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Gul Dolen: Social Cognition, MDMA, Oxytocin, Metaplasticity, Critical Periods, Autism & Octopuses

Updated: Mar 16, 2022

Full episode transcript below. Beware of typos!

Nick Jikomes

Professor Gul Dolan, thank you for joining me.

Gul Dolen 6:12

Thank you for having me.

Nick Jikomes 6:14

Can you tell everyone a little bit about yourself who you are, what your background is? And what your lab studies?

Gul Dolen 6:21

Sure, um, my name, you know, you said already gold Dolan. I am an associate professor of neuroscience at Johns Hopkins University. And I've had my my lab at Hopkins since 2014. And we studied the social behaviors, the neurobiological basis of social behaviors. And we're interested in understanding that from a therapeutic point of view, and also from a basic science point of view. So we're interested in, you know, development, evolution, synaptic plasticity, and how those things understanding those mechanisms can help us to find new cures for diseases like autism and schizophrenia and PTSD, and others.

Nick Jikomes 7:12

What kind of organisms do you guys work on in the lab?

Gul Dolen 7:15

Yeah, so mostly, the lab is focused on mouse work. We mice are incredible animals that, you know, offer us a really unique set of opportunities in terms of looking at synaptic circuit and molecular mechanisms. So, you know, the bulk of our work is focused on on the mouse brain. But you know, as we have gotten into different areas, concerning things like evolution, we found it to be really useful to branch out a little bit and study, octopuses. And we are also more recently getting more and more into human clinical trials, because some of our results really suggest some novel opportunities to help some brain diseases that we hadn't really thought of before. But, you know, we're just sort of always following the rabbit down the rabbit hole, and then that has led us to wanting to do some human clinical trials as well.

Nick Jikomes 8:18

Interesting. So So you study the neurobiological basis of social behavior. And you do stuff in rodents, mainly, but you're also touching humans, and cephalopods. So so your work is spanning? I mean, what is that hundreds of millions of years of evolution?

Gul Dolen 8:36

That's right. So yeah, our last common ancestor with octopuses was 650 million years ago. And just to kind of put that into perspective, you know, the dinosaurs are much closer relatives, you know, we were we were separated from them something like two 300 million years ago, right. So it's, it's, you know, it's a lot of evolutionary time. But, you know, I think that one of the things that the field of neuroscience has done is focused completely on trying to understand the human brain by either looking directly in humans using imaging techniques or, you know, clever psychological experiments. And then whatever we couldn't answer using those techniques, go to our nearest relative, you know, primate brain and try and extrapolate, you know, what is going on in a primate brain and then extrapolate that to human brains and then whatever we could do in them in a monkey, you know, we kind of go work our way further and further away from us in terms of evolutionary time. And, you know, a lot of the mechanisms that we know about how the brain works come actually from from mice, which are, you know, pretty close relatives of humans when you think of, you know, all of evolutionary time. So, the optimist approach is really Taking a radically different view, the octopus approach is to say, look, rather than focusing on, you know, brains that are similar to humans, maybe what we need to do to learn about the rules and the motifs and the mechanisms for building complexity out of synapses in circuits and molecules, is to go for the animal that is maximally different from humans, and yet can do some of the same repertoire of complex behaviors. And whatever we learned from there, we can be more confident that it's not some sort of accident of evolutionary history, but rather, you know, a genuine sort of rule or motif that is required for building that level of complex behavior. And this idea of like, looking for the maximally different is actually not mine. That idea of approaching, you know, understanding neural circuits came from Jay Z Jung, you know, who is the famous neuroscientist because he sort of discovered the squid giant axon, you know, his students, Hodgkin and Huxley, you know, we're, you know, very much using the squid axon to understand the basic principles of electrophysiology. But JC Jung himself said, you know, okay, split is interesting, but, you know, really the most interesting animal is the octopus, because it has these complex, you know, learned behaviors. And it's bringing so much different than, than a human brain. So he wrote about this in a book called a model of the brain. And we are really just taking up his call to action, if you will, you know, 5060 years later. And the reason that, you know, it took so long for anybody to, you know, want to do this isn't because, you know, neuroscientists forgot about it or not interested in that question. It's because, you know, octopuses are just didn't, didn't jump to the front of the line in terms of what kind of molecular tools were available to study them. Right. So the most important sort of tool that octopuses, you know, we haven't been able to get at, is that most studies of octopuses to date have been in wild caught animals, right? Because we have no way of reading them in a laboratory setting. And so we have no idea what happens in early development, we have no control over what life experiences they've had, you know, whether they were traumatized by a shark attack when they were to write like, we have no control over that if they're wild caught animals. And so, um, you know, I think they just kind of sat on the backburner. And so now, I think with this sort of renewed interest in pursuing this avenue, and some of the technical advances that have made it possible, you know, I think, I think now it's now's the time to return to those questions.

Nick Jikomes 13:15

I see. So So if one is interested in understanding, like, the very most general principles of nervous system function, it actually is an efficient approach to study widely divergent nervous systems, because you'll be able to triangulate those things that are common to all of them.

Gul Dolen 13:31

Right. Right. And I mean, basically, you know, I think that a good example of how we can be misled if we don't do that is the story of the cortex, right. So, you know, I think that if anybody, you know, if you've seen pictures of the cortex across different species, so what you will notice is that the human brain cortex is what we call giants to phallic, it has lots of folds. And that is thought to those folds are thought to be there to help us pack in a lot more neurons into a small amount of space. And then if you look at, you know, near relatives, the number of those folds goes down. And that reflects the fact that there are, you know, fewer layers of cortical neurons. And people have sort of taken that appreciation of the number of layers of Cortex correlated it to rough, you know, sort of approximations of intelligence and said, Well, look, humans are the most intelligent, they have the most layers of cortex. Therefore, having extra layers of cortex is the thing that makes that's really important. And you know, this whole concept of the lizard brain you know, that they don't even have a Cortex, right. So it's kind of built on this idea that you know, the cortex is the thing that makes us humans so special Right, and having extra layers of it, right. But an octopus doesn't have a Cortex, it doesn't have a basal ganglia, it doesn't have, you know, the lizard brain, right? It doesn't have any of the organizational principles that we have put so much emphasis on in terms of trying to come up with anatomical explanations for differences in, you know, intelligence across species. And so in my view, this sort of Cortex story is a little bit of a, you know, it's true for humans, and our primate relatives, relatives that the number of, you know, cortical layers seems to correlate with intelligence. But it's not a generalized rule that we can apply across the evolutionary tree. And it's not a and therefore, it can't be a requirement, it just seems it suggests that what it is, is a accident of evolutionary history, a contingent, albeit necessary, insufficient, if you will, fact, of our of our particular evolutionary history, but it's not a generalized rule. And if someday we ever found, you know, an alien who's an intelligent alien and another planet, the chances that they would have a cortex are pretty slim, actually. And that that could be the explanation for why they're so much smarter, you know, they're so smart as to be able to find us, that is unlikely to be the explanation.

Nick Jikomes 16:27

So I want to build up from for people some knowledge of, you know, some of the some of the key facts, some of the key molecules and circuits and things that the nervous system is using, with respect to social behavior and how it develops. So if we switch gears and go to rodents for a minute, where a lot of your work has been done, a lot of other work has been done. Can you maybe sketch for people, some of the normal behavioral milestones that exist in mouse social development, and what those are and the parallels that might exist in humans?

Gul Dolen 17:04

Yeah, sure. So um, you know, a mouse, you know, is a is actually a social animal. They, they exhibit a number of social behaviors that are very similar to human social behavior. So, you know, they, they, the moms take care of the pups, the dads, not so much as in humans, that other rodents do do that. So that's in Prairie voles, you know, both parents will take care of the rodents, but mice don't do that so much, myself. So don't pair bond the way that prairie voles and humans do. But on the other hand, mice do seem to in the wild, live in communities, so you know, between three to 10 animals living together, sometimes more than that, and that sort of communal living aspect of social behaviors in mice is something that the prairie voles don't have, but that humans do, right. So, variables live in, you know, just their pair, but they, you know, will attack any other, any other interloper who might be trying to come into their, to their little pear nest, whereas my sir, are more promiscuous than that, but also, you know, they allo parents, so they'll help each other take care of the pups, so one generation of females will help another generation of females, raise the pups, they'll take care of each other, and then they will, you know, they exhibit some amount of cooperative behavior, you know, in terms of foraging and protection from predation is really the the main reason that you know, sociality is thought to have evolved in this in this kind of peer peer social interaction. And so, you know, my stew exhibit changes across their development in what what types of social social interactions are the priority, you know, thing to invest emotionally in and this is also similar to humans. So, in mice, you know, when they're born, they're their social world is mom, and, you know, and brothers and sisters, if you will, and that sort of continues until, you know, they start to leave those nest and are become much more mobile and are able to forage further and further away from the nest. So around postnatal day 21 is when that really starts to happen. And what we see in you know, the research from my lab is is that as they switch into this mode of caring more about their group members, so, you know, other peers of the same age, there is what we call a critical period for that sort of forming of a group learning from the social cues of the group, understanding the sort of hierarchical dynamics and like what things the group values and when That group doesn't. And that's similar also to humans, right? So as humans, we learn all kinds of things about what's appropriate in our culture, and in our particular social environment. From our peers, right, like we, when I was growing up, we learned that like, bell bottoms were not cool, but acid washed jeans were like, the jam, right. And, like, we just, we learned that from our environment. And we also learned what was appropriate what what kind of behaviors are appropriate for girls, and what pattern of appropriate behaviors are appropriate when you're talking to adults versus talking to people that are younger than you. And we, we learn all of that information, because we are expressly, you know, sensitive to the sort of positive and negative cues rewarding and punishing cues we get from our social environment. And, you know, that's why teenagers are so much more susceptible to peer pressure. You know, they just care a lot what their peers think. But then after a while we and mice, it turns out, sort of outgrow that, you know, really intense focus on what our peers think about us. And, you know, anybody who's kind of made it through, you know, adolescence, you know, breathes a sigh of relief, when they can kind of stop caring so much about what everybody else thinks of them, you know, for me, you know, I love that I don't, you know, I wear comfortable shoes, even if they're ugly, and, you know, I threw out the acid washed jeans long ago, you know,

it's, you know, it's we outgrow it. And as we get older, part of, you know, one of the ideas about why we outgrow it is is that a it's emotionally taxing to care so much all the time about what people are thinking of you. And B, you know, it helps to stabilize your social group, right. So I belong to a social group of scientists. And so I have adopted the norms and values of my social group, you know, the things I care about, like, a lot are data and nerdy, being nerd delicious, is like something that I just love, right. And I don't belong to another social group of, say, football players, right. And so there are norms and values I don't care about, and I'm not trying to live up to them, I don't incorporate them in my value system. And so one idea about how those sort of social groups form is, is that the critical period closes, so that once you're in your group, you're sort of stably attached to those norms, and you're not quickly switching between all of them. And that helps to stabilize group memberships. Rather than just, you know, inviting scientists into the like, jocks club all the time, or inviting football players to come, you know, hang and so, you know, it's, um, it's, it's something that we see in mice and in humans, and we think that this is a really cool insight about social behaviors. But we don't think that this critical period for peer peer social learning, is the only social critical period. Right. So there are other ones. You know, we suspect that there's a critical period for, you know, mating and being interested in the opposite sex in the case of mice, although mice don't pair balance, so I'm not 100% sure how much that that exists. But certainly there, we would expect there to be a critical period for attachment to parents, attachment ups, right. So we think those are probably governed by, you know, slightly different neural circuits and different brain regions.

Nick Jikomes 23:54

Yeah. And the idea of a critical period, I think, is to have to most people, it makes sense, from our own experience that relatively early in life, we're very sensitive to certain things that has certain benefits for learning. But then at some point, there needs to be this consolidation process where things sort of get set in stone, so to speak, or at least partially, because you need to get good and figure out what particular niche you're actually going to operate in for your adult life. And it's interesting to see some of these parallels in mice that we see in in humans in our own lives. And I'm wondering if we could put a little bit more meat on this now in terms of what we know about the mechanisms involved from the rodent research. So with respect to some of these critical periods and mouse social behavior, what are some of the brain regions and brain circuits involved? And what are some of the the key molecules that one talks about there?

Gul Dolen 24:48

Right. So you know, I have to just back up and say that, you know, I did my PhD at MIT in the lab that studied the ocular dominance plasticity critical period. So, you know, almost all of my ideas about the critical period for social reward learning, which we discovered in my lab, are really just taking the principles that we learned from ocular dominance, plasticity and asking, are they the same for social critical period, right. Um, and the some of the mechanisms that have been proposed for ocular dominance, plasticity, include things like, you know, changes in excitatory, inhibitory balance, things like changes in the ability to induce synaptic plasticity, so not plasticity itself, but the ability to induce it. And this this difference between plus the city itself and the ability, the changing ability to induce it, it's called meta plasticity. And I bring it up because, you know, that is sort of clear in the visual cortex, what that means. But when we now take those ideas and try and bring them to the nucleus to come in, we have to be a little bit more precise in the way that we talk about them because plasticity in the nucleus accumbens, which is the brain region that my lab mostly focuses on. You know, most famously, the thing the plasticity in the nucleus accumbens has been associated with his addiction, because the nucleus accumbens is, you know, part of the mesocorticolimbic reward system. It's one of the nodes of this, you know, sex, drugs and rock and roll part of the brain, right? And so it's part of that circuit, and drugs like cocaine, for example, induced massive hyper plasticity in the nucleus accumbens, which you can measure either by doing, you know, electrical, you know, wholesale patch clamp electrophysiology type of experiments, but you can even see it, you know, just by imaging, the morphology of the neurons in the accumbens, right. So, that's, that's sort of hyper plasticity. And what we figured out is that in the comments, the critical period for social reward learning also corresponds to meta plasticity of a new type of synaptic plasticity, that we also discovered. It's called oxytocin, Ltd, or long term depression, and it is a synaptic Lea evoked hetero synaptic form of plasticity, you bath apply oxytocin, and then the responses that you're able to evoke by electrical simulation, change over time, and in the case of the accumbens, it's it's, they get smaller, but the direction of the change is not really, you know, it's not really, it's not really important. I mean, it is important, but it's not like, you know, more is more memory and less is less memory. Sometimes, a larger memory is encoded as a smaller electrical response. And that probably has to do with the fact that the neurons in the accumbens are, you know, the principal's cells, the ones that are sending projections outside of the nucleus accumbens to other brain regions are inhibitory. So I say that's a detail. But

Nick Jikomes 28:24

so before we unpack some of that stuff a little bit, I feel like it would be good to describe for people, how do you actually measure something like social the behavioral side of this, so so when you have adolescent or teenage mice, or whatever age they are, how are you actually measuring their social interactions and how much they like that, and those types of things? Right. So

Gul Dolen 28:45

basically, there is an assay that people who study reward and reward based learning have been using for 25 years. It's called conditioned place preference. And what this behavioral assay is, is, you know, you put the mice in a in a home cage bedding, so whatever bedding they were, they were raised on, and then you move them from that bedding one at a time into a new chamber, where they have two types of bedding, which they've never seen before. And you just measure how much time they spend on each of the two types of bedding. And that's just sort of the baseline response. And then you condition them for 24 hours on one of the types of bedding with one condition, and then another and then the next 24 hours on the other type of bedding with the other condition and so historically, when people have been studying, you know, drugs of abuse, you know, that would be like cocaine on one side and saline on the other side. And if they spend more time in the cocaine side of the bedding, then you know, they liked it, and we're able to form that learned association between the positive feeling of cocaine and that neutral bedding, right. And so we did not invent This behavior the Panksepp and law, this 2007 paper is the one that actually, that came up with this adapting this sort of drug reward conditioned place preference behavior, to social behavior. And now what we're doing is comparing, you know, the association learned association between, you know, neutral bedding and a social group, versus being in a neutral bedding by yourself. And the mice will form that learned Association, really, really well, when they are juveniles. So up until about postnatal day 42, which is, you know, basically they're teenagers, that's when they become sexually mature, that is sort of the peak of it, and then it kind of goes down. And by the time, the animals are mature adults, they're sort of neutral on it, right. And the way that I sort of explain the kind of learning and memory this is, right, it's not operative learning and memory. In other words, like, if I push this button, you know, a delicious, hot, steamy coffee is gonna drop down, and I'm gonna be able to drink it immediately that it's not that kind of like a conscious, learn sing, it's more of a sort of passive Association. And the best example, I can think of that kind of recapitulates that in our daily life is that, you know, people of a certain age, for example, really love mid sir meant mid century modern furniture. And that probably has something to do with the fact that, you know, we have warm and fuzzy associations between mid century modern furniture and our favorite grandma, right. And that sort of passively learned association is kind of the type of memory that we're learning that we're measuring here.

Nick Jikomes 31:52

I see. So, so adolescent mice have this kind of passive learning, they're really good at where they learn to prefer social contexts over ones where they are by themselves, basically, and this window closes over time. So so whatever is going on, is changing as the mouse develops such that when they're young, there's this passive form of learning that's enabled to happen. And eventually, it closes. And you mentioned before, oxytocin, which, you know, pot in the popular press, you always hear this referred to as the cuddle hormone. So what exactly is oxytocin at a very, very basic level? And what does that molecule have to do with this kind of change across development?

Gul Dolen 32:39

Right, so oxytocin is a peptide hormone. But it's not like a, it's, it's basically in this context. And I can get into sort of different ways that the brain uses oxytocin, if you're interested. But we have spent a lot of time trying to figure out you know, synaptic versus sort of more hormone like volume transmission type of functions of oxytocin. But in this context, what we're talking about is oxytocin working as a neurotransmitter. And so it is being released in very small amounts, and in a very synapse specific way. And so, you know, I think that the cuddle hormone idea is really much more of an accurate descriptor of oxytocin, sort of more released into the CSF going everywhere, kind of affecting everything in a in a general kind of way. So, I, the way I, the way I talk about it, the two types of oxytocin, really, I talked about is Mad Love, versus platonic love, right? So Mad Love is these magnocellular oxytocin neurons, they just don't like massive quantities of oxytocin into the bloodstream and, and into the cerebral spinal fluid. And so they just be the whole brain in, in sort of oxytocin, right. And that, for that sort of bathing of the brain and oxytocin enables, you know, very long lasting, powerful kind of attachments, but they're not really sort of sophisticated. So like, I mean, or narrow, right? So like, you know, when you fall in love with somebody, you know what this feels like, right? It's like, everything is roses, and you don't even notice that he never puts the toilet seat down, and then he, you know, leave, you know, as a procrastinator on everything that, you know, taxes and cleaning and whatever, but you just don't notice that he's like, Oh, but he's so cute. I love him, you know, and, and so that sort of big, big love is, in a sense, a little bit crazy. You know, it's a mad love, you know, I'm madly in love with somebody. And I think, you know, when parents fall in love with their babies, it's the same thing. You know, it's that sort of, if you had to care about all those The details of the love right? Here might you might not ever want to fall in love with the baby, because, you know, in some sense, they're sort of needy psychopaths who, you know, take all of your attention and give nothing back. But of course, as a species, we would never survive unless we were able to follow them madly in love with their babies. And so we just disregard all of that information. But that's very different, that mad love kind of function of oxytocin is very different from oxytocin's, you know, what I call platonic love. And so this platonic love is what we are using oxytocin, which is released by these other neurons, the parvocellular neurons in much, much smaller quantities, and in very specific synapse specific ways. And those parvocellular release mechanisms, we think, are well suited for the type of attachments that we think the parvocellular neurons are good for, which is sort of peer peer attachments, right. So when you're deciding whether or not you're going to let somebody into your, you know, social group, you know, you're evaluating them is this person going to have my back when I need it is this person, you know, reliable, and, you know, gonna be sort of loyal to the group. So you're, you're not just, you know, evaluating them, and you're not just like falling in love, you're sort of deciding whether they, you really want to include them in your group. And also, you know, you're not going to have like, systemic responses to them. So your eyes aren't going to dilate, you're going to be able to sort of play poker a little bit and, and keep your emotional response to the person a little bit more hidden, so that you can not let them know necessarily whether or not you're going to include them or not include them. And in fact, we think that that ability to kind of keep your your love close, if you will, and before you decide whether you're going to

let someone in your social group, that font, that type of obstacles, and that parvocellular, platonic oxytocin, we think is something that, you know, is important for social cognition, you know, and so social cognition is this idea that, you know, you are able to make a guess, a reasonable guess about what somebody else might be thinking, so that you can anticipate your behaviors based on what you think they're thinking, right. And so this has also been called theory of mind, it's something that you absolutely have to have, if you're going to play poker, right? You have to be able to say, I think that guy's got my jack and whatever, I don't really play poker, but you know, you need to be able to sort of make that guess. It turns out, it's the kind of thing that people with autism are very bad at. It's one of the things that's impaired in autism. Yeah, I

Nick Jikomes 38:01

never, I never thought of this particular thing before. But, and I don't want to get into autism quite yet. But But I would suppose that an autistic person would would not be very good at poker.

Gul Dolen 38:11

That's right. Right. I mean, autistic, like in the hospital, you know, when you see patients with autism, you know, they are, they're sort of unaffected in the way that they're sweet and kind. And because they're not very good at playing these, you know, mind games, in fact, I would suggest that there's a little bit of an opposite between autism and psychopathy, or antisocial personality disorders, the way we talk about that. Because people with who are psychopaths, they're actually very good at these Theory of Mind type of, or social cognition games, right there. In fact, they use their ability to say, I know that, you know, that I know that, you know, right? They use that ability to, to manipulate people, right? It's, it's one of their gifts, right? They use it so that they can get what they want. Whereas autistic people are, you know, are not not as good at this. And so, one idea is that, you know, and if you ask, if you ask patients about this, you know, people with who are psychopaths, if you say, why did you hurt my feelings? They will say, because it was interesting, I wanted to know what would happen, right? Whereas if you ask a person with autism, why did you hurt my feelings? Their answers, more likely to be something like because I didn't know I was hurting their feelings if I ever would have done it, right. And so this difference between the two types of, you know, the social cognition, so, you know, this importance of what we think is really important for this other type of oxytocin neuron, we think is the key to understanding some of these other diseases. of the social brain, which we can get to in a moment.

Nick Jikomes 40:02

Yeah. Okay, so, so to summarize where we're at so far, so you said something that was kind of interesting, you made this distinction of these two modes in which oxytocin can act and a neuroscience, you know, I've had many guests on the podcast, before I talk about this, there's this nice distinction between a neurotransmitter so it's a molecule that's used for point to point communication between this neuron and that neuron, and the neuromodulators, which sort of get released over wide swaths of brain tissue, and they have this sort of less specific, more general modulatory effect. And what you've told us is that oxytocin actually gets used in both ways. And that's sort of interesting, in the sense that you sort of talking about different kinds of social behavior that that the different roads have. So there's this sort of more specific form of social learning. And this what you called the Mad Love type of learning. Do you have that right so far, is accessing us both as a transmitter and demodulator? Is that tied into these different types of social behavior?

Gul Dolen 41:06

Um, almost basically, it's I mean, the general concept is right, but basically, just I want to be a little bit nitpicky about the terminology, because in both cases, oxytocin is a transmitter and a neuromodulator. But it's an it's not like, technically, you know, if it's a hormone, it should be getting into the cell and causing changes to DNA, you know, translation or transcription. But, so I don't really want to like break it down by those kinds of definitions. In both cases, it's acting as a transmitter and a modulator. And, you know, the classical modulators that we think of are things like dopamine and serotonin. And it turns out that oxytocin seems to be able to recruit serotonin release at the synapse. And the real difference between the two modes of oxytocin isn't really by those kinds of definitions, but more like, just by the amount of oxytocin that's being released. So one of them is kind of huge amounts of it, you know, kind of roaming around the whole brain just circulating through the CSF. And the other one, even though it's not, you know, released in very small amounts, like super small, I mean, basically, let me just say that words, because it's easier than trying to dance around. So there's large, dense core vesicles, which are the, the vesicles that oxytocin in that mad love state get released from and those hold about 200 or so oxytocin molecules, per vesicle. And typically, those release sites are like hundreds of them, you know, packed into a very small area. And so when you get released, you're, you're releasing, you know, 10s of 1000s of molecules into the circulating cerebrospinal fluid at one time, that's the Mad Love. The sort of Platonic love mode of oxytocin release is through medium dense core vesicles. And so now you're talking about two or three oxytocin molecules per vesicle. And where they're getting released is not into like massive amounts into the CSF, but rather into this space that we call it carry synaptic. So it's right at the border of the synapse. So it's able to kind of influence two or three synapses is the way I imagined it, two or three synapses locally, but not you know, everything that the CSF hits, right. So you know, sort of volume transmission is the way that we talk about that. And then and then you've got neurotransmitters, small molecule neurotransmitters like, you know, so what I'm thinking of is more like GABA and glutamate, right? So those are the main sort of neurotransmitters that most people are thinking about when they're talking about fast acting transmitters. And those get released from even smaller vesicles called Small synaptic vesicles. Right, so teeny tiny ones compared to the dense core vesicles and serotonin and dopamine are more like those medium dense core vesicles that we see for the medium version. So for oxytocin platonic love, it's probably more similar to the modulators like dopamine and serotonin. And the Mad Love is something that we don't see for anything else. I mean, it's just mad, right? I mean, they suppress and also we see that and then the small synaptic vesicles are for the fast transmitters like glutamate and GABA.

Nick Jikomes 45:00

So, so with respect to this critical period for social reward learning and mice, how exactly is oxytocin governing? That? Is it turning it on? Is it turning it off? What does that look like?

Gul Dolen 45:12

Right? So, you know, it's we looked for, you know, can we see any big changes in like the number of cells that oxytocin cells that are projecting to the nucleus accumbens, or number of cells in the nucleus accumbens that have receptors for oxytocin. And when we looked at those sort of big things, we didn't see any big changes across development, although some people have reported the receptor densities do, you know change in a way that that, that correspond to that peak of the critical period in the nucleus accumbens, but we were able to sort of measure and find a reliable correlate to the oxytocin to the social reward behavior was a change in the ability of oxytocin to induce synaptic plasticity. So earlier work that I had done when I was a postdoc at Stanford, I had shown me that if we give oxytocin in the nucleus accumbens, it induces a form of synaptic plasticity and novel form of synaptic plasticity, by recruiting serotonin. And so the way I think about that synaptic plasticity is it's sort of like, you know, the oxytocin molecule is saying, this is this is social, and the serotonin molecule is saying, This feels good. And when we have them happening together, the glutamatergic response properties change in a reliable way. And so that form of synaptic plasticity, we were able to correlate to the, to the social reward learning in juveniles. But then when we wanted to look to see if there was something that corresponded to this developmental change this critical period for social reward learning, what we discovered is that just like the learning behavior goes away with adulthood, so does the ability to induce that oxytocin Ltd. So that oxytocin induced synaptic plasticity in adults is also gone. So just like they can't learn the behavior anymore, they can't the synaptic plasticity induced by oxytocin is gone.

Nick Jikomes 47:24

I see. So so. So in a juvenile, oxytocin gets released, and then plasticity results. But after a certain age, you can you can release oxytocin at the same place at the same synapse, but the the plasticity that used to be triggered by that no longer is.

Gul Dolen 47:40

That's right. That's right. And what's interesting about that, is that, you know, even though we know that synapse, the oxytocin and serotonin are working together to enable social reward learning, the serotonin plasticity that we induce, so we can do the same manipulation, we bath apply serotonin, and then we get this massive synaptic plasticity in juveniles, we also get the same massive synaptic plasticity as adults, right. So that doesn't change over adult never over over development. And so even though they work together to encode social reward learning, there's a decoupling of the seratonin sort of plasticity mechanisms from the developmental regulation that we see that's being imposed on oxytocin plasticity.

Nick Jikomes 48:28

Interesting. So when we think about, you know, so So we've talked about social reward learning, and this idea of critical periods and some of the some of the molecular underpinnings related to these things. When we think about something like a deficit in social behavior, such as, you know, the phenotypes that you see with autism, to what extent do we know, you know, is this is this the failure of a critical period to open? Is this the failure to be in the right learning context? While that sensitive period is open? What what do we know there if anything about something like autism?

Gul Dolen 49:06

Yeah, I mean, this is an amazing question. And actually, you know, sort of the underlying sort of thread that we are we are pursuing. So just to kind of explain what we think is going on. You know, I will back up and say that when I was a graduate student, you know, working on those critical periods of ocular dominance, plasticity, my my thesis work was to test this idea called the M glue our theory of fragile X and autism. And the idea there was is that autism is caused by a biochemical imbalance in the way that another form of synaptic plasticity this time induced by the metabotropic glutamate receptor five and floor five, that this, this Molech the biochemical mechanisms that constrain You know how much plasticity is induced with any given stimulus, that the in the absence of one of these genes that's implicated in autism, which is fragile X or FMR, one, that there's an imbalance there, and that the way to correct autism is to sort of restore that balance between M Gu R, and FMR. One by reducing M Lu our signaling, right? And so that idea caught on in a big way. And everybody, you know, 26 other labs reproduce those results of our findings. And, you know, preclinically, this was, you know, everybody was just thrilled, right? Like, everybody agreed, this is a good mechanism, right? And then we went into human clinical trials, and the clinical trials failed. And so a lot of the people who, you know, don't really put that much investment into mechanistic studies in in, you know, animal models were like, well, obviously, they failed, a mouse is not a human, and we should just stop doing any, you know, research in animal models, but the authors of the clinical trial themselves, you know, when they wrote up the review of what they thought might be going on, actually suggested that maybe the reason the clinical trials failed, is because in all of the animal studies that we did, we intervene, right at the beginning of, you know, development, right, so either medically right at Genesis, or very early on right after the animals were born, but in the human clinical trials, all of our interventions, by necessity because of ethical requirements of doing trials, first in adults, before you move them to humans, all of the interventions happen in adults. So what they proposed is that there must be a critical period for social behaviors, right, that has already closed, that by the time we did our biochemical intervention, we were no longer able to correct because the we corrected the imbalance, but the relevant critical period was closed, so they weren't able to learn it. So, you know, I think this notion of a critical period, you know, if we could figure out a way to reopen this critical period in adulthood, and then Pair that with the biochemical imbalance that, you know, say an M glue R type of mechanism, then maybe we would get therapeutic efficacy. And so we don't have any results on that yet. Well, that's a theory that we are testing. And we have a lot of really sophisticated sort of technical ways that we can we can get it that. But But that's, that's sort of the idea that we're testing. Right?

Nick Jikomes 52:42

So, so one question related to this. The most famous critical period probably is, is the one for language acquisition in humans. You've talked about a bonafide critical period in rodents. And of course, in animals, we can really define these things in quite a bit of detail, a level of detail, we can't in humans, for social behavior related critical periods in humans. Has anyone formally clearly demonstrated these things in humans? Or is it the type of thing that certainly looks like it's true, but no one's like, actually really characterized it yet?

Gul Dolen 53:18

Well, I'll tell you, when I first started presenting this critical period data, I have a friend Linda, Will, Brett, who, you know, is much more advanced in her decision to sort of straddle the human literature and the human literature. And she's, she's actually much more actively involved in doing sort of studies of social critical periods in humans, but she was part of this society for cognitive development. Flux, Congress is what it's called, and, you know, they're most of the people are really interested in these, like, questions of human brain development. And, you know, I went to the talk, and literally, I was the only person who studies rodents at the whole meeting, besides Linda, and, you know, every single talk one after another felt like, to me anyway, like, would stand up and be like, you know, we looked at, you know, the children at age four, and we compare them to age 16. And we saw this differences in the way that they value social interactions. And this suggests, but does not prove that there must be a critical period, right? And then somebody else would describe some other behavior, right? But the problem is, is that in a human study, it's very expensive, right? So you know, in a human study cost millions of dollars to be able to do a study with like, you know, two ages and you know, maybe 10 people in a huge in each age, right, it's expensive. Whereas, you know, in a mouse study, we can we, we literally looked at 900 Mice both sexes across 15 Different ages, and so then we can like really map out a beautiful, bonafide critical period. And that ends up being sort of something that the people who study human social behaviors and human social development really can hang a hat on. Because what it means is, is that these nuanced differences that we see in humans across ages are not some artifact of culture or, you know, something that we just see in this one small population of teenagers. But rather, this is an evolutionarily conserved old mechanism that we see across mammals. And that I think gives it a little bit more support to kind of make the claim that these changes we're seeing across human development are sort of evolutionarily old conserved mechanisms that we can also measure in the road.

Nick Jikomes 55:54

Yeah, and I guess when you sort of take the bird's eye view, based on all of the forms of plants, developmental plasticity that have been observed in various different animal models, at the very least, it would be remarkably surprising if there weren't some kind of developmental sensitivities playing out in humans as well. And it sure does look like that. If you just sort of passively look at look at what we do throughout throughout our own development. I want to put a pin in the stuff for a moment, because we're going to come back to it in a very interesting way, based on some of the work that you've done. But before we get there, you know, we've kind of talked about rodents, and we're just talking about humans a bit. We've been talking about this critical period stuff and social reward learning. But of course, at the beginning, you mentioned these other creatures you work with, which are not really known very much to be social animals. So can you talk a little bit about the octopuses here and what their social behavior does or doesn't look like at a very high level?

Gul Dolen 56:50

Yeah. I mean, so basically, when I started my lab, you know, I had this dream of, you know, maybe studying brain evolution. And I was just kind of hemming and hawing. How am I going to do this? What am I gonna, what's gonna be my entry point for this. And then one day, I saw this paper, published in, you know, very high profile journal, showing that the genome of the octopus had been sequenced, and this is Carrie Albertans work. She's now at the Woods Hole, Marine Biological Laboratory. And the genome, it turns out is like the entryway right to be able to study evolution. And and so I started looking it up. And I was like, I wonder if there are any social behaviors in octopuses? Are there any social octopuses because I knew that they were a social in general. And it turns out that there is of the 300 or so species of octopus that we know of, there's only one that has a social behavior, that is like a bonafide social behavior, some people will claim that there are some species octopus tetricus, in Australia, people have tried to make it claim that it's social, but really what it is, is it's socially tolerant. So it will, if you put too, you know, tetricus, you know, in a, in a tank together, they won't kill each other. But by my definition of sociality, that's just tolerant. And it's actually an indication that they're not actually a social species. Because if you think about really, really social species, and if you take two random people, you know, humans are very social. But if you take two random people and make them live, you know, in a pandemic in the same room together, the chances that they'll be able to, you know, that both will come out alive, especially if one's a Trump supporter. You know, Biden's supporter are are slim, right, like, what are social behaviors, one of our social behaviors is, you know, territoriality and

Nick Jikomes 58:46

sort of versus out group discrimination.

Gul Dolen 58:49

Right. And so, you know, we're and we're very tribal in the way that we differentiate between in group and out group, right. So, I would say that that's not a very social species. In fact, the only social species of octopus that we know of, is the larger Pacific striped octopus, who's, you know, I can tell you the story of that species because it's super interesting, but it will be a digression. So kind of depends on how much you want to go in that direction.

Nick Jikomes 59:17

But let's let's let's focus on what species do you have? I mean, you have octopuses in in your lab that like, are in a big tank.

Gul Dolen 59:26

No, so right now, we are not doing any sort of lab work on octopuses right now for us. Right now we are really focused on trying to get the genome done of this other species of octopus, which turns out to be the sister species. So very closely related to that social l larger Pacific striped octopus. We are doing the genome of that and octopus cerchi i, which is the pygmy zebra octopus. And so that's what we're mostly We're working on right now. But in the past, we've worked on the species whose genome is already done. And that was the California to spot Octopus, octopus by Mackey ladies,

Nick Jikomes 1:00:13

what is their I mean, just what is their like wild type social behavior look like as far as we know.

Gul Dolen 1:00:18

They're not social. So if you put two of them in the same tank together, they will kill each other. They avoid each other socially, they want to be as maximally far apart as possible. And they will suspend that a sociality during meeting, but only for about two minutes. And then they go back into attack.

Nick Jikomes 1:00:40

Gotcha, gotcha. So so we've got three different species we've discussed so far. Rodents, humans and octopuses, the particular rodents you work on, are social creatures, you've defined this critical period for social reward learning, it has something very much to do with oxytocin in terms of its mechanistic basis, we, we know that there are likely to be similar kinds of things happening in the human brain, we're very interested in understanding how we might fix social deficits, such as autism. And you, you also have done work with these non social, even anti social creatures, these these particular octopuses. And some of the experiments you've done, you know, one of the some of the subtext of what we were talking about before was, you know, if there are certain molecules in combination at certain circuits that can open and close critical periods, and that's going to be key for whether or not someone develops normally or abnormally, it sure would be nice if we could figure out some of those details to reopen some of these critical periods to fix things like autism. And you've done some very interesting work that has to do with a lot of that stuff. And it has involved giving different creatures, MDMA. And so I want to talk about some of those experiments right now, if you could very, very briefly just describe the typical effects of MDMA in adult humans, and then we'll go into the mouse work.

Gul Dolen 1:02:05

Okay, great. Yeah. So MDMA is, you know, a psychedelic drug that has been used recreationally for, you know, decades. It's also called he or Molly or X. Sure, there are other names, but I'm not hip enough to know what they are. But anyway, that's what the sort of street name is. And, you know, MDMA has these remarkable pro social qualities, right. So in a recreational setting, people take it and, you know, they have this desire to form these, you know, 30 person cuddle puddles, where they're all hugging and touching. And it doesn't matter if it's like, you know, a festival in the desert. And it's super hot, people are just, you know, really interested in, in being social touch, you know, hugging and being social. And that is something that makes MDMA a little bit different from the other psychedelic drugs, right? So all psychedelic drugs have this property of inducing an altered state of consciousness, which MDMA does as well, but MDMA specific character, it's like, what colors it's acute effects, really, an differentiates it from the rest is that it has this pro social character quality.

Nick Jikomes 1:03:27

And so we know, you know, we know that that's the effect in humans. Lots of people have taken MDMA in both recreational settings and clinical settings. And we'll talk about some of the clinical work, I think, but you've also given MDMA to mice. So do adult mice respond in the same way, broadly speaking, that humans do and have more pro social behaviors they exhibit?

Gul Dolen 1:03:51

Yeah, yeah. And in fact, we didn't discover that that's been known for, you know, a couple decades at least that that, you know, if you just, you know, you put mice in a chamber that has another mouse in it and, and, and chamber that has a toy in it. And, you know, you give them MDMA, they'll spend significantly more time in the side that has the other mouse in it. And that's, you know, that three chambered social approach task is the way that we measure, you know, how much they like social interactions in a rodent. And this is true for mice. It's true for rats. And so, yeah, that's been known for a really long time. And yeah, and so, yeah, that's been no.

Nick Jikomes 1:04:33

And so what did you guys discover in terms of MDMA, its ability to interact with this critical period that you define for social reward learning?

Gul Dolen 1:04:43

Yeah, so for the critical period, what we wanted to do is take a slightly different approach. So we said okay, we know that they're pro social is that the drug is pro social in an acute setting. But let's just set that aside for a second and ask What the long lasting effects of MDMA are going to be in the brain. So what we did is we took animals that were adults, so these are animals whose social critical period is already closed, okay? And then we gave them MDMA. And then we waited for 48 hours. So, you know, the acute subjective effects lasts anywhere from three to six hours in a day in humans. And in mice, it seems to have the same time course, and, and then we just waited so but at 48 hours, they're not actively feeling the acute effects of MDMA anymore. But when we measured social reward learning now that they were right back to their juvenile levels of social reward learning, so in a sense, what we showed is that we were able to reopen that critical period by giving MDMA, and what was super important for us to do as a control under their circumstances, was to compare this effect to what happens if we gave cocaine, right? Because MDMA is a stimulant drug, it's, you know, sort of pro social, and maybe, you know, all it was is that we gave them MDMA, they had a good time, and remember how much they like being social. And that's all and then we're just we're just reward, you know, measuring the lasting rewarding effects of that fun time that they had with their buddies, right. If that were the case, then cocaine should have reopened the critical period as well. And it didn't, okay. And so this is super, super important for our argument that what is actually going on with MDMA is that it's, it's opening a critical period, and that this critical period reopening is the property of these drugs, that makes them so valuable in a clinical setting, and differentiates them from drugs like cocaine, which you know, are plastic and do all kinds of interesting things, but are not therapeutically useful. They're mostly just addictive drugs that are stimulants, and they don't have these amazing therapeutic properties that psychedelics do.

Nick Jikomes 1:07:08

So MDMA is a stimulant as cocaine is, but obviously, they have quite different effects. But the you know, they interact with some of the same knobs in the brain, and some of the some of the areas that that we care about here. And yet, cocaine was not able to have the effect that MDMA was with respect to making the adult mice look like juvenile mice in terms of their their social reward preferences. So maybe it would be useful here, if you could describe for people when you give MDMA to an animal, in this case of rodent, what is actually happening in the brain that underlies to cute subjective effects, what kinds of transmitters and things are being influenced?

Gul Dolen 1:07:48

Yeah, so I mean, the the, the proximal effect of MDMA is is that it binds to the selective serotonin reuptake inhibitor. So the I'm sorry, sorry, the selective serotonin reuptake transporter, right. And so this is we call it cert. And it's the serotonin transporter, but anybody who's on an SSRI or know somebody who's on an SSRI, like Prozac, or citalopram, or any of the other classes of drugs in this class, is familiar with this transporter because, you know, this the same thing that Prozac binds to right and so this what is this transporter do so this transporter under normal circumstances, if there's serotonin in the synapse that's been released by the serotonin neurons. The serotonin transporter is there to sort of vacuum up any extra leftover serotonin so that serotonin can continue to be an effective on off, you know, signal that you know, the postsynaptic neuron can receive, right? And so what Prozac does is it sits in in the binding pocket, the same binding pocket that serotonin sits in, and it blocks it. So now the transporter isn't able to vacuum up that extra serotonin and there's more serotonin available in the synapse, and so that either directly or indirectly through other things that happen downstream of that is thought to be how Prozac works. What MDMA does, is it sits in that transporter, and now it reverses the direction of the transporter. So instead of vacuuming up serotonin, you're just dumping massive amounts of serotonin into the synapse. And so this is the main action of what MDMA is thought to do, although it's not super selective. So it also has a little bit of this activity at some of the other transmitters like the norepinephrine transmitter and the dopamine transmitter but transporter but you know, most mostly people think that most of its activity is is happening Because of its action at the serotonin transporter,

Nick Jikomes 1:10:02

I see So so what MDMA is doing is it's effectively running little molecular machines in reverse such that more transmitters than would otherwise be in the synapse, or in the synapse, serotonin accounts for most of that. But not all of that, given the subjective effects of MDMA, one would expect that oxytocin is also affected. So what is the connection here?

Gul Dolen 1:10:25

Yeah, so this is something that we were really interested in for exactly the reason that you just said, and what was known when we started doing these studies is that when you looked in the hypothalamus, which is where a lot of those magnocellular I mean, what are the magnocellular and parvocellular oxytocin neurons slid, if you just took a little sample of the cerebrospinal fluid around the those neurons, after you gave MDMA there would be like a massive dose dependent increase in the amount of sorry, in the amount of oxytocin after you give MDMA. And so, you know, we thought, okay, somehow, there's an interaction between that serotonin that's being released because MDMA doesn't bind to oxytocin receptors directly. And so somehow, there must be a relationship between serotonin which has 14 different receptors, right? So it's complicated. And the receptors do different things in different brain regions. And in combination with each other. Sometimes, you know, one receptor can be directly counteracting the other receptor. And that's probably because serotonin receptors are some of the oldest receptors we have, evolutionarily speaking. And so there's a huge diversity. And it's super complicated, right? But basically, what we think and we're still, you know, working this out, but what we think is, is that when oxytocin, I mean, when serotonin gets released from the serotonin transporter, being operating in an opposite direction, that binds to serotonin, for receptors, and then that triggers oxytocin release, which then triggers serotonin, one B activation. So it's a combination of serotonin four and one, B, and oxytocin, that we think is what's responsible for those acute pro social effects of MDMA. Now, how that relates to critical period reopening, we're not sure. Because I'll just hint to you that we thought when we first started these experiments, that the ability of MDMA to reopen this critical period was because of these acute pro social effects. But now we have evidence that actually it's not, because it this property, this ability to reopen critical periods, generalizes, across all psychedelics, whether they have acute pro social or not. And so think that social thing, in some sense, is a red herring. And that, you know, there's some other mechanism that's common across psychedelics that, you know, is responsible for this drug class to be able to do this.

Nick Jikomes 1:13:16

I see. I see. And we'll come back to that, because I think I had some questions related to some of the things there. But you give MDMA to humans. And and, you know, we've described what those effects are. There's, of course, the famous clinical work that's been done showing MDMA effect to treat things like PTSD. And then you've done these experiments in rodents, where you are using MDMA to basically reopen a critical period of plasticity that has to do with social reward learning. But you know, basically, MDMA effects in humans look a lot like the effects in rodents, or both social creatures, it has this pro social plasticity promoting effect. And then we're gonna come back to the octopus. The octopus is not social, as you described. And yet you did this, you did an experiment where you gave them MDMA. So before you tell us what that result is, what even made you think to do this, given that this is not a social animal? Yeah,

Gul Dolen 1:14:15

I mean, basically, the idea was, you know, we had the genome, we knew that they had the social the serotonin transporter that I just described as the thing that binds to the MDMA. And we knew that the part of the transporter that MDMA binds to has molecular similarity to the is almost identical in that little binding pocket to humans and every actually everything across this tree of life. So even though there are differences, the the part that binds to serotonin is the same across the whole tree of life. And so that was like, Okay, well, maybe MDMA is going to bind to that transporter, but maybe because they Tonin is super old as a transporter and has been implicated in everything from feeding behaviors to temperature regulation to, you know, social reward. It's just really implicated in Okay, huge diversity of behaviors, you know, maybe it was going to bind to it and do something totally different, especially since, as you mentioned, you know, the octopus is normally a social and really only suspend the, a social behaviors for mating. On the other hand, because they can do this social behavior during mating, right, and they can suspend it and be, you know, not all octopuses, by the way, suspend it. I mean, some species never suspend that a sociality. In fact, they've never even found the body of a male of one species where the female is so aggressive that he like literally puts the SEC to coddle this arm in her mantle, and then, you know, dislocates it and then runs off. And so we've only ever found the arm of a male and never found the rest of the body. Right. So that's a very aggressive species that doesn't suspend a sociality during meeting. But this this is does suspend it during meeting. And so we thought, okay, well, maybe they have the brain circuits and know, under normal circumstances, those brains are considered just sort of suppressed, and they're just not doing the social behavior for whatever evolutionary selection pressure reasons that we haven't discovered yet. So it was a question like, how old is serotonin social function? And is it possible that MDMA because it has this very powerful pro social function in mammals can override this sort of a social behavior that they exhibit most of the time, and only suspend during meeting? So that was the reason why we wanted to know.

Nick Jikomes 1:16:52

Okay, and then, so what happens?

Gul Dolen 1:16:56

Basically, we did the same test that I mentioned, we use them in rodents, and humans, to kind of demonstrate that they have these acute prosocial effects. The three chambered social approach staff, we measured how much time they spend in each of the three chambers before MDMA, and not at all, surprisingly, the octopuses spent most of their time in the little toy object side as far away from the other octopus as possible. And then we gave them MDMA. And when we gave them sort of high doses of MDMA was sort of typical, like stimulant activity, just like, you know, amphetamine would do in a human realm, sort of hyper vigilant and but then when we kind of eased back to the dose that is, you know, pro social, and makes, you know, the recreational dose that people use it raves and stuff, then the octopuses turned their behavior radically shifted. And so, you know, subjectively, and sort of just anecdotally, you know, they were sort of floating around, and like they had all eight arms out and just kind of looked like they were dancing, or you know, about or just enjoying the flow of water on their outspread arms, they were playing with the airstone, which we used to aerate the aquarium. And then they were sort of doing these play behaviors, like backflips and kind of, you know, just playing. And then and the part that we actually measured was how much time they spent in the social chamber. And then they spent significantly more time in the social chamber than in the nonsocial. chamber.

Nick Jikomes 1:18:39

I see. So it's not just like they spend a couple minutes where they spend no time to their before they're actually spending a majority of their time in the social chamber. Yeah. So what is this? I mean, what, what is the start to tell us about, you know, we started out the conversation with you talking about the strategy of setting very, very distinct nervous systems that you can kind of triangulate some of these core core principles of nervous system function. What is the starting tell us there?

Gul Dolen 1:19:07

Yeah, so I mean, my lab has invested a huge amount of energy into figuring out the neural circuits and, you know, implicating the nucleus accumbens, and projections from the hypothalamus. Other Labs is implicated the amygdala, still others have been focused on the prefrontal cortex and, you know, sort of the fMRI studies are all about default mode network. And an octopus doesn't have any of those brain regions. So no cortex, no accumbens, no amygdala, and yet, they are able to have the same behavioral response to MDMA, a drug that they never saw before, they did not co evolve with it's completely synthetic and not in their natural environment, right. And they have the same response, which tells us that the sort of business end of the mechanism is at the level of those molecular and reactions. And that what we think we're learning when we, you know, do when we give drugs to a human and put them in an FMRI machine? And we say, oh, yeah, that part of the brain lit up. We're not learning quite as much as we thought from those experiments. Because the truth is, is that you don't need those brain regions. An animal like the octopus has solved this problem in a different way. And I will tell you, that people who study flies and worms have been, you know, saying this for years, right. And they've had this insight for a long time. But when you're someone like me, who studies rodents, you can be a little bit dismissive of, you know, invertebrates as like, well, you know, whatever you learn in there, that's just habits and reflexes, it doesn't pertain to the really interesting behaviors, like falling in love and social cognition, you know, and I think we're just wrong about that. Like, I think, just, this is a snobbery that we have, because we are so used to, you know, thinking in a human centric way. And it's much harder to make that argument with an animal like the octopus, because, you know, the octopus is capable of doing some complex behaviors, and, you know, they're, they get a credit for being a lot smarter than they are. But nevertheless, they're not there, they do have more of a sort of learned repertoire, and flexible behaviors. And so you can't just say, oh, that's just a habit or a reflex. And so I think that this makes the point that the fly and, and the worm people have been making in a very powerful way.

Nick Jikomes 1:21:45

Um, you know, one thing, just to speak off the cuff for a second, you know, we've we've talked a lot about the diversity of these organisms, obviously, they're very different in many ways octopus, mouse, human, etc, you know, fly worm, you name it. But one, you know, one thing that I think is useful here that gets me thinking is, no matter what the animal is, no matter no matter what its level of sociality is they, they all behave as if their nervous system is tracking some notion of their position in a hierarchy. So in a cephalopod, that's always aggressive towards the nonspecific, you know, you might say, that they're, they're effectively saying, Well, I'm at the top of the hierarchy, and everyone else is below me. And that's, that's sort of maybe why I'm aggressive or something. You mentioned some things about the rodents. You know, when you think about mice versus prairie voles, they have these interesting distinctions between their behavior where, on the one hand, the prairie voles will be pair bonded, and these monogamous pair bonds, and yet they'll be very aggressive to intruders that come in. And we can sort of think about these different kinds of behaviors in different animal species. But is something is there something here perhaps to do with the way that a compound like MDMA is influencing the animal's perception of its place in a social hierarchy that maybe generalizes across all of these otherwise behaviorally distinct animals?

Gul Dolen 1:23:16

Hmm, you know, I don't? I don't know. I feel like that's a super interesting question that we don't have enough information to answer. What I would, what I would say is that, I think it's sort of getting at, you know, a little bit of a chicken or the egg kind of kind of problem with understanding where social behaviors come from. So you know, I think that, especially for really complex social behaviors, like social cognition, the assumption has always been that humans are very good at it, because we're very social. But I think that there's a little bit of evidence from this one species of social octopus that, you know, they also seem to have some of this this, this. I'll call it social cognition or theory of mind, like behavior, but they don't use it in a social context. They use it in a predator prey context, right. So when they are trying to catch a shrimp, they will use something to anthropomorphize, which I know is dangerous, but, you know, it just is a way of describing what it looks like. They use something like that shoulder tap prank that kids use, you know, they tap you in the wrong shoulder, you know, they use something like that to catch shrimp, right? And these are wild caught animals, right? So they've learned their, their natural environment in this way. And so, it begs the question, you know, did these complex social cognition behaviors actually evolve first from predator prey relationships? And the reason I sort of think that that might be dictated Is that the sister species of octopus? Octopus? churchy AI, which is not social, uses some of that sort of trickery that to a human looks like social trickery. Also to catch Trump right. So what it does is it's more like it to me it looks more like, um, you know, in the 50s and 60s there were all those like, the man at the movie who's like, yawning and trying to get his arm around his date, like, that's the way that the that sort of maneuver of like slowly I'm not doing anything wrong here kind of act is the way that the octopus a social octopus churchy eye, you know, approaches his prey. And so, you know, it's interesting, you bring up hierarchy, maybe it's not hierarchy, maybe it's predator prey, and disentangling, you know, which came first, the predator prey or the social and did Which one did we adapt, and it probably, you know, was a process where there was a lot of cross pollination and the different types of behaviors. And it's not clear to me how MDMA is gonna, and oxytocin are going to play out in those in those when we when we think about them, but this is another case to study this, this stuff in octopuses, because it turns out that an octopus has a molecule that's not the same as oxytocin, it's sort of like ancestor molecule halfway between oxytocin and vasopressin. And it's called up depressant. And so off depressant, you know, understanding the function of off depressant will tell us a lot about these kinds of things.

Nick Jikomes 1:26:41

Um, so a couple other thing light bulbs are going off for me is, I don't know if this is true, but you can imagine that there might be a kind of mapping between an animal's distinction between an in group and out group member, and its mapping between, you know, a conspecific, versus a prey species or something like that. And, you know, we've been talking about oxytocin and stuff for for a while now. There's a result that I, you know, I don't know the details, but I remember reading about a result, where I believe giving oxytocin to adult animals, perhaps even humans, caused the sort of heightened pro social behavior towards in group members, but it actually caused the heightened distinction or aggressiveness towards out group members. And, you know, I'm also wondering, you know, in most mammalian species, new mothers are famously, you know, extremely, extremely pro social, and altruistic towards their offspring, but also very aggressive towards intruders or strangers. And so does oxytocin or, or any of the circuitry tie into this in group out group distinction? And is there maybe anything interesting going on there?

Gul Dolen 1:27:57

Yeah, and I think that, you know, there's a lot of work to be done in trying to disentangle those ideas. And some of its going to be that I think oxytocin and vasopressin, which is the one that's based depressant is also I mean, oxytocin and vasopressin are very similar molecules, right? They're only different by two amino acids, they're, they're evolutionarily related, they probably came from the same original molecule and broke off and, you know, and got duplicated, and now they're theirs to, you know, this variation. And base suppressant has been more attributed to those sort of aggressive outgroup or, you know, protecting the pups from intruders kind of behavior and the pair bonding sort of protecting behavior. But, um, and they're, they're similar enough that the receptors sometimes get confused. And so if you have this depressant, it combined to the oxytocin receptor, you know, not as well as its own receptor, but not terribly, not bad, like, sort of a little bit, right. And so the devil is going to be in the details, because the proportion of the two different types of activation is going to also dependent be dependent on what type of receptors are right. So let's say that, you know, you've got oxytocin being released, but, you know, there aren't that many oxytocin receptors because they've been downregulated in the base press and receptors have been upregulated, then it's, you know, it doesn't matter that there's still oxytocin nergic inputs or that you're giving oxytocin in some other way. It's not responding. And so, you know, the anatomical and molecular balance of these two types working together is going to matter a lot and probably is going to change across the light dark cycle, and we are on the hunt for this, but it's probably going to take us another 10 years to figure out, you know, how the two molecular identities of the cells switch back and forth, how that changes occur. Last Day, brain region, etc, etc. So it's complicated, basically is my answer.

Nick Jikomes 1:30:05

So I'm switching to the clinical side of this, to what extent are people actively pursuing today, the use of something like MDMA or other psycho classes, such as psychedelics, for things like autism? What's what's going on in that area right now?

Gul Dolen 1:30:24

Yeah, so you sort of, I just have to pause for a second and say that I hate the term psycho plastic gin, I think it's wrong. And I think that, you know, there's one part that's a medicinal chemist is really pushing that as like a neologism to kind of, you know, describe what psychedelics are doing. And the reason that I hate it is because I am a synaptic physiologist. And I know that there are a lot of things that induce plasticity, like cocaine, and, in fact, they induce hyper plasticity. And so plastic surgeon is something that you can easily attribute as a characteristic of, of cocaine as well. And it is not an accurate description of what psychedelics are doing, because psychedelics don't seem to be inducing plasticity. In fact, the only report where they're like inducing it straight up is a study done in vitro where, you know, the all of the conditions that sort of regulate plasticity, like inhibitory, excitatory, balance, extracellular matrix, all those things were gone. And so then they saw this, like massive growth, which when we've tried to reproduce those findings in, in an ex vivo setting we have not been able to do. And then there are other studies that were you know, more well controlled and more done in the appropriate setting, where people have noticed that there's like a small amount of increase in decrease in the number of dendritic spines, but always, they are very, very subtle, occurring in less than 5% of the neurons. And what they're doing is there are dendritic spines is that they're not necessarily sprouting a bunch of new ones, they are taking old ones that got disappeared because of stress or whatever manipulation and then being replaced. And so when we think one of those other studies are doing is sort of that's what you would expect if the real property of psychedelics is not hyper plasticity, but meta plasticity. Yeah. So I just wanted this. I don't want to use the word psycho. I make a big distinction between hydro plasticity and meta plasticity, I see that psychedelics are inducing meta plasticity and not hyper plasticity.

Nick Jikomes 1:32:49

Okay. Well, two, so two questions related to everything you just said, just to clarify. So for a drug like cocaine, it induces plasticity, does it induce plasticity that clearly outlasts the presence of the drug itself? For say, days at a time? Month? I see. Okay. Okay. So that so that is, I see exactly what you're saying now. So related to the the concept of meta plasticity, where compounds can induce a metaplastic state, but they're not triggering plasticity per se. What happens? And we can tie this to your experiments in mice, for example, what happens if you let's, I guess I'll just do that it'll, it'll make it more concrete. Let's say you give MDMA to the adult mouse, but you simply don't expose it to any social stimuli? Is there any measurable change in the mouse that or any deficit develops? You can imagine, you know, maybe some circuits sort of go away, or something's anything like that happening?

Gul Dolen 1:33:45

Yeah, so basically, you know, one of the things that we wanted to be able to demonstrate, we were trying to make the, the connection between this meta plasticity critical period reopening idea and the therapeutic results that we see in human clinical trials is that the therapeutic results are context dependent, right? So you can't just take MDMA and go to a rave, and suddenly your PTSD is shattered. I mean, unless you happen to be at a rave with your therapist, and they were like, but in general, that's not going to be what happens, right? So the context dependence of MDMA is therapeutic effects. We were able to recapitulate when we did the mouse study. So if we gave MDMA and then put the animal in a isolation context all by himself, that it didn't reopen the critical period, and only reopen the critical period if we gave them the right social context. Right. And that to us, that's, you know, really important evidence that what is happening is is that But you're bringing back the possibility of, you know, making a change, but not the change itself, right? So it's not that you are mate, you taking MDMA in everybody, like in the long run and the clinical, you know, you know, the acute effects of it, this, this pro social part of it, or this social zeolitic part of MDMA, those are not context dependent, right. So like the, the, there are zeolitic properties of MDMA. And there are anti depressive properties of s of psychedelics like LSD and psilocybin, but those are not context dependent. And I think the excitement around psychedelics for therapeutics is not because we're imagining that these drugs are just next generation Exalytics, or next generation, anti depressive, but because they are able to cause a, you know, sea change in the way that people are thinking about their PTSD or whatever traumatic event or their smoking or their depression. And this, we think, is because they are able to induce a context dependent reorganization of their steps.

Nick Jikomes 1:36:20

Yeah, I mean, it's really interesting. It's, it's, it's interesting, too, because if they were just sort of inducing plasticity all over the place, you might think, Okay, well, they're kind of kind of turning everything into jelly. And you might actually risk some problems happening as a consequence of that. But if this meta plasticity thing is really what we're talking about, you know, I guess there's a lower worry for collateral damage, and there's a lot more room to use this as a very context specific tool.

Gul Dolen 1:36:47

Right. And actually, this is, I'm so glad you brought this up. Because, you know, when I was a graduate student, you know, there was this idea floating around, that, you know, if we figured out how critical periods closed in the ocular dominance facility, visual cortex, that we could come up with, like a master key for unlocking all critical periods. And I remember at the time thinking, like, that's crazy, anything that could do that would either melt the brain, cause seizures or be a massive amnestic. And so, we are beginning to see evidence that psychedelics are maybe that master key, but the reason that they don't melt the brain, and they don't, you know, cause seizures, and they don't cause amnesia, is because they have this added requirement of only being able to change the memories in, you know, that are activated under the right context and the way that we're describing that we're calling that open state and grand modification. So open state being the critical period opening and and grand modification is Engram is just a neuroscientist way of saying, the neurons are the neural circuit or the the pattern of activation that constitutes a memory, right? I see or have a memory,

Nick Jikomes 1:38:06

so So to use your terminology, and tie this to say, the PTSD research with MDMA, the person with PTSD has this traumatic memory where the the episodic memory, the thing that they're remembering is tied to this very negative emotional state, but the engram is in this closed state. And those two things are locked, locked together. And MDMA in this case, is putting it into the open state, which won't dissociate those two things on its own, but will put you in this metaplastic state where in this case, the psychotherapy then can decouple the negative affective component from the actual

Gul Dolen 1:38:39

memory. Perfect. Exactly, exactly. Right.

Nick Jikomes 1:38:43

So let's, um, let's get back to the autism stuff is. So autism is interesting with respect to MDMA. So even though you've told us everything about, you know, MDMA, that the acute effects might not be the thing that has to do with this critical period reopening. Autism is interesting with respect to MDMA, in particular, because you can imagine that this sort of meta plasticity inducing effect is useful, but also for autism itself, as opposed to other conditions, the acute effects seemed like they would be quite useful as well. And so is anyone looking actively right now at at human clinical trials for MDMA for autism?

Gul Dolen 1:39:21

Yeah, so um, there, there has been one study that was led by maps and Mira Yes, artisan ski is the first author on it that has looked at MDMA, acute pro social effects, and its ability to attenuate social anxiety phenotypes in autism. And so what they found is but I just want to clarify that, you know, autism, even though people, you know, think of it as a disease of the social brain, and certainly there are subtypes of autism where social anxiety is a big part of the disease socially. Anxiety is not actually a central core symptom of of autism, it's, it's, you know, seen in some causes, but not others, right? The core feature of autism, social impairments really center around this social cognition, which, you know, I draw the distinction because I think that MDMA, what it's doing in the acute setting, is it's triggering, you know, widespread oxytocin release, probably from those magnocellular oxytocin neurons, as well as the parvocellular. And that social anxiety component of it seems to be the magnocellular neurons, you know, that the those neurons send projections to the amygdala, and, you know, they really seem to that social anxiety, part of it seems to be mostly around the amygdala, but that is, but they were not able to with the acute sort of effects of MDMA, they were not able to correct the sort of classical autism symptoms, the the, the sort of social cognition, part of the disease, right. So it was a help, but it wasn't for that, and so that that's interesting. And, you know, very, um, I'm glad that study got done. But, and it will probably be useful to some people. But, you know, it's different from the way that we are thinking about how we might use MDMA to help people with autism. And I have to say, we have to be a little bit careful here, because, you know, one of the things that we found when when I was a graduate student with autism is is that their ocular dominance plasticity phenotype in the FMR, one knockout mice that we were studying as a model for autism, they seem to have a little bit of hyper plasticity, so they their critical periods don't closes is fully, and they're able to sort of induce a little bit more plasticity than normal, and when they're juveniles, and so, you know, I think we're gonna, we're going to want to really test this a lot. In human patient, I mean, in in animal models, before we jump to the idea that even in the first scenario I described, where we would sort of, you know, pair the biochemical intervention with their critical period reopening, you know, before, I would recommend that we jump into clinical trials to do that, I would want to make sure that we're not going to have some other impact on critical period reopening, in general, now that we think that, you know, the psychedelics might be the sort of master key, so I want to be a little careful there.

Nick Jikomes 1:42:48

Um, and so given that multiple psychedelics have this effect, given some of the mechanistic commonalities that some of these drugs have, and the evolutionary conservation of some of these receptors, when you think about just like the core molecular basis for meta plasticity, is it the serotonin system that's specifically involved here? How much how much work has been done at the very mechanistic level in terms of meta meta plasticity? Generally?

Gul Dolen 1:43:17

Yeah, so basically, we literally just submitted this paper on Monday. So I'm not really able to talk about, you know, some of the results until they're, they're published. But what I can sort of tell you is that, you know, the dominant theory in the field is, is that, you know, it's sort of focused on this idea that there are serotonin, psychedelics, and non serotonin psychedelics. And there's been some really beautiful work from Brian Ross lab showing the crystal structure of LSD bind to the serotonin to a receptor, and it just sits in there and sits it activates it for a really long time and triggers a different mode of biochemical signaling through beta arrestin. And I think it's got a lot of people excited about the idea that that seratonin to a beta arrestin combo sort of explains both the psychedelic and the therapeutic effects of psychedelics, but what we are, you know, what we've been working on is we have some evidence now that it's not that right that, that while LSD and psilocybin require the to a receptor, the rest of the psychedelics that are able to reopen this critical period can do it. Even if we blocked the serotonin to a receptor, even if we block the even if we genetically engineer the beta arrest and knockouts right, like even under those circumstances, we're able to do it so while it seems to be a mechanism, it is not the universal mechanism.

Nick Jikomes 1:44:54

What's an example of that? Where you were, you reopen something after blocking to a are preventing that pathway from coming on.

Gul Dolen 1:45:02

I mean, without getting into too many details, in this paper that we just submitted, we looked at a bunch of different psychedelics, I see I reopened that critical period. And some of them but not others required the to a receptor. Right? Okay, some of them, but not others require the beta arrestin mechanism. And so the goal of that paper really is to say, Okay, if it's not, the universal mechanism is not at the level of receptors. If it's not at the level one downstream of that biochemistry, what's the universe? I see? We have some ideas. So stay tuned, because we have some some good ideas about what is the universal that all of them are able to trigger in order to be open critical?

Nick Jikomes 1:45:48

Are there any examples of these meta plasticity inducing drugs? That we know of where there isn't a strong psychoactive component? And what are your thoughts on whether or not such a drug could be engineered?

Gul Dolen 1:46:04

Yeah, so I know that there's a big push, especially from the sort of people who are hoping to, you know, come up with a marketable alternative to kind of engineer out the psychedelic, quote unquote, side effects of the psychedelic drugs. And again, in this paper that we've just submitted, we have some evidence that that approach will fail. And that any attempt to remove or to shorten the time course of, you know, the psychedelic activity will interfere with their ability to keep the critical period reopen. Furthermore, just sort of mechanistically you know, what I would suggest is that the, the what it feels like to be having this big psychedelic experience is actually what it feels like to reopen critical periods. Right. So if you think about what people on psychedelics look like, right, it's like herding kittens, right? Like, they're all over the place. They're

Nick Jikomes 1:47:13

like children.

Gul Dolen 1:47:15

Exactly, then they will report I felt like a childlike wonder for the world again, right. And they notice everything, and they spend an hour like, putting on a shoe and you know, whatever, like, and it's just like, when children like, if you ever try to get children out the door on a snow day, oh, my God, it's, you know, impossible, right? They, they just cannot focus. And so even though habits get a terrible rep, you know, that we're all habit based, whatever, you know, they make us efficient, they make it possible for us to get out the door. And so, you know, this is probably why critical periods close. But, you know, it's also we think, just what it feels like to be in the open state. And so we think that if you try and engineer out that, that world is strange, psychedelic experience, you're going to basically get rid of the thing that is making all of these plastic rearrangements possible.

Nick Jikomes 1:48:20

I see your idea is really that the experiential component here is it effects the the psychedelic effects themselves, or an experiential marker, perhaps, of the underlying molecular changes that are actually operative on the therapeutic side here?

Gul Dolen 1:48:36

Yeah. Right. And I think that the reason that people have been have missed this in the past is, is that they've been overly focused on the non context dependent markers, like anti depressive effects or zeolitic effects, right, which we think are part of they are properties of these drugs, but they are not the properties that account for these sort of miraculous therapeutic effects, right, like people who are people who are quitting smoking after like a mega dose, not a micro dose, a macro dose of psilocybin, you know, they describe things like, you know, smoking a cigarette just seems silly now, because, you know, I had this revelation that's the equivalent of like, Santa Claus isn't real. And smoking a cigarette seems to silly now after my revelation, as you know, leaving cookies and expecting presence the next morning, like it's just people have had this like, massive reappraisal, cognitive reappraisal. And I think that that's that's not something that is being captured by these attempts to model the anti depressive effects or the zeolitic effects effects because those things don't capture that that context and

Nick Jikomes 1:49:59

I see, well, this is an interesting, you know, I've had discussions with everyone from David Nicholls to David Olson where, you know, one says, I don't think you'll create these non psychedelic psychedelics, and one says, I think they will, you're adding a very interesting twist to this, which is, it sounds like you would agree that Sure, we might make new drugs derived from psychedelics that are next generation anxiolytics say, but they're actually not going to work for the things that do require these critical period, plasticity modulations that you've been talking about?

Gul Dolen 1:50:31

Right. And I will tell you, we already have a little bit of evidence that that's true. So if you compare the clinical trials that were done for MDMA assisted psychotherapy, right, so there, you know, the model was very much in line with this sort of context dependence and the importance of focusing on you know, the psychedelic is the adjunct, but the therapy is actually the, the psychotherapy, this sort of getting at the root cause. And if you talk to the clinicians who carried out those trials, you know, very much during the acute subjective effects of the MDMA, they were, you know, making sure that the patient was, uh, you know, coming back to those traumatic memories, right. And they're in those clinical trials. And this is the Jenny Mitchell, Nature Neuroscience paper, then you saw, you know, big effects on PTSD, like Cure, like Cure, just what we've never seen with SSRIs before, right. So like, massive improvement over what's available now. Whereas in the psilocybin trial, that were, you know, this is the one led by Robin Carhartt. Harris, you know, in that trial, they just kind of treated psilocybin as like, you know, an SSRI and they got basically the same results. Yeah, yeah, they got a system MRI results, right, because they did not necessarily focus on that important context dependence. Right. And so, you know, I, I really think that, you know, both David Olson and David Nicholls are medicinal chemists and they have a medicinal chemists view of the brain, which is, you know, we can do put it in a dish, we can we identify the receptor, we'll be able to identify the mechanism, and we're done, right. But as a neuroscientist, I know that you know, memories, the things that make us behaviorally complex and rich, have being able to speak, you know, English in one context, and in my case, Turkish in another context, and not having any clue of how I'll ever learn Japanese, right? These richness of our behavioral repertoire are because of learned, experience dependent context dependent capabilities of the brain that are not captured by just, you know, neurons in a dish.

Nick Jikomes 1:53:05

Interesting. Well go. Dolan, we've covered a lot of interesting ground here. Are there any final thoughts you want to leave people with? Or maybe some exciting research questions that that you're embarking on in the present?

Gul Dolen 1:53:18

Oh, I think I've laid up enough hints for now. So, you know, stay tuned. Hopefully this, this paper will see the light of day soon. We'll see. You know, it's, it's a, it's a lot of work to get these papers published. But hopefully, you'll have me back and I can tell you about those results when we have them.

Nick Jikomes 1:53:36

Great. Thank you very much. Thank you.

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