug, or you can even have multiple drug administrators same time to which then they have different targets. And, yes, traditionally, I think people try to, you know, hunt for that single receptor that might then be mechanistically responsible for the disease, and try to be trying to be exact in that case. But I think increasingly, it's also shown that those strategies tend to not work very well, I mean, it because I think biology is complex. And also, you know, these receptors, they, you know, to a receptors, for example, is not only expressed in the brain, right, but it's also expressed in very high concentration in blood cells. So, even though you're targeting just one receptor, you're targeting that receptor in different places. So the idea is that a dirty drug might, through a combination action on a combination of receptors or targets, may be able to activate, you know, some function but also be more moderate in terms of the other side effects. So I think there's a lot of potential in there that's unexplored in terms of ketamine and Psycho and psilocybin. So I think psilocybin is pretty clear that as multiple action, ketamine also, I mean, ketamine is the NMDA receptor antagonists, but it's a pretty weak one, it's actually not as high affinity some of the many of the other NMDA receptor antagonists. And now I think other people are also studying is action and other receptors, like, for example, the opiate receptors. And then also, some of our work also showed that even if you just activate the NMDA receptor, it can also activate those receptors in different cell types, that then also lead to some kind of circuit or conversion effect. That is not a specific right, that is also if you will, kind of this dirty drug idea where it has a has a more complex effect. Again, I think that's possibly why ketamine is in some ways unique because of the this this kind of this dirtiness or these poly Pharmacol but not by family, but this sturdiness, you know, why? Why some of the other NMDA receptors, antagonists Could not you know, reproduce them or ketamine, any depressant effect, why why does search has not been successful so far? Again, it has this particular pharmacodynamics and also this particular multiple action and the different elements of the circuit that that makes it unique.


Nick Jikomes 1:03:04

Have you done any experiments comparable to what we just looked at? For for the plasticity in the dendrites with ketamine? Does it also have this effect on spine formation?


Alex Kwan 1:03:14

Yeah, so that's, that's where my labs research actually started. So we only started looking at psychedelics maybe about two years ago. Before that, we were actually quite interested in ketamine. So we probably started about eight years ago, or so maybe, I think when I joined the Department of Psychiatry in Galle, again, here, you know, the antidepressant effect was discovered. So there was a lot of interest. I'm going back now a little bit, but we how we started was, you know, we, before then I wasn't even aware of drugs, and I wasn't very interested in it. But once I got into the apartment, again, because of so much activity, both clinical and basic science, and knowing some of these drugs have these interesting psychoactive properties and also beneficial action, we got interested in it. So the first thing we started was actually ketamine and we apply some of these very similar in vivo dendritic imaging methods. And there we have done more work in terms of both looking at the structure of the dendritic spine as well as some of the function and chemical signaling there. So in other structure, yeah, ketamine seems to also do same similar things. So we have another study that was earlier before the southern work, where we look at turnover dendritic spine, and we see that ketamine also seem to have similar things in terms of promoting the increase in the dendritic spines in the mouse's brain.


Nick Jikomes 1:04:39

Interesting. So can you remind us to what the difference is that we know about so far in the time course of the antidepressant effects of ketamine versus psilocybin? So my understanding is psilocybin has somewhat lasting effects. It appears in humans at least I'm not sure about animals. Ketamine seems to have this almost immediate effect. Within hours, and it lasts I think you said previously for about a week. So is there clear evidence that the psilocybin effect lasts longer than ketamine? Are we seeing that in animals? What, what do we know about that?


Alex Kwan 1:05:13

Yeah, so those time scales, I would say, from the clinical studies, right, that beneficiary faxing human in a mouse? Yeah, I'm not actually sure. So in our first study, we did not actually look that far. So we have looked at about, I think, two weeks later. This is actually a very common question. So I've been already been asked this maybe two to three times, how does the ketamine compared to the psilocybin in terms of the temporary expired turnover? We should really do that and also look like a month out, and then see what ketamine does. I think there's a lot of interest in that. And even for psilocybin, you know, initially, we were even not even gonna look for a month out. But it was actually the post doc ninja who did the study. He was like, Oh, I still have these mice, they actually go and look at them again. She was the one who really Oh, yeah, well, let's go see, and it's still there. So I think, yeah, we should definitely do some follow up study to, you know, really chart that time course even more precisely.


Nick Jikomes 1:06:13

So what are the what are some of the research questions your group is asking right now?


Alex Kwan 1:06:20

Yeah, so my lab we're, we're, I think, interested in the basic action of these drugs. You know, I think our angle is that we're not clinicians, or we're not going to study humans and the drugs actually human. We're also not chemists, so we're not gonna identify different new compounds. But we are at the end, I will say neuroscientists, and also to some degree bio engineers. So we're very, I'm very interested in just the fundamental actions of these drugs on different neurons and the neuro circuit. And then for that purpose, I think psilocybin is an excellent drug to start in terms of, again, of its relevance. So right now in the lab, we're very interested in the mechanisms of how it actually causes these dendritic plasticity. And to search for that what we're doing right now is we're trying to do different kinds of measurements, in terms of how psilocybin affects things like calcium signaling in the dendrites. So some of the second messenger within the dendrite, the dynamics that could then lead to the eventual plasticity, some of the earliest steps. Were also very interested in the different cell types. So in this study, looking at a turnover spine, we look at one cell type, which is the pyramidal excitatory neurons, the one that we saw, but presumably, and is known the other cell type also have serotonin receptors. So we also want to look at some of the other cell types and see what they how they respond to psilocybin. And really, the hope is that, you know, by knowing about how this one drug, psilocybin acts on different parts of the, of the cortical neural circuit, we can develop a more coherent picture and what the drugs do and manifest to be able to facts, and then from there, maybe provide some insight to find other drugs that have similar kind of systems wide effect on the neural circuits.


Nick Jikomes 1:08:12

Is anyone doing functional imaging and awake mice for psilocybin or anything like that?


Alex Kwan 1:08:19

You mean, that kind of like the the kind of study that we're doing related to


Nick Jikomes 1:08:23

where the mouse is actually awake, and you're doing functional imaging of neural circuit dynamics, for example?


Alex Kwan 1:08:30

I see. So, yeah, we're doing some of it. I mean, so the spine imaging study, that structural study we just talked about was when the mouse was an exercise. But many of the other study we talked about in terms of recording spiking activity, motor cell types, or looking at calcium signaling, those are all done in awake mice. So there will be do Yeah, it's is to do to mouse when they're when they're awakened. In the with it with a similar kind of microscopy technique. There, I think a few other groups is also doing very similar kind of study. I think, again, that the topic is emerging, and it's getting very exciting. So I think more and more labs are getting interested in


Nick Jikomes 1:09:10

it sounded like you got interested in ketamine because you were in a department where it was studied. So it was a very entrenched in that department. And you were right next to some of the experts in the field. What actually got you interested in psilocybin and psychedelics?


Alex Kwan 1:09:27

Yeah, so I don't have a very interesting origin story in here. I have thought about it. There was anything I think, I thought about what happened is, I think, you know, I, I, I grew up and was raised in Hong Kong. So there was just very strict drug law, I think, just consistent with most of Asia. So I the only time I would read about drug is like in a newspaper and maybe the police is confiscate drugs. And the notion is like many of the drugs are very dangerous and And then the flip side of that is I just don't know anything about drugs because they there's no no no information about it. And that's kind of persist for a long time. And I, and I was trained as an engineer, so I have an engineering degree as an undergrad, and also apply physics degrees PhD. And I was building microscopes. And that was what I was doing that would have application for neuroscience. So again, that the interest in drug really started when I joined the department at Yale and realize that it's actually a very fascinating topic. And I feel like, you know, drugs are fairly defined subject, right, they have a particular chemical structure. They are what they are, you know, what you're studying. So, yeah, and then in terms of psychedelics, yeah, that happened about two years ago. At that moment, at that juncture, my research, I think we we did already a fair amount of work in ketamine. And we were just very interested to know whether some of the findings that we have in ketamine with generalized to other compounds, and psychedelics have also very intriguing behavioral effects, and in some ways, also comparable, beneficial actions. So, so that's how we got started. And


Nick Jikomes 1:11:13

how difficult is it to actually do this research with psilocybin? Is it cumbersome to actually get all of the approvals to work with scheduled substance like this?


Alex Kwan 1:11:26

It takes about it takes about half a year, I think to get. So I mean, one good thing is you have a year to get their license and some of the approval at the university to have the proper approval to do it. I think one of the is easier than human research, right? So we're looking to animals so that there's a lot less liability, another issue. And then we were also fortunate to be able to partner with Zona Institute. So you Sona is the nonprofit that's trying to seek to test psilocybin for different disorders, particularly depression. So they were I was able to be part of their drug supply program that provide investigator for research purposes, supplier psilocybin, which is what allow us to perform this study.


Nick Jikomes 1:12:16

Interesting. And so you did your PhD in the United States. Did you get your earlier education in China?


Alex Kwan 1:12:24

I, yeah. So I grew up in Hong Kong, and then my family immigrated to Canada. So I did my undergraduate studies in Canada in Simon Fraser University. Yeah, so I was I was an engineering physics major there. In fact, I never wanted to do biology. So I didn't take any biology class at university. And then, but no life life changes, right? Is it you know it the path changes over time?


Nick Jikomes 1:12:51

So did you just get into the neuroscience stuff? Because you were working on microscopes that were being used by neuroscientists?


Alex Kwan 1:12:58

Pretty much yeah, in graduate school, I built microscopes. So as I mentioned, the lab that I was working in, was the first to develop these two photon microscopes. I obviously came after that. So I was not part of the early cohort. But we were still very much into developing different kinds of microscopy techniques. And these type of microscope, the main application is neuroscience. It's particularly useful for imaging tissue that has scattering, and the brain is one that scatters a lot of light. It's very dense. And then by the end of my PhD, I was I was collaborating other neuroscientists, I was like, I'm kind of sick of working on other people's project. But I don't want to just build a microscope and look at other people's projects. I want to have my own project and actually do some neuroscience work. So then for a postdoc, and after that I turned into a bonafide neuroscientists and went to do neuroscience research. So what


Nick Jikomes 1:13:47

do you think some of the biggest questions in the field generally are in terms of psychedelics or other drugs and how they're affecting the brain with respect to antidepressant effects?


Alex Kwan 1:14:04

I think there are a lot of big questions. We've talked about a few. I think, one that for example, a lot people are interested in the whether these effects can be dissociated, like the so genic effect with the behavioral effects. I think it's also quite fascinating. Again, the variety of psychedelic compounds and the different, the slight kind of subtle nuances in the behavioral effect that they inserted humans. Again, for me, personally, going back again, I think I'm just at the core basic scientists, I feel there's a big opportunity to understand what these compounds do on on just brain cells and neural circuits at a basic level. Yeah, again, I think, if I can understand, what did they do to dendrites to induce these plasticity? Do they increase calcium decrease calcium, is that even essential? What are some of the other signaling pathways And then yeah, in terms of the cell types, they act on excitatory neuron, but what about inter neurons? And what is the totality of that effect? I think that kind of fundamental understanding and what on what the drugs do to neuro circuits. This is kind of a Systems Neuroscience level, that would be very satisfying to me.


Nick Jikomes 1:15:20

And are there there's certainly a lot more clinical research on psilocybin and psychedelics going on right now than there were 10 years ago, or even five years ago, there's a lot of new startups going into that space and actually doing clinical research, is there also been a large increase in the amount of basic research happening last few years.


Alex Kwan 1:15:42

I think there's some definitely, I think it comes with the awareness, just the popular media on these compounds, you know, becoming decriminalized in different areas, and also the press with it going through different kinds of clinical trials are very positive outcomes. So the interest in academia for basic research is also increasing. I think one of the difficult part here, and a lot of people know that is the lack of funding to pursue some of these research. In particular, I think, you know, most of the in academia, most of the support that we used to do these research come from the federal agencies, like the National Institutes of Health, and traditionally, it was not easy to get funding funding to study psychedelics, although I think things are changing, but still, it's it's slowing coming. And then that then there's an interesting, I think, tension now with a lot of companies, as you mentioned, like venture capitals, and other startup that see the profit and promise in this area. And they also want to actually then do a lot of industry sponsored research. So I think as academic this, there is a bit of a tug of war there, right? Like, because I want to do some of the basic science and be kind of not attached and, and pursue my passion. But then there's this big pool on the other side of sponsored research to do other things. So that's what I think. So I think there's a lot of interest that interests come from different sources.


Nick Jikomes 1:17:09

Well, Alex, I don't want to take too much more of your time. Are there any final thoughts on your research or this general topic that you want to leave listeners with?


Alex Kwan 1:17:19

I think that the final thought is, I hope I convey the excitement, I think in this area. Again, it's a basic scientist, basic New Scientist. There's a lot of cutting edge tools now. For example, the optical imaging that we talked about, by other techniques like optogenetics, and clear brain like anatomy, mapping, your neuroscience has come a long way. But on the other hand, the study of psychedelics has been standard, I think, and delay again, because of some regulation, but or other factors. So there's just a big opportunity in terms of applying some of these bleeding edge tools to understand what these compound or these drugs do, which I think is fascinating and could have a lot of translational value. So I encourage Yeah, neuroscientists, you know, if you're interested to get into the field is it has been exciting for us and, you know, we look forward to doing more of that as well.


Nick Jikomes 1:18:15

All right, Alex quad. Thank you for your time. Thank you.



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